[The effect of cytostatic therapy with vincristin sulphate on disaccarchidases of rat intestinal mucosa (author's transl)].

PubMed

Hartwich, G; Leicher, H; Müller, H; Domschke, W; Matzkies, F

1976-01-01

This report shows that appropriate doses of vincristin sulphate may decrease disaccharidase activities of intestinal mucosa. With the higher doses of the cytostatic drug, the drastic drop of enzyme activities is associated with morphological alterations of the mucosa; disacchardiase activities remain depressed at least for a couple of days even after full morphological restoration of the mucosa. Studies in man should reveal whether similar intestinal lesions occur due to therapeutic doses of vincristin sulphate.

Evaluation of the first cytostatically active 1-aza-9-oxafluorenes as novel selective CDK1 inhibitors with P-glycoprotein modulating properties.

PubMed

Brachwitz, Kristin; Voigt, Burkhardt; Meijer, Laurent; Lozach, Olivier; Schächtele, Christoph; Molnár, Josef; Hilgeroth, Andreas

2003-02-27

The first series of synthetic 1-aza-9-oxafluorenes with cytostatic activities in the micromolar range was evaluated as cyclin-dependent kinase (CDK1) inhibitors. Activity was found to be selective in comparison to the inhibition of other kinases within the CDK family. Compounds were shown to inhibit the membrane-efflux pump P-glycoprotein responsible for multidrug resistance in cancer cells. First structure-activity relationships are discussed.

Studies on constituents with cytotoxic and cytostatic activity of two Turkish medicinal plants Phlomis armeniaca and Scutellaria salviifolia.

PubMed

Saracoglu, I; Inoue, M; Calis, I; Ogihara, Y

1995-10-01

Ten known glycosidic compounds, betulalbuside A (1), 8-hydroxylinaloyl,3-O-beta-D-glucopyranoside (2) (monoterpen glycosides), ipolamide (3) (iridoid glycoside), acteoside (verbascoside) (4), leucosceptoside A (5), martynoside (6), forsythoside B (7), phlinoside B (8), phlinoside C (9), and teuerioside (10) (phenylpropanoid glycosides) were isolated from methanolic extracts of Phlomis armeniaca and Scutellaria salviifolia (Labiatae). Structure elucidations were carried out using 1H-, 13C-NMR and FAB-MS spectra, as well as chemical evidence. The cytotoxic and cytostatic activities of isolated compounds were investigated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method. Among the glycosides obtained here, caffeic acid-containing phenylpropanoid (or phenethyl alcohol, or phenylethanoid) glycosides were found to show activity against several kinds of cancer cells. However, they didn't affect the growth and viability of primary-cultured rat hepatocytes. Study of the structure-activity relationship indicated that ortho-dihydroxy aromatic systems of phenylpropanoid glycosides are necessary for their cytotoxic and cytostatic activities.

Flow Injection Analysis with Electrochemical Detection for Rapid Identification of Platinum-Based Cytostatics and Platinum Chlorides in Water

PubMed Central

Kominkova, Marketa; Heger, Zbynek; Zitka, Ondrej; Kynicky, Jindrich; Pohanka, Miroslav; Beklova, Miroslava; Adam, Vojtech; Kizek, Rene

2014-01-01

Platinum-based cytostatics, such as cisplatin, carboplatin or oxaliplatin are widely used agents in the treatment of various types of tumors. Large amounts of these drugs are excreted through the urine of patients into wastewaters in unmetabolised forms. This phenomenon leads to increased amounts of platinum ions in the water environment. The impacts of these pollutants on the water ecosystem are not sufficiently investigated as well as their content in water sources. In order to facilitate the detection of various types of platinum, we have developed a new, rapid, screening flow injection analysis method with electrochemical detection (FIA-ED). Our method, based on monitoring of the changes in electrochemical behavior of analytes, maintained by various pH buffers (Britton-Robinson and phosphate buffer) and potential changes (1,000, 1,100 and 1,200 mV) offers rapid and cheap selective determination of platinum-based cytostatics and platinum chlorides, which can also be present as contaminants in water environments. PMID:24499878

Inhibition of Cryptococcus neoformans replication by nitrogen oxides supports the role of these molecules as effectors of macrophage-mediated cytostasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alspaugh, J.A.; Granger, D.L.

Activated macrophages are able to inhibit the replication of intracellular microbes and tumor cells. In the murine system, this cytostatic effect is associated with the oxidation of L-arginine to L-citrulline, nitrite, and nitrate and is thought to be mediated by an intermediate of this reaction, possibly nitric oxide (NO.). By exposing replicating Cryptococcus neoformans cells to conditions under which NO. is chemically generated, we have observed a cytostatic effect similar to that caused by activated murine macrophages. Nitric oxide is formed as a decomposition product of nitrite salts in acidic, aqueous solutions. Although C. neoformans replicates well in the presencemore » of high nitrite concentrations at physiologic pH, its growth in acidic media can be inhibited by the addition of low concentrations of sodium nitrite. The degree of cytostasis is dependent on both the pH and the nitrite concentration of the NO. generating solution. The cytostatic effector molecule appears to be a gas since, in addition to inhibiting C. neoformans replication in solution, it is able to exert its inhibitory effect across a gas-permeable but ion-impermeable membrane. At high nitrite concentrations, a fungicidal effect occurs. We propose that the growth inhibition of C. neoformans upon exposure to chemically generated NO. or some related oxide of nitrogen represents a cell-free system simulating the cytostatic effect of activated murine macrophages.« less

Studies on cytostatics used as photosensitizing material in photodynamic therapy

NASA Astrophysics Data System (ADS)

Pascu, Mihail-Lucian; Danaila, Leon; Carstocea, Benone D.; Staicu, Angela; Truica, Sorina; Gazdaru, Doina M.

2002-10-01

Introduction of the photosensitizer properties of cytostatics drus was made, pointing out that the fact that besides the biochemical action of the cytostatics their effects could be enhanced by the exposure to light at different doses. A spectroscopical characterisation of methotrexate and fluorouracil, cytostatic drugs used frequently in cancer therpy was performed. The absorption, emission and excitation spectra were measured for methotrexate solutions in natural saline and sodium hydroxide at concentration in the range 10-5 -10-6M and pH 8.4. The absorption, emission and excitation spectra were measured for fluorouracil solutions in natural saline at concentration in the range 10-4 -10-5M. The absorption spectrum exhibits spectral bands in the range 250nm -450nm for both drugs. The fluorescence excitatioan for methotrexate was made at 340nm and 370nm, the fluorescence emission was detected in the spectral range 400nm - 500nm with a maximum at 470nm. The fluorescence excitation was measured in teh range 200nm-500nm with the emission centred on 530nm, for Xe lamp irradiation, and 300nm for Hg lamp and laser irradiation. The fluorescence emission spectra was monitored in the spectral range 400nm - 600nm. The effects of irradiation on spectroscopic characteristics of methrotrexate and fluorouracil were investigated. The irraditaion was made using a UV classic lamp with Xe, for the first experimental part and for the second one it was used both a class Hg lamp and a nytorgen pulsed laser.

Comparative analysis of TGF-β/Smad signaling dependent cytostasis in human hepatocellular carcinoma cell lines.

PubMed

Dzieran, Johanna; Fabian, Jasmin; Feng, Teng; Coulouarn, Cédric; Ilkavets, Iryna; Kyselova, Anastasia; Breuhahn, Kai; Dooley, Steven; Meindl-Beinker, Nadja M

2013-01-01

Hepatocellular carcinoma (HCC) is a major public health problem due to increased incidence, late diagnosis and limited treatment options. TGF-β is known to provide cytostatic signals during early stages of liver damage and regeneration, but exerts tumor promoting effects in onset and progression of liver cancer. To understand the mechanistic background of such a switch, we systematically correlated loss of cytostatic TGF-β effects with strength and dynamics of its downstream signaling in 10 HCC cell lines. We demonstrate that TGF-β inhibits proliferation and induces apoptosis in cell lines with low endogenous levels of TGF-β and Smad7 and strong transcriptional Smad3 activity (PLC/PRF/5, HepG2, Hep3B, HuH7), previously characterized to express early TGF-β signatures correlated with better outcome in HCC patients. TGF-β dependent cytostasis is blunted in another group of cell lines (HLE, HLF, FLC-4) expressing high amounts of TGF-β and Smad7 and showing significantly reduced Smad3 signaling. Of those, HLE and HLF exhibit late TGF-β signatures, which is associated with bad prognosis in HCC patients. RNAi with Smad3 blunted cytostatic effects in PLC/PRF/5, Hep3B and HuH7. HCC-M and HCC-T represent a third group of cell lines lacking cytostatic TGF-β signaling despite strong and prolonged Smad3 phosphorylation and low Smad7 and TGF-β expression. Inhibitory linker phosphorylation, as in HCC-T, may disrupt C-terminally phosphorylated Smad3 function. In summary, we assort 10 HCC cell lines in at least two clusters with respect to TGF-β sensitivity. Cell lines responsive to the TGF-β cytostatic program, which recapitulate early stage of liver carcinogenesis exhibit transcriptional Smad3 activity. Those with disturbed TGF-β/Smad3 signaling are insensitive to TGF-β dependent cytostasis and might represent late stage of the disease. Regulation of this switch remains complex and cell line specific. These features may be relevant to discriminate stage dependent TGF-β functions for the design of efficient TGF-β directed therapy in liver cancer.

Lysosomotropic cationic drugs induce cytostatic and cytotoxic effects: Role of liposolubility and autophagic flux and antagonism by cholesterol ablation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parks, Alexandre; Marceau, François, E-mail: franc

Cation trapping in acidic cell compartments determines an antiproliferative effect that has a potential interest in oncology, as shown by clinical data and trials involving chloroquine and hydroxychloroquine. To further characterize the mechanism of this effect, we studied a series of 6 substituted triethylamine (s-Et{sub 3}N) drugs that encompasses a wide range of liposolubility (amiodarone, quinacrine, chloroquine, hydroxychloroquine, lidocaine, and procainamide). Three tumor cell lines and primary human endothelial cells were exploited in proliferation assays (48 h, cell counts). Accumulation of the autophagic effector LC3 II and the apoptotic marker cleaved PARP1 (immunoblots), cytotoxicity, cell cycle analysis and endocytic functionmore » were further tested in the p53-null histiocytic lymphoma U937 line. A profound and desynchronized antiproliferative effect was observed in response to all s-Et{sub 3}Ns with essentially no cell type specificity. Predictors of s-Et{sub 3}N potency were liposolubility and the acute accumulation of the autophagic effector LC3 II (6 h-treatments). For each s-Et{sub 3}N, there was an antiproliferative concentration range where cytotoxicity and apoptosis were not triggered in U937 cells (24–48 h-treatments). Quinacrine was the most potent cytostatic drug (1–5 μM). Co-treatment of cells with inhibitors of cholesterol, β-cyclodextrin or lovastatin, partially reversed the antiproliferative effect of each s-Et{sub 3}N. The cytopathology induced by cationic drug accumulation includes a cytostatic effect. Its intensity is cell type- and p53-independent, but predicted by the inhibition of autophagic flux and by the liposolubility of individual drugs and alleviated by cholesterol ablation. The superiority of quinacrine, biomarker value of LC3 II and antagonism by a statin may be clinically relevant. - Highlights: • Cation trapping in acidic cell compartments induces a cytostatic effect. • A series of substituted triethylamines has been studied in 4 cell types. • Cytostatic potency is predicted by lipophilicity and autophagic flux inhibition. • β-Cyclodextrin or lovastatin co-treatment reverses the antiproliferative effect.« less

Autophagy contributes to gefitinib-induced glioma cell growth inhibition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, Cheng-Yi; Graduate Institute of Pharmaceutical Science and Technology, Central Taiwan University of Science and Technology, Taichung 406, Taiwan; Kuan, Yu-Hsiang

Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, have been evaluated in patients with malignant gliomas. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma are incompletely understood. In the present study, the cytostatic potential of gefitinib was demonstrated by the inhibition of glioma cell growth, long-term clonogenic survival, and xenograft tumor growth. The cytostatic consequences were accompanied by autophagy, as evidenced by monodansylcadaverine staining of acidic vesicle formation, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), degradation of p62, punctate pattern of GFP-LC3, and conversion of GFP-LC3 to cleaved-GFP. Autophagy inhibitor 3-methyladenosine and chloroquine and geneticmore » silencing of LC3 or Beclin 1 attenuated gefitinib-induced growth inhibition. Gefitinib-induced autophagy was not accompanied by the disruption of the Akt/mammalian target of rapamycin signaling. Instead, the activation of liver kinase-B1/AMP-activated protein kinase (AMPK) signaling correlated well with the induction of autophagy and growth inhibition caused by gefitinib. Silencing of AMPK suppressed gefitinib-induced autophagy and growth inhibition. The crucial role of AMPK activation in inducing glioma autophagy and growth inhibition was further supported by the actions of AMP mimetic AICAR. Gefitinib was shown to be capable of reducing the proliferation of glioma cells, presumably by autophagic mechanisms involving AMPK activation. - Highlights: • Gefitinib causes cytotoxic and cytostatic effect on glioma. • Gefitinib induces autophagy. • Gefitinib causes cytostatic effect through autophagy. • Gefitinib induces autophagy involving AMPK.« less

Evaluation of the anti-proliferative and cytostatic effect of Citrus sinensis (orange) fruit juice.

PubMed

Chinedu, Enegide; Arome, David; Ameh, Solomon F; Ameh, Gift E

2014-09-01

This work has been designed to evaluate the anti-proliferative and cytostatic effects of Citrus sinensis (orange) fruit juice on rapidly proliferating cells. The study was carried out on the seeds of Sorghum bicolor for 72 h. The mean radicle length (mm) of the seeds was taken at 48 and 72 h. The result showed that when compared with the control, methotrexate, the standard drug showed a significant (P < 0.001) anti-proliferative effect throughout the experiment. The inhibition of the radicle growth was more after 72 h (87.42%). At a dose of 5% (v/v), the juice showed a slightly significant (P < 0.05) effect affect after 72 h; however, there was no significant effect at 48 h. The juice at doses of 10% and 20% (v/v) showed a highly significant (P < 0.001) anti-proliferative effect throughout the experiment; however, the percentage inhibitions were higher at 72 h. At 72 h, the percentage inhibition for juice at 10% (v/v) was 72.37% and at 20% (v/v) was 91.96%. The concentrations of 40% and 60% (v/v) showed cytostatic effects as no appreciable growth of the radicles of the seeds was observed throughout the experiment. The percentage inhibition for 40% (v/v) was 100% and 99.72% for 48 and 72 h, respectively, while that for the juice concentration of 60% (v/v) was 100% throughout the study. The experiment has shown that C. sinensis fruit juice has a potential for causing both anti-proliferative and cytostatic effects on fast proliferating cells and hence cancerous cells.

Screening of Venezuelan medicinal plant extracts for cytostatic and cytotoxic activity against tumor cell lines.

PubMed

Taylor, Peter; Arsenak, Miriam; Abad, María Jesús; Fernández, Angel; Milano, Balentina; Gonto, Reina; Ruiz, Marie-Christine; Fraile, Silvia; Taylor, Sofía; Estrada, Omar; Michelangeli, Fabian

2013-04-01

There are estimated to be more than 20,000 species of plants in Venezuela, of which more than 1500 are used for medicinal purposes by indigenous and local communities. Only a relatively small proportion of these have been evaluated in terms of their potential as antitumor agents. In this study, we screened 308 extracts from 102 species for cytostatic and cytotoxic activity against a panel of six tumor cell lines using a 24-h sulphorhodamine B assay. Extracts from Clavija lancifolia, Hamelia patens, Piper san-vicentense, Physalis cordata, Jacaranda copaia, Heliotropium indicum, and Annona squamosa were the most cytotoxic, whereas other extracts from Calotropis gigantea, Hyptis dilatata, Chromolaena odorata, Siparuna guianensis, Jacaranda obtusifolia, Tapirira guianensis, Xylopia aromatica, Protium heptaphyllum, and Piper arboreum showed the greatest cytostatic activity. These results confirm previous reports on the cytotoxic activities of the above-mentioned plants as well as prompting further studies on others such as C. lancifolia and H. dilatata that have not been so extensively studied. Copyright © 2012 John Wiley & Sons, Ltd.

Synthesis, structure and in vitro cytostatic activity of ferrocene-Cinchona hybrids.

PubMed

Kocsis, László; Szabó, Ildikó; Bősze, Szilvia; Jernei, Tamás; Hudecz, Ferenc; Csámpai, Antal

2016-02-01

Exploring copper(I)- and ruthenium(II)-catalyzed azide-alkyne cycloadditions and a Sonogashira protocol, novel cytostatic ferrocene-cinchona hybrids were synthetized displaying significant in vitro activity on HepG-2 and HT-29 cells. Preliminary SAR studies disclosed that compounds incorporating linkers with 1,2,3-triazole and chalchone residues can be considered as promising lead structures. According to the best of our knowledge this is the first letter on the incorporation of ferrocene nucleus in the reputed cinchona family via triazole and chalcone linkers with established pharmaceutical profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

Glutathione modified CdTe quantum dots as a label for studying DNA interactions with platinum based cytostatics.

PubMed

Ryvolova, Marketa; Smerkova, Kristyna; Chomoucka, Jana; Hubalek, Jaromir; Adam, Vojtech; Kizek, Rene

2013-03-01

Cisplatin, carboplatin, and oxaliplatin represent three generations of platinum based drugs applied successfully for cancer treatment. As a consequence of the employment of platinum based cytostatics in the cancer treatment, it became necessary to study the mechanism of their action. Current accepted opinion is the formation of Pt-DNA adducts, but the mechanism of their formation is still unclear. Nanomaterials, as a progressively developing branch, can offer a tool for studying the interactions of these drugs with DNA. In this study, fluorescent CdTe quantum dots (QDs, λem = 525 nm) were employed to investigate the interactions of platinum cytostatics (cisplatin, carboplatin, and oxaliplatin) with DNA fragment (500 bp, c = 25 μg/mL). Primarily, the fluorescent behavior of QDs in the presence of platinum cytostatics was monitored and major differences in the interaction of QDs with tested drugs were observed. It was found that the presence of carboplatin (c = 0.25 mg/mL) had no significant influence on QDs fluorescence; however cisplatin and oxaliplatin quenched the fluorescence significantly (average decrease of 20%) at the same concentration. Subsequently, the amount of platinum incorporated in DNA was determined by QDs fluorescence quenching. Best results were reached using oxaliplatin (9.4% quenching). Linear trend (R(2) = 0.9811) was observed for DNA platinated by three different concentrations of oxaliplatin (0.250, 0.125, and 0.063 mg/mL). Correlation with differential pulse voltammetric measurements provided linear trend (R(2) = 0.9511). As a conclusion, especially in the case of oxaliplatin-DNA adducts, the quenching was the most significant compared to cisplatin and nonquenching carboplatin. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of the anti-proliferative and cytostatic effect of Citrus sinensis (orange) fruit juice

PubMed Central

Chinedu, Enegide; Arome, David; Ameh, Solomon F; Ameh, Gift E

2014-01-01

Aim: This work has been designed to evaluate the anti-proliferative and cytostatic effects of Citrus sinensis (orange) fruit juice on rapidly proliferating cells. Materials and Methods: The study was carried out on the seeds of Sorghum bicolor for 72 h. The mean radicle length (mm) of the seeds was taken at 48 and 72 h. Result: The result showed that when compared with the control, methotrexate, the standard drug showed a significant (P < 0.001) anti-proliferative effect throughout the experiment. The inhibition of the radicle growth was more after 72 h (87.42%). At a dose of 5% (v/v), the juice showed a slightly significant (P < 0.05) effect affect after 72 h; however, there was no significant effect at 48 h. The juice at doses of 10% and 20% (v/v) showed a highly significant (P < 0.001) anti-proliferative effect throughout the experiment; however, the percentage inhibitions were higher at 72 h. At 72 h, the percentage inhibition for juice at 10% (v/v) was 72.37% and at 20% (v/v) was 91.96%. The concentrations of 40% and 60% (v/v) showed cytostatic effects as no appreciable growth of the radicles of the seeds was observed throughout the experiment. The percentage inhibition for 40% (v/v) was 100% and 99.72% for 48 and 72 h, respectively, while that for the juice concentration of 60% (v/v) was 100% throughout the study. Conclusion: The experiment has shown that C. sinensis fruit juice has a potential for causing both anti-proliferative and cytostatic effects on fast proliferating cells and hence cancerous cells. PMID:25298937

[Participation of final products of lipid peroxidation in the anticancer mechanism of ionizing radiation and radiomimetic cytostatics].

PubMed

Przybyszewski, W M

2001-01-01

This review reports the evidence for the participation of final products of lipid peroxidation in the anticancer mechanism of ionising radiation and radiomimetic cytostatics. Processes of lipid peroxidation occur endogenously in response to oxidative stress and great diversity of reactive metabolites is formed. However, direct observation of radical reaction in pathophysiology of cells, tissues and organs is limited technically. Most investigations focused on the indirect assessment of their final products, aldehydes. The peroxidative breakdown of polyunsaturated fatty acids is believed to be involved in the regulation of cell division, and antitumor effect through biochemical and genetic processes.

G2 accumulation and melanin overproduction in malignant melanocytes treated with a new nitrosourea.

PubMed

Buchdahl, C; Papon, J; Communal, Y; Bourges, M; Madelmont, J C

1998-12-01

Cystemustine (N'-(2-chloroethyl)-N-(2-(methylsulphonyl)ethyl)-N'-nitrosourea), a new anticancer chloroethylnitrosourea (CENU) is being tested in a phase II clinical trial of disseminated melanoma. The antitumour effect of this drug is mainly due to DNA damage in malignant melanocytes. Recently, we have shown that this damage can induce apoptosis in some melanoma cell lines. In others, apoptosis is not clearly observed, although there is a strong cytostatic effect. In this paper, we have characterized the cytological effect of cystemustine on murine malignant melanocytes (B16 cell line) which are resistant to apoptosis induced by this CENU. The results show that 3 days after cystemustine treatment, these melanocytes had accumulated in phase G2 of the cell cycle. There was then a strong morphological modification during a long cytostatic phase up to 30 days after treatment. During this cytostatic phase, there was uncontrolled DNA synthesis and marked swelling. Also, tyrosinase activity, melanin content and the number of mature melanosomes were greatly increased. These results suggest that when malignant melanocytes are not able to undergo apoptosis after treatment with CENU, they accumulate in G2 and this is followed by enhancement of melanogenesis.

Withania somnifera Induces Cytotoxic and Cytostatic Effects on Human T Leukemia Cells

PubMed Central

Turrini, Eleonora; Calcabrini, Cinzia; Sestili, Piero; Catanzaro, Elena; de Gianni, Elena; Diaz, Anna Rita; Hrelia, Patrizia; Tacchini, Massimo; Guerrini, Alessandra; Canonico, Barbara; Papa, Stefano; Valdrè, Giovanni; Fimognari, Carmela

2016-01-01

Cancer chemotherapy is characterized by an elevated intrinsic toxicity and the development of drug resistance. Thus, there is a compelling need for new intervention strategies with an improved therapeutic profile. Immunogenic cell death (ICD) represents an innovative anticancer strategy where dying cancer cells release damage-associated molecular patterns promoting tumor-specific immune responses. The roots of Withania somnifera (W. somnifera) are used in the Indian traditional medicine for their anti-inflammatory, immunomodulating, neuroprotective, and anticancer activities. The present study is designed to explore the antileukemic activity of the dimethyl sulfoxide extract obtained from the roots of W. somnifera (WE). We studied its cytostatic and cytotoxic activity, its ability to induce ICD, and its genotoxic potential on a human T-lymphoblastoid cell line by using different flow cytometric assays. Our results show that WE has a significant cytotoxic and cytostatic potential, and induces ICD. Its proapoptotic mechanism involves intracellular Ca2+ accumulation and the generation of reactive oxygen species. In our experimental conditions, the extract possesses a genotoxic potential. Since the use of Withania is suggested in different contexts including anti-infertility and osteoarthritis care, its genotoxicity should be carefully considered for an accurate assessment of its risk–benefit profile. PMID:27187469

Acute and chronic toxicity of six anticancer drugs on rotifers and crustaceans.

PubMed

Parrella, Alfredo; Lavorgna, Margherita; Criscuolo, Emma; Russo, Chiara; Fiumano, Vittorio; Isidori, Marina

2014-11-01

The growing use of cytostatic drugs is gaining relevance as an environmental concern. Environmental and distribution studies are increasing due to the development of accurate analytical methods, whereas ecotoxicological studies are still lacking. The aim of the present study was to investigate the acute and chronic toxicity of six cytostatics (5-fluorouracil, capecitabine, cisplatin, doxorubicin, etoposide, and imatinib) belonging to five classes of Anatomical Therapeutic Classification (ATC) on primary consumers of the aquatic chain (Daphnia magna, Ceriodaphnia dubia, Brachionus calyciflorus, and Thamnocephalus platyurus). Acute ecotoxicological effects occurred at concentrations in the order of mgL(-)(1), higher than those predicted in the environment, and the most acutely toxic drugs among those tested were cisplatin and doxorubicin for most aquatic organisms. For chronic toxicity, cisplatin and 5-fluorouracil showed the highest toxic potential in all test organisms, inducing 50% reproduction inhibition in crustaceans at concentrations on the order of μgL(-)(1). Rotifers were less susceptible to these pharmaceuticals. On the basis of chronic results, the low effective concentrations suggest a potential environmental risk of cytostatics. Thus, this study could be an important starting point for establishing the real environmental impact of these substances. Copyright © 2014 Elsevier Ltd. All rights reserved.

Determining the pharmacological activity of Physalis peruviana fruit juice on rabbit eyes and fibroblast primary cultures.

PubMed

Pardo, Juan Manuel; Fontanilla, Marta Raquel; Ospina, Luis Fernando; Espinosa, Lady

2008-07-01

The pharmacologic activity of compounds isolated from Physalis peruviana has been demonstrated. The use of this fruit juice for treating pterygium has been reported in Colombian traditional medicine. However, studies demonstrating the fruit juice's pharmacologic activity when used in this disease have not been published to date. In the present study the anti-inflammatory and cytostatic activities of P. peruviana fruit juice in a rabbit eye inflammatory model were investigated. A novel rabbit eye inflammation model was developed for studying the juice's anti-inflammatory activity (based on an adaptation of the Draize test). Cytostatic activity was evaluated by measuring and comparing growth rates of cultured fibroblasts exposed and not exposed to various fruit juice concentrations. P. peruviana fruit juice exhibited a mild anti-inflammatory activity compared with methylprednisolone, a known anti-inflammatory drug. An interesting dose-dependent cytostatic effect on cultured fibroblasts was also established. The data found suggest that the P. peruviana fruit juice anti-pterygium effect described in traditional medicine may be related to its inhibiting fibroblast growth. The present study contributes to the pharmacologic knowledge regarding a remedy commonly used in Colombian traditional medicine.

Curcumin augments the cytostatic and anti-invasive effects of mitoxantrone on carcinosarcoma cells in vitro.

PubMed

Luty, Marcin; Kwiecień, Edyta; Firlej, Magdalena; Łabędź-Masłowska, Anna; Paw, Milena; Madeja, Zbigniew; Czyż, Jarosław

2016-01-01

Numerous adverse effects limit the applicability of mitoxantrone for the treatment of drug-resistant tumors, including carcinosarcoma. Here, we estimated the additive effects of mitoxantrone and curcumin, a plant-derived biomolecule isolated from Curcuma longa, on the neoplastic and invasive potential of carcinosarcoma cells in vitro. Curcumin augmented the cytostatic, cytotoxic and anti-invasive effects of mitoxantrone on the Walker-256 cells. It also strengthened the inhibitory effects of mitoxantrone on the motility of drug-resistant Walker-256 cells that had retained viability after a long-term mitoxantrone/curcumin treatment. Thus, curcumin reduces the effective doses of mitoxantrone and augments its interference with the invasive potential of drug-resistant carcinosarcoma cells.

[Failure mode effect analysis applied to preparation of intravenous cytostatics].

PubMed

Santos-Rubio, M D; Marín-Gil, R; Muñoz-de la Corte, R; Velázquez-López, M D; Gil-Navarro, M V; Bautista-Paloma, F J

2016-01-01

To proactively identify risks in the preparation of intravenous cytostatic drugs, and to prioritise and establish measures to improve safety procedures. Failure Mode Effect Analysis methodology was used. A multidisciplinary team identified potential failure modes of the procedure through a brainstorming session. The impact associated with each failure mode was assessed with the Risk Priority Number (RPN), which involves three variables: occurrence, severity, and detectability. Improvement measures were established for all identified failure modes, with those with RPN>100 considered critical. The final RPN (theoretical) that would result from the proposed measures was also calculated and the process was redesigned. A total of 34 failure modes were identified. The initial accumulated RPN was 3022 (range: 3-252), and after recommended actions the final RPN was 1292 (range: 3-189). RPN scores >100 were obtained in 13 failure modes; only the dispensing sub-process was free of critical points (RPN>100). A final reduction of RPN>50% was achieved in 9 failure modes. This prospective risk analysis methodology allows the weaknesses of the procedure to be prioritised, optimize use of resources, and a substantial improvement in the safety of the preparation of cytostatic drugs through the introduction of double checking and intermediate product labelling. Copyright © 2015 SECA. Published by Elsevier Espana. All rights reserved.

DNA interaction with platinum-based cytostatics revealed by DNA sequencing.

PubMed

Smerkova, Kristyna; Vaculovic, Tomas; Vaculovicova, Marketa; Kynicky, Jindrich; Brtnicky, Martin; Eckschlager, Tomas; Stiborova, Marie; Hubalek, Jaromir; Adam, Vojtech

2017-12-15

The main mechanism of action of platinum-based cytostatic drugs - cisplatin, oxaliplatin and carboplatin - is the formation of DNA cross-links, which restricts the transcription due to the disability of DNA to enter the active site of the polymerase. The polymerase chain reaction (PCR) was employed as a simplified model of the amplification process in the cell nucleus. PCR with fluorescently labelled dideoxynucleotides commonly employed for DNA sequencing was used to monitor the effect of platinum-based cytostatics on DNA in terms of decrease in labeling efficiency dependent on a presence of the DNA-drug cross-link. It was found that significantly different amounts of the drugs - cisplatin (0.21 μg/mL), oxaliplatin (5.23 μg/mL), and carboplatin (71.11 μg/mL) - were required to cause the same quenching effect (50%) on the fluorescent labelling of 50 μg/mL of DNA. Moreover, it was found that even though the amounts of the drugs was applied to the reaction mixture differing by several orders of magnitude, the amount of incorporated platinum, quantified by inductively coupled plasma mass spectrometry, was in all cases at the level of tenths of μg per 5 μg of DNA. Copyright © 2017 Elsevier Inc. All rights reserved.

Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma.

PubMed

Yamamoto, J; Ohnuma, K; Hatano, R; Okamoto, T; Komiya, E; Yamazaki, H; Iwata, S; Dang, N H; Aoe, K; Kishimoto, T; Yamada, T; Morimoto, C

2014-04-29

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo. Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression. We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens. Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.

Effect of vitamin B1 and mixtures of B1 with other vitamins on cytostatic efficiency of sanazole under irradiation. A study in vitro

NASA Astrophysics Data System (ADS)

Heinrich, Edith; Getoff, Nikola

2003-06-01

Experiments in vitro, using bacteria Escherichia coli (AB 1157) as a biological model, showed that the cytostatic efficiency of sanazole (AK-2123, a nitrotriazole-type radiosensitizer) in radiation treatment can be strongly influenced by the presence of various vitamins. In airfree media the sanazole action is increased by a factor of 2.5 in the presence of vitamin (vit.) B1, vit. C E-acetate and β-carotene, whereas vit. B1 used individually possesses a 2.7-times higher cytostatic activity than sanazole itself. In media containing air the highest increase of sanazole action is observed in the presence of vit. B1 and C, whereas the individual use of vit. B1 shows a radiation protection effect. In media saturated with N 2O the addition of the vit. B1 and C causes a 1.8-times larger sanazole activity, but the application of vit. B1 alone brings about a very high radiation protection. From studies of vit. B1-radiolysis it can be concluded that OH radicals are the major primary transients leading to substrate degradation. The results are of interest for the radiation therapy of cancer.

Optimization and application of fabric phase sorptive extraction coupled to ultra-high performance liquid chromatography tandem mass spectrometry for the determination of cytostatic drug residues in environmental waters.

PubMed

Santana-Viera, Sergio; Guedes-Alonso, Rayco; Sosa-Ferrera, Zoraida; Santana-Rodríguez, José Juan; Kabir, Abuzar; Furton, Kenneth G

2017-12-22

Every year, hundreds of tons of organic pollutants reach the environment through effluents released from wastewater treatment plants worldwide, and many of these compounds have harmful effects on the aquatic ecosystem. A new class of emerging pollutants of high concern is cytostatic drugs, which are designed to treat different types of cancers by attacking cells. Environmental concentrations of cytostatic drugs are known to be in the range of ngL -1 , and for this reason, it is imperative to develop analytical methods of extraction and preconcentration to allow for subsequent instrumental analysis of these drugs. In this work, a rapid, simple and green method for the analysis of seven cytostatic drug compounds that are commonly used in anti-cancer therapies was developed using a novel extraction process based on a powerful miniaturized technique, fabric phase sorptive extraction (FPSE) coupled to ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The major parameters that affect the extraction process were optimized. The new method shows good linearity, with a relative standard deviation (RSD) of less than 12%. Relative recoveries higher than 40% were obtained for the studied compounds, and the detection limit of the method was within the values at which these compounds are usually found in environmental water (0.20ngL -1 to 80ngL -1 ). The Limit of Quantification ranged from 0.68 to 267ngL -1 . Significant suppression of the signal due to the matrix effect, a common shortcoming attributed to interference from the extraction process as well as the use of ionization mode, was not observed. Subsequently, the method was applied to real wastewater samples from an effluent obtained from a hospital area and three wastewater treatment plants located in Gran Canaria Island, Spain. Copyright © 2017 Elsevier B.V. All rights reserved.

Whole Body Microwave Irradiation for Improved Dacarbazine Therapeutical Action in Cutaneous Melanoma Mouse Model

PubMed Central

Albulescu, Lucian; Iacob, Nicusor; Ighigeanu, Daniel

2013-01-01

A cutaneous melanoma mouse model was used to test the efficacy of a new therapeutical approach that uses low doses of cytostatics in conjunction with mild whole body microwave exposure of 2.45 GHz in order to enhance cytostatics antitumoral effect. Materials and Methods. A microwave exposure system for C57BL/6 mouse whole body microwave irradiation was designed; groups of 40 mice (males and females) bearing experimental tumours were subjected to a combined therapy comprising low doses of dacarbazine in combination with mild whole body irradiation. Clinical parameters and serum cytokine testing using xMAP technology were performed. Results. The group that was subjected to combined therapy, microwave and cytostatic, had the best clinical evolution in terms of overall survival, tumour volume, and metastatic potential. At day 14 the untreated group had 100% mortality, while in the combined therapy group 40% of mice were surviving. Quantifying serum IL-1β, IL-6, IL-10, IL-12 (p70), IFN-γ, GM-CSF, TNF-α, MIP-1α, MCP-1, and KC during tumorigenesis and therapy found that the combined experimental therapy decreases all the inflammatory cytokines, except chemokine MCP-1 that was found increased, suggesting an increase of the anti-tumoral immune response triggered by the combined therapy. The overall metastatic process is decreased in the combined therapy group. PMID:24377047

Whole body microwave irradiation for improved dacarbazine therapeutical action in cutaneous melanoma mouse model.

PubMed

Neagu, Monica; Constantin, Carolina; Martin, Diana; Albulescu, Lucian; Iacob, Nicusor; Ighigeanu, Daniel

2013-01-01

A cutaneous melanoma mouse model was used to test the efficacy of a new therapeutical approach that uses low doses of cytostatics in conjunction with mild whole body microwave exposure of 2.45 GHz in order to enhance cytostatics antitumoral effect. Materials and Methods. A microwave exposure system for C57BL/6 mouse whole body microwave irradiation was designed; groups of 40 mice (males and females) bearing experimental tumours were subjected to a combined therapy comprising low doses of dacarbazine in combination with mild whole body irradiation. Clinical parameters and serum cytokine testing using xMAP technology were performed. Results. The group that was subjected to combined therapy, microwave and cytostatic, had the best clinical evolution in terms of overall survival, tumour volume, and metastatic potential. At day 14 the untreated group had 100% mortality, while in the combined therapy group 40% of mice were surviving. Quantifying serum IL-1 β , IL-6, IL-10, IL-12 (p70), IFN- γ , GM-CSF, TNF- α , MIP-1 α , MCP-1, and KC during tumorigenesis and therapy found that the combined experimental therapy decreases all the inflammatory cytokines, except chemokine MCP-1 that was found increased, suggesting an increase of the anti-tumoral immune response triggered by the combined therapy. The overall metastatic process is decreased in the combined therapy group.

Impact of common cytostatic drugs on pollen fertility in higher plants.

PubMed

Mišík, Miroslav; Kundi, Michael; Pichler, Clemens; Filipic, Metka; Rainer, Bernhard; Mišíková, Katarina; Nersesyan, Armen; Knasmueller, Siegfried

2016-08-01

Cytostatic drugs are among the most toxic chemicals which are produced. Many of them cause damage of the genetic material which may affect the fertility of higher organisms. To study the impact of the widely used anticancer drugs [cisplatin (CisPt), etoposide (Et), and 5-fluorouracil (5-FU)] on the reproduction of higher plants, pollen abortion experiments were conducted with species which belong to major plant families, namely with Tradescantia paludosa (Commelinaceae), Arabidopsis thaliana (Brassicaceae), Chelidonium majus (Papaveraceae), and Alisma plantago-aquatica (Alismataceae). All compounds increased the frequencies of abortive grains. The lowest effective doses were in general in a narrow range (i.e., 1 and 10 mg/kg of dry soil). The effects of the individual drugs were similar in T. paludosa, A. plantago-aquatica, and Ch. majus, while A. thaliana was consistently less sensitive. The highest abortion rate was obtained in most experiments with CisPt, followed by 5-FU and Et. Comparisons of the doses which caused effects in the present experiments in the different species with the predicted environment concentrations and with the levels of the cytostatics which were detected in hospital wastewaters show that the realistic environmental concentrations of the drugs are 4-6 orders of magnitude lower. Therefore, it is unlikely that these drugs affect the fertility of higher plants in aquatic and terrestrial ecosystems.

Morphometric analysis of cisplatin-induced neurite outgrowth in N1E-115 neuroblastoma cells.

PubMed

Konings, P N; Philipsen, R L; van den Broek, J H; Ruigt, G S

1994-08-29

Cisplatin, a widely used cytostatic drug for the control of a variety of neoplastic tumors, unexpectedly induced neurite outgrowth in N1E-115 neuroblastoma cells and this phenomenon was studied further in detail with morphometric analysis. As expected, cisplatin dose-dependently reduced cell number. At the same time, however, cisplatin affected the morphology of the neuroblastoma cells that changed from small rounded cell bodies into large flat cell bodies with neurites. The neurite length/cell as a function of cisplatin concentration showed a bell-shaped curve. The maximal effect (1200% of control) on neurite length/cell was observed at 1 microgram/ml cisplatin. In conclusion, cisplatin induced cellular differentiation in N1E-115 neuroblastoma cells at and just above threshold doses for cytostatic activity.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wenzel, Carsten; Riefke, Björn; Gründemann, Stephan

Cancer cells in poorly vascularized tumor regions need to adapt to an unfavorable metabolic microenvironment. As distance from supplying blood vessels increases, oxygen and nutrient concentrations decrease and cancer cells react by stopping cell cycle progression and becoming dormant. As cytostatic drugs mainly target proliferating cells, cancer cell dormancy is considered as a major resistance mechanism to this class of anti-cancer drugs. Therefore, substances that target cancer cells in poorly vascularized tumor regions have the potential to enhance cytostatic-based chemotherapy of solid tumors. With three-dimensional growth conditions, multicellular tumor spheroids (MCTS) reproduce several parameters of the tumor microenvironment, including oxygenmore » and nutrient gradients as well as the development of dormant tumor regions. We here report the setup of a 3D cell culture compatible high-content screening system and the identification of nine substances from two commercially available drug libraries that specifically target cells in inner MCTS core regions, while cells in outer MCTS regions or in 2D cell culture remain unaffected. We elucidated the mode of action of the identified compounds as inhibitors of the respiratory chain and show that induction of cell death in inner MCTS core regions critically depends on extracellular glucose concentrations. Finally, combinational treatment with cytostatics showed increased induction of cell death in MCTS. The data presented here shows for the first time a high-content based screening setup on 3D tumor spheroids for the identification of substances that specifically induce cell death in inner tumor spheroid core regions. This validates the approach to use 3D cell culture screening systems to identify substances that would not be detectable by 2D based screening in otherwise similar culture conditions. - Highlights: • Establishment of a novel method for 3D cell culture based high-content screening. • First reported high-content screen for the identification of compounds that target cells in dormant tumor spheroid regions. • Metabolite profiling by NMR spectroscopy on 3D tumor spheroids. • Identification of respiratory chain inhibitors to specifically induce cell death in inner tumor spheroid regions. • Respiratory chain inhibitors enhance cytostatic based therapy in vitro.« less

Cellular injury evidenced by impedance technology and infrared microspectroscopy

NASA Astrophysics Data System (ADS)

le Roux, K.; Prinsloo, L. C.; Meyer, D.

2015-03-01

Fourier Transform Infrared (FTIR) spectroscopy is finding increasing biological application, for example in the analysis of diseased tissues and cells, cell cycle studies and investigating the mechanisms of action of anticancer drugs. Cancer treatment studies routinely define the types of cell-drug responses as either total cell destruction by the drug (all cells die), moderate damage (cell deterioration where some cells survive) or reversible cell cycle arrest (cytostasis). In this study the loss of viability and related chemical stress experienced by cells treated with the medicinal plant, Plectranthus ciliatus, was investigated using real time cell electronic sensing (RT-CES) technology and FTIR microspectroscopy. The use of plants as medicines is well established and ethnobotany has proven that crude extracts can serve as treatments against various ailments. The aim of this study was to determine whether FTIR microspectroscopy would successfully distinguish between different types of cellular injury induced by a potentially anticancerous plant extract. Cervical adenocarcinoma (HeLa) cells were treated with a crude extract of Pciliatus and cells monitored using RT-CES to characterize the type of cellular responses induced. Cell populations were then investigated using FTIR microspectroscopy and statistically analysed using One-way Analysis of Variance (ANOVA) and Principal Component Analysis (PCA). The plant extract and a cancer drug control (actinomycin D) induced concentration dependent cellular responses ranging from nontoxic, cytostatic or cytotoxic. Thirteen spectral peaks (915 cm-1, 933 cm-1, 989 cm-1, 1192 cm-1, 1369 cm-1, 1437 cm-1, 1450 cm-1, 1546 cm-1, 1634 cm-1, 1679 cm-1 1772 cm-1, 2874 cm-1 and 2962 cm-1) associated with cytotoxicity were significantly (p value < 0.05, one way ANOVA, Tukey test, Bonferroni) altered, while two of the bands were also indicative of early stress related responses. In PCA, poor separation between nontoxic and cytostatic responses was evident while clear separation was linked to cytotoxicity. RT-CES detected morphological changes as indicators of cell injury and could distinguish between viable, cytostatic and cytotoxic responses. FTIR microspectroscopy confirmed that cytostatic cells were viable and could still recover while also describing early cellular stress related responses on a molecular level.

Butanol is cytotoxic to Lactococcus lactis while ethanol and hexanol are cytostatic.

PubMed

Hviid, Anne-Mette Meisner; Ruhdal-Jensen, Peter; Kilstrup, Mogens

2017-04-01

Lactic acid bacteria currently used extensively by the dairy industry have a superior tolerance towards short-chain alcohols, which makes them interesting targets for use in future bio-refineries. The mechanism underlying the alcohol tolerance of lactic acid bacteria has so far received little attention. In the present study, the physiological alcohol stress response of Lactococcus lactis subsp. cremoris MG1363 towards the primary, even-chain alcohols ethanol, butanol and hexanol, was characterized. The alcohol tolerance of L. lactis was found to be comparable to those reported for highly alcohol-resistant lactic acid bacteria. Combined results from alcohol survival rate, live/dead staining, and a novel usage of the β-galactosidase assay, revealed that while high concentrations of ethanol and hexanol were cytostatic to L. lactis, high concentrations of butanol were cytotoxic, causing irreparable damages to the cell membrane.

Effects of an inhibitor of tripeptidyl peptidase II (Ala-Ala-Phe-chloromethylketone) and its combination with an inhibitor of the chymotrypsin-like activity of the proteasome (PSI) on apoptosis, cell cycle and proteasome activity in U937 cells.

PubMed

Bury, M; Młynarczuk, I; Pleban, E; Hoser, G; Kawiak, J; Wójcik, C

2001-01-01

AAF-AMC is not a specific TPP II substrate, since it is also hydrolyzed by purified proteasomes. Moreover, AAF-cmk, claimed to be a specific TPP II inhibitor, also inhibits the chymotrypsin-like activity of the proteasome. While AAF-cmk itself is mildly cytostatic to U-937 cells and induces cell cycle block in G1, its combination with PSI does not induce an increase in the cytostatic/cytotoxic effects. This suggests that TPP II is possibly less important for cell metabolism than it was previously believed and it is less probable that it can be able to fully compensate for the loss of the proteasome function.

Differentiation of HL-60 cells distinguishes between cytostatic and cytotoxic effects of the alkylphospholipid ET-18-OCH3.

PubMed

Civoli, F; Pauig, S B; Daniel, L W

1996-01-01

The synthetic dialkylphospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) inhibits growth of the acute myelogenous leukemia cell line HL-60. Incubation of HL-60 cells with demethyl-sulfoxide causes the cells to differentiate to a granulocyte-like phenotype and become quiescent. Incubation of the DMSO-treated cells with ET-18-OCH3 results in a reduction in cell numbers due to cytotoxicity. In contrast, treatment of undifferentiated HL-60 cells with lower concentrations of ET-18-OCH3 leads to growth inhibition. These data indicate that the model of differentiated HL-60 cells currently used for the study of resistance to growth inhibition is inappropriate. HL-60 cells can be used to measure growth inhibition and at higher doses cytotoxicity. However, the differentiated, nonproliferative, cells can only be used to measure direct cytotoxicity. Therefore, the results of studies directly comparing the effects of ET-18-OCH3 in proliferative HL-60 cells and quiescent DMSO-treated HL-60 cells should be reevaluated. An evaluation of the effects of low concentrations of ET-18-OCH3 (0.5-1.5 microM) in proliferative HL-60 cells indicated that ET-18-OCH3 was an effective cytostatic agent at nontoxic concentrations. In summary, studies on the mechanism of action of ET-18-OCH3, or related ether lipids, should carefully investigate differences in the effects at cytostatic versus cytotoxic concentrations.

Chemotherapy inhibits skeletal muscle ubiquitin-proteasome-dependent proteolysis.

PubMed

Tilignac, Thomas; Temparis, Sandrine; Combaret, Lydie; Taillandier, Daniel; Pouch, Marie-Noëlle; Cervek, Matjaz; Cardenas, Diana M; Le Bricon, Thierry; Debiton, Eric; Samuels, Susan E; Madelmont, Jean-Claude; Attaix, Didier

2002-05-15

Chemotherapy has cachectic effects, but it is unknown whether cytostatic agents alter skeletal muscle proteolysis. We hypothesized that chemotherapy-induced alterations in protein synthesis should result in the increased incidence of abnormal proteins, which in turn should stimulate ubiquitin-proteasome-dependent proteolysis. The effects of the nitrosourea cystemustine were investigated in skeletal muscles from both healthy and colon 26 adenocarcinoma-bearing mice, an appropriate model for testing the impact of cytostatic agents. Muscle wasting was seen in both groups of mice 4 days after a single cystemustine injection, and the drug further increased the loss of muscle proteins already apparent in tumor-bearing animals. Cystemustine cured the tumor-bearing mice with 100% efficacy. Surprisingly, within 11 days of treatment, rates of muscle proteolysis progressively decreased below basal levels observed in healthy control mice and contributed to the cessation of muscle wasting. Proteasome-dependent proteolysis was inhibited by mechanisms that include reduced mRNA levels for 20S and 26S proteasome subunits, decreased protein levels of 20S proteasome subunits and the S14 non-ATPase subunit of the 26S proteasome, and impaired chymotrypsin- and trypsin-like activities of the enzyme. A combination of cisplatin and ifosfamide, two drugs that are widely used in the treatment of cancer patients, also depressed the expression of proteasomal subunits in muscles from rats bearing the MatB adenocarcinoma below basal levels. Thus, a down-regulation of ubiquitin-proteasome-dependent proteolysis is observed with various cytostatic agents and contributes to reverse the chemotherapy-induced muscle wasting.

Experimental evidence for killing the resistant cells and raising the efficacy and decreasing the toxicity of cytostatics and irradiation by mixtures of the agents of the passive antitumor defense system in the case of various tumor and normal cell lines in vitro.

PubMed

Kulcsár, Gyula

2009-02-01

Despite the substantial decline of the immune system in AIDS, only a few kinds of tumors increase in incidence. This shows that the immune system has no absolute role in the prevention of tumors. Therefore, the fact that tumors do not develop in the majority of the population during their lifetime indicates the existence of other defense system(s). According to our hypothesis, the defense is made by certain substances of the circulatory system. Earlier, on the basis of this hypothesis, we experimentally selected 16 substances of the circulatory system and demonstrated that the mixture of them (called active mixture) had a cytotoxic effect (inducing apoptosis) in vitro and in vivo on different tumor cell lines, but not on normal cells and animals. In this paper, we provide evidence that different cytostatic drugs or irradiation in combination with the active mixture killed significantly more cancer cells, compared with either treatments alone. The active mixture decreased, to a certain extent, the toxicity of cytostatics and irradiation on normal cells, but the most important result was that the active mixture destroyed the multidrug-resistant cells. Our results provide the possibility to improve the efficacy and reduce the side-effects of chemotherapy and radiation therapy and to prevent the relapse by killing the resistant cells.

Involvement of Mos-MEK-MAPK pathway in cytostatic factor (CSF) arrest in eggs of the parthenogenetic insect, Athalia rosae.

PubMed

Yamamoto, Daisuke S; Tachibana, Kazunori; Sumitani, Megumi; Lee, Jae Min; Hatakeyama, Masatsugu

2008-01-01

Extensive survey of meiotic metaphase II arrest during oocyte maturation in vertebrates revealed that the mitogen-activated protein kinase (MAPK) pathway regulated by the c-mos proto-oncogene product, Mos, has an essential role in cytostatic activity, termed cytostatic factor (CSF). In contrast, little is known in invertebrates in which meiotic arrest occurs in most cases at metaphase I (MI arrest). A parthenogenetic insect, the sawfly Athalia rosae, in which artificial egg activation is practicable, has advantages to investigate the mechanisms of MI arrest. Both the MAPK/extracellular signal-regulated protein kinase kinase (MEK) and MAPK were phosphorylated and maintained active in MI-arrested sawfly eggs, whereas they were dephosphorylated soon after egg activation. Treatment of MI-arrested eggs with U0126, an inhibitor of MEK, resulted in dephosphorylation of MAPK and MI arrest was resumed. The sawfly c-mos gene orthologue encoding a serine/threonine kinase was cloned and analyzed. It was expressed in nurse cells in the ovaries. To examine CSF activity of the sawfly Mos, synthesized glutathione S-transferase (GST)-fusion sawfly Mos protein was injected into MI-resumed eggs in which MEK and MAPK were dephosphorylated. Both MEK and MAPK were phosphorylated again upon injection. In these GST-fusion sawfly Mos-injected eggs subsequent mitotic (syncytial) divisions were blocked and embryonic development was ceased. These results demonstrated that the MEK-MAPK pathway was involved in maintaining CSF arrest in sawfly eggs and Mos functioned as its upstream regulatory molecule.

Design and Synthesis of Curcumin-Like Diarylpentanoid Analogues as Potential Anticancer Agents.

PubMed

Qudjani, Elahe; Iman, Maryam; Davood, Asghar; Ramandi, Mahdi F; Shafiee, Abbas

2016-01-01

Curcumin is a polyphenolic natural compound with multiple targets that used for the prophylaxis and treatment of some type of cancers like cervical and pancreatic cancers. Some recent patent for curcumin for cancer has also been reviewed. In this study, ten new curcumin derivatives were designed and synthesized and their cytostatic activity evaluated against the Hela and Panc cell lines that some of them showed more activity than curcumin. In the present study, a series of mono-carbonyl derivatives of curcumin were designed and prepared. The details of the synthesis and chemical characterization of the synthesized compounds are described. The cytostatic activities of the designed compounds are assessed in two different tumor cell lines using MTT test. In vitro screening for human cervix carcinoma cell lines (Hela) and pancreatic cell lines (Panc-1) at 24 and 48 hour showed that all the analogs possessed good activity against these tumor cell lines and compounds 5a, 5c and 6 with high potency can be used as a new lead compounds for the designing and finding new and potent cytostatic agents. Docking studies indicated that compound 5c readily binds the active site of human glyoxalase I protein via two strong hydrogen bonds engaging residues of Glu-99 and Lys-156. Our results are useful in guiding a design of optimized ligands with improved pharmacokinetic properties and increased of anti-cancer activity vs. the prototype curcumin compound.

Enhanced cytostatic activity of the sesquiterpene lactone eupatoriopicrin by glutathione depletion.

PubMed Central

Woerdenbag, H. J.; Lemstra, W.; Malingré, T. M.; Konings, A. W.

1989-01-01

Eupatoriopicrin (EUP), a sesquiterpene lactone from Eupatorium cannabinum L., possesses cytostatic activity. This was demonstrated for FIO 26 cells in vitro with the aid of a clonogenic assay and in vivo by tumour growth delay in FIO 26 and Lewis lung tumour-bearing mice. In vitro the IC50 for 1 h exposure to EUP was 1.5 microgram ml-1 (4.1 nmol ml-1). This concentration depleted about 25% of its cellular GSH concentration. Pretreatment of FIO 26 cells with BSO, resulting in greater than 99%. GSH depletion, enhanced the cytotoxic effect of EUP. The dose-enhancement factor at the level of 10% cell survival was 2.3. Growth inhibition of the Lewis lung carcinoma and the FIO 26 fibrosarcoma, solidly growing in C57Bl mice, was found after i.v. injection of 20 or 40 mg kg-1 EUP, at a tumour volume of about 500 microliters. Pretreatment with BSO at a dose of 4 mmol kg-1 i.p., 6 h before EUP administration, resulted in a significantly stronger growth delay of both tumours compared with EUP only. At the time of EUP treatment, cellular GSH in the tumours was reduced by BSO treatment to about 60%. It is concluded that EUP possesses antitumour activity in vivo and that chemosensitisation of EUP may be accomplished by pretreatment with BSO, indicating that endogenous GSH protects against the cytostatic action of EUP. PMID:2757925

[Electronic data processing-assisted high dosage therapy with stem cell transplantation at the Donauspital].

PubMed

Habertheuer, K H; Kier, P; Ruckser, R; Scherz, M; Höniger, S; Sebesta, C; Tiefengraber, E; Schmid, A; Mandl, A; Sterz, M

1995-01-01

Organization of high dose chemotherapy with stem cell transplantation essentially requires EDV-support. "ONCOBASE" has been adapted into the Donauspital network on May 1, 1992. We report about the 2-year clinical experience with ONCOBASE: 1. ONCOBASE effectively supports communication between the ward, ambulance and hospital pharmacy (where all cytostatics are prepared). 2. ONCOBASE provides better surveillance concerning all therapeutic procedures including cytostatic drugs and supportive therapies. 3. ONCOBASE allows the generation of medical letters which include all drugs and supportive therapies delivered. 4. Since ONCOBASE is a database program, all informations concerning the patients are registered. These include cumulative drug doses, information on side effects, blood cell kinetics after previous therapies, kinetics of tumor markers and results of further examinations. 5. ONCOBASE permits rapid data exchange with other hospital networks using the communication data record governed by the "Arbeitskreis für EDV der deutschen Gesellschaft für Hämatoonkologie".

Cytostatic action of aspirin and its effect on mitomycin C activity. A study in vitro under irradiation

NASA Astrophysics Data System (ADS)

Kammerer, Cornelia; Getoff, Nikola

2001-04-01

Experiments in vitro using E. coli bacteria (AB 1157) proved that aspirin possesses a cytostatic ability under various experimental condition (pH=7.4) in airfree, aerated as well as in media containing N 2O (converting e aq- into OH- radicals). In the last case the highest effect of aspirin was observed. The combination of aspirin with the well-known cytostaticum, mitomycin C (MMC) leads in airfree as well as in aerated media to a significant decrease of the MMC activity. However, the mixture of aspirin and MMC in the presence of N 2O causes a synergistic effect, resulting in an enhancement of the MMC activity by a factor of 1.5. Probable reaction steps are presented and discussed. Using the pulse radiolysis method the rate constants for the reactions of e aq-, H and OH- species with aspirin were also determined.

Cytotoxic activity of interferon alpha induced dendritic cells as a biomarker of glioblastoma

NASA Astrophysics Data System (ADS)

Mishinov, S. V.; Stupak, V. V.; Tyrinova, T. V.; Leplina, O. Yu.; Ostanin, A. A.; Chernykh, E. R.

2016-08-01

Dendritic cells (DCs) are the most potent antigen presenting cells that can play direct role in anti-tumor immune response as killer cells. DC tumoricidal activity can be stimulated greatly by type I IFN (IFNα and IFNβ). In the present study, we examined cytostatic and cytotoxic activity of monocyte-derived IFNα-induced DCs generated from patients with brain glioma and evaluated the potential use of these parameters in diagnostics of high-grade gliomas. Herein, we demonstrated that patient DCs do not possess the ability to inhibit the growth of tumor HEp-2 cell line but low-grade and high-grade glioma patients do not differ significantly in DC cytostatic activity. However, glioma patient DCs are characterized by reduced cytotoxic activity against HEp-2 cells. The impairment of DC cytotoxic function is observed mainly in glioblastoma patients. The cytotoxic activity of DCs against HEp-2 cells below 9% is an informative marker for glioblastomas.

γ-H2AX as a biomarker for DNA double-strand breaks in ecotoxicology.

PubMed

Gerić, Marko; Gajski, Goran; Garaj-Vrhovac, Vera

2014-07-01

The visualisation of DNA damage response proteins enables the indirect measurement of DNA damage. Soon after the occurrence of a DNA double-strand break (DSB), the formation of γ-H2AX histone variants is to be expected. This review is focused on the potential use of the γ-H2AX foci assay in assessing the genotoxicity of environmental contaminants including cytostatic pharmaceuticals, since standard methods may not be sensitive enough to detect the damaging effect of low environmental concentrations of such drugs. These compounds are constantly released into the environment, potentially representing a threat to water quality, aquatic organisms, and, ultimately, human health. Our review of the literature revealed that this method could be used in the biomonitoring and risk assessment of aquatic systems affected by wastewater from the production, usage, and disposal of cytostatic pharmaceuticals. Copyright © 2014 Elsevier Inc. All rights reserved.

Development and Internal Validation of a Prediction Model to Estimate the Probability of Needing Aggressive Immunosuppressive Therapy With Cytostatics in de Novo Lupus Nephritis Patients.

PubMed

Restrepo-Escobar, Mauricio; Granda-Carvajal, Paula Andrea; Jaimes, Fabián

2017-07-18

To develop a multivariable clinical prediction model for the requirement of aggressive immunosuppression with cytostatics, based on simple clinical record data and lab tests. The model is defined in accordance with the result of the kidney biopsies. Retrospective study conducted with data from patients 16 years and older, with SLE and nephritis with less than 6 months of evolution. An initial bivariate analysis was conducted to select the variables to be included in a multiple logistic regression model. Goodness of fit was evaluated using a Hosmer-Lemeshow test (H-L) and the discrimination capacity of the model by means of the area under the ROC (AUC) curve. Data from 242 patients was gathered; of these, 18.2% (n=44) did not need an addition of cytostatics according to the findings of their kidney biopsies. The variables included in the final model were 24-h proteinuria, diastolic blood pressure, creatinine, C3 complement and the interaction of hematuria with leukocyturia in urinary sediment. The model showed excellent discrimination (AUC=0.929; 95% CI=0.894-0.963) and adequate calibration (H-L, P=.959). In recent-onset LN patients, the decision to use or not to use intensive immunosuppressive therapy could be performed based on our prediction model as an alternative to kidney biopsies. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Mixed response and time-to-event endpoints for multistage single-arm phase II design.

PubMed

Lai, Xin; Zee, Benny Chung-Ying

2015-06-04

The objective of phase II cancer clinical trials is to determine if a treatment has sufficient activity to warrant further study. The efficiency of a conventional phase II trial design has been the object of considerable debate, particularly when the study regimen is characteristically cytostatic. At the time of development of a phase II cancer trial, we accumulated clinical experience regarding the time to progression (TTP) for similar classes of drugs and for standard therapy. By considering the time to event (TTE) in addition to the tumor response endpoint, a mixed-endpoint phase II design may increase the efficiency and ability of selecting promising cytotoxic and cytostatic agents for further development. We proposed a single-arm phase II trial design by extending the Zee multinomial method to fully use mixed endpoints with tumor response and the TTE. In this design, the dependence between the probability of response and the TTE outcome is modeled through a Gaussian copula. Given the type I and type II errors and the hypothesis as defined by the response rate (RR) and median TTE, such as median TTP, the decision rules for a two-stage phase II trial design can be generated. We demonstrated through simulation that the proposed design has a smaller expected sample size and higher early stopping probability under the null hypothesis than designs based on a single-response endpoint or a single TTE endpoint. The proposed design is more efficient for screening new cytotoxic or cytostatic agents and less likely to miss an effective agent than the alternative single-arm design.

Tunicate cytostatic factor TC14-3 induces a polycomb group gene and histone modification through Ca2+ binding and protein dimerization

PubMed Central

2012-01-01

Background As many invertebrate species have multipotent cells that undergo cell growth and differentiation during regeneration and budding, many unique and interesting homeostatic factors are expected to exist in those animals. However, our understanding of such factors and global mechanisms remains very poor. Single zooids of the tunicate, Polyandrocarpa misakiensis, can give off as many as 40 buds during the life span. Bud development proceeds by means of transdifferentiation of very limited number of cells and tissues. TC14-3 is one of several different but closely related polypeptides isolated from P. misakiensis. It acts as a cytostatic factor that regulates proliferation, adhesion, and differentiation of multipotent cells, although the molecular mechanism remains uncertain. The Polycomb group (PcG) genes are involved in epigenetic control of genomic activity in mammals. In invertebrates except Drosophila, PcG and histone methylation have not been studied so extensively, and genome-wide gene regulation is poorly understood. Results When Phe65 of TC14-3 was mutated to an acidic amino acid, the resultant mutant protein failed to dimerize. The replacement of Thr69 with Arg69 made dimers unstable. When Glu106 was changed to Gly106, the resultant mutant protein completely lost Ca2+ binding. All these mutant proteins lacked cytostatic activity, indicating the requirement of protein dimerization and calcium for the activity. Polyandrocarpa Eed, a component of PcG, is highly expressed during budding, like TC14-3. When wild-type and mutant TC14-3s were applied in vivo and in vitro to Polyandrocarpa cells, only wild-type TC14-3 could induce Eed without affecting histone methyltransferase gene expression. Eed-expressing cells underwent trimethylation of histone H3 lysine27. PmEed knockdown by RNA interference rescued cultured cells from the growth-inhibitory effects of TC14-3. Conclusion These results show that in P. misakiensis, the cytostatic activity of TC14-3 is mediated by PmEed and resultant histone modification, and that the gene expression requires both the protein dimerization and Ca2+-binding of TC14-3. This system consisting of a humoral factor, PcG, and histone methylation would contribute to the homeostatic regulation of cell growth and terminal differentiation of invertebrate multipotent cells. PMID:22296827

3D high-content screening for the identification of compounds that target cells in dormant tumor spheroid regions.

PubMed

Wenzel, Carsten; Riefke, Björn; Gründemann, Stephan; Krebs, Alice; Christian, Sven; Prinz, Florian; Osterland, Marc; Golfier, Sven; Räse, Sebastian; Ansari, Nariman; Esner, Milan; Bickle, Marc; Pampaloni, Francesco; Mattheyer, Christian; Stelzer, Ernst H; Parczyk, Karsten; Prechtl, Stefan; Steigemann, Patrick

2014-04-15

Cancer cells in poorly vascularized tumor regions need to adapt to an unfavorable metabolic microenvironment. As distance from supplying blood vessels increases, oxygen and nutrient concentrations decrease and cancer cells react by stopping cell cycle progression and becoming dormant. As cytostatic drugs mainly target proliferating cells, cancer cell dormancy is considered as a major resistance mechanism to this class of anti-cancer drugs. Therefore, substances that target cancer cells in poorly vascularized tumor regions have the potential to enhance cytostatic-based chemotherapy of solid tumors. With three-dimensional growth conditions, multicellular tumor spheroids (MCTS) reproduce several parameters of the tumor microenvironment, including oxygen and nutrient gradients as well as the development of dormant tumor regions. We here report the setup of a 3D cell culture compatible high-content screening system and the identification of nine substances from two commercially available drug libraries that specifically target cells in inner MCTS core regions, while cells in outer MCTS regions or in 2D cell culture remain unaffected. We elucidated the mode of action of the identified compounds as inhibitors of the respiratory chain and show that induction of cell death in inner MCTS core regions critically depends on extracellular glucose concentrations. Finally, combinational treatment with cytostatics showed increased induction of cell death in MCTS. The data presented here shows for the first time a high-content based screening setup on 3D tumor spheroids for the identification of substances that specifically induce cell death in inner tumor spheroid core regions. This validates the approach to use 3D cell culture screening systems to identify substances that would not be detectable by 2D based screening in otherwise similar culture conditions. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Suicidal death of erythrocytes in cancer and its chemotherapy: A potential target in the treatment of tumor-associated anemia.

PubMed

Lang, Elisabeth; Bissinger, Rosi; Qadri, Syed M; Lang, Florian

2017-10-15

In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis characterized by cell shrinkage and cell membrane scrambling. Eryptotic erythrocytes are rapidly cleared from circulating blood and may adhere to the vascular wall. Stimulation of eryptosis thus impairs microcirculation and leads to anemia as soon as the loss of erythrocytes cannot be fully compensated by enhanced erythropoiesis. Signaling stimulating eryptosis includes increase of cytosolic Ca 2+ -activity, ceramide, caspases, calpain, p38-kinase, protein-kinase C, Janus-activated kinase 3, casein-kinase 1α, and cyclin-dependent kinase 4. Eryptosis is inhibited by AMP-activated kinase, p21-activated kinase 2, cGMP-dependent protein-kinase, mitogen- and stress-activated kinase, and sorafenib- and sunitinib-sensitive tyrosine-kinases. Eryptosis is triggered by complement, hyperosmotic shock, energy-depletion, oxidative stress, multiple xenobiotics including diverse cytostatic drugs, diabetes, hepatic failure, iron-deficiency, chronic kidney disease, hemolytic-uremic-syndrome, fever, systemic lupus erythematosus, infections, sepsis, sickle cell anemia, thalassemia, glucose-6-phosphate-dehydrogenase deficiency, and Wilson´s disease. Compelling evidence points to a decisive role of eryptosis in anemia of malignancy. As shown for lung cancer, eryptosis inducing plasma components accumulate in cancer patients and trigger oxidative stress and ceramide. The tumor-induced eryptosis leads to anemia despite increased erythropoiesis. The stimulation of eryptosis in malignancy is compounded by cytostatic treatment, as a large number of cytostatic agents trigger eryptosis. Inhibiting eryptosis may be a useful strategy in reducing tumor-induced anemia and impaired microcirculation. Inhibitors of eryptosis may, however, be harmful, if they similarly interfere with death of tumor cells. Clearly, additional experimental effort is required to achieve killing of tumor cells with simultaneous avoidance of stimulated eryptosis. © 2017 UICC.

Mycotoxins' activity at toxic and sub-toxic concentrations: differential cytotoxic and genotoxic effects of single and combined administration of sterigmatocystin, ochratoxin A and citrinin on the hepatocellular cancer cell line Hep3B.

PubMed

Anninou, Nikolia; Chatzaki, Ekaterini; Papachristou, Fotini; Pitiakoudis, Muichail; Simopoulos, Constantinos

2014-02-07

Food safety organizations indicate the likelihood of constant human and animal exposure to mycotoxin mixtures as a possible negative public health impact. Risk assessment demonstrates that certain mycotoxins of Aspergillus and Penicillium spp. are toxic and hold a significant genotoxic efficacy at nanomolar concentrations. The aim of the current study was to investigate the potential cytogenetic effects of sterigmatocystin (STER), ochratoxin A (OTA) and citrinin (CTN) alone or in combination, at pM to μΜ concentrations, on the human hepatocellular cancer cell line Hep3B. MTT reduction, mitotic divisions, cell cycle delays and sister chromatid exchange rates (SCE) were determined as endpoints of metabolic activity, cytotoxicity, cytostaticity, and genotoxicity, respectively. All mycotoxin treatments induce SCE rates from 10-12 M, while their cytotoxic and cytostatic potential varies. In PRI and MI assays, but not at MTT, STER alone or in combination with OTA + CTN appeared cytostatic and cytotoxic, even at 10-12 M, while CTN alone and all other combinations displayed substantial cellular survival inhibition in doses ≥ 10-8 M. Co-administration of STER + OTA or STER + CTN in concentrations ≤ 10-1 M, increased the MI and MTT activity, while it did not affect the PRI. Mycotoxin co-treatments revealed in general similar-to-additive or antagonistic genotoxic and cytotoxic effects. Our results for the first time describe that STER alone or in combination with OTA and/or CTN share a cytotoxic and cytogenetic potential even at picoMolar concentrations on human hepatoma cells in vitro.

Therapeutic potential of target of rapamycin inhibitors.

PubMed

Easton, John B; Houghton, Peter J

2004-12-01

Target of rapamycin (TOR) functions within the cell as a transducer of information from various sources, including growth factors, energy sensors, and hypoxia sensors, as well as components of the cell regulating growth and division. Blocking TOR function mimics amino acid, and to some extent, growth factor deprivation and has a cytostatic effect on proliferating cells in vivo. Inhibition of TOR in vivo, utilising its namesake rapamycin, leads to immunosuppression. This property has been exploited successfully with the use of rapamycin and its derivatives as a therapeutic agent in the prevention of organ rejection after transplantation with relatively mild side effects when compared to other immunosuppressive agents. The cytostatic effect of TOR on vascular smooth muscle cell proliferation has also recently been exploited in the therapeutic application of rapamycin to drug eluting stents for angioplasty. These stents significantly reduce the amount of arterial reblockage that results from proliferating vascular smooth muscle cells. In cancer, the effect of blocking TOR function on tumour growth and disease progression is currently of major interest and is the basis for a number of ongoing clinical trials. However, different cell types and tumours respond differently to TOR inhibition, and TOR is clearly not cytostatic for all types of cancer cells in vitro or in vivo. As the molecular details of how TOR functions and the targets of TOR activity are further elucidated, tumour and tissue specific functions are being identified that implicate TOR in angiogenesis, apoptosis, and the reversal of some forms of cellular transformation. This review will describe our current understanding of TOR function, describe the current strategies for employing TOR inhibitors in clinical and preclinical development, and outline future strategies for appropriate targets of TOR inhibitors in the treatment of disease.

Cytotoxic, Cytostatic and HIV-1 PR Inhibitory Activities of the Soft Coral Litophyton arboreum

PubMed Central

Ellithey, Mona S.; Lall, Namrita; Hussein, Ahmed A.; Meyer, Debra

2013-01-01

Bioassay-guided fractionation using different chromatographic and spectroscopic techniques in the analysis of the Red Sea soft coral Litophyton arboreum led to the isolation of nine compounds; sarcophytol M (1), alismol (2), 24-methylcholesta-5,24(28)-diene-3β-ol (3), 10-O-methyl alismoxide (4), alismoxide (5), (S)-chimyl alcohol (6), 7β-acetoxy-24-methylcholesta-5-24(28)-diene-3,19-diol (7), erythro-N-dodecanoyl-docosasphinga-(4E,8E)-dienine (8), and 24-methylcholesta-5,24(28)-diene-3β,7β,19-triol (9). Some of the isolated compounds demonstrated potent cytotoxic- and/or cytostatic activity against HeLa and U937 cancer cell lines and inhibitory activity against HIV-1 protease (PR). Compound 7 was strongly cytotoxic against HeLa cells (CC50 4.3 ± 0.75 µM), with selectivity index of SI 8.1, which was confirmed by real time cell electronic sensing (RT-CES). Compounds 2, 7, and 8 showed strong inhibitory activity against HIV-1 PR at IC50s of 7.20 ± 0.7, 4.85 ± 0.18, and 4.80 ± 0.92 µM respectively. In silico docking of most compounds presented comparable scores to that of acetyl pepstatin, a known HIV-1 PR inhibitor. Interestingly, compound 8 showed potent HIV-1 PR inhibitory activity in the absence of cytotoxicity against the cell lines used. In addition, compounds 2 and 5 demonstrated cytostatic action in HeLa cells, revealing potential use in virostatic cocktails. Taken together, data presented here suggest Litophyton arboreum to contain promising compounds for further investigation against the diseases mentioned. PMID:24336129

Current concepts for chronochemotherapy of cancer.

PubMed

Laerum, O D; Smaaland, R; Abrahamsen, J F

1995-01-01

In this article, a survey on the concepts and scientific basis for applying chemotherapy against malignant tumors on a circadian schedule is given. The idea is to give the cytostatic drugs at times of the day when optimal effect on the tumor is achieved, but at the same time causing minimal toxic side effects. Following a brief description of the complexity of cancer tissue, some aspects of the present status of cancer chemotherapy in general are reviewed. Applications of chronobiology in cancer treatment are then surveyed together with possibilities to increase cytostatic doses and reduce side effects. When optimal tumor cell kill is achieved, the next step is to address the circadian aspects of normal organs, including the proliferative behavior of tissues with rapid cell renewal. Finally, the question of how regulatory mechanisms responsible for normal circadian rhythms can be interfered with is addressed. Cancer chronochemotherapy today combined with modern infusional technology is a promising field for improving cancer treatment in general and reducing side effects and is expected to make important progress in the near future.

[New toxicity of fotemustine: diffuse interstitial lung disease].

PubMed

Bertrand, M; Wémeau-Stervinou, L; Gauthier, S; Auffret, M; Mortier, L

2012-04-01

Fotemustine is an alkylating cytostatic drug belonging to the nitrosourea family and is used in particular in the treatment of disseminated malignant melanoma. Herein, we report a case of interstitial lung disease associated with fotemustine. An 81-year-old man treated with fotemustine for metastatic melanoma presented acute interstitial lung disease 20 days after a fourth course of fotemustine monotherapy. The condition regressed spontaneously, with the patient returning to the clinical, radiological and blood gas status that had preceded fotemustine treatment. After other potential aetiologies had been ruled out, acute fotemustine-induced lung toxicity was considered and this treatment was definitively withdrawn. Other cytostatic agents belonging to the nitrosourea family can cause similar pictures, with a number of cases of interstitial lung disease thus being ascribed to fotemustine and dacarbazine. To our knowledge, this is the first case of interstitial lung disease induced by fotemustine monotherapy. This diagnosis should be considered where respiratory signs appear in melanoma patients undergoing fotemustine treatment. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Biotin-tagged platinum(iv) complexes as targeted cytostatic agents against breast cancer cells.

PubMed

Muhammad, Nafees; Sadia, Nasreen; Zhu, Chengcheng; Luo, Cheng; Guo, Zijian; Wang, Xiaoyong

2017-09-05

A biotin-guided platinum IV complex is highly cytotoxic against breast cancer cells but hypotoxic against mammary epithelial cells. The mono-biotinylated Pt IV complex is superior to the di-biotinylated one and hence a promising drug candidate for the targeted therapy of breast cancer.

[Current guidelines for prevention and management of chemotherapy extravasation].

PubMed

Bahyrycz, Jan; Pityński, Kazimierz; Ludwin, Artur; Ludwin, Inga; Gawlik, Małgorzata

2012-01-01

Cytostatic drugs extravasation is the serious side effect of chemotherapy. It may lead to health-threatening complications as well as to impairment of cancer patients quality of life. Prevention, early diagnosis and appropriate treatment significantly reduce the consequences of extravasation. Training of medical staff and patients education have enormous importance on this point.

BIOCHEMICAL CHANGES IN TUMOR CELLS AFTER TREATMENT WITH X RAYS, IODOACETATE, HYDROGEN PEROXIDE, AND ETHYLENIMINOBENZOQUINONE (in German)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maass, H.; Kunkel, H.A.

1960-07-01

Results are reported from biochemical investigations on tumor cells after treatment with various physical and chemical agents. If the effects of x rays, iodo-acetate, H/sub 2/O/sub 2/, and several ethyleneimino-benzoquinones on the carbchydrate metabolism are compared, very similar mechanisms of action are observed. These four agents inhibit the dehydrogenation of triosephosphate; but in the case of iodoacetate. an inactivation of triosephosphatedehydrogenase seems to be the reason for this inhibition. In irradiated cells, however, this enzyme is not inactivated, the delay of dehydrogenation being caused mainly by a loss of DPN. After application of cytostatic agents and H/sub 2/O/sub 2/, amore » similar mechanism can be suggested although both agents are also able to block this enzyme. On the other hand, the reaction of the DNA-synthesis is different. Here a much greater sensitivity to x rays and to cytostatic agents than in the case of glycolysis is observed. lodo-acetate, however, inhibits DNA-synthesis in the same range of concentrations in which the glycolysis is blocked. (auth)« less

[Current treatment strategy in malignant pleural effusion].

PubMed

Türler, A; Walter, M; Schmitz-Rixen, T

1996-01-01

Malignant pleural effusions are a grave consequence of advanced cancer disease. The successful suppression of pleural fluid reaccumulation can make a major contribution to the management and palliative care of patients with disseminated cancer. Many treatment concepts have been reported in the literature. The recommended therapy in malignant pleural effusions consists of intrapleural instillation of a sclerotic agent to produce pleurodesis. Different substances have been used, including tetracyclines, cytostatic agents, fibrin, talc, Corynebacterium parvum, cytokines and others. We reviewed the most frequently used techniques of pleurodesis in order to define the most effective treatment concept. In 15 prospective randomized trials the success rates varied from 13% with bleomycin to 100% with talc or Corynebacterium parvum. Talc was superior to other agents in 6 of 6, Corynebacterium parvum in 3 of 4 and bleomycin or tetracycline only in 3 of 8 studies. Adverse effects were frequently observed with cytostatic agents, but were very rare in the case of talc or fibrin instillation. Comparing the recently published data pleurodesis with talc appears to be the most effective treatment strategy, followed by Corynebacterium parvum, bleomycin and tetracycline.

Modeling the effects of space structure and combination therapies on phenotypic heterogeneity and drug resistance in solid tumors.

PubMed

Lorz, Alexander; Lorenzi, Tommaso; Clairambault, Jean; Escargueil, Alexandre; Perthame, Benoît

2015-01-01

Histopathological evidence supports the idea that the emergence of phenotypic heterogeneity and resistance to cytotoxic drugs can be considered as a process of selection in tumor cell populations. In this framework, can we explain intra-tumor heterogeneity in terms of selection driven by the local cell environment? Can we overcome the emergence of resistance and favor the eradication of cancer cells by using combination therapies? Bearing these questions in mind, we develop a model describing cell dynamics inside a tumor spheroid under the effects of cytotoxic and cytostatic drugs. Cancer cells are assumed to be structured as a population by two real variables standing for space position and the expression level of a phenotype of resistance to cytotoxic drugs. The model takes explicitly into account the dynamics of resources and anticancer drugs as well as their interactions with the cell population under treatment. We analyze the effects of space structure and combination therapies on phenotypic heterogeneity and chemotherapeutic resistance. Furthermore, we study the efficacy of combined therapy protocols based on constant infusion and bang-bang delivery of cytotoxic and cytostatic drugs.

Optical properties of cytostatic drugs used in cancer treatment

NASA Astrophysics Data System (ADS)

Pascu, Mihail-Lucian; Mogos, Ioan; Enescu, Mironel; Staicu, Angela; Truica, Sorina; Voicu, Letitia; Gazdaru, Doina M.; Pascu, Mihaela O.; Radu, Alina

2001-10-01

A spectroscopical characterization of methotrexate, cytostatic drug used frequently in cancer therapy, was performed. The absorption, emission and excitation spectra were measured for methotrexate solutions in natural saline and sodium hydroxide at concentration in the range 10-5 M -10-6 M and pH 8.4. The absorption bands are noticed in the spectral range 250 nm - 450 nm. The fluorescence excitation was made at 340 nm and 370 nm; the fluorescence emission was detected in the spectral range 400 nm - 500 nm with a maximum at 450 nm. The behavior of absorption and fluorescence spectra of methotrexate solution exposed to uv-visible light was investigated. The irradiation was made using an Xe lamp (emission between 325 nm and 420 nm and power density of 11 mW/cm2). The exposure time was between 15 min. and 3 h. Major modifications on absorption bands for irradiation times longer than 1 hour were observed. Furthermore, the methotrexate solutions become strongly fluorescent after irradiation. The observed changes are not linear with the exposure time indicating complex photochemical processes which implies, at least, one intermediate product.

Chemotherapy changes cytotoxic activity of NK-cells in cancer patients

NASA Astrophysics Data System (ADS)

Stakheyeva, M.; Yunusova, N.; Patysheva, M.; Mitrofanova, I. V.; Faltin, V.; Tuzikov, S.; Slonimskaya, E.

2017-09-01

In recent years, it has been shown that under certain conditions cytostatic agents (chemotherapy and radiotherapy) can restore the functioning of the immune system impaired by malignancy burden. The modifications of biological properties by cytostatics acting make cancer cells visible for the immune system recognition and elimination. Eighteen patients diagnosed with primary local breast (8) and gastric (10) cancer between 2014 and 2016 were enrolled in the investigation. The phenotypic features of NK were assessed by flow cytometry using mAb (BD Pharmingen) against CD45 (common leukocyte antigen) and CD56 (NK-marker) for surface staining, CD107a (LAMP-1), Perforin (PF) and Gransime B (GB) for intracellular staining. We examined NK populations in the peripheral blood of cancer patients before treatment and in 5 days after second course of NACT. We found that NK populations produced PF in cancer patents, which were absent before treatment, increased after NACT. Their emergence can be associated with the immunoactivating effects of chemotherapy, realized by the modification of tumor cells or elimination of immunosuppressive cells.

Degradation of the cytostatic 5-Fluorouracil in water by Fenton and photo-assisted oxidation processes.

PubMed

Governo, Mariana; Santos, Mónica S F; Alves, Arminda; Madeira, Luís M

2017-01-01

Cytostatics are part of the forefront research topics due to their high prescription, high toxicity, and the lack of effective solutions to stop their entrance and spread in the environment. Among them, 5-Fluorouracil (5-Fu) has received particular attention because is one of the most prescribed active substances in chemotherapy worldwide. The degradation of 5-Fu by advanced oxidation processes (AOPs) is a poorly addressed topic, and this work brings valuable inputs concerning this matter. Herein, the efficacy of Fenton's process in the degradation of 5-Fu is explored for the first time; the study of the main variables and its successful application to the treatment of real wastewaters is demonstrated. Moreover, hydrogen peroxide-based and photo-assisted techniques (direct photolysis, photodegradation with H 2 O 2 and photo-Fenton) are also investigated for purposes of comparison. Under the best operation conditions obtained (T = 30 °C, [Fe 2+ ] 0  = 0.5 mM; [H 2 O 2 ] 0  = 240 mM and pH = 3 for [5-Fu] 0  = 0.38 mM), 5-Fu was completely eliminated after 2 h of Fenton's reaction and about 50 % of mineralization was reached after 8 h. The best performance was obtained by the photo-Fenton process, with 5-Fu mineralization level as high as 67 %, using an iron dose within the legal limits required for direct water discharge. Toxicity (towards Vibrio fischeri) of the effluents that resulted from the application of the above-mentioned AOPs was also evaluated; it was found that the degradation products generated from the photo-assisted processes are less toxic than the parent compound, putting into evidence the relevance of such technologies for degradation of cytostatics like 5-Fu.

Radiofrequency currents exert cytotoxic effects in NB69 human neuroblastoma cells but not in peripheral blood mononuclear cells

PubMed Central

HERNÁNDEZ-BULE, MARÍA LUISA; ROLDÁN, ERNESTO; MATILLA, JOAQUÍN; TRILLO, MARÍA ÁNGELES; ÚBEDA, ALEJANDRO

2012-01-01

Recently, a number of electric and electrothermal therapies have been applied to the treatment of specific cancer types. However, the cellular and molecular mechanisms involved in the response to such therapies have not been well characterized yet. Capacitive-resistive electric transfer (CRET) therapy uses electric currents at frequencies within the 0.45–0.6 MHz range to induce hyperthermia in target tissues. Preliminary trials in cancer patients have shown consistent signs that CRET could slow down growth of tumor tissues in brain gliomas, without inducing detectable damage in the surrounding healthy tissue. Previous studies by our group have shown that subthermal treatment with 0.57-MHz electric currents can induce a cytostatic, not cytotoxic response in HepG2 human hepatocarcinoma cells; such effect being mediated by cell cycle alterations. In contrast, the study of the response of NB69 human neuroblastoma cells to the same electric treatment revealed consistent indications of cytotoxic effects. The present study extends the knowledge on the response of NB69 cells to the subthermal stimulus, comparing it to that of primary cultures of human peripheral blood mononuclear cells (PBMC) exposed to the same treatment. The results showed no sensitivity of PBMC to the 0.57 MHz subthermal currents and confirmed that the treatment exerts a cytotoxic action in NB69 cells. The data also revealed a previously undetected cytostatic response of the neuroblastoma cell line. CRET currents affected NB69 cell proliferation by significantly reducing the fraction of cells in the phase G2/M of the cell cycle at 12 h of exposure. These data provide new information on the mechanisms of response to CRET therapy, and are consistent with a cytotoxic and/or cytostatic action of the electric treatment, which would affect human cells of tumor origin but not normal cells with a low proliferation rate. PMID:22843038

Radiofrequency currents exert cytotoxic effects in NB69 human neuroblastoma cells but not in peripheral blood mononuclear cells.

PubMed

Hernández-Bule, María Luisa; Roldán, Ernesto; Matilla, Joaquín; Trillo, María Angeles; Ubeda, Alejandro

2012-10-01

Recently, a number of electric and electrothermal therapies have been applied to the treatment of specific cancer types. However, the cellular and molecular mechanisms involved in the response to such therapies have not been well characterized yet. Capacitive-resistive electric transfer (CRET) therapy uses electric currents at frequencies within the 0.45-0.6 MHz range to induce hyperthermia in target tissues. Preliminary trials in cancer patients have shown consistent signs that CRET could slow down growth of tumor tissues in brain gliomas, without inducing detectable damage in the surrounding healthy tissue. Previous studies by our group have shown that subthermal treatment with 0.57-MHz electric currents can induce a cytostatic, not cytotoxic response in HepG2 human hepatocarcinoma cells; such effect being mediated by cell cycle alterations. In contrast, the study of the response of NB69 human neuroblastoma cells to the same electric treatment revealed consistent indications of cytotoxic effects. The present study extends the knowledge on the response of NB69 cells to the subthermal stimulus, comparing it to that of primary cultures of human peripheral blood mononuclear cells (PBMC) exposed to the same treatment. The results showed no sensitivity of PBMC to the 0.57 MHz subthermal currents and confirmed that the treatment exerts a cytotoxic action in NB69 cells. The data also revealed a previously undetected cytostatic response of the neuroblastoma cell line. CRET currents affected NB69 cell proliferation by significantly reducing the fraction of cells in the phase G2/M of the cell cycle at 12 h of exposure. These data provide new information on the mechanisms of response to CRET therapy, and are consistent with a cytotoxic and/or cytostatic action of the electric treatment, which would affect human cells of tumor origin but not normal cells with a low proliferation rate.

The antitumor efficacy of cisplatin in combination with triptorelin and exemestane therapy for an ovarian cancer ascites model in Wistar rats.

PubMed

Tkalia, I G; Vorobyova, L I; Grabovoy, A N; Svintsitsky, V S; Tarasova, T O

2015-03-01

To study antitumor activity of triptorelin - agonist of gonadotropin-releasing hormone and exemestane - inhibitor of aromatase in combination with cisplatin on the model of receptor-positive for estrogens and progesterone malignant transplantable ascites ovarian tumor (OT); to assess tumor response to treatment and VEGF expression in tumor cells under different combinations of cytostatic and hormonal drugs. 36 female Wistar rats, which underwent intraperitoneal transplantation of ascites OT (5×10(6) cells per animal), have been involved in the study. Rats were distributed into 4 groups (9 rats in each group): group 1 - animals, which received combination of cisplatin and triptorelin; group 2 - rats treated with combination of cisplatin and exemestane; group 3 - animals, which were administered with combination of cisplatin, triptorelin and exemestane; group 4 - rats, which received combination of triptorelin and exemestane. Histological study with assessment of treatment pathomorphosis in OT and immunohistochemical study have been carried out to analyze VEGF expression in OT cells. Survival of animals has been evaluated. Combination of cytostatic agent with triptorelin or exemestane has demonstrated significantly higher rates of treatment pathomorphosis (10.1 ± 0.1% and 16.2 ± 0.3%, respectively) and antiangiogenic activity in OT (21.4 ± 1.4% and 15.0 ± 1.3%, respectively), as well as the highest survival of animals (100.0 and 85.7%, respectively) as compared with the same in rats treated in regimen of monotherapy with cisplatin, triptorelin, exemestane or by combination of hormonal drugs. Among animals treated by combination of cytostatic drug with triptorelin, two were cured (22.2%), and among rats, which received cisplatin and exemestane, one animal (11.1%) was cured. Triptorelin and exemestane increase antitumor activity of cisplatin in respect to the transplantable malignant ascites OT and significantly increase survival of animals, especially when triptorelin and cisplatin are used in combination.

Simultaneous and Dose Dependent Melanoma Cytotoxic and Immune Stimulatory Activity of Betulin

PubMed Central

Arlt, Olga; Neske, Christina; Dehelean, Cristina; Pfeilschifter, Josef M.; Radeke, Heinfried H.

2015-01-01

Conventional cytostatic cancer treatments rarely result in the complete eradication of tumor cells. Therefore, new therapeutic strategies focus on antagonizing the immunosuppressive activity of established tumors. In particular, recent studies of antigen-loaded dendritic cells (DCs) eliciting a specific antitumor immune response has raised the hopes of achieving the complete elimination of tumor tissue. Genistein, fingolimod and betulin have already been described as active compounds in different types of cancer. Herein, we applied an integrated screening approach to characterize both their cytostatic and their immune-modulating properties side-by-side. As will be described in detail, our data confirmed that all three compounds exerted proapoptotic and antiproliferative activity in different B16 melanoma cell lines to a given extent, as revealed by an MTT assay, CFSE and DAPI staining. However, while genistein and fingolimod also affected the survival of primary bone marrow (BM) derived DCs of C57BL/6 mice, betulin exhibited a lower cytotoxicity for BMDCs in comparison to the melanoma cells. Moreover, we could show for the first time, that only betulin caused a simultaneous, highly specific immune-stimulating activity, as measured by the IL-12p70 release of Toll-like receptor 4-stimulated BMDCs by ELISA, which was due to increased IL-12p35 mRNA expression. Interestingly, the activation of DCs resulted in enhanced T lymphocyte stimulation, indicated by increased IL-2 and IFN-γ production of cytotoxic T cells in spleen cell co-culture assays which led to a decreased viability of B16 cells in an antigen specific model system. This may overcome the immunosuppressive environment of a tumor and destroy tumor cells more effectively in vivo if the immune response is specific targeted against the tumor tissue by antigen-loaded dendritic cells. In summary, cytostatic agents, such as betulin, that simultaneously exhibit immune stimulatory activity may serve as lead compounds and hold great promise as a novel approach for an integrated cancer therapy. PMID:25756279

Anticancer drugs in surface waters: what can we say about the occurrence and environmental significance of cytotoxic, cytostatic and endocrine therapy drugs?

PubMed

Besse, Jean-Philippe; Latour, Jean-François; Garric, Jeanne

2012-02-01

This study considers the implications and research needs arising from anticancer (also referred to as antineoplastic) drugs being released into the aquatic environment, for the entire therapeutic classes used: cytotoxic, cytostatic and endocrine therapy drugs. A categorization approach, based on French consumption amounts, allowed to highlight parent molecules and several metabolites on which further occurrence and ecotoxicological studies should be conducted. Investigations of consumption trends at a national and a local scale show an increase in the use of anticancer drugs between 2004 and 2008, thus leading to increased levels released in the environment. It therefore appears necessary to continue surveying their presence in surface waters and in wastewater treatment plant (WWTP) effluents. Furthermore, due to the rise of anticancer home treatments, most of the prescribed molecules are now available in town pharmacies. Consequently, hospital effluents are no longer the main expected entry route of anticancer drugs into the aquatic environment. Concerning ecotoxicological risks, current knowledge remains insufficient to support a definitive conclusion. Risk posed by cytotoxic molecules is still not well documented and it is not possible to conclude on their long-term effects on non-target organisms. To date, ecotoxicological effects have been assessed using standardized or in vitro assays. Such tests however may not be suitable for anticancer drugs, and further work should focus on full-life cycle or even multigenerational tests. Environmental significance (i.e. occurrence and effects) of cytostatics (protein kinases inhibitors and monoclonal antibodies), if any, is not documented. Protein kinases inhibitors, in particular, deserve further investigation due to their universal mode of action. Finally, concerning endocrine therapy drugs, molecules such as antiestrogen Tamoxifen and its active metabolites, could be of concern. Overall, to accurately assess the ecotoxicological risk of anticancer drugs, we discuss the need to break away from tests on isolated molecules and to test effects of mixtures at the low ng.l(-1) range. Copyright © 2011 Elsevier Ltd. All rights reserved.

Risk management of extravasation of cytostatic drugs at the Adult Chemotherapy Outpatient Clinic of a university hospital.

PubMed

Adami, Nilce Piva; de Gutiérrez, Maria Gaby Rivero; da Fonseca, Selma Montosa; de Almeida, Elizabeth Pinto Magalhães

2005-08-01

To verify the incidence of extravasation of cytostatic drugs in patients treated on an outpatient basis at a university hospital in the city of São Paulo, Brazil, during the period from 1998 to 2002, and to assess the quality of care provided by the nursing team using a protocol adopted for the treatment of this adverse event as a parameter. The movement for quality in healthcare services has been a recent event in Brazil, mainly as the result of the Brazilian Program of Hospital Accreditation instituted in 1998. Considering the emphasis on risk management, it is important to mention the monitoring of the occurrence of extravasations of cytostatic drugs in order to improve the quality of nursing care provided to cancer patients. An evaluative study with a descriptive, prospective and longitudinal design was conducted, based on the documentary analysis of the notification of 216 extravasations of vesicant and irritant drugs that occurred between 1998 and 2002 and the corresponding prescriptions of cold or hot compresses. The mean incidence of extravasations ranged from 0.2 to 1.4% over the five years of the study. Incorrect prescription of the type of compress was observed for three patients. Undesired effects were ulcers caused by the extravasation of vinblastine and dacarbazine in two cases. The low incidence of both extravasation and tissue damage demonstrates the adequate quality of nursing care provided to cancer patients at the outpatient clinic studied. However, the identification of the lack of 12 records of thermal treatment and of three erroneous prescriptions requires the implementation of educational measures to prevent these types of incident. The relevance of this study to clinical practice is to increase the awareness and involvement of the nursing team in the maintenance of a continuous surveillance system of the process and results of chemotherapy administration in order to increase the quality of care and the safety of the patient.

Contribution to the spectroscopic study of cytostatics molecules

NASA Astrophysics Data System (ADS)

Staicu, Angela; Pascu, Mihail-Lucian; Mogos, Ioan; Enescu, Mironel; Truica, Sorina; Voicu, Letitia; Gazdaru, Doina M.; Radu, Alina; Gazdaru, S.

2001-06-01

The effect of UV irradiation of methotrexate was investigated by steady state absorption and fluorescence spectroscopy. Major modifications on absorption bands were detected upon irradiation fluence greater than 59J/cm2. In addition the irradiated solutions become strongly fluorescent. The detected changes are not linear with the exposure time suggesting that the photo-induced chemical processes are complex.

[Prognostic significance of the cyclic AMP concentration in acute leukemias].

PubMed

Paietta, E; Mittermayer, K; Schwarzmeier, J D

1979-01-01

In patients with acute leukemia (myeloblastic, lymphoblastic, undifferentiated) proliferation kinetics and cyclic adenosine-3', 5'-monophosphate (cAMP) concentration of the leukemic cells were studied for their significance in the prediction of responsiveness to cytostatic therapy. Patients with good clinical response had significantly faster turnover and lower cAMP-levels than those who failed to respond to treatment.

Current recommendations for prevention and therapy of extravasation reactions in dermato-oncology.

PubMed

Kähler, Katharina C; Mustroph, Dieter; Hauschild, Axel

2009-01-01

Despite the introduction of many targeted therapies, a wide variety of cytostatic agents are still frequently used in dermato-oncology. In order to avoid further morbidity in tumor patients, prevention of extravasation reactions is of highest importance. The optimal management of extravasation requires an early diagnosis, the application of specific antidotes and a well-trained oncology team.

Zytoprotektion mit Amifostin (Ethyol®) in der Chemotherapie: Meta-Analyse zum pharmakokinetischen Interaktionspotential mit Zytostatika.

PubMed

Czejka, Martin; Schüller, Johannes; Kletzl, Heidemarie

2017-08-25

The cytoprotective agent amifostine (AMI) is capable to protect healthy cells (contrary to tumor cells) due to higher activity of alkaline phosphatase at the membrane site of normal cells. In seven clinical trials the influence of AMI on the pharmacokinetics of different cytostatics was investigated. Preadministration of AMI increased Cmax of doxorubicin (+ 44 %, p < 0.06), epirubicin (+ 31 %, P < 0.08), mitomycin C (+ 41 %, p < 0.01) and docetaxel (+ 31 % and + 17 %, not significant). In contrary, the peak concentration of pirarubicin , the tetrahydropyranyl-prodrug of doxorubicin was decreased (- 50 %, P < 0.03), leading to an equal higher concentrationof doxorubicin in the blood . In accordance to the peak concentrations, the AUC'ast was increased by chemoprotection: doxorubicin + 53 % (p < 0.01) and epirubicin + 23 % (not significant), docetaxel + 25 % and + 31 % (not significant). AUC'ast of mitomycin C and paclitaxel seemed to be unaffected by preadministered AMI. A particular inhibition of the protein binding by AMI has been identified as one reason for higher serum concentrations of anthracycline drugs. After cytoprotection, a possible increase of the cytostatic's Serum concentrations should be taken into account for optimal dosage schedules.

[Introduction of a clinical protocol for extravasation at the National Institute of Oncology, Budapest, Hungary].

PubMed

Bartal, Alexandra; Mátrai, Zoltán; Rosta, András; Szûcs, Attila

2011-03-01

Extravasation of cytostatics occurs when an infusion containing a cytotoxic drug leaks into the surrounding perivascular and subcutaneous tissues. Incidence of cytostatic extravasation is found to be 0.1-6% according to the literature. Depending on the severity of complications, pain, loss of function in the extremities, or in extreme cases tissue necrosis necessitating an amputation may develop, drawing consequences like delay or interruption of the chemotherapy. Extent of complications is greatly influenced by the type of medication administered, general condition of the patient, and professional preparedness of staff providing the oncological health service. The protocol recently implemented in the National Institute of Oncology is a short, compact guidance for physicians and nurses providing oncological care, so by quick and adequate management of extravasation cases, severe complications could be prevented. More complex practical guidelines including algorithms could be created as a result of a wider collaboration, with the help of which oncological health professionals could easily cope with this rare problem. The authors describe in their review the implementation of the use of dry warm and cold packs, dymethylsulfoxide and hyaluronidase and their function within the algorithm of extravasation treatment.

Cytostatic versus Cytocidal Activities of Chloroquine Analogues and Inhibition of Hemozoin Crystal Growth

PubMed Central

Gorka, Alexander P.; Alumasa, John N.; Sherlach, Katy S.; Jacobs, Lauren M.; Nickley, Katherine B.; Brower, Jonathan P.; de Dios, Angel C.

2013-01-01

We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365–374, 2013). PMID:23114783

Cytostatic versus cytocidal activities of chloroquine analogues and inhibition of hemozoin crystal growth.

PubMed

Gorka, Alexander P; Alumasa, John N; Sherlach, Katy S; Jacobs, Lauren M; Nickley, Katherine B; Brower, Jonathan P; de Dios, Angel C; Roepe, Paul D

2013-01-01

We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365-374, 2013).

Chromosome instability on children with asthma.

PubMed

Lialiaris, Theodore; Polyzou, Aggeliki; Mpountoukas, Panagiotis; Tsiggene, Anthi; Kouskoukis, Alexandros; Pouliliou, Stamatia; Paraskakis, Emmanouil; Tentes, Ioannis; Trypsianis, Grigorios; Chatzimichail, Athanasios

2009-10-01

Asthma is a complex disease with multiple interactions between genetic and environmental factors. The aim of our study was to investigate the possible genetic instability in asthmatic patients (AP) with asthma in human cultured peripheral blood lymphocytes. Furthermore, the presence of either cytostaticity or cytotoxicity was demonstrated. Human peripheral blood lymphocytes were cultured from 18 admitted children to the Pediatric Clinic of the University Hospital of Alexandroupolis (average age 7.2 years), and 9 healthy blood donors were used as control subjects (average age 6.5 years), none of whom was receiving drugs for medical or other reasons. A significant (p < 0.05) increase in spontaneous sister chromatid exchanges (SCEs) frequency in asthmatic patients compared with control subjects was observed. No statistically significant modification in the spontaneous proliferation rate index (PRI) in AP compared with the controls was demonstrated. Finally, MMC induced a statistically significant increase in SCEs frequency both to controls and to AP, with the MMC-induced SCEs rates in AP being statistically (p < 0.01) higher compared to the MMC-induced SCEs in controls. We try to improve a new diagnostic process of possible genetic instability by a combination of genotoxic, cytostatic and cytotoxic effects of asthma on human peripheral lymphocytes.

Development of an analytical method for the determination of anthracyclines in hospital effluents.

PubMed

Mahnik, Susanne N; Rizovski, Blanka; Fuerhacker, Maria; Mader, Robert M

2006-11-01

Little is known about the fate of cytostatics after their elimination from humans into the environment. Being often very toxic compounds, their quantification in hospital effluents may be necessary to individualise the putative magnitude of pollution problems. We therefore developed a method for the determination of the very important group of anthracyclines (doxorubicin, epirubicin, and daunorubicin) in hospital effluents. Waste water samples were enriched by solid phase extraction (concentration factor 100), analysed by reversed-phase high performance liquid chromatography (RP-HPLC), and monitored by fluorescence detection. This method is reproducible and accurate within a range of 0.1-5 micro g l(-1) for all compounds (limits of quantification: 0.26-0.29 micro g l(-1) ; recoveries >80%). The applicability of the method was proven by chemical analysis of hospital sewage samples (range: 0.1-1.4 micro g l(-1) epirubicin and 0.1-0.5 micro g l(-1) doxorubicin). Obtained over a time period of one month, the results were in line with those calculated by an input-output model. These investigations show that the examined cytostatics are easily detectable and that the presented method is suitable to estimate the dimension of pharmaceutical contamination originating from hospital effluents.

Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article.

PubMed

Satriano, J

2004-07-01

An early response to an acute inflammatory insult, such as wound healing or experimental glomerulonephritis, is the conversion of arginine to the cytostatic molecule nitric oxide (NO). This 'anti-bacterial' phase is followed by the conversion of arginine to ornithine, which is the precursor for the pro-proliferative polyamines as well as proline for the production of extracellular matrix. This latter, pro-growth phase constitutes a 'repair' phase response. The temporal switch of arginine as a substrate for the cytostatic iNOS/NO axis to the pro-growth arginase/ ornithine/polyamine and proline axis is subject to regulation by inflammatory cytokines as well as interregulation by the arginine metabolites themselves. Arginine is also the precursor for another biogenic amine, agmatine. Here we describe the capacity of these three arginine pathways to interregulate, and propose a model whereby agmatine has the potential to serve in the coordination of the early and repair phase pathways of arginine in the inflammatory response by acting as a gating mechanism at the transition from the iNOS/NO axis to the arginase/ODC/polyamine axis. Due to the pathophysiologic and therapeutic potential, we will further examine the antiproliferative effects of agmatine on the polyamine pathway.

To the nucleolar bodies (nucleoli) in cells of the lymphocytic lineage in patients suffering from B - chronic lymphocytic leukemia.

PubMed

Smetana, K; Karban, J; Trneny, M

2010-01-01

The present study was undertaken to provide more information on nucleoli in lymphocytes of B - chronic lymphocytic leukemia. The computer assisted nucleolar and cytoplasmic RNA image densitometry, reflecting the nucleolar and cytoplasmic RNA concentration at the single cell level, demonstrated a remarkable stability during the differentiation and maturation of B- lymphocytes. In contrast, as it was expected, the nucleolar diameter during the lymphocytic development markedly decreased. Thus the nucleolar RNA content of leukemic B-lymphocytes was apparently related to the nucleolar size. In both immature and mature lymphocytes, the cytostatic treatment increased the incidence of micronucleoli, which represent the "inactive" type of nucleoli. However, the decreased values of the nucleolar diameter were statistically significant only in mature lymphocytes of treated patients. On the other hand, despite such observation, it must be mentioned that "large active" and "ring shaped resting" nucleoli were still present in immature and mature lymphocytes after the cytostatic therapy and such cells might represent a potential pool of proliferating cells. As it is generally accepted "large active nucleoli" with multiple fibrillar centers are known to be characteristic for proliferating cells. "Ring shaped resting nucleoli" are present in sleeping cells, which may be stimulated to return to the cell cycle and to proliferate again. In addition, the nucleolar RNA distribution also indicated that Gumprecht ghosts mostly originated from mature lymphocytes. Increased ratio of the nucleolar to cytoplasmic RNA density in Gumprecht ghosts or apoptotic cells and apoptotic bodies of the lymphocytic origin was related to the decreased cytoplasmic RNA concentration. The increased nucleolar size together with the markedly decreased cytoplasmic RNA concentration characteristic for Gumprecht ghosts just reflected the spreading of lymphocytes during smear preparations. In apoptotic cells or bodies of the lymphocytic origin, the "frozen" nucleolar RNA concentration accompanied by a reduced RNA concentration in the cytoplasm exhibited a remarkable similarity to the apoptotic process induced in vitro by the cytostatic treatment. B-chronic lymphocytic leukemia; lymphocytes; nucleolar classes; size; nucleolar RNA image density -concentration.

Piperine impairs cell cycle progression and causes reactive oxygen species-dependent apoptosis in rectal cancer cells.

PubMed

Yaffe, Paul B; Doucette, Carolyn D; Walsh, Mark; Hoskin, David W

2013-02-01

Piperine, an alkaloid phytochemical found in the fruit of black and long pepper plants, is reported to inhibit the growth of cancer cells; however, the mechanism of action in human cancer cells is not clear. In this study we investigated the effect of piperine on the growth of HRT-18 human rectal adenocarcinoma cells. MTT assays showed that piperine inhibited the metabolic activity of HRT-18 cells in a dose- and time-dependent fashion, suggesting a cytostatic and/or cytotoxic effect. Flow cytometric analysis of Oregon Green 488-stained and propidium iodide-stained HRT-18 cells showed that piperine inhibited cell cycle progression. Piperine also caused HRT-18 cells to die by apoptosis, as determined by Annexin-V-FLUOS staining and characteristic changes in cell morphology. Flow cytometric analysis of dihydroethidium- and 2',7'-dichlorofluorescein diacetate-stained HRT-18 cells showed increased production of reactive oxygen species in piperine-treated cells. Furthermore, the antioxidant N-acetylcysteine reduced apoptosis in cultures of piperine-treated HRT-18 cells, indicating that piperine-induced cytotoxicity was mediated at least in part by reactive oxygen species. The cytostatic and cytotoxic effects of piperine on rectal cancer cells suggest that this dietary phytochemical may be useful in cancer treatment. Copyright © 2012 Elsevier Inc. All rights reserved.

Antitumoral Effect of Hibiscus sabdariffa on Human Squamous Cell Carcinoma and Multiple Myeloma Cells.

PubMed

Malacrida, Alessio; Maggioni, Daniele; Cassetti, Arianna; Nicolini, Gabriella; Cavaletti, Guido; Miloso, Mariarosaria

2016-10-01

Cancer is a leading cause of death worldwide. Despite therapeutic improvements, some cancers are still untreatable. Recently there has been an increasing interest in the use of natural substances for cancer prevention and treatment. Hibiscus sabdariffa (HS) is a plant, belonging to Malvaceae family, widespread in South Asia and Central Africa. HS extract (HSE) used in folk medicine, gained researchers' interest thanks to its antioxidant, anti-inflammatory, and chemopreventive properties. In the present study, we initially assessed HSE effect on a panel of human tumor cell lines. Then we focused our study on the following that are most sensitive to HSE action cell lines: Multiple Myeloma (MM) cells (RPMI 8226) and Oral Squamous Cell Carcinoma (OSCC) cells (SCC-25). In both RPMI 8226 and SCC-25 cells, HSE impaired cell growth, exerted a reversible cytostatic effect, and reduced cell motility and invasiveness. We evaluated the involvement of MAPKs ERK1/2 and p38 in HSE effects by using specific inhibitors, U0126 and SB203580, respectively. For both SCC-25 and RPMI 8226, HSE cytostatic effect depends on p38 activation, whereas ERK1/2 modulation is crucial for cell motility and invasiveness. Our results suggest that HSE may be a potential therapeutic agent against MM and OSCC.

Genotoxic potential of selected cytostatic drugs in human and zebrafish cells.

PubMed

Gajski, Goran; Gerić, Marko; Žegura, Bojana; Novak, Matjaž; Nunić, Jana; Bajrektarević, Džejla; Garaj-Vrhovac, Vera; Filipič, Metka

2016-08-01

Due to their increasing use, the residues of anti-neoplastic drugs have become emerging pollutants in aquatic environments. Most of them directly or indirectly interfere with the cell's genome, which classifies them into a group of particularly dangerous compounds. The aim of the present study was to conduct a comparative in vitro toxicological characterisation of three commonly used cytostatics with different mechanisms of action (5-fluorouracil [5-FU], cisplatin [CDDP] and etoposide [ET]) towards zebrafish liver (ZFL) cell line, human hepatoma (HepG2) cells and human peripheral blood lymphocytes (HPBLs). Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and acridine orange/ethidium bromide staining. All three drugs induced time- and dose-dependent decreases in cell viability. The sensitivity of ZFL and HepG2 cells towards the cytotoxicity of 5-FU was comparable (half maximal inhibitory concentration (IC50) 5.3 to 10.4 μg/mL). ZFL cells were more sensitive towards ET- (IC50 0.4 μg/mL) and HepG2 towards CDDP- (IC50 1.4 μg/mL) induced cytotoxicity. Genotoxicity was determined by comet assay and cytokinesis block micronucleus (CBMN) assay. ZFL cells were the most sensitive, and HPBLs were the least sensitive. In ZFL cells, induction of DNA strand breaks was a more sensitive genotoxicity endpoint than micronuclei (MNi) induction; the lowest effective concentration (LOEC) for DNA strand break induction was 0.001 μg/mL for ET, 0.01 μg/mL for 5-FU and 0.1 μg/mL for CDDP. In HepG2 cells, MNi induction was a more sensitive genotoxicity endpoint. The LOEC values were 0.01 μg/mL for ET, 0.1 μg/mL for 5-FU and 1 μg/mL for CDDP. The higher sensitivity of ZFL cells to cytostatic drugs raises the question of the impact of such compounds in aquatic ecosystem. Since little is known on the effect of such drugs on aquatic organisms, our results demonstrate that ZFL cells provide a relevant and sensitive tool to screen genotoxic potential of environmental pollutant in the frame of hazard assessment.

Discovery and Development of Therapeutic Drugs Against Lethal Human RNA-Viruses: A Multidisciplinary Assault

DTIC Science & Technology

1989-08-21

extract of Balanites aegyptiaca Del afforded four new cytostatic saponins named balanitin-4 (I), -5 (I), -6 (11) and -7 (IV). On the basis of enzymatic...the investigator(s) adherel to policies of applicable Federal Law 45 CFR 46. In concucting research utilizing recombinant DNA technology , the...of novel antiviral substances from confirmed active extracts of marine organisms and both higher and lower plants. Maximum effort would be devoted to

[Disaccharidases of the intestinal mucosa of the rat after cytostatic combined therapy with vincristin sulphate and ifosfamide (author's transl)].

PubMed

Hartwich, G; Domschke, W; Matzkies, F

1976-01-01

Vincristin sulphate or 3-(2-chloroethyl)-2-(2-chloroethyl-amino)-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (ifosfamide)--given alone--may reduce intestinal disaccharidase activities in the rat. However, combined administration of both the drugs, as used as a therapeutic means, results in a much more drastic decrease in enzyme activities. Consequently, also in man maldigestion of disaccharides might occur due to that polychemotherapy.

Extravasation of chemotherapy.

PubMed

Langer, Seppo W

2010-07-01

Extravasation of chemotherapy is a feared complication of anticancer therapy. The accidental leakage of cytostatic agents into the perivascular tissues may have devastating short-term and long-term consequences for patients. In recent years, the increased focus on chemotherapy extravasation has led to the development of international guidelines that have proven useful tools in daily clinical practice. Moreover, the tissue destruction in one of the most dreaded types of extravasation (ie, anthracycline extravasation) now can effectively be prevented with a specific antidote, dexrazoxane.

Synergistic Lethality of Mifepristone and LY294002 in Ovarian Cancer Cells

PubMed Central

Wempe, Stacy L.; Gamarra-Luques, Carlos D.; Telleria, Carlos M.

2013-01-01

We have previously shown that the antiprogestin and antiglucocorticoid mifepristone inhibits the growth of ovarian cancer cells. In this work, we hypothesized that cellular stress caused by mifepristone is limited to cytostasis and that cell killing is avoided as a consequence of the persistent activity of the PI3K/Akt survival pathway. To investigate the role of this pathway in mifepristone-induced growth inhibition, human ovarian cancer cells of various histological subtypes and genetic backgrounds were exposed to cytostatic doses of mifepristone in the presence or absence of the PI3K inhibitor, LY294002. The activation of Akt in ovarian cancer cells, as marked by its phosphorylation on Ser473, was not modified by cytostatic concentrations of mifepristone, but it was blocked upon treatment with LY294002. The combination mifepristone/LY294002, but not the individual drugs, killed ovarian cancer cells via apoptosis, as attested by genomic DNA fragmentation and cleavage of caspase-3, and the concomitant downregulation of antiapoptotic proteins Bcl-2 and XIAP. From a pharmacological standpoint, when assessing cell growth inhibition using a median-dose analysis algorithm, the interaction between mifepristone and LY294002 was synergistic. The lethality caused by the combination mifepristone/LY294004 in 2-dimensional cell cultures was recapitulated in organized, 3-dimensional spheroids. This study demonstrates that mifepristone and LY294002 when used individually cause cell growth arrest; yet, when combined, they cause lethality. PMID:23420486

Nuclear translocation of Skp2 facilitates its destruction in response to TGFβ signaling

PubMed Central

Wu, George

2011-01-01

Skp2, a F-box protein that determines the substrate specificity for SCF ubiquitin ligase, has recently been demonstrated to be degraded by Cdh1/APC in response to TGFβ signaling. The TGFβ-induced Skp2 proteolysis results in the stabilization of p27 that is necessary to facilitate TGFβ cytostatic effect. Previous observation from immunocytochemistry indicates that Cdh1 principally localizes in the nucleus while Skp2 mainly localizes in the cytosol, which leaves us a puzzle on how Skp2 is recognized and then ubiquitylated by Cdh1/APC in response to TGFβ stimulation. Here, we report that Skp2 is rapidly translocated from the cytosol to the nucleus upon the cellular stimulation with TGFβ. Using a combinatorial approach of immunocytochemistry, biochemical-fraction-coupled immunoprecipitation, mutagenesis as well as protein degradation assay, we have demonstrated that the TGFβ-induced Skp2 nucleus translocation is critical for TGFβ cytostatic effect that allows physical interaction between Cdh1 and Skp2 and in turn facilitates the Skp2 ubquitylation by Cdh1/APC. Disruption of nuclear localization motifs on Skp2 stabilizes Skp2 in the presence of TGFβ signaling, which attenuates TGFβ-induced p27 accumulation and antagonizes TGFβ-induced growth inhibition. Our finding reveals a cellular mechanism that facilitates Skp2 ubiquitylation by Cdh1/APC in response to TGFβ. PMID:21212736

Preclinical evaluation of amiodarone for the treatment of murine leukemia P388. In vivo and in vitro investigation.

PubMed

Papageorgiou, A D; Dalezis, P; Mourelatos, C; Lioutas, K; Sahpazidou, D; Geromichalou, E; Geromichalos, G; Lialiaris, Th; Athanasiadou, P; Athanasiadis, P

2010-01-01

The purpose of the present study was the investigation of antileukemic effect of amiodarone in leukemia P388 BDF1 bearing mice and its genotoxic and cytostatic effect in cultured normal human lymphocytes. Leukemia P388 was used in this study. BDF1 mice were used for chemotherapy evaluation in vivo. The antitumor activity was assessed by the oncostatic parameter T/C, representing the increase of life span of drug-treated animals vs. controls. Lymphocyte cultures were used to study the genotoxic and cytostatic effect in vitro, expressed by enhanced sister chromatid exchange (SCE) and reduced proliferation rate indices (PRIS). Amiodarone was found to exert antileukemic potency against leukemia P388 bearing mice at all three different treatment schedules used, yielding T/C values of 155%, 163% with one cure and 230%. In the in vitro cytogenic experiments, significant increase of SCE rates by amiodarone was observed at 0.2 μM, while at the same concentration significant suppression of PRIS was achieved. According to the National Cancer Institute (NCI), a compound is characterized as potential chemotherapeutic deserving further evaluation if it produces T/C values≥125%. On the other hand the SCE assay has predictive value as a clinical assay for drugs exhibiting a strong correlation between cell killing and induction of SCEs. Further studies are warranted to clarify the structure-activity relationship of amiodarone.

Choline and/or folic acid deficiency is associated with genomic damage and cell death in human lymphocytes in vitro.

PubMed

Lu, Lin; Ni, Juan; Zhou, Tao; Xu, Weijiang; Fenech, Michael; Wang, Xu

2012-04-01

Choline and folate are interrelated methyl donors. Previous studies showed that folate prevents genomic damage in human lymphocytes in vitro; however, the association between choline and human genomic stability is uncertain. To explore the genotoxicity, cytotoxicity, and cytostatic effects and possible interactions of choline and/or folate deficiency on the human genome, lymphocytes from 6 volunteers were cultured in 18 combinations of choline (CC) and folic acid (FA) media for 9 days. The genotoxicity was evaluated by micronuclei, nucleoplasmic bridges, and nuclear buds in the binucleated cell; the cytotoxicity indices included apoptosis and necrosis, and the cytostatic effects were indicated by nuclear division index (NDI). Across all choline concentrations, the frequencies of all biomarkers except NDI were diminished when FA concentration was more than or equal to 120 nmol/L. The frequencies of micronuclei, buds, and necrosis were significantly higher at lower levels of CC (0-6 μmol/L) compared with higher concentrations of CC (12-21.5 μmol/L) while maintaining the same FA concentration. We concluded that both choline and folate significantly impact genomic stability and cell death, although effects of folate were 2.5- to 6.2-fold greater, depending on the biomarker and dose. A combination of 12 μmol/L CC and 120 nmol/L FA appears to be optimal for genomic integrity in vitro.

Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers.

PubMed

Van Goietsenoven, Gwendoline; Mathieu, Véronique; Lefranc, Florence; Kornienko, Alexander; Evidente, Antonio; Kiss, Robert

2013-03-01

The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs. © 2012 Wiley Periodicals, Inc.

Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics.

PubMed

Cragg, Mark S; Harris, Claire; Strasser, Andreas; Scott, Clare L

2009-05-01

Therapeutic targeting of tumours on the basis of molecular analysis is a new paradigm for cancer treatment but has yet to fulfil expectations. For many solid tumours, targeted therapeutics, such as inhibitors of oncogenic kinase pathways, elicit predominantly disease-stabilizing, cytostatic responses, rather than tumour regression. Combining oncogenic kinase inhibitors with direct activators of the apoptosis machinery, such as the BH3 mimetic ABT-737, may unlock potent anti-tumour potential to produce durable clinical responses with less collateral damage.

Difluoromethylornithine in cancer: new advances.

PubMed

Alexiou, George A; Lianos, Georgios D; Ragos, Vassileios; Galani, Vasiliki; Kyritsis, Athanassios P

2017-04-01

Difluoromethylornithine (DFMO; eflornithine) is an irreversible suicide inhibitor of the enzyme ornithine decarboxylase which is involved in polyamine synthesis. Polyamines are important for cell survival, thus DFMO was studied as an anticancer agent and as a chemoprevention agent. DFMO exhibited mainly cytostatic activity and had single agent efficacy as well as activity in combination with other chemotherapeutic drugs for some cancers and leukemias. Herewith, we summarize the current knowledge of the anticancer and chemopreventive properties of DFMO and assess the status of clinical trials.

Antiproliferative activity of Greek propolis.

PubMed

Pratsinis, Harris; Kletsas, Dimitris; Melliou, Eleni; Chinou, Ioanna

2010-04-01

The butanolic extract and the isolated chemical constituents, mainly diterpenes and flavonoids, from Greek propolis have been tested for their cytostatic activities against human malignant and normal cell strains. The extract and the diterpenes were found to be the most active against HT-29 human colon adenocarcinoma cells, without affecting normal human cells. Manool, a diterpene isolated for the first time from Greek propolis, was the most active compound, arresting the cancer cells at the G(2)/M phase of the cell cycle.

Proximicin A, B and C, novel aminofuran antibiotic and anticancer compounds isolated from marine strains of the actinomycete Verrucosispora.

PubMed

Fiedler, Hans-Peter; Bruntner, Christina; Riedlinger, Julia; Bull, Alan T; Knutsen, Gjert; Goodfellow, Michael; Jones, Amanda; Maldonado, Luis; Pathom-aree, Wasu; Beil, Winfried; Schneider, Kathrin; Keller, Simone; Sussmuth, Roderich D

2008-03-01

A family of three novel aminofuran antibiotics named as proximicins was isolated from the marine Verrucosispora strain MG-37. Proximicin A was detected in parallel in the marine abyssomicin producer "Verrucosispora maris" AB-18-032. The characteristic structural element of proximicins is 4-amino-furan-2-carboxylic acid, a hitherto unknown gamma-amino acid. Proximicins show a weak antibacterial activity but a strong cytostatic effect to various human tumor cell lines.

Surface active stabilizer Tyloxapol in colloidal dispersions exerts cytostatic effects and apoptotic dismissal of cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kristl, Julijana; Teskac, Karmen; Milek, Miha

Solid lipid nanoparticles (SLN) have been praised for their advantageous drug delivery properties such as biocompatibility, controlled release and passive drug targeting. However, the cytotoxicity of SLN and their ingredients, especially over a longer time period, has not been investigated in detail. We examined the critical issues regarding the use of a surface active stabilizer Tyloxapol (Tyl) for the preparation of solid lipid particles (SLP) and their effects on cellular functions and viability. SLP composed of behenate, phospholipids and a stabilizer, Tyloxapol or Lutrol (Lut), were prepared by the lipid melt method, labeled with a fluorescent dye and tested onmore » Jurkat or HEK293 cells. The nano-sized particles were rapidly internalized and exhibited cytoplasmic localization. Incubation of cells with SLP-Tyl resulted in a dose- and time-dependent cytostatic effect, and also caused moderate and delayed cytotoxicity. Tyloxapol solution or SLP-Tyl dispersion caused the detachment of HEK293 cells, a decrease in cell proliferation and alterations in cellular morphology. Cell cycle analysis revealed that, while the unfavourable effects of SLP-Tyl and Tyloxapol solution are similar initially, longer incubation results in partial recovery of cells incubated with the dispersion of SLP-Tyl, whereas the presence of Tyloxapol solution induces apoptotic cell death. These findings indicate that Tyloxapol is an unfavourable stabilizer of SLP used for intracellular delivery and reinforce the role of stabilizers in a design of SLP with minimal cytotoxic properties.« less

Studies on activated cytostatic fluorouracil as photosensitizer: to use in eye tumor treatment

NASA Astrophysics Data System (ADS)

Pascu, Mihail-Lucian; Carstocea, Benone D.; Brezeanu, Mihail; Voicu, Letitia; Staicu, Angela; Gazdaru, Doina M.; Pascu, Ruxandra A.

2004-09-01

Hydroxypyrimidine 5-fluorouracil (5-FU) belongs to the cytostatics group known as antimetabolites. The effect of UV irradiation on 5-FU was investigated by absorption and fluorescence spectroscopy. The study of the photosensitizer properties of 5-FU was made since their effects could be enhanced by exposure to UV radiation at different doses. Solutions 2.5x10-4M in natural saline water (0.8% NaCl), irradiated with optical beams emitted by N2 laser and UV Hg classic lamp, were used. The 5-FU was chosen due to its strong absorption along a large spectral range which makes possible the fluorescence excitation in UV. The absorption spectra exhibit bands between 250 - 450 nm. The emission fluorescence was measured in the 400-550 nm spectral range, with λex=320 and 350 nm for samples irradiated with Hg lamp and with λex=360 nm for samples irradiated with N2 laser. The excitation fluorescence was measured in the spectral range 200-400 nm, with λem=440 nm for samples irradiated with N2 laser. The spectra reveal a fluorescence enhancement with the exposure time, with a maximum at 3 min due to the transformation of 5-FU molecule into a fluorescent tautomeric form. The destruction more rapid than usual of the neovascularisation was observed for conjunctive of rabbit eyes, when they are impregnated with 5-FU solution and exposed to incoherent UV and visible light.

Optimal Anti-cancer Drug Profiles for Effective Penetration of the Anti-cancer Drug Market by Generic Drugs in Japan.

PubMed

Shibata, Shoyo; Matsushita, Maiko; Saito, Yoshimasa; Suzuki, Takeshi

2017-01-01

The increased use of generic drugs is a good indicator of the need to reduce the increasing costs of prescription drugs. Since there are more expensive drugs compared with other therapeutic areas, "oncology" is an important one for generic drugs. The primary objective of this article was to quantify the extent to which generic drugs in Japan occupy each level of the Anatomical Therapeutic Chemical (ATC) classification system. The dataset used in this study was created from publicly available information obtained from the IMS Japan Pharmaceutical Market database. Data on the total amount of sales and number of prescriptions for anti-cancer drugs between 2010 and 2016 in Japan were selected. The data were categorized according to the third level of the ATC classification system. All categories of the ATC classification system had increased market shares in Japan between 2010 and 2016. The barriers to market entry were relatively low in L01F (platinum anti-neoplastics), L01C (plant-based neoplastics), L02B (cytostatic hormone antagonists), and L01D (anti-neoplastic antibiotics) but were high in L02A (cytostatic hormones), L01H (protein kinase inhibitors), and L01B (anti-metabolites). Generic cancer drugs could bring savings to Japanese health care systems. Therefore, their development should be directed toward niche markets, such as L02A, L01H, and L01B, and not competitive markets.

Cytostatic response of NB69 cells to weak pulse-modulated 2.2 GHz radar-like signals.

PubMed

Trillo, María A; Cid, María Antonia; Martínez, Maria Antonia; Page, Juan E; Esteban, Jaime; Úbeda, Alejandro

2011-07-01

The present study investigates the response of two human cancer cell lines to a 24-h treatment with a 2.2-GHz, pulse-modulated (5 µs pulse duration, 100 Hz repetition rate) radar-like signal at an average SAR = 0.023 W/kg, using a newly designed setup for in vitro exposure to radiofrequency (RF) fields. A complete discretized model of the setup was created for numerical dosimetry using finite-difference time-domain (FDTD) software, SEMCAD X. The average dose of RF radiation absorbed by the cultures was calculated to be subthermal (ΔT < 0.1 °C). The RF exposure induced a consistent, statistically significant reduction in the cell number (13.5% below controls, P < 0.001) in the neuroblastoma NB69 line. This effect was accompanied with slight but statistically significant increases in the proportions of cells in phases G0/G1 and G2/M of the cell cycle (6% and 9%, respectively; P < 0.05 over controls). By contrast, the hepatocarcinoma cell line HepG2 did not respond to the same RF treatment. These results indicate that a pulse-modulated RF radiation with high instantaneous amplitude and low average power can induce cytostatic responses on specific, sensitive cancer cell lines. The effect would be mediated, at least in part, by alterations in the kinetics of the cell cycle. Copyright © 2011 Wiley-Liss, Inc.

Saponin B, a novel cytostatic compound purified from Anemone taipaiensis, induces apoptosis in a human glioblastoma cell line.

PubMed

Wang, Yuangang; Tang, Haifeng; Zhang, Yun; Li, Juan; Li, Bo; Gao, Zhenhui; Wang, Xiaoyang; Cheng, Guang; Fei, Zhou

2013-11-01

Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors. Saponin B, a novel compound isolated from the medicinal plant, Anemone taipaiensis, has been found to have a strong time- and dose-dependent cytostatic effect on human glioma cells and to suppress the growth of U87MG GBM cells. In this study, we investigated whether saponin B induces the apoptosis of glioblastoma cells and examined the underlying mechanism(s) of action of saponin B. Saponin B significantly suppressed U87MG cell proliferation. Flow cytometric analysis of DNA in the U87MG cells confirmed that saponin B blocked the cell cycle at the S phase. Furthermore, treatment of the U87MG cells with saponin B induced chromatin condensation and led to the formation of apoptotic bodies, as observed under a fluorescence microscope, and Annexin V/PI assay further suggested that phosphatidylserine (PS) externalization was apparent at higher drug concentrations. Treatment with saponin B activated the receptor-mediated pathway of apoptosis, as western blot analysis revealed the activation of Fas-l. Saponin B increased the Bax and caspase-3 ratio and decreased the protein expression of Bcl-2. The results from the present study demonstrate that the novel compound, saponin B, effectively induces the apoptosis of GBM cells and inhibits glioma cell growth and survival. Therefore, saponin B may be a potential candidate for the development of novel cancer therapeutics with antitumor activity against gliomas.

Drugs of abuse, cytostatic drugs and iodinated contrast media in tap water from the Madrid region (central Spain):A case study to analyse their occurrence and human health risk characterization.

PubMed

Mendoza, A; Zonja, B; Mastroianni, N; Negreira, N; López de Alda, M; Pérez, S; Barceló, D; Gil, A; Valcárcel, Y

2016-01-01

This work analyses the presence of forty-eight emerging pollutants, including twenty-five drugs of abuse and metabolites, seventeen cytostatic drugs and six iodinated contrast media, in tap water from the Madrid Region. Analysis of the target compounds in the tap water was performed by means of (on-line or off-line) solid-phase extraction followed by analysis by liquid chromatography-tandem mass spectrometry. A preliminary human health risk characterization was undertaken for each individual compound and for different groups of compounds with a common mechanism of action found in tap water. The results of the study showed the presence of eight out of the twenty-five drugs of abuse and metabolites analysed, namely, the cocainics cocaine and benzoylecgonine, the amphetamine-type stimulants ephedrine, 3,4-methylenedioxymethamphetamine and methamphetamine, the opioid methadone and its metabolite 2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine and, finally caffeine at concentrations ranging from 0.11 to 502 ng L(-1). Four out of the six analysed iodinated contrast media, namely, diatrizoate, iohexol, iomeprol and iopromide, were detected in at least one sample, with concentration values varying between 0.4 and 5 ng L(-1). Cytostatic compounds were not detected in any sample. Caffeine was the substance showing the highest concentrations, up to 502 ng L(-1), mainly in the drinking water sampling point located in Madrid city. Among the other drugs of abuse, the most abundant compounds were cocaine and benzoylecgonine, detected at concentrations ranging from 0.11 to 86 ng L(-1) and from 0.11 to 53 ng L(-1), respectively. Regarding iodinated contrast media, iohexol was the most ubiquitous and abundant compound, with a frequency of detection of 100% and concentrations from 0.5 to 5.0 ng L(-1) in basically the same range in all sampling points. Taking into account the results and types of treatment applied, ozonisation plus granular activated carbon filtration appears to be efficient in the removal of cocaine and benzoylecgonine. For the amphetamine-type stimulants, opioids and caffeine, ozonisation plus granular activated carbon filtration and ultrafiltration plus reverse osmosis showed higher removal efficiency than sand filtration. The human health risk characterization performed indicates that the lifetime consumption of the tap waters analysed has associated a negligible human health concern. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cutting the brakes and flooring the gas: how TMEPAI turns TGF-β into a tumor promoter.

PubMed

Cichon, Magdalena A; Radisky, Derek C

2014-09-01

In normal or nonmalignant cells, TGF-β inhibits cellular proliferation through activation of the SMAD-dependent canonical signaling pathway. Recent findings demonstrate that the protein TMEPAI1 can block the cytostatic effects of the canonical TGF-β signaling pathway, while activating cellular proliferation through the noncanonical, SMAD-independent TGF-β signaling pathway. As TMEPAI1 shows increased expression in the poor prognosis basal and HER2 intrinsic subtypes of breast cancer, these findings point to a new avenue of targeted therapy with considerable therapeutic potential.

Nanopharmacology in translational hematology and oncology

PubMed Central

Tomuleasa, Ciprian; Braicu, Cornelia; Irimie, Alexandra; Craciun, Lucian; Berindan-Neagoe, Ioana

2014-01-01

Nanoparticles have displayed considerable promise for safely delivering therapeutic agents with miscellaneous therapeutic properties. Current progress in nanotechnology has put forward, in the last few years, several therapeutic strategies that could be integrated into clinical use by using constructs for molecular diagnosis, disease detection, cytostatic drug delivery, and nanoscale immunotherapy. In the hope of bringing the concept of nanopharmacology toward a viable and feasible clinical reality in a cancer center, the present report attempts to present the grounds for the use of cell-free nanoscale structures for molecular therapy in experimental hematology and oncology. PMID:25092977

[The interauricular laser therapy of rheumatoid arthritis].

PubMed

Sidorov, V D; Mamiliaeva, D R; Gontar', E V; Reformatskaia, S Iu

1999-01-01

Investigations have proved the ability of interauricular low-intensity infrared laser therapy (0.89 nm, 7.6 J/cm) to produce anti-inflammatory, immunomodulating action in patients with rheumatoid arthritis. The method has selective, pathogenetically directed immunomodulating effect the mechanism of which is similar to that of basic antirheumatic drugs and of intravenous laser radiation of blood. This laser therapy can be used as an alternative to intravenous blood radiation being superior as a noninvasive method. Interauricular laser therapy can potentiate the effects of nonsteroid anti-inflammatory drugs, cytostatics and diminish their side effects.

Biodistribution of doxorubicin and nanostructured ferrocarbon carrier particles in organism during magnetically controlled drug delivery

NASA Astrophysics Data System (ADS)

Kuznetsov, Anatoly A.; Filippov, Victor I.; Nikolskaya, Tatiana A.; Budko, Andrei P.; Kovarskii, Alexander L.; Zontov, Sergei V.; Kogan, Boris Ya.; Kuznetsov, Oleg A.

2009-05-01

Biodistribution of doxorubicin and ferrocarbon carrier particles in organism during and after magnetically controlled anti-tumor drug delivery and deposition was studied. Animal tests show high concentration of the cytostatic drug in the target zone, while its concentration is three orders of magnitude lower in bloodstream and other organs. A significant depot of the drug remains on the deposited particles days after the procedure. Macrophages actively phagocytose the ferrocarbon (FeC) particles and remain viable long enough to carry them to the lymph nodes.

[High-dosed gestagen therapy of the metastatic mammary carcinoma (author's transl)].

PubMed

Firusian, N; Becher, R

1981-12-01

Thirty patients with histologically proven metastatic mammary carcinoma were treated, after exhaustion of hormonal and cytostatic therapeutic means, with high-dosed medroxyprogesterone acetate (MPA) during a ten-day induction phase with 1000 mg MPAi.m. per day and then with 600 mg oral MPA per day. In eleven patients a complete or partial remission was achieved. The median period of remission comprised ten months. A positive relationship was found between the response to high-dosed MPA therapy and the length of free intervals. Side effects were tolerable.

[Antitumor action and other regulatory effects of low intensity electromagnetic and chemical factors in experiment].

PubMed

Garkavi, L Kh; Zhukova, G V; Shikhliarova, A I; Evstratova, O F; Barteneva, T A; Gudtskova, T N; Bragina, M I; Mashchenko, N M; Grigorov, S V; Skakun, P G

2014-01-01

This paper presents a brief overview of the results of the original researches of biological responses induced by agents of cytostatic and regulatory actions in small doses, as well as weak electromagnetic radiation of different frequency bands. The possibility of obtaining the expressed antitumor, antistress and geroprotective effects has been shown. The question of the relation of system mechanisms of realization of these effects with structural rearrangements in biological fluids, as well as the promising directions for optimizing the therapeutic properties of the informational impacts are discussed.

Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells.

PubMed

Morley, Karen L; Ferguson, Peter J; Koropatnick, James

2007-06-18

Tangeretin and nobiletin are citrus flavonoids that are among the most effective at inhibiting cancer cell growth in vitro and in vivo. The antiproliferative activity of tangeretin and nobiletin was investigated in human breast cancer cell lines MDA-MB-435 and MCF-7 and human colon cancer line HT-29. Both flavonoids inhibited proliferation in a dose- and time-dependent manner, and blocked cell cycle progression at G1 in all three cell lines. At concentrations that resulted in significant inhibition of proliferation and cell cycle arrest, neither flavonoid induced apoptosis or cell death in any of the tumor cell lines. To test the ability of arrested cells to recover, cells that were incubated with tangeretin and nobiletin for 4 days were then cultured in flavonoid-free medium for an additional 4 days. Cells resumed proliferation similar to untreated control within a day of flavonoid removal. Cell cycle distribution was similar to that of control within 4 days of flavonoid removal. These data indicate that, in these cell lines at concentrations that inhibit proliferation up to 80% over 4 days, tangeretin and nobiletin are cytostatic and significantly suppress proliferation by cell cycle arrest without apoptosis. Such an agent could be expected to spare normal tissues from toxic side effects. Thus, tangeretin and nobiletin could be effective cytostatic anticancer agents. Inhibition of proliferation of human cancers without inducing cell death may be advantageous in treating tumors as it would restrict proliferation in a manner less likely to induce cytotoxicity and death in normal, non-tumor tissues.

Oxcarbazepine-induced cytotoxicity and genotoxicity in human lymphocyte cultures with or without metabolic activation.

PubMed

Atlı Şekeroğlu, Zülal; Kefelioğlu, Haluk; Kontaş Yedier, Seval; Şekeroğlu, Vedat; Delmecioğlu, Berrin

2017-03-01

There has been considerable debate about the relationship between epilepsy and cancer. Oxcarbazepine (OXC) is used for treating certain types of seizures in patients with epilepsy. There have been no detailed investigations about genotoxicity of OXC and its metabolites. Therefore, the aim of this study is to investigate the cytotoxic and genotoxic effects of OXC and its metabolites on cultured human lymphocytes. The cytotoxicity and genotoxicity of OXC on human peripheral blood lymphocytes were examined in vitro by sister chromatid exchange (SCE), chromosomal aberration (CA) and micronucleus (MN) tests. Cultures were treated with 125, 250 and 500 μg/ml of OXC in the presence (3 h treatment) and absence (24 h and 48 h treatment) of a metabolic activator (S9 mix). Dimethyl sulfoxide (DMSO) was used as a solvent control. OXC showed cytotoxic activities due to significant decreases in mitotic index (MI), proliferation index (PI) and nuclear division index (NDI) in the absence of S9 mix when compared with solvent control. Metabolites of OXC also significantly reduced MI and PI in cultures with S9 mix. OXC significantly increased the CAs, aberrant cells, SCE and MN values in the presence and absence of S9 mix. Our results indicated that both OXC and its metabolites have cytotoxic, cytostatic and genotoxic potential on human peripheral blood lymphocyte cultures under the experimental conditions. Further studies are necessary to elucidate the relationship between cytotoxic, cytostatic and genotoxic effects, and to make a possible risk assessment in patients receiving therapy with this drug.

Enhanced cellular uptake and in vitro antitumor activity of short-chain fatty acid acylated daunorubicin-GnRH-III bioconjugates.

PubMed

Hegedüs, Rózsa; Manea, Marilena; Orbán, Erika; Szabó, Ildikó; Kiss, Eva; Sipos, Eva; Halmos, Gábor; Mező, Gábor

2012-10-01

Here we report on the synthesis and biochemical characterization (enzymatic stability, cellular uptake, in vitro antitumor activity, membrane interaction and GnRH-receptor binding affinity) of novel short-chain fatty acid (SCFA) acylated daunorubicin-GnRH-III bioconjugates, which may serve as drug delivery systems for targeted cancer chemotherapy. Ser in position 4 of GnRH-III was replaced by Lys, followed by the acylation of its ε-amino group with various fatty acids. SCFAs are potentially chemoprotective agents by suppressing the growth of cancer cells and therefore may enhance the antitumor activity of the bioconjugates. We found that all synthesized bioconjugates had high cytostatic effect in vitro, were stable in cell culture medium for 6 h and degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond-linked daunorubicin-Lys as the smallest active metabolite. In the presence of α-chymotrypsin, all compounds were digested, the degradation rate strongly depending on the type of fatty acid. The bioconjugate containing Lys(nBu) in position 4 was taken up most efficiently by the cancer cells and exerted higher in vitro cytostatic effect than the previously developed GnRH-III((4)Lys(Ac), (8)Lys(Dau = Aoa)) or the parent GnRH-III(Dau = Aoa) bioconjugate. Our results could be explained by the increased binding affinity of the newly developed compound containing Lys(nBu) to the GnRH receptors. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca2+ release

PubMed Central

Lamoral-Theys, Delphine; Wauthoz, Nathalie; Heffeter, Petra; Mathieu, Véronique; Jungwirth, Utte; Lefranc, Florence; Nève, Jean; Dubois, Jacques; Dufrasne, François; Amighi, Karim; Berger, Walter; Gailly, Philippe; Kiss, Robert

2012-01-01

Abstract Cancer cells exhibit de-regulation of multiple cellular signalling pathways and treatments of various types of cancers with polyphenols are promising. We recently reported the synthesis of a series of 33 novel divanillic and trivanillic polyphenols that displayed anticancer activity, at least in vitro, through inhibiting various kinases. This study revealed that minor chemical modifications of a trivanillate scaffold could convert cytotoxic compounds into cytostatic ones. Compound 13c, a tri-chloro derivative of trivanillic ester, displayed marked inhibitory activities against FGF-, VEGF-, EGF- and Src-related kinases, all of which are implicated not only in angiogenesis but also in the biological aggressiveness of various cancer types. The pan-anti-kinase activity of 13c occurs at less than one-tenth of its mean IC50in vitro growth inhibitory concentrations towards a panel of 12 cancer cell lines. Of the 26 kinases for which 13c inhibited their activity by >75%, eight (Yes, Fyn, FGF-R1, EGFR, Btk, Mink, Ret and Itk) are implicated in control of the actin cytoskeleton organization to varying degrees. Compound 13c accordingly impaired the typical organization of the actin cytoskeleton in human U373 glioblastoma cells. The pan-anti-kinase activity and actin cytoskeleton organization impairment provoked by 13c concomitantly occurs with calcium homeostasis impairment but without provoking MDR phenotype activation. All of these anticancer properties enabled 13c to confer therapeutic benefits in vivo in a mouse melanoma pseudometastatic lung model. These data argue in favour of further chemically modifying trivanillates to produce novel and potent anticancer drugs. PMID:21810170

Mitochondrial genome-knockout cells demonstrate a dual mechanism of action for the electron transport complex I inhibitor mycothiazole.

PubMed

Meyer, Kirsten J; Singh, A Jonathan; Cameron, Alanna; Tan, An S; Leahy, Dora C; O'Sullivan, David; Joshi, Praneta; La Flamme, Anne C; Northcote, Peter T; Berridge, Michael V; Miller, John H

2012-04-01

Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC(50) 0.36-13.8 nM) include HeLa, P815, RAW 264.7, MDCK, HeLa S3, 143B, 4T1, B16, and CD4/CD8 T cells. Insensitive cell lines (IC(50) 12.2-26.5 μM) include HL-60, LN18, and Jurkat. Thus, there is a 34,000-fold difference in sensitivity between HeLa and HL-60 cells. Some sensitive cell lines show a biphasic response, suggesting more than one mechanism of action. Mitochondrial genome-knockout ρ(0) cell lines are insensitive to mycothiazole, supporting a conditional mitochondrial site of action. Mycothiazole is cytostatic rather than cytotoxic in sensitive cells, has a long lag period of about 12 h, and unlike the complex I inhibitor, rotenone, does not cause G(2)/M cell cycle arrest. Mycothiazole decreases, rather than increases the levels of reactive oxygen species after 24 h. It is concluded that the cytostatic inhibitory effects of mycothiazole on mitochondrial electron transport function in sensitive cell lines may depend on a pre-activation step that is absent in insensitive cell lines with intact mitochondria, and that a second lower-affinity cytotoxic target may also be involved in the metabolic and growth inhibition of cells.

Cell-penetrating conjugates of pentaglutamylated methotrexate as potential anticancer drugs against resistant tumor cells.

PubMed

Szabó, Ildikó; Orbán, Erika; Schlosser, Gitta; Hudecz, Ferenc; Bánóczi, Zoltán

2016-06-10

The emerging resistance of tumor cells against methotrexate (MTX) is one of the major limitations of the MTX treatment of tumorous diseases. The disturbance in the polyglutamation which is a main step in the mechanism of methotrexate action is often the reason of the resistance. Delivery of polyglutamylated MTX into cells may evade the mechanisms that are responsible for drug resistance. In this study conjugates of methotrexate and its pentaglutamylated derivatives with cell-penetrating peptides - penetratin and octaarginine - were investigated. The cellular-uptake and in vitro cytostatic activity of conjugates were examined on breast cancer cell cultures (MDA-MB-231 as resistant and MCF-7 as sensitive cell culture). These cell cultures showed very different behaviour towards the conjugates. Although the presence of pentaglutamyl moiety significantly decreased the internalisation of conjugates, some of them were significantly active in vitro. All of the conjugates were able to penetrate in some extent into both cell types, but only the conjugates of penetratin showed in vitro cytostatic activity. The most effective conjugates were the MTX-Glu5-Penetratin(desMet) and MTX-Glu5-GFLG-Penetratin(desMet). The latter was effective on both cell cultures while the former was active only on the resistant tumor cells. Our results suggest that the translocation of polyglutamylated MTX may be a new way to treat sensitive and more importantly resistant tumors. While both penetratin and octaarginine peptides were successfully used to deliver several kinds of cargos earlier in our case the activity of penetratin conjugates was more pronounced. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Vitamin free radicals and their anticancer action. Review.

PubMed

Getoff, Nikola

2009-01-01

The antimumor effect of antioxidant vitamins (C, E and beta-carotene) as well as of the vitamins B1 up to B6 and B11 under the action of oxidizing (OH, O(2)(*-)) and reducing free radicals (e(aq)(-), H) is discussed. In addition, the synergistic action of vitamins on cytostatic agents under the influence of free radicals and the involved reaction mechanisms are briefly discussed. The very fast kinetics of electron transfer taking place within a biological molecule (vitamin B11) is shown for demonstration of the complicated free radical processes in the organism.

Modified 5-fluorouracil: Uridine phosphorylase inhibitor

NASA Astrophysics Data System (ADS)

Lashkov, A. A.; Shchekotikhin, A. A.; Shtil, A. A.; Sotnichenko, S. E.; Mikhailov, A. M.

2016-09-01

5-Fluorouracil (5-FU) is a medication widely used in chemotherapy to treat various types of cancer. Being a substrate for the reverse reaction catalyzed by uridine phosphorylase (UPase), 5-FU serves as a promising prototype molecule (molecular scaffold) for the design of a selective UPase inhibitor that enhances the antitumor activity of 5-FU and exhibits intrinsic cytostatic effects on cancer cells. The chemical formula of the new compound, which binds to the uracil-binding site and, in the presence of a phosphate anion, to the phosphate-binding site of UPase, is proposed and investigated by molecular simulation methods.

[Cytostatic hyperthermic isolated limb perfusion (HILP) in VFN (General Faculty Hospital in Prague)].

PubMed

Spacek, M; Mitás, P; Lacina, L; Krajsová, I; Hodková, G; Salmay, M; Spunda, R; Brlicová, L; Lindner, J

2011-01-01

Hyperthermic isolated limb perfusion (HILP) is a standardized method of treatment in selected patients with in-transient locoregional recurrence/methastasis of melanoma or, some other soft tissue tumors (incl. sarcoma etc.) Authors present history and current status of this treatment modality in General University Hospital in Prague. During one year period (7/2009-6/2010) 10 patients were indicated for this procedure. We performed 13 procedures (3x redo), 11 in lower extremity and 2 in upper extremity. There was no serious complication in this cohort of patiens. Multidisciplinar approach is indicated in melanoma patients care.

Comparative pharmacokinetics of ifosfamide, 4-hydroxyifosfamide, chloroacetaldehyde, and 2- and 3-dechloroethylifosfamide in patients on fractionated intravenous ifosfamide therapy.

PubMed

Kurowski, V; Wagner, T

1993-01-01

The initial metabolism of the oxazaphosphorine cytostatic ifosfamide (IF) consists of two different pathways: ring oxidation at carbon-4 forms the cytostatically active metabolite 4-hydroxyifosfamide (4-OH-IF, "activated ifosfamide"), whereas side-chain oxidation with liberation of the presumably neurotoxic compound chloroacetaldehyde (CAA) that may also be responsible for IF-associated nephrotoxicity results in the formation of the cytostatically inactive metabolites 2-dechloroethylifosfamide (2-DCE-IF) and 3-dechloroethylifosfamide (3-DCE-IF). The pharmacokinetics of IF and its metabolites were investigated in 11 patients with bronchogenic carcinoma receiving IF on a 5-day divided-dose schedule (1.5 g/m2 daily). Blood samples were drawn on days 1 and 5 for up to 24 h after the start of the IF infusion. IF, 2-DCE-IF, and 3-DCE-IF were simultaneously quantified by gas chromatography (GC) with an NIP flame-ionization detector (NPFID), CAA was determined by GC with an electron-capture detector (ECD), and the highly unstable compound 4-OH-IF was measured using a high-performance liquid chromatography (HPLC) assay with fluorometric detection of 7-OH-quinoline, which is formed by the condensation of 4-OH-IF-derived acrolein with m-aminophenol. As compared with the values obtained on day 1, on day 5 the terminal half-life and AUC values determined for IF were reduced by 30% (6.36 vs 4.06 h and 1781 vs 1204 nmol h ml-1, respectively), whereas the maximal concentration (Cmax) values were not affected significantly (199.1 vs 181.1 nmol ml-1). This known phenomenon is explained by autoinduction of hepatic IF metabolism and was paralleled by increased metabolite levels. The mean Cmax values determined for 4-OH-IF, CAA, 3-DCE-IF, and 2-DCE-IF (on day 1/on day 5) were 1.51/2.59, 2.69/4.85, 12.9/26.5, and 8.6/16.7 nmol ml-1, respectively. The corresponding AUC values were 11.3/16.5, 30.3/34.3, 146/354, and 111/209 nmol h ml-1, respectively. As calculated by intraindividual comparison, the mean Cmax (day 5): Cmax (day 1) ratios for 4-OH-IF, CAA, 3-DCE-IF, and 2-DCE-IF were 1.94*, 2.05*, 2.52*, and 2.33*, respectively; the corresponding AUC (day 5): AUC (day 1) ratios were 1.51*, 1.29, 2.34*, and 2.23*, respectively (* P < 0.05). These data reveal that during fractionated-dose IF therapy the cancerotoxic effect of the drug increases. If the assumed role of CAA in IF-associated neurotoxicity and nephrotoxicity is a dose-dependent phenomenon, the probability of developing these side effects would also increase during prolonged IF application.

Effects of Tacrolimus or Sirolimus on the adhesion of vascular wall cells: Controlled in-vitro comparison study.

PubMed

Krüger-Genge, A; Hiebl, B; Franke, R P; Lendlein, A; Jung, F

2017-01-01

In drug eluting stents the cytostatic drugs Sirolimus or Tacrolimus are used to inhibit blood vessel restenosis by limiting the proliferation of smooth muscle cells. However, the cytostatic activity of both drugs was shown to be not cell specific and could also affect the stent endothelialisation, respectively. Currently, only limited in vitro data are available about the impact of Sirolimus and Tacrolimus on endothelial cell proliferation over a broad concentration range. To answer this question the following study was performed.Commercially obtained HUVEC were expanded with DMEM cell culture medium (GIBCO, Germany) supplemented with 5 vol% fetal calf serum on non-coated regular polystyrene-based 24-multiwell plates. For drug testings 2×104 cells/cm2 were seeded and grown for 24 h until 30-40% of the multiwell surfaces were covered and then exposed to Sirolimus (1.0×10-11 - 1.0×10-5 mol/l) or Tacrolimus (2.0×10-8 - 6.2×10-5 mol/l), both dissolved in DMSO. 12, 24 and 48 h after adding the drugs cell numbers per area were quantified by counting the cells in six wells with four fields of view per well, representing 0.6 mm2, using a confocal laser microscope.After 48 h of cell growth in the drug-free cell culture medium, the HUVEC number increased from 2.0×104 to 3.55×104 cells/cm2 (mean cell doubling time: 53.6 h, n = 6). At lower concentrations (≤2.0×10-6 mol/l) Tacrolimus reduced the number of adherent HUVEC significantly less than Sirolimus (p < 0.05). However, at higher concentrations (≥2.07×10-5 mol/l) the effect of Tacrolimus on the number of adherent endothelial cells was significantly greater than that of Sirolimus (p < 0.05). At the highest concentration applied (6.22×10-5 mol/l), Tacrolimus induced detachment of all HUVECs within 12 h after drug application. The number of adherent HUVEC decreased only slightly (about 9%) after Sirolimus application at the highest concentration (1.09×10-5 mol/l).These data show that in a non-flow model the cytostatic drug Tacrolimus reduced the number of adherent endothelial cells less than Sirolimus, as long as the drug concentration did not surpass 10-6 mol/l. At the limits of solubility, Sirolimus (1×10-5 mol/l) reduced the number of adherent endothelial cells less than Tacrolimus (6×10-5 mol/l), which induced detachment of endothelial cells.

Rapid strain improvement through optimized evolution in the cytostat.

PubMed

Gilbert, Alan; Sangurdekar, Dipen P; Srienc, Friedrich

2009-06-15

Acetate is present in lignocellulosic hydrolysates at growth inhibiting concentrations. Industrial processes based on such feedstock require strains that are tolerant of this and other inhibitors present. We investigated the effect of acetate on Saccharomyces cerevisiae and show that elevated acetate concentrations result in a decreased specific growth rate, an accumulation of cells in the G1 phase of the cell cycle, and an increased cell size. With the cytostat cultivation technology under previously derived optimal operating conditions, several acetate resistant mutants were enriched and isolated in the shortest possible time. In each case, the isolation time was less than 5 days. The independently isolated mutant strains have increased specific growth rates under conditions of high acetate concentrations, high ethanol concentrations, and high temperature. In the presence of high acetate concentrations, the isolated mutants produce ethanol at higher rates and titers than the parental strain and a commercial ethanol producing strain that has been analyzed for comparison. Whole genome microarray analysis revealed gene amplifications in each mutant. In one case, the LPP1 gene, coding for lipid phosphate phosphatase, was amplified. Two mutants contained amplified ENA1, ENA2, and ENA5 genes, which code for P-type ATPase sodium pumps. LPP1 was overexpressed on a plasmid, and the growth data at elevated acetate concentrations suggest that LPP1 likely contributes to the phenotype of acetate tolerance. A diploid cross of the two mutants with the amplified ENA genes grew faster than either individual haploid parent strain when 20 g/L acetate was supplemented to the medium, which suggests that these genes contribute to acetate tolerance in a gene dosage dependent manner. 2009 Wiley Periodicals, Inc.

Multiple Pharmacological Properties of a Novel Parthenin Analog P16 as Evident by its Cytostatic and Antiangiogenic Potential Against Pancreatic Adenocarcinoma PANC -1 Cells.

PubMed

Goswami, Akshra; Shah, Bhahwal Ali; Batra, Navneet; Kumar, Ajay; Guru, Santosh Kumar; Bhushan, Shashi; Malik, Fayaz Ahmad; Joshi, Amit; Singh, Jagtar

2016-01-01

Pancreatic ductal adenocarcinoma (PDA) remains one of the deadliest types of cancers. Median survival rate is very poor with the currently available chemotherapeutical regimens. Therefore, discovery of new antineoplastic agents against PDA is one of the focused areas of contemporary research. The present study was undertaken to explore the antitumour activity of a potent parthenin analog P16. Among PANC-1, Mia PaCa-2 and AsPC-1 pancreatic cancer cells, PANC-1 showed highest sensitivity to P16 with an IC50 value of 3.4 μM. Time dependent cell cycle studies revealed that P16 suppressed the growth of PANC-1 cells by arresting the progression through the cell cycle in G2/M phase via downregulation of cyclin B1 and cyclin A. However, P16 did not alter the expressions of CDK-1 and CDC25C in PANC-1 cells. The P16 induced cell cycle arrest, which consequently, led to induction of apoptosis, which was accompanied by activation of caspase-9 and -3. Interestingly, PANC-1 cells displayed increasing loss of mitochondrial potential, which seemed to be correlated to the activation of caspase-3. Additionally, P16 was also able to down-regulate the cell migration in PANC-1 cells. Furthermore, P16 treatment of hypoxic PANC-1 cells strongly suppressed the expression of proangiogenic factors VEGFR-2, HIF1α and HIF1β. Antiangiogenic ability of P16 was also reflected in the human umbilical vascular endothelial cells (HUVECs), where it effectively suppressed the migration and inhibited the formation of the tube in a matrigel based assay. Therefore, cytostatic and antiangiogenic properties of P16 against pancreatic adenocarcinoma cells make it a suitable candidate for further investigation.

KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models

PubMed Central

Kenessey, István; Kói, Krisztina; Horváth, Orsolya; Cserepes, Mihály; Molnár, Dávid; Izsák, Vera; Dobos, Judit; Hegedűs, Balázs

2016-01-01

Background In non-small cell lung cancer (NSCLC) KRAS-mutant status is a negative prognostic and predictive factor. Nitrogen-containing bisphosphonates inhibit prenylation of small G-proteins (e.g. Ras, Rac, Rho) and thus may affect proliferation and migration. In our preclinical work, we investigated the effect of an aminobisphosphonate compound (zoledronic acid) on mutant and wild type KRAS-expressing human NSCLC cell lines. Results We confirmed that zoledronic acid was unable to inhibit the prenylation of mutant K-Ras unlike in the case of wild type K-Ras. In case of in vitro proliferation, the KRAS-mutant human NSCLC cell lines showed resistance to zoledronic acid wild-type KRAS-cells proved to be sensitive. Combinatory application of zoledronic acid enhanced the cytostatic effect of cisplatin. Zoledronic acid did not induce significant apoptosis. In xenograft model, zoledronic acid significantly reduced the weight of wild type KRAS-EGFR-expressing xenograft tumor by decreasing the proliferative capacity. Futhermore, zoledronic acid induced VEGF expression and improved in vivo tumor vascularization. Materials and methods Membrane association of K-Ras was examined by Western-blot. In vitro cell viability, apoptotic cell death and migration were measured in NSCLC lines with different molecular background. The in vivo effect of zoledronic acid was investigated in a SCID mouse subcutaneous xenograft model. Conclusions The in vitro and in vivo inhibitory effect of zoledronic acid was based on the blockade of cell cycle in wild type KRAS-expressing human NSCLC cells. The zoledronic acid induced vascularization supported in vivo cytostatic effect. Our preclinical investigation suggests that patients with wild type KRAS-expressing NSCLC could potentially benefit from aminobisphosphonate therapy. PMID:27780929

Toll like receptors TLR1/2, TLR6 and MUC5B as binding interaction partners with cytostatic proline rich polypeptide 1 in human chondrosarcoma.

PubMed

Galoian, Karina; Abrahamyan, Silva; Chailyan, Gor; Qureshi, Amir; Patel, Parthik; Metser, Gil; Moran, Alexandra; Sahakyan, Inesa; Tumasyan, Narine; Lee, Albert; Davtyan, Tigran; Chailyan, Samvel; Galoyan, Armen

2018-01-01

Metastatic chondrosarcoma is a bone malignancy not responsive to conventional therapies; new approaches and therapies are urgently needed. We have previously reported that mTORC1 inhibitor, antitumorigenic cytostatic proline rich polypeptide 1 (PRP-1), galarmin caused a significant upregulation of tumor suppressors including TET1/2 and SOCS3 (known to be involved in inflammatory processes), downregulation of oncoproteins and embryonic stem cell marker miR-302C and its targets Nanog, c-Myc and Bmi-1 in human chondrosarcoma. To understand better the mechanism of PRP-1 action it was very important to identify the receptor it binds to. Nuclear pathway receptor and GPCR assays indicated that PRP-1 receptors are not G protein coupled, neither do they belong to family of nuclear or orphan receptors. In the present study, we have demonstrated that PRP-1 binding interacting partners belong to innate immunity pattern recognition toll like receptors TLR1/2 and TLR6 and gel forming secreted mucin MUC5B. MUC5B was identified as PRP-1 receptor in human chondrosarcoma JJ012 cell line using Ligand-receptor capture technology. Toll like receptors TLR1/2 and TLR6 were identified as binding interaction partners with PRP-1 by western blot analysis in human chondrosarcoma JJ012 cell line lysates. Immunocytochemistry experiments confirmed the finding and indicated the localization of PRP-1 receptors in the tumor nucleus predominantly. TLR1/2, TLR6 and MUC5B were downregulated in human chondrosarcoma and upregulated in dose-response manner upon PRP-1 treatment. Experimental data indicated that in this cellular context the mentioned receptors had tumor suppressive function.

Toll like receptors TLR1/2, TLR6 and MUC5B as binding interaction partners with cytostatic proline rich polypeptide 1 in human chondrosarcoma

PubMed Central

Galoian, Karina; Abrahamyan, Silva; Chailyan, Gor; Qureshi, Amir; Patel, Parthik; Metser, Gil; Moran, Alexandra; Sahakyan, Inesa; Tumasyan, Narine; Lee, Albert; Davtyan, Tigran; Chailyan, Samvel; Galoyan, Armen

2018-01-01

Metastatic chondrosarcoma is a bone malignancy not responsive to conventional therapies; new approaches and therapies are urgently needed. We have previously reported that mTORC1 inhibitor, antitumorigenic cytostatic proline rich polypeptide 1 (PRP-1), galarmin caused a significant upregulation of tumor suppressors including TET1/2 and SOCS3 (known to be involved in inflammatory processes), downregulation of oncoproteins and embryonic stem cell marker miR-302C and its targets Nanog, c-Myc and Bmi-1 in human chondrosarcoma. To understand better the mechanism of PRP-1 action it was very important to identify the receptor it binds to. Nuclear pathway receptor and GPCR assays indicated that PRP-1 receptors are not G protein coupled, neither do they belong to family of nuclear or orphan receptors. In the present study, we have demonstrated that PRP-1 binding interacting partners belong to innate immunity pattern recognition toll like receptors TLR1/2 and TLR6 and gel forming secreted mucin MUC5B. MUC5B was identified as PRP-1 receptor in human chondrosarcoma JJ012 cell line using Ligand-receptor capture technology. Toll like receptors TLR1/2 and TLR6 were identified as binding interaction partners with PRP-1 by western blot analysis in human chondrosarcoma JJ012 cell line lysates. Immunocytochemistry experiments confirmed the finding and indicated the localization of PRP-1 receptors in the tumor nucleus predominantly. TLR1/2, TLR6 and MUC5B were downregulated in human chondrosarcoma and upregulated in dose-response manner upon PRP-1 treatment. Experimental data indicated that in this cellular context the mentioned receptors had tumor suppressive function. PMID:29138803

Genotoxicity of citrate-coated silver nanoparticles to human keratinocytes assessed by the comet assay and cytokinesis blocked micronucleus assay.

PubMed

Bastos, V; Duarte, I F; Santos, C; Oliveira, H

2017-02-01

Silver nanoparticles (AgNPs) are widely used in industrial, cosmetic, and biomedical products, and humans are frequently exposed to these products through the skin. It is widely recognized that the characteristics of AgNPs (e.g., size, coating) may influence their cytotoxic effects, but their correlation with DNA damage and mitotic disorders remains poorly explored. In this study, human keratinocytes (HaCaT cell line) were exposed to well-characterized 30 nm AgNPs coated with citrate, and their effects on viability, DNA fragmentation (assessed by the comet assay), and micronuclei (MNi) induction (assessed by the cytokinesis-block micronucleus cytome assays, CBMN) were investigated. The results showed that 10 and 40 μg/mL AgNPs decreased cell proliferation and viability, and induced a significant genetic damage. This was observed by an increase of DNA amount in comet tail, which linearly correlated with dose and time of exposure. Also, cytostaticity (increase of mononucleated cells) and MNi rates increased in treated cells. In contrast, no significant changes were observed in nucleoplasmatic bridges (NPBs) or nuclear buds (NBUDs), although NBUDs tended to increase in all conditions and periods. The cytostatic effects on HaCaT cells were also shown by the decrease of their nuclear division index. Thus, both comet and CBMN assays supported the observation that citrate-AgNPs induced genotoxic effects on HaCaT cells. Considering that AgNPs are present in a vast number of consumer products and also in multiple nanomedicine skin applications and formulations, more research is needed to determine the properties that confer less toxicity of AgNPs to different cell lines.

Antiviral effects of artesunate on polyomavirus BK replication in primary human kidney cells.

PubMed

Sharma, Biswa Nath; Marschall, Manfred; Henriksen, Stian; Rinaldo, Christine Hanssen

2014-01-01

Polyomavirus BK (BKV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) in renal and bone marrow transplant patients, respectively. Antiviral drugs with targeted activity against BKV are lacking. Since the antimalarial drug artesunate was recently demonstrated to have antiviral activity, the possible effects of artesunate on BKV replication in human primary renal proximal tubular epithelial cells (RPTECs), the host cells in PyVAN, were explored. At 2 h postinfection (hpi), RPTECs were treated with artesunate at concentrations ranging from 0.3 to 80 μM. After one viral replication cycle (approximately 72 hpi), the loads of extracellular BKV DNA, reflecting viral progeny production, were reduced in a concentration-dependent manner. Artesunate at 10 μM reduced the extracellular BKV load by 65%; early large T antigen mRNA and protein expression by 30% and 75%, respectively; DNA replication by 73%; and late VP1 mRNA and protein expression by 47% and 64%, respectively. Importantly, the proliferation of RPTECs was also inhibited in a concentration-dependent manner. At 72 hpi, artesunate at 10 μM reduced cellular DNA replication by 68% and total metabolic activity by 47%. Cell impedance and lactate dehydrogenase measurements indicated a cytostatic but not a cytotoxic mechanism. Flow cytometry and 5-ethynyl-2'-deoxyuridine incorporation revealed a decreased number of cells in S phase and suggested cell cycle arrest in G0 or G2 phase. Both the antiproliferative and antiviral effects of artesunate at 10 μM were reversible. Thus, artesunate inhibits BKV replication in RPTECs in a concentration-dependent manner by inhibiting BKV gene expression and genome replication. The antiviral mechanism appears to be closely connected to cytostatic effects on the host cell, underscoring the dependence of BKV on host cell proliferative functions.

Antiviral Effects of Artesunate on Polyomavirus BK Replication in Primary Human Kidney Cells

PubMed Central

Sharma, Biswa Nath; Marschall, Manfred; Henriksen, Stian

2014-01-01

Polyomavirus BK (BKV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) in renal and bone marrow transplant patients, respectively. Antiviral drugs with targeted activity against BKV are lacking. Since the antimalarial drug artesunate was recently demonstrated to have antiviral activity, the possible effects of artesunate on BKV replication in human primary renal proximal tubular epithelial cells (RPTECs), the host cells in PyVAN, were explored. At 2 h postinfection (hpi), RPTECs were treated with artesunate at concentrations ranging from 0.3 to 80 μM. After one viral replication cycle (approximately 72 hpi), the loads of extracellular BKV DNA, reflecting viral progeny production, were reduced in a concentration-dependent manner. Artesunate at 10 μM reduced the extracellular BKV load by 65%; early large T antigen mRNA and protein expression by 30% and 75%, respectively; DNA replication by 73%; and late VP1 mRNA and protein expression by 47% and 64%, respectively. Importantly, the proliferation of RPTECs was also inhibited in a concentration-dependent manner. At 72 hpi, artesunate at 10 μM reduced cellular DNA replication by 68% and total metabolic activity by 47%. Cell impedance and lactate dehydrogenase measurements indicated a cytostatic but not a cytotoxic mechanism. Flow cytometry and 5-ethynyl-2′-deoxyuridine incorporation revealed a decreased number of cells in S phase and suggested cell cycle arrest in G0 or G2 phase. Both the antiproliferative and antiviral effects of artesunate at 10 μM were reversible. Thus, artesunate inhibits BKV replication in RPTECs in a concentration-dependent manner by inhibiting BKV gene expression and genome replication. The antiviral mechanism appears to be closely connected to cytostatic effects on the host cell, underscoring the dependence of BKV on host cell proliferative functions. PMID:24145549

Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years

PubMed Central

Panczyk, Mariusz

2014-01-01

During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation, as a result of large international research projects (Human Genome Project, the 1000 Genomes Project International HapMap Project, and Programs for Genomic Applications NHLBI-PGA). This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer. For clinical use in the treatment of patients with colorectal cancer (CRC), in addition to fluoropyrimidines, another two new cytostatic drugs were allowed: irinotecan and oxaliplatin. Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted. The last 20 years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance. One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells. Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine. Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics. Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential. This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy. The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review. PMID:25110414

Erlotinib 150 mg daily plus chemotherapy in advanced pancreatic cancer: an interim safety analysis of a multicenter, randomized, cross-over phase III trial of the 'Arbeitsgemeinschaft Internistische Onkologie'.

PubMed

Boeck, Stefan; Vehling-Kaiser, Ursula; Waldschmidt, Dirk; Kettner, Erika; Märten, Angela; Winkelmann, Cornelia; Klein, Stefan; Kojouharoff, Georgi; Gauler, Thomas; Fischer von Weikersthal, Ludwig; Clemens, Michael R; Geissler, Michael; Greten, Tim F; Hegewisch-Becker, Susanna; Neugebauer, Sascha; Heinemann, Volker

2010-01-01

To date, only limited toxicity data are available for the combination of erlotinib with either capecitabine or gemcitabine as front-line therapy for advanced pancreatic cancer. Within a randomized phase III trial, 281 treatment-naive patients were randomly assigned between capecitabine (2000 mg/m/day, for 14 days, once every 3 weeks) plus erlotinib (150 mg/day, arm A) and gemcitabine (1000 mg/m as a 30-min infusion) plus erlotinib (150 mg/day, arm B). In case of treatment failure, patients were crossed over to a second-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was the time to treatment failure of second-line therapy (TTF2). This interim analysis of toxicity contains safety data from the first 127 randomized patients. During first-line therapy, patients received a median number of three treatment cycles (range 0-13) in both the arms. Regarding chemotherapy, a treatment delay was observed in 12% of the cycles in arm A and in 22% of the cycles in arm B. Dose reductions of the cytostatic drug were performed in 18 and 27% of treatment cycles, respectively. Erlotinib dose reductions were performed in 6 and 11% of all cycles. Grade 3/4 hematological toxicity was <10% in both the arms; major grade 3/4 toxicities in arms A and B were diarrhea (9 vs. 7%), skin rash (4 vs. 12%), and hand-foot syndrome (7 vs. 0%). No treatment-related death was observed. In conclusion, this interim safety analysis suggests that treatment with erlotinib 150 mg/day is feasible in combination with capecitabine or gemcitabine.

Coexpression of human somatostatin receptor-2 (SSTR2) and SSTR3 modulates antiproliferative signaling and apoptosis

PubMed Central

2012-01-01

Background Somatostatin (SST) via five Gi coupled receptors namely SSTR1-5 is known to inhibit cell proliferation by cytostatic and cytotoxic mechanisms. Heterodimerization plays a crucial role in modulating the signal transduction pathways of SSTR subtypes. In the present study, we investigated human SSTR2/SSTR3 heterodimerization, internalization, MAPK signaling, cell proliferation and apoptosis in HEK-293 cells in response to SST and specific agonists for SSTR2 and SSTR3. Results Although in basal conditions, SSTR2 and SSTR3 colocalize at the plasma membrane and exhibit heterodimerization, the cell surface distribution of both receptors decreased upon agonist activation and was accompanied by a parallel increase in intracellular colocalization. Receptors activation by SST and specific agonists significantly decreased cAMP levels in cotransfected cells in comparison to control. Agonist-mediated modulation of pERK1/2 was time and concentration-dependent, and pronounced in serum-deprived conditions. pERK1/2 was inhibited in response to SST; conversely receptor-specific agonist treatment caused inhibition at lower concentration and activation at higher concentration. Strikingly, ERK1/2 phosphorylation was sustained upon prolonged treatment with SST but not with receptor-specific agonists. On the other hand, SST and receptor-specific agonists modulated p38 phosphorylation time-dependently. The receptor activation in cotransfected cells exhibits Gi-dependent inhibition of cell proliferation attributed to increased PARP-1 expression and TUNEL staining, whereas induction of p21 and p27Kip1 suggests a cytostatic effect. Conclusion Our study provides new insights in SSTR2/SSTR3 mediated signaling which might help in better understanding of the molecular interactions involving SSTRs in tumor biology. PMID:22651821

Transport and biotransformation of the new cytostatic complex cis-diammineplatinum(II)-chlorocholylglycinate (Bamet-R2) by the rat liver.

PubMed

Macias, R I; Monte, M J; El-Mir, M Y; Villanueva, G R; Marin, J J

1998-09-01

Rat liver uptake and bile output of the cytostatic complex cis-diammineplatinum(II)-chlorocholylglycinate (Bamet-R2) were studied. Up to 100 microM, Bamet-R2 uptake by rat hepatocytes in primary culture followed saturation kinetics (Vmax = 0.65 +/- 0.12 nmol/5 min per mg protein; K(M) = 45.2 +/- 10.7 microM). Bamet-R2 uptake was lower than that of cholylglycinate (CG) but higher than that of cisplatin. Replacement of 116 mM NaCl by 116 mM choline chloride did not significantly reduce Bamet-R2 uptake. Addition of 500 microM CG, cholic acid, estrone sulfate, or ouabain to 50 microM Bamet-R2-containing incubation media inhibited Bamet-R2 uptake. No liver biotransformation of Bamet-R2 occurred, as indicated by HPLC analysis of bile collected from anesthetized rats after intravenous administration of the drug. Bamet-R2 uptake and secretion into bile by isolated rat livers exceeded those of cisplatin but were lower than those of CG. Differences between Bamet-R2 and CG were more marked for bile output than for liver uptake. Thus, higher Bamet-R2 than CG or cisplatin liver content was found. Co-administration of Bamet-R2 and CG revealed that CG induced a slight reduction in Bamet-R2 uptake and a marked inhibition in Bamet-R2 bile output. By contrast, Bamet-R2 had no effect on CG on either liver uptake or bile output. In sum, the present data indicate that Bamet-R2 is efficiently taken up and secreted into bile by the rat liver by mechanisms shared in part by natural bile acids.

Cytostatic inhibition of cancer cell growth by lignan secoisolariciresinol diglucoside.

PubMed

Ayella, Allan; Lim, Soyoung; Jiang, Yu; Iwamoto, Takeo; Lin, Dingbo; Tomich, John; Wang, Weiqun

2010-11-01

Our previous study demonstrated that lignan metabolites enterolactone and enterodiol inhibited colonic cancer cell growth by inducing cell cycle arrest and apoptosis. However, the dietary lignans are naturally present as glycoside precursors, such as secoisolariciresinol diglucoside (SDG), which have not been evaluated yet. This study tested the hypothesis that dietary SDG might have a different effect than its metabolites in human colonic SW480 cancer cells. Treatment with SDG at 0 to 40 μmol/L for up to 48 hours resulted in a dose- and time-dependent decrease in cell numbers, which was comparable to enterolactone. The inhibition of cell growth by SDG did not appear to be mediated by cytotoxicity, but by a cytostatic mechanism associated with an increase of cyclin A expression. Furthermore, high-performance liquid chromatography analysis indicated that SDG in the media was much more stable than enterolactone (95% of SDG survival vs 57% of enterolactone after 48-hour treatment). When the cells were treated with either enterolactone or SDG at 40 μmol/L for 48 hours, the intracellular levels of enterolactone, as measured by high-performance liquid chromatography-mass spectrometry/electron spray ionization, were about 8.3 × 10(-8) nmol per cell; but intracellular SDG or potential metabolites were undetectable. Taken together, SDG demonstrated similar effects on cell growth, cytotoxicity, and cell cycle arrest when compared with its metabolite enterolactone. However, the reliable stability and undetectable intracellular SDG in treated cells may suggest that metabolism of SDG, if exposed directly to the colonic cells, could be different from the known degradation by microorganisms in human gut. Copyright © 2010 Elsevier Inc. All rights reserved.

Growth inhibition induced by antiprogestins RU-38486, ORG-31710, and CDB-2914 in ovarian cancer cells involves inhibition of cyclin dependent kinase 2.

PubMed

Goyeneche, Alicia A; Seidel, Erin E; Telleria, Carlos M

2012-06-01

Antiprogestins have been largely utilized in reproductive medicine, yet their repositioning for oncologic use is rapidly emerging. In this study we investigated the molecular mediators of the anti-ovarian cancer activity of the structurally related antiprogestins RU-38486, ORG-31710 and CDB-2914. We studied the responses of wt p53 OV2008 and p53 null SK-OV-3 cells to varying doses of RU-38486, ORG-31710 and CDB-2914. The steroids inhibited the growth of both cell lines with a potency of RU-38486 > ORG-31710 > CDB-2914, and were cytostatic at lower doses but lethal at higher concentrations. Antiprogestin-induced lethality associated with morphological features of apoptosis, hypodiploid DNA content, DNA fragmentation, and cleavage of executer caspase substrate PARP. Cell death ensued despite RU-38486 caused transient up-regulation of anti-apoptotic Bcl-2, ORG-31710 induced transient up-regulation of inhibitor of apoptosis XIAP, and CDB-2914 up-regulated both XIAP and Bcl-2. The antiprogestins induced accumulation of Cdk inhibitors p21(cip1) and p27(kip1) and increased association of p21(cip1) and p27(kip1) with Cdk-2. They also promoted nuclear localization of p21(cip1) and p27(kip1), reduced the nuclear abundances of Cdk-2 and cyclin E, and blocked the activity of Cdk-2 in both nucleus and cytoplasm. The cytotoxic potency of the antiprogestins correlated with the magnitude of the inhibition of Cdk-2 activity, ranging from G1 cell cycle arrest towards cell death. Our results suggest that, as a consequence of their cytostatic and lethal effects, antiprogestin steroids of well-known contraceptive properties emerge as attractive new agents to be repositioned for ovarian cancer therapeutics.

Inhibitory effects of cytostatically active 6-aminobenzo[c]phenanthridines on cytochrome P450 enzymes in human hepatic microsomes.

PubMed

Zebothsen, Inga; Kunze, Thomas; Clement, Bernd

2006-07-01

Besides assays for the evaluation of efficacy new drug candidates have to undergo extensive testings for enhancement of pharmaceutical drug safety and optimization of application. The objective of the present work was to investigate the pharmacokinetic drug drug interaction potential for the cytostatically active 6-aminobenzo[c]phenanthridines BP-11 (6-amino-11,12-dihydro-11-(4-hydroxy-3,5-dimethoxyphenyl)benzo[c]phenanthridine) and BP-D7 (6-amino-11-(3,4,5-trimethoxyphenyl)benzo[c]phenanthridine) in vitro through incubation with human hepatic microsomes and marker substrates. For these studies the cytochrome P-450 isoenzymes and corresponding marker substrates recommended by the EMEA (The European Agency for the Evaluation of Medicinal Products) were chosen. In detail these selective substrates were caffeine (CYP1A2), coumarin (CYP2A6), tolbutamide (CYP2C9), S-(+)-mephenytoin (CYP2C19), dextromethorphane (CYP2D6), chlorzoxazone (CYP2E1) and testosterone (CYP3A4). Incubations with each substrate were carried out without a possible inhibitor and in the presence of a benzo[c]phenanthridine or a selective inhibitor at varying concentrations. Marker activities were determined by HPLC (high performance liquid chromatography). For the isoenzymes showing more than 50% inhibition by the addition of 20 microM BP-11 or BP-D7 additional concentrations of substrate and inhibitor were tested for a characterization of the inhibition. The studies showed a moderate risk for BP-11 for interactions with the cytochrome P-450 isoenzymes CYP1A2, CYP2C9, CYP2D6 and CYP3A4. BP-D7, the compound with the highest cytotstatic efficacy, showed only a moderate risk for interactions with drugs, also metabolized by CYP3A4.

Adjuvant cytostatic therapy of breast cancer as an important factor in the postponing of a relapse and longer survival period.

PubMed

Stula, N

1992-01-01

This prospective clinical study shows the results of the adjuvant cytostatic therapy (ACT) in breast cancer applied to patients in the premenopausal age. Cyclophosphamide, methotrexate, 5-fluorouracil (CMF) group (70 patients): after operative and radiotherapeutic treatment the ACT is applied over the period of six months (six cycles). Control group (71 patients): only operative and radiotherapeutic treatment. Protocol of the ACT: cyclophosphamide, methotrexate, 5-fluorouracil (CMF) over 5 days with a 4-week break. Total 6 cycles. Control period: 10 years. Stratification of patients was made on the basis of the following risk factors: size of the tumour, number of positive lymph nodes of ipsilateral axilla, grade of the differentiation of the tumour, hormonal dependence of the tumour. Statistical method of analysis: actuary calculation, the Hi square test. The results show that the application of the ACT is statistically significant (P < 0.05) in regard to the disease-free interval. However, concerning the survival, the usefulness of its application is present but not statistically significant on the significance level of 5%. The usefulness of the ACT application as regards high risk factors (T3, T4 > or = 4 lymph nodes, grade of differentiation II, III, ER-PR-) is statistically significant (P < 0.05) both in regard to the DFI and survival. Regarding low risk factors the ACT application adversely influenced the results in the control group. This is probably the result of the ACT toxicity. The patients have a favourable prognosis in this subgroup in regard to the staging and biological nature of the tumour. The ACT in the premenopausal age of patients with high risk factors gives a significantly better results concerning the procrastination of relapse and the length of the survival period.

The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells.

PubMed

Ujhelyi, Zoltán; Kalantari, Azin; Vecsernyés, Miklós; Róka, Eszter; Fenyvesi, Ferenc; Póka, Róbert; Kozma, Bence; Bácskay, Ildikó

2015-07-21

The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations.

The biological effect of prolonged radiation and ways of selecting new anti-radiation drugs effective in this kind of radiation injury

NASA Technical Reports Server (NTRS)

Rogozkin, V. D.; Chertkov, K. S.; Nikolov, I.

1974-01-01

The basic characteristics of prolonged radiation - increased tolerance of radiation injury - are attributed to cellular kinetics; as dose rate is reduced, the population rate is not disturbed, particularly that of stem cells which makes it possible for the organism to tolerate higher radiation loads. It is concluded that this effect makes approved radio protectors, whose effect contains an established cytostatic component, unsuitable for prolonged radiation. It is better to correct the stem pool formation process by either accelerating the proliferation of cells or limiting the effect of stimuli causing cells to lose colony forming properties.

Enhancing the activity of cannabidiol and other cannabinoids in vitro through modifications to drug combinations and treatment schedules.

PubMed

Scott, Katherine Ann; Shah, Sini; Dalgleish, Angus George; Liu, Wai Man

2013-10-01

Cannabinoids are the bioactive components of the Cannabis plant that display a diverse range of therapeutic qualities. We explored the activity of six cannabinoids, used both alone and in combination in leukaemic cells. Cannabinoids were cytostatic and caused a simultaneous arrest at all phases of the cell cycle. Re-culturing pre-treated cells in drug-free medium resulted in dramatic reductions in cell viability. Furthermore, combining cannabinoids was not antagonistic. We suggest that the activities of some cannabinoids are influenced by treatment schedules; therefore, it is important to carefully select the most appropriate strategy in order to maximise their efficacy.

Antibiotic Action of Solanum incanum Linnaeus

PubMed Central

Beaman-Mbaya, V.; Muhammed, S. I.

1976-01-01

The fruits of Solanum incanum Linnaeus are extensively used in Kenya for the treatment of cutaneous mycotic infections and other pathological conditions. The therapeutic activity of the berries has been attributed to their content of solanine and related glycoalkaloids, which are saponins and cytostatic poisons. In the present study, however, a simpler more potent antimicrobial substance with a phosphorylated structure similar to the purine adenine was isolated from the berries. The crystals of this compound were effective inhibitors of the growth of gram-positive and -negative bacteria, yeasts, dermatophytes, and some pathogens of agricultural produce. High concentrations of the substance caused hemolysis of erythrocytes. Images PMID:945715

New nitrosoureas and their spin-labeled derivatives influence dopa-oxidase activity of tyrosinase.

PubMed

Rachkova, M; Raikova, E; Raikov, Z

1991-06-01

Tyrosinase is a key enzyme in melanine biosynthesis. The modulating effect of cytostatic agents on DOPA-oxidase activity of tyrosinase could be linked with the drug treatment of melanoma tumors. Two groups of nitrosoureas which influence DOPA-oxidase activity of tyrosinase were studied: new nitrosoureas and their spin-labeled derivatives synthesized in our laboratory. Using Burnett's spectrophotometric method (Burnett et al., 1967) the following effects were established: inhibition by CCNU, inhibition and the activating effects of the other investigated nitrosoureas depend on their physicochemical half-life. The predominant activating effect of the spin-labeled derivatives is due to the nitroxyl radical present in these compounds.

Increase of antitumor activity of cisplatin using agonist of gonadotropin-realising hormone and inhibitor of aromatase on the model of ascites ovarian tumor.

PubMed

Tkalia, I G; Vorobyova, L I; Grabovoy, A N; Svintsitsky, V S; Tarasova, T O; Lukyanova, N Y; Todor, I N; Chekhun, V F

2014-09-01

To study antitumor activity of triptorelin - agonist of gonadotropin-releasing hormone and exemestane - inhibitor of aromatase in monotherapy and in combination with cisplatin on the model of receptor-positive for estrogens and progesterone malignant ascites transplantable ovarian tumor (TOT), to assess therapeutic pathomorphosis and level of VEGF expression in tumor cells using diffe-rent combinations of cytostatics and hormonal drugs. 72 female Wistar rats, which underwent intraperitoneal transplantation of ascitic TOT, by 5·10(6) cells per animal, have been involved in the study. Rats were divided into 8 groups, 9 rats in each group. Histological study with assessment of therapeutic pathomorphosis in TOT and immunohistochemical study has been carried out. Survival of animals in the studied groups has been evaluated. Among animals treated in regimen of monotherapy, the most pronounced antiangiogenic activity in TOT has been observed on application of hormonal drugs (triptorelin - 39.4 ± 1.9 and exemestane - 33.9 ± 1.4%; р = 0.003), the highest grade of treatment pathomorphosis in TOT has been observed at treatment with cisplatin (11.7%; р = 0.001). Combination of triptorelin and exemestane has amplified antiangiogenic activity in TOT (12.2 ± 0.9%; р = 0.001), but has not significantly changed rates of pathomorphosis (22.1 ± 0.4%; р=0.005) and survival of animals (32.2%; р = 0.007) as compared with the same rates in rats treated with hormonal drugs in monotherapy. Significant correlation between VEGF expression and pathomorphosis has been established (relative part of viable tumor tissue (RPVTT)) in TOT (r = 0.712; р = 0.001), as well as between RPVTT and life-span of animals (r = -0.320; р = 0.007). However, lack of correlation between VEGF expression in cells of TOT and survival of rats has been determined (r = -0.194; р = 0.11). Combination of cytostatic agent with triptorelin or exemestane has demonstrated significantly high rates of therapeutic pathomorphosis (10.1 ± 0.1% and 16.2 ± 0.3%, respectively) and antiangiogenic activity in TOT (21.4 ± 1.4% and 15.0 ± 1.3%, respectively) as well as the highest survival of animals (100.0%, increase of life-span (ILS) = 231.9% and 85.7%, ILS = 205.8%, respectively) as compared with the same one in rats treated in regimen of monotherapy with cisplatin, triptorelin, exemestane or by combination of hormonal drugs. Among animals treated by combination of cytostatic drug with triptorelin, two were cured, and among rats, which received cisplatin and exemestane, one animal was cured. Triptorelin and exemestane increase antitumor activity of cisplatin in respect to the malignant ascitic TOT and significantly increase survival of animals, especially when triptorelin and cisplatin are used in combination.

On the MTD paradigm and optimal control for multi-drug cancer chemotherapy.

PubMed

Ledzewicz, Urszula; Schättler, Heinz; Gahrooi, Mostafa Reisi; Dehkordi, Siamak Mahmoudian

2013-06-01

In standard chemotherapy protocols, drugs are given at maximum tolerated doses (MTD) with rest periods in between. In this paper, we briey discuss the rationale behind this therapy approach and, using as example multidrug cancer chemotherapy with a cytotoxic and cytostatic agent, show that these types of protocols are optimal in the sense of minimizing a weighted average of the number of tumor cells (taken both at the end of therapy and at intermediate times) and the total dose given if it is assumed that the tumor consists of a homogeneous population of chemotherapeutically sensitive cells. A 2-compartment linear model is used to model the pharmacokinetic equations for the drugs.

Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents.

PubMed

Galluzzi, Lorenzo; Buqué, Aitziber; Kepp, Oliver; Zitvogel, Laurence; Kroemer, Guido

2015-12-14

The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological "side" effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. Copyright © 2015 Elsevier Inc. All rights reserved.

[New drugs for small animals in 2010].

PubMed

Emmerich, I U

2011-01-01

In 2010, no active pharmaceutical ingredients were released on the German market for small animals. Furthermore, no additional substances were authorized for additional species. Only one drug with an interesting new pharmaceutical form, two products with a new strength and one drug, which is interesting because of other criteria, were added to the market for small animals. In addition, nine active pharmaceutical ingredients with approval for use in human medicine, which are of potential interest for veterinary medicine, entered the market in 2010. Those are the analgesic Tapentadol, the antiallergicum Bilastine, the antiarrhythmics Dronedarone and Vernakalant, the antihaemorrhagic Eltrombopag, the bronchodilator Roflumilast, the hormone Corifollitropin alfa, the laxative Prucalopride and the cytostatic Mifamurtide.

Right hemihepatectomy.

PubMed

Haglund, Ulf H; Norén, Agneta; Urdzik, Jozef; Duraj, Frans F

2008-07-01

A right hemihepatectomy is frequently required for surgical removal of colorectal liver metastases. Today, this procedure can be performed quite safely provided the remaining liver is free from significant disease including steatohepatitis due to prolonged cytostatic treatment. Standard surgical techniques for liver resection are described in surgical textbooks. However, each center has developed its own modifications of important details. In this paper, we describe our technique to resect the right liver lobe using conventional surgical techniques as well as a vascular stapler and an ultrasonic dissector. This technique has proven to be quite safe, and blood loss is most often not significant despite we do not routinely apply the Pringle's manoeuvre during the division of the liver parenchyma.

Synthesis of an N-aminopyrazinonium analogue of cytidine.

PubMed

Lee, T C; Chello, P L; Chou, T C; Templeton, M A; Parham, J C

1983-02-01

An N-aminated pyrazine analogue of cytidine, in which the pyrimidine N(3) ring nitrogen and C(4) amino group were replaced by a C-amino and an N-amino function, respectively, was prepared as a potential deaminase-resistant cytidine antimetabolite. The nucleoside 1,2-diamino-4-beta-D-ribofuranosylpyrazin-2-onium chloride (6) was a mild cytostatic agent but was neither a substrate for nor an inhibitor of mouse kidney cytidine deaminase. It ionized with a lower pKa than expected. The anion did not undergo the dimerization usually observed with N-imino heterocyclic ylides but unerwent hydrolysis of the 2-amino group to yield a 1-aminopyrazine-2,3-dione nucleoside.

New sesquiterpene lactones from Ambrosia cumanensis Kunth.

PubMed

Jimenez-Usuga, Nora Del Socorro; Malafronte, Nicola; Cotugno, Roberta; De Leo, Marinella; Osorio, Edison; De Tommasi, Nunziatina

2016-09-01

Eleven sesquiterpene lactones, including three new natural products (1-3), were isolated from the n-butanolic extract of Ambrosia cumanensis Kunth. aerial parts. The structure of all isolated compounds was elucidated by 1D- and 2D-NMR, and MS analyses. All compounds were tested for their antiproliferative activity on HeLa, Jurkat, and U937 cell lines. Compound 3, 2,3-dehydropsilostachyn C, showed cytotoxic activity with different potency in all cell lines. By means of flow cytometric studies, compound 3 was demonstrated to induce in Jurkat cells a G2/M cell cycle block, while in U937 elicited both cytostatic and cytotoxic responses. Copyright © 2016 Elsevier B.V. All rights reserved.

The apoptotic effect of somatostatin analogue SMS 201-995 on human lymphocytes.

PubMed

Lattuada, D; Casnici, C; Venuto, A; Marelli, O

2002-12-01

The antiproliferative effect of a synthetic octapeptide, somatostatin analogue SMS 201-995 (SMS), and its capacity to bind were evaluated on human peripheral blood lymphocytes (PBL) activated by phytohemoagglutinin (PHA). We then addressed our work to investigate if SMS inhibits PHA activation of PBL by a cytostatic rather than a cytotoxic mechanism. Consequently, we studied the cell cycle distribution and the activation of caspase-3, measuring the presence of the cleavage product of poly(ADP-ribose) polymerases (PARP), and we evaluated the presence of apoptotic DNA by using a monoclonal antibody specific for the single-stranded regions of DNA. All our results indicate that SMS induces apoptosis in activated lymphocytes.

[Polymyositis and essential thrombocytopenia. A case report].

PubMed

Auzary, C; Lhote, F; Buoncuore, A; Casassus, P; Piquet, V; Babinet, P

2000-11-01

The occurrence of polymyositis (PM) correlates with an increased risk of solid tumor. Among hematologic malignancies that are sporadically associated with PM or dermatopolymyositis (DM), lymphoma and chronic lymphoid leukemia are the most frequent. The association between PM and myeloproliferative disorders remains exceptional. We describe the simultaneous revelation of a PM and an essential thrombocytemia (ET). The sensitivity of the PM to corticosteroids was noteworthy and allowed a quick and definitive control of clinical and biological inflammation. Despite the efficiency of a cytostatic agent upon the thrombocytemia, the patient died after numerous thrombotic and hemorrhagic complications of ET. This is the first published case of such an association between PM and TE. The paraneoplastic significance of the PM is discussed.

A theoretical investigation on bio-transformation of third generation anti-cancer drug Heptaplatin and its interaction with DNA purine bases

NASA Astrophysics Data System (ADS)

Reddy B., Venkata P.; Mukherjee, Subhajit; Mitra, Ishani; Moi, Sankar Ch.

2017-12-01

Heptaplatin is an approved platinum based cytostatic drug for the treatment of gastric cancers. The hydrolytic bio-transformation of Heptaplatin and the platination processes of guanine (G) and adenine (A) with resulting mono and di-aquated species of Heptaplatin have been investigated using density functional theory (DFT) combined with the conductor like dielectric continuum model (CPCM) approach, to spotlight the drug activation energy profiles and their binding mechanisms. The stationary points on the potential energy surfaces were fully optimized and characterized. The mono-functional binding of Heptaplatin, guanine as target over adenine due to electronic factors and more favorable hydrogen-bonds pattern.

[Magnesium in cardiology].

PubMed

Topalov, V; Kovacević, D; Topalov, A; Kovacević, D

2000-01-01

Magnesium is an oligo-element which has an important effect on the myocardial function and peripheral vascular system. The experiences of other authors as well as other papers have been analyzed. Magnesium participates in over 300 enzymatic reactions in the human organism. It may be found in drinking water and food through which it is substituted. According to WHO, there is a good correlation between Ca++/Mg++ ratio in drinking water and frequency of cardiac events. Higher Mg++ quantity reduces coronary disease. Decreased Mg++ quantity in plasma has been registered in patients with acute myocardial infarction (AMI), coronary patients and patients with heart failure. Various rhythm disturbances, particularly Torsade de points are related to hypomagnesemia. Diuretics and some cytostatics, and antibiotics decrease Mg++ in plasma, erythrocytes and muscles. Decreased Mg++ have been found in alcoholics, diabetics and Crohn disease, which are in certain cases related to existing heart rhythm disturbances. In cardiology it is proved that Mg++ are beneficial in AMI, protection during open heart surgery and treatment and prevention of heart surgery and heart rhythm disturbances. The use of Mg++ in vasospastic angina pectoris, Raynaud's disease and cardiomyopathies due to cytostatics is still in the process of investigation. It is still a matter of discussion whether Mg++ should be administered in these conditions or only when its quantities are reduced. Do Mg++ values in plasma indicate its total presence in the organism? Where should Mg++ be administered as therapy, in which doses and how rapidly? Should preventive addition of Mg++ in drinking water reduce heart disease and prolong life? There are neither many answers nor real conclusions on Mg++ significance in cardiology. However, some encouraging results about its use indicate the significance of further investigations. It has been accepted by the authors all over the world that the role of magnesium is of great importance in prevention and treatment of cardiac patients. Our first experiences are in accordance with other studies.

Interaction of human organic anion transporter 2 (OAT2) and sodium taurocholate cotransporting polypeptide (NTCP) with antineoplastic drugs.

PubMed

Marada, Venkata V V R; Flörl, Saskia; Kühne, Annett; Müller, Judith; Burckhardt, Gerhard; Hagos, Yohannes

2015-01-01

The ability of an antineoplastic drug to exert its cytostatic effect depends largely on the balance between its uptake into and extrusion from the cancer cells. ATP driven efflux transporter proteins drive the export of antineoplastic drugs and play a pivotal role in the development of chemoresistance. As regards uptake transporters, comparably less is known on their impact in drug action. In the current study, we characterized the interactions of two uptake transporter proteins, expressed mainly in the liver; the organic anion transporter 2 (OAT2, encoded by the SLC22A7 gene) and the sodium taurocholate cotransporting polypeptide (NTCP, encoded by the SLC10A1 gene), stably transfected in human embryonic kidney cells, with some antineoplastic agents that are routinely being used in cancer chemotherapy. Whereas NTCP did not show any strong interactions with the cytostatics tested, we observed a very strong inhibition of OAT2 mediated [(3)H] cGMP uptake in the presence of bendamustine, irinotecan and paclitaxel. The Ki values of OAT2 for bendamustine, irinotecan and paclitaxel were determined to be 43.3±4.33μM, 26.4±2.34μM and 10.4±0.45μM, respectively. Incubation of bendamustine with OAT2 expressing cells increased the caspase-3 activity, and this increase was inhibited by simultaneous incubation with bendamustine and probenecid, a well-known inhibitor of OATs, suggesting that bendamustine is a substrate of OAT2. A higher accumulation of irinotecan was observed in OAT2 expressing cells compared to control pcDNA cells by HPLC analysis of cell lysates. The accumulation was diminished in the presence of cGMP, the substrate we used to functionally characterize OAT2, suggesting specificity of this uptake and the fact that OAT2 mediates uptake of irinotecan. Copyright © 2014 Elsevier Ltd. All rights reserved.

Somatostatin receptors 1, 2, and 5 cooperate in the somatostatin inhibition of C6 glioma cell proliferation in vitro via a phosphotyrosine phosphatase-eta-dependent inhibition of extracellularly regulated kinase-1/2.

PubMed

Barbieri, Federica; Pattarozzi, Alessandra; Gatti, Monica; Porcile, Carola; Bajetto, Adriana; Ferrari, Angelo; Culler, Michael D; Florio, Tullio

2008-09-01

Somatostatin inhibits cell proliferation through the activation of five receptors (SSTR1-5) expressed in normal and cancer cells. We analyzed the role of individual SSTRs in the antiproliferative activity of somatostatin in C6 rat glioma cells. Somatostatin dose-dependently inhibited C6 proliferation, an effect mimicked, with different efficacy or potency, by BIM-23745, BIM-23120, BIM-23206 (agonists for SSTR1, -2, and -5) and octreotide. The activation of SSTR3 was ineffective, although all SSTRs are functionally active, as demonstrated by the inhibition of cAMP production. All SSTRs induced cytostatic effects through the activation of the phosphotyrosine phosphatase PTPeta and the inhibition of ERK1/2. For possible synergism between SSTR subtypes, we tested the effects of the combined treatment with two agonists (SSTR1+2 or SSTR2+5) or bifunctional compounds. The simultaneous activation of SSTR1 and SSTR2 slightly increased the efficacy of the individual compounds with an IC50 in between the single receptor activation. SSTR2+5 activation displayed a pattern of response superimposable to that of the SSTR5 agonist alone (low potency and higher efficacy, as compared with BIM-23120). The simultaneous activation of SSTR1, -2, and -5 resulted in a response similar to somatostatin. In conclusion, the cytostatic effects of somatostatin in C6 cells are mediated by the SSTR1, -2, and -5 through the same intracellular pathway: activation of PTPeta and inhibition of ERK1/2 activity. Somatostatin is more effective than the individual agonists. The combined activation of SSTR1 and -2 shows a partial synergism as far as antiproliferative activity, whereas SSTR2 and -5 activation results in a response resembling the SSTR5 effects.

That which does not kill me makes me stronger; combining ERK1/2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance

PubMed Central

Sale, Matthew J; Cook, Simon J

2013-01-01

Oncogenic mutations in RAS or BRAF can drive the inappropriate activation of the ERK1/2. In many cases, tumour cells adapt to become addicted to this deregulated ERK1/2 signalling for their proliferation, providing a therapeutic window for tumour-selective growth inhibition. As a result, inhibition of ERK1/2 signalling by BRAF or MEK1/2 inhibitors is an attractive therapeutic strategy. Indeed, the first BRAF inhibitor, vemurafenib, has now been approved for clinical use, while clinical evaluation of MEK1/2 inhibitors is at an advanced stage. Despite this progress, it is apparent that tumour cells adapt quickly to these new targeted agents so that tumours with acquired resistance can emerge within 6–9 months of primary treatment. One of the major reasons for this is that tumour cells typically respond to BRAF or MEK1/2 inhibitors by undergoing a G1 cell cycle arrest rather than dying. Indeed, although inhibition of ERK1/2 invariably increases the expression of pro-apoptotic BCL2 family proteins, tumour cells undergo minimal apoptosis. This cytostatic response may simply provide the cell with the opportunity to adapt and acquire resistance. Here we discuss recent studies that demonstrate that combination of BRAF or MEK1/2 inhibitors with inhibitors of pro-survival BCL2 proteins is synthetic lethal for ERK1/2-addicted tumour cells. This combination effectively transforms the cytostatic response of BRAF and MEK1/2 inhibitors into a striking apoptotic cell death response. This not only augments the primary efficacy of BRAF and MEK1/2 inhibitors but delays the onset of acquired resistance to these agents, validating their combination in the clinic. Linked Articles This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8 PMID:23647573

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

PubMed Central

Schuster, Sabine; Biri-Kovács, Beáta; Szeder, Bálint; Farkas, Viktor; Buday, László; Szabó, Zsuzsanna; Halmos, Gábor

2018-01-01

Gonadotropin releasing hormone-III (GnRH-III), a native isoform of the human GnRH isolated from sea lamprey, specifically binds to GnRH receptors on cancer cells enabling its application as targeting moieties for anticancer drugs. Recently, we reported on the identification of a novel daunorubicin–GnRH-III conjugate (GnRH-III–[4Lys(Bu), 8Lys(Dau=Aoa)] with efficient in vitro and in vivo antitumor activity. To get a deeper insight into the mechanism of action of our lead compound, the cellular uptake was followed by confocal laser scanning microscopy. Hereby, the drug daunorubicin could be visualized in different subcellular compartments by following the localization of the drug in a time-dependent manner. Colocalization studies were carried out to prove the presence of the drug in lysosomes (early stage) and on its site of action (nuclei after 10 min). Additional flow cytometry studies demonstrated that the cellular uptake of the bioconjugate was inhibited in the presence of the competitive ligand triptorelin indicating a receptor-mediated pathway. For comparative purpose, six novel daunorubicin–GnRH-III bioconjugates have been synthesized and biochemically characterized in which 6Asp was replaced by D-Asp, D-Glu and D-Trp. In addition to the analysis of the in vitro cytostatic effect and cellular uptake, receptor binding studies with 125I-triptorelin as radiotracer and degradation of the GnRH-III conjugates in the presence of rat liver lysosomal homogenate have been performed. All derivatives showed high binding affinities to GnRH receptors and displayed in vitro cytostatic effects on HT-29 and MCF-7 cancer cells with IC50 values in a low micromolar range. Moreover, we found that the release of the active drug metabolite and the cellular uptake of the bioconjugates were strongly affected by the amino acid exchange which in turn had an impact on the antitumor activity of the bioconjugates. PMID:29719573

[Alterations in tears aqueous layer during cytostatics treatment].

PubMed

Wojciechowska, Katarzyna; Wieckowska-Szakiel, Marzena; Rózalska, Barbara; Jurowski, Piotr

2013-01-01

The aim of the study was to evaluate tears secretion, pH and lysozyme activity in tears aqueous layer during chemotherapy in lung, breast and bowel cancer. 36 patients were enrolled to the study. Depending on the type of cancer and type of chemotherapy patients were divided into three groups. Group I (12 patients) diagnosed with non-small-cell lung cancer treated with PE schema (cisplatin, etoposide), Group II (12 patients) with breast cancer treated with FAC schema (fluorouracil, doxorubicin, cyclophosphamide), Group III (12 patients) with bowel cancer treated with FU/LV schema (fluorouracil, leucovorin). In all the patients: Schirmer's I test, pH measurements and lysozyme test were performed. Patients were examined before chemotherapy, after 2nd, 4th, 6th cycle. In group I and II lowering of tears secretion (p < 0.001) was revealed. In group III there was higher tears secretion (p < 0.001). PH was lowered after 2nd chemotherapy course in group I and II. In further treatment pH value were in the same lower level as after the second course. In group III there was higher pH--more alkaline (p < 0.001) after 2nd cycle of treatment and it was on the same level to the end of the examination process. Lowering of lysozyme activity in the tears film in all groups (p < 0.001) was established. The higher alterations of the lysozyme activity were observed in group treated with FAC schema. Cytostatic treatment has major influence on tears aqueous layer causing alterations of tears secretions. PH alterations depending on type of chemotherapy was observed. Lowering of lysozyme activity in tears was observed. All the deteriorations aggravate with duration of chemotherapy. Alterations of tears film parameters during chemotherapy may influence upon eye surface homeostasis and infectious complication. tears aqueous layer, Schirmer's test, lysozyme activity, tears pH.

p53-dependent and p53-independent anticancer activity of a new indole derivative in human osteosarcoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cappadone, C., E-mail: concettina.cappadone@unibo.it; Stefanelli, C.; Malucelli, E.

2015-11-13

Osteosarcoma (OS) is the most common primary malignant tumor of bone, occurring most frequently in children and adolescents. The mechanism of formation and development of OS have been studied for a long time. Tumor suppressor pathway governed by p53 gene are known to be involved in the pathogenesis of osteosarcoma. Moreover, loss of wild-type p53 activity is thought to be a major predictor of failure to respond to chemotherapy in various human cancers. In previous studies, we described the activity of a new indole derivative, NSC743420, belonging to the tubulin inhibitors family, capable to induce apoptosis and arrest of themore » cell cycle in the G2/M phase of various cancer cell lines. However, this molecule has never been tested on OS cell line. Here we address the activity of NSC743420 by examine whether differences in the p53 status could influence its effects on cell proliferation and death of OS cells. In particular, we compared the effect of the tested molecule on p53-wild type and p53-silenced U2OS cells, and on SaOS2 cell line, which is null for p53. Our results demonstrated that NSC743420 reduces OS cell proliferation by p53-dependent and p53-independent mechanisms. In particular, the molecule induces proliferative arrest that culminate to apoptosis in SaOS2 p53-null cells, while it brings a cytostatic and differentiating effect in U2OS cells, characterized by the cell cycle arrest in G0/G1 phase and increased alkaline phosphatase activity. - Highlights: • The indole derivative NSC743420 induces antitumor effects on osteosarcoma cells. • p53 status could drive the activity of antitumor agents on osteosarcoma cells. • NSC743420 induces cytostatic and differentiating effects on U2OS cells. • NSC743420 causes apoptosis on p53-null SaOS2 cells.« less

Diterpenoid natural compound C4 (Crassin) exerts cytostatic effects on triple-negative breast cancer cells via a pathway involving reactive oxygen species.

PubMed

Richards, Cathy E; Vellanki, Sri H; Smith, Yvonne E; Hopkins, Ann M

2018-02-01

Triple-negative breast cancers (TNBC) lack expression of three common cell surface receptors, i.e., estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). Accordingly, TNBCs are associated with fewer treatment options and a relatively poor prognosis. Having screened a National Cancer Institute natural compound library, the purpose of this study was to investigate the bioactivity of compound C4 (Crassin) in TNBC cells. Cell viability assays were performed in two TNBC cell lines, MDA-MB-231 and 4T1, following C4 treatment in the presence or absence of the antioxidant N-acetyl-L-cysteine (NAC). Phosphorylation of Akt and ERK was assessed by Western blotting. Apoptosis, necrosis, autophagy, necroptosis, ferroptosis and cytostasis assays were performed to explain viability deficits resulting from C4 exposure. We found that the viability of the TNBC cells tested decreased in a concentration- and time-dependent fashion following C4 treatment. This decrease coincided with an unexpected increase in the expression of the cell survival effectors pAkt and pERK. In addition, we found that both the decreased cell viability and the increased pAkt/pERK levels could be rescued by the antioxidant NAC, suggesting a central role for reactive oxygen species (ROS) in the mechanism of action of C4. Necrosis, apoptosis, necroptosis and ferroptosis could be ruled out as cell death mechanisms. Instead, we found that C4 induced cytostasis downstream of ROS activation. Finally, we observed a synergistic effect between C4 and the chemotherapeutic drug doxorubicin in TNBC cells. From our in vitro data we conclude that C4 exerts cytostatic effects on triple-negative breast cancer cells via a pathway involving reactive oxygen species. Its potential value in combination with cytotoxic therapies merits deeper investigation in pre-clinical models.

Occurrence and fate of the cytostatic drugs cyclophosphamide and ifosfamide in wastewater and surface waters.

PubMed

Buerge, Ignaz J; Buser, Hans-Rudolf; Poiger, Thomas; Müller, Markus D

2006-12-01

The two oxazaphosphorine compounds cyclophosphamide and ifosfamide are important cytostatic drugs used in the chemotherapy of cancer and in the treatment of autoimmune diseases. Their mechanism of action, involving metabolic activation and unspecific alkylation of nucleophilic compounds, accounts for genotoxic effects described in the literature and is reason for environmental concern. The occurrence and fate of cyclophosphamide and ifosfamide were studied in wastewater treatment plants (WWTPs) and surface waters in Switzerland, using a highly sensitive analytical method based on solid-phase extraction and liquid chromatography tandem mass spectrometry. The compounds were detected in untreated and treated wastewater at concentrations of <0.3-11 ng/L, which corresponded well with concentrations predicted from consumption data and typical renal excretion rates. Weekly loads determined in influent and effluent wastewater were comparable and suggested a high persistence in WWTPs. Furthermore, no degradation was observed in activated sludge incubation experiments within 24 h at concentrations of approximately 100 ng/L. Processes that may be relevant for elimination in natural waterbodies were studied with a set of incubation experiments in the laboratory. After extrapolation to natural conditions in surface waters, a slow dark-chemical degradation (half-lives on the order of years) is the most important transformation process. Degradation by photochemically formed HO* radicals may be of some relevance only in shallow, clear, and nitrate-rich waterbodies but could be further exploited for elimination of these compounds by advanced oxidation processes, i.e., in a treatment of hospital wastewater. In surface waters, concentrations ranged from < or =50 to 170 pg/L and were thus several orders of magnitude lower than the levels at which acute ecotoxicological effects have been reported in the literature (mg/L range). However, due to a lack of studies on chronic effects on aquatic organisms and data on occurrence and effects of metabolites, a final risk assessment cannot be made.

Noble Hybrid Nanostructures as Efficient Anti-Proliferative Platforms for Human Breast Cancer Cell.

PubMed

Tavangar, Amirhossein; Premnath, Priyatha; Tan, Bo; Venkatakrishnan, Krishnan

2016-04-27

Nanomaterials have proven to possess great potential in biomaterials research. Recently, they have suggested considerable promise in cancer diagnosis and therapy. Among others, silicon (Si) nanomaterials have been extensively employed for various biomedical applications; however, the utilization of Si for cancer therapy has been limited to nanoparticles, and its potential as anticancer substrates has not been fully explored. Noble nanoparticles have also received considerable attention owing to unique anticancer properties to improve the efficiency of biomaterials for numerous biological applications. Nevertheless, immobilization and control over delivery of the nanoparticles have been challenge. Here, we develop hybrid nanoplatforms to efficiently hamper breast cancer cell adhesion and proliferation. Platforms are synthesized by femtosecond laser processing of Si into multiphase nanostructures, followed by sputter-coating with gold (Au)/gold-palladium (Au-Pd) nanoparticles. The performance of the developed platforms was then examined by exploring the response of normal fibroblast and metastatic breast cancer cells. Our results from the quantitative and qualitative analyses show a dramatic decrease in the number of breast cancer cells on the hybrid platform compared to untreated substrates. Whereas, fibroblast cells form stable adhesion with stretched and elongated cytoskeleton and actin filaments. The hybrid platforms perform as dual-acting cytophobic/cytostatic stages where Si nanostructures depress breast cancer cell adhesion while immobilized Au/Au-Pd nanoparticles are gradually released to affect any surviving cell on the nanostructures. The nanoparticles are believed to be taken up by breast cancer cells via endocytosis, which subsequently alter the cell nucleus and may cause cell death. The findings suggest that the density of nanostructures and concentration of coated nanoparticles play critical roles on cytophobic/cytostatic properties of the platforms on human breast cancer cells while having no or even cytophilic effects on fibroblast cells. Because of the remarkable contrary responses of normal and cancer cells to the proposed platform, we envision that it will provide novel applications in cancer research.

Enhanced enzymatic stability and antitumor activity of daunorubicin-GnRH-III bioconjugates modified in position 4.

PubMed

Manea, Marilena; Leurs, Ulrike; Orbán, Erika; Baranyai, Zsuzsa; Öhlschläger, Peter; Marquardt, Andreas; Schulcz, Ákos; Tejeda, Miguel; Kapuvári, Bence; Tóvári, József; Mezo, Gábor

2011-07-20

Here, we report on the synthesis, enzymatic stability, and antitumor activity of novel bioconjugates containing the chemotherapeutic agent daunorubicin attached through an oxime bond to various gonadotropin-releasing hormone-III (GnRH-III) derivatives. In order to increase the enzymatic stability of the bioconjugates (in particular against chymotrypsin), (4)Ser was replaced by N-Me-Ser or Lys(Ac). A compound in which (4)Lys was not acetylated was also prepared, with the aim of investigating the influence of the free ε-amino group on the biochemical properties. The in vitro cytostatic effect of the bioconjugates was determined on MCF-7 human breast, HT-29 human colon, and LNCaP human prostate cancer cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Their stability/degradation (1) in human serum, (2) in the presence of rat liver lysosomal homogenate, and (3) in the presence of digestive enzymes (trypsin, chymotrypsin, and pepsin) was analyzed by liquid chromatography in combination with mass spectrometry. The results showed that (1) all synthesized bioconjugates had in vitro cytostatic effect, (2) they were stable in human serum at least for 24 h, and (3) they were hydrolyzed in the presence of lysosomal homogenate. All compounds were stable in the presence of (1) pepsin and (2) trypsin (except for the (4)Lys containing bioconjugate). In the presence of chymotrypsin, all bioconjugates were digested; the degradation rate strongly depending on their structure. The bioconjugates in which (4)Ser was replaced by N-Me-Ser or Lys(Ac) had the highest enzymatic stability, making them potential candidates for oral administration. In vivo tumor growth inhibitory effect of two selected bioconjugates was evaluated on orthotopically developed C26 murine colon carcinoma bearing mice. The results indicated that the compound containing Lys(Ac) in position 4 had significantly higher antitumor activity than the parent bioconjugate.

Exact tests using two correlated binomial variables in contemporary cancer clinical trials.

PubMed

Yu, Jihnhee; Kepner, James L; Iyer, Renuka

2009-12-01

New therapy strategies for the treatment of cancer are rapidly emerging because of recent technology advances in genetics and molecular biology. Although newer targeted therapies can improve survival without measurable changes in tumor size, clinical trial conduct has remained nearly unchanged. When potentially efficacious therapies are tested, current clinical trial design and analysis methods may not be suitable for detecting therapeutic effects. We propose an exact method with respect to testing cytostatic cancer treatment using correlated bivariate binomial random variables to simultaneously assess two primary outcomes. The method is easy to implement. It does not increase the sample size over that of the univariate exact test and in most cases reduces the sample size required. Sample size calculations are provided for selected designs.

Poly(diol-co-citrate)s as Novel Elastomeric Perivascular Wraps for the Reduction of Neointimal Hyperplasia

PubMed Central

Serrano, M. Concepcion; Vavra, Ashley K.; Jen, Michele; Hogg, Melissa E.; Murar, Jozef; Martinez, Janet; Keefer, Larry K.; Ameer, Guillermo A.; Kibbe, Melina R.

2014-01-01

The synthesis of poly(diol-co-citrate) elastomers that are biocompatible with vascular cells and can modulate the kinetics of the NO release based on the diol of selection is reported. NO-mediated cytostatic or cytotoxic effects can be controlled depending on the NO dose and the exposure time. When implanted in vivo in a rat carotid artery injury model, these materials demonstrate a significant reduction of neointimal hyperplasia. This is the first report of a NO-releasing polymer fabricated in the form of an elastomeric perivascular wrap for the treatment of neointimal hyperplasia. These elastomers also show promise for other cardiovascular pathologies where NO-based therapies could be beneficial. PMID:21341372

Different Efficiency of Liposomal Forms with Hydrophilic and Hydrophobic Antitumor Agents in Relation to Solid Transplants of Mouse Tumor and Its Metastases in the Liver.

PubMed

Popova, N A; Kaledin, V I; Nikolin, V P; Bogdanova, L A; Morozkova, T S; Tornuev, Yu V

2016-10-01

Experiments were performed on the model of transplanted mouse tumor with high incidence of liver metastases. Hydrophilic drug cycloplatam (injected intravenously in liposomes) was more potent than "free cycloplatam" (injected intravenously or intraperitoneally in physiological saline) in inhibiting the growth of natural and experimental metastases in the liver. By contrast, liposomal cycloplatam had lower efficiency than free cycloplatam in suppressing the growth of solid tumor. Liposomal and free cortifen (hydrophobic hormonal cytostatic) produced nearly the same effects on solid tumor growth. Our results suggest that liposomal forms of hydrophobic compounds producing nonselective effect on tumor cells (e.g., actinomycin D or Cosmegen), should not have advantages over free forms.

[New drugs for small animals in 2014].

PubMed

Emmerich, I U

2015-01-01

In 2014, six active pharmaceutical ingredients were released on the German market for small animals. Those are the ektoparasiticide of the isoxazoline group afoxolaner (NexGard®) and fluralaner (Bravecto®) and the neonicotinoid dinotefuran (Vectra 3D, Vectra Felis), the antidiabetic protamine zinc insulin of human origin (ProZinc®), the antifungal agent ketoconazole (Fugazid®) as well as the cytostatic drug oclacitinib (Apoquel®). Two substances were authorized for an additional species. The antiparasiticide eprinomectin and the antibiotic clindamycin were also authorized for use in cats. In addition, two active pharmaceutical ingredients, which were approved 2014 for use in human medicine and are of potential interest to veterinary medicine, are discussed. These are the antihypertensive drug riociguat and the urological substance mirabegron.

Occupational hazards in hospitals: accidents, radiation, exposure to noxious chemicals, drug addiction and psychic problems, and assault.

PubMed Central

Gestal, J J

1987-01-01

Except for infectious diseases all the main occupational hazards affecting health workers are reviewed: accidents (explosions, fires, electrical accidents, and other sources of injury); radiation (stochastic and non-stochastic effects, protective measures, and personnel most at risk); exposure to noxious chemicals, whose effects may be either local (allergic eczema) or generalised (cancer, mutations), particular attention being paid to the hazards presented by formol, ethylene oxide, cytostatics, and anaesthetic gases; drug addiction (which is more common among health workers than the general population) and psychic problems associated with promotion, shift work, and emotional stress; and assault (various types of assault suffered by health workers, its causes, and the characterisation of the most aggressive patients). PMID:3307896

Dodecyltriphenylphosphonium inhibits multiple drug resistance in the yeast Saccharomyces cerevisiae.

PubMed

Knorre, Dmitry A; Markova, Olga V; Smirnova, Ekaterina A; Karavaeva, Iuliia E; Sokolov, Svyatoslav S; Severin, Fedor F

2014-08-08

Multiple drug resistance pumps are potential drug targets. Here we asked whether the lipophilic cation dodecyltriphenylphosphonium (C12TPP) can interfere with their functioning. First, we found that suppression of ABC transporter gene PDR5 increases the toxicity of C12TPP in yeast. Second, C12TPP appeared to prevent the efflux of rhodamine 6G - a fluorescent substrate of Pdr5p. Moreover, C12TPP increased the cytostatic effects of some other known Pdr5p substrates. The chemical nature of C12TPP suggests that after Pdr5p-driven extrusion the molecules return to the plasma membrane and then into the cytosol, thus effectively competing with other substrates of the pump. Copyright © 2014 Elsevier Inc. All rights reserved.

Topographic PIXE analysis of platinum levels in kidney slices from CIS-platin treated patients

NASA Astrophysics Data System (ADS)

Dikhoff, T. G. M. H.; Van Der Heide, J. A.; McVie, J. G.

1985-05-01

Concentrations of platinum and several other trace elements have been measured exploiting a 50 × 50 μ proton beam for PIXE analysis. The thickness of a selective germanium absorber for the spectral resolution of platinum L β and selenium K α peaks optimized, taking into account the fluorescent X-rays excited in the absorber material. The measurements have been performed in the framework of a project on the assessment of the toxicity of cytostatic platinum compounds. The lateral distributions of platinum in human kidneys and in dog tissues were measured. The highest concentrations of platinum were seen in arterial walls, followed by glomeruli and tubules. Chronic kidney damage may be correlated to this pattern of retention.

Molecular Imaging and Precision Medicine in Lung Cancer.

PubMed

Zukotynski, Katherine A; Gerbaudo, Victor H

2017-01-01

Precision medicine allows tailoring of preventive or therapeutic interventions to avoid the expense and toxicity of futile treatment given to those who will not respond. Lung cancer is a heterogeneous disease functionally and morphologically. PET is a sensitive molecular imaging technique with a major role in the precision medicine algorithm of patients with lung cancer. It contributes to the precision medicine of lung neoplasia by interrogating tumor heterogeneity throughout the body. It provides anatomofunctional insight during diagnosis, staging, and restaging of the disease. It is a biomarker of tumoral heterogeneity that helps direct selection of the most appropriate treatment, the prediction of early response to cytotoxic and cytostatic therapies, and is a prognostic biomarker in patients with lung cancer. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Predicting selective drug targets in cancer through metabolic networks

PubMed Central

Folger, Ori; Jerby, Livnat; Frezza, Christian; Gottlieb, Eyal; Ruppin, Eytan; Shlomi, Tomer

2011-01-01

The interest in studying metabolic alterations in cancer and their potential role as novel targets for therapy has been rejuvenated in recent years. Here, we report the development of the first genome-scale network model of cancer metabolism, validated by correctly identifying genes essential for cellular proliferation in cancer cell lines. The model predicts 52 cytostatic drug targets, of which 40% are targeted by known, approved or experimental anticancer drugs, and the rest are new. It further predicts combinations of synthetic lethal drug targets, whose synergy is validated using available drug efficacy and gene expression measurements across the NCI-60 cancer cell line collection. Finally, potential selective treatments for specific cancers that depend on cancer type-specific downregulation of gene expression and somatic mutations are compiled. PMID:21694718

FLAX OIL FROM TRANSGENIC LINUM USITATISSIMUM SELECTIVELY INHIBITS IN VITRO PROLIFERATION OF HUMAN CANCER CELL LINES.

PubMed

Gebarowski, Tomasz; Gebczak, Katarzyna; Wiatrak, Benita; Kulma, Anna; Pelc, Katarzyna; Czuj, Tadeusz; Szopa, Jan; Gasiorowski, Kazimierz

2017-03-01

Emulsions made of oils from transgenic flaxseeds significantly decreased in vitro proliferation of six tested human cancer cell lines in 48-h cultures, as assessed with the standard sulforhodamine assay. However, the emulsions also increased proliferation rate of normal human dermal fibroblasts and, to a lower extend, of keratinocytes. Both inhibition of in vitro proliferation of human cancer cell lines and stimulation of proliferation of normal dermal fibroblasts and keratinocytes were especially strong with the emulsion type B and with emulsion type M. Oils from seeds of transgenic flax type B and M should be considered as valuable adjunct to standard cytostatic therapy of human cancers and also could be applied to improve the treatment of skin lesions in wound healing.

Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal junction cancer.

PubMed

Janmaat, Vincent T; Steyerberg, Ewout W; van der Gaast, Ate; Mathijssen, Ron Hj; Bruno, Marco J; Peppelenbosch, Maikel P; Kuipers, Ernst J; Spaander, Manon Cw

2017-11-28

Almost half of people with esophageal or gastroesophageal junction cancer have metastatic disease at the time of diagnosis. Chemotherapy and targeted therapies are increasingly used with a palliative intent to control tumor growth, improve quality of life, and prolong survival. To date, and with the exception of ramucirumab, evidence for the efficacy of palliative treatments for esophageal and gastroesophageal cancer is lacking. To assess the effects of cytostatic or targeted therapy for treating esophageal or gastroesophageal junction cancer with palliative intent. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Web of Science, PubMed Publisher, Google Scholar, and trial registries up to 13 May 2015, and we handsearched the reference lists of studies. We did not restrict the search to publications in English. Additional searches were run in September 2017 prior to publication, and they are listed in the 'Studies awaiting assessment' section. We included randomized controlled trials (RCTs) on palliative chemotherapy and/or targeted therapy versus best supportive care or control in people with esophageal or gastroesophageal junction cancer. Two authors independently extracted data. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated pooled estimates of effect using an inverse variance random-effects model for meta-analysis. We identified 41 RCTs with 11,853 participants for inclusion in the review as well as 49 ongoing studies. For the main comparison of adding a cytostatic and/or targeted agent to a control arm, we included 11 studies with 1347 participants. This analysis demonstrated an increase in overall survival in favor of the arm with an additional cytostatic or targeted therapeutic agent with a hazard ratio (HR) of 0.75 (95% confidence interval (CI) 0.68 to 0.84, high-quality evidence). The median increased survival time was one month. Five studies in 750 participants contributed data to the comparison of palliative therapy versus best supportive care. We found a benefit in overall survival in favor of the group receiving palliative chemotherapy and/or targeted therapy compared to best supportive care (HR 0.81, 95% CI 0.71 to 0.92, high-quality evidence). Subcomparisons including only people receiving second-line therapies, chemotherapies, targeted therapies, adenocarcinomas, and squamous cell carcinomas all showed a similar benefit. The only individual agent that more than one study found to improve both overall survival and progression-free survival was ramucirumab. Palliative chemotherapy and/or targeted therapy increased the frequency of grade 3 or higher treatment-related toxicity. However, treatment-related deaths did not occur more frequently. Quality of life often improved in the arm with an additional agent. People who receive more chemotherapeutic or targeted therapeutic agents have an increased overall survival compared to people who receive less. These agents, administered as both first-line or second-line treatments, also led to better overall survival than best supportive care. With the exception of ramucirumab, it remains unclear which other individual agents cause the survival benefit. Although treatment-associated toxicities of grade 3 or more occurred more frequently in arms with an additional chemotherapy or targeted therapy agent, there is no evidence that palliative chemotherapy and/or targeted therapy decrease quality of life. Based on this meta-analysis, palliative chemotherapy and/or targeted therapy can be considered standard care for esophageal and gastroesophageal junction carcinoma.

Oncogenic Smad3 signaling induced by chronic inflammation is an early event in ulcerative colitis-associated carcinogenesis.

PubMed

Kawamata, Seiji; Matsuzaki, Koichi; Murata, Miki; Seki, Toshihito; Matsuoka, Katsuyoshi; Iwao, Yasushi; Hibi, Toshifumi; Okazaki, Kazuichi

2011-03-01

Both chronic inflammation and somatic mutations likely contribute to the pathogenesis of ulcerative colitis (UC)-associated dysplasia and cancer. On the other hand, both tumor suppression and oncogenesis can result from transforming growth factor (TGF)-β signaling. TGF-β type I receptor (TβRI) and Ras-associated kinases differentially phosphorylate a mediator, Smad3, to become C-terminally phosphorylated Smad3 (pSmad3C), linker phosphorylated Smad3 (pSmad3L), and both C-terminally and linker phosphorylated Smad3 (pSmad3L/C). The pSmad3C/p21(WAF1) pathway transmits a cytostatic TGF-β signal, while pSmad3L and pSmad3L/C promote cell proliferation by upregulating c-Myc oncoprotein. The purpose of this study was to clarify the alteration of Smad3 signaling during UC-associated carcinogenesis. By immunostaining and immunofluorescence, we compared pSmad3C-, pSmad3L-, and pSmad3L/C-mediated signaling in colorectal specimens representing colitis, dysplasia, or cancer from eight UC patients with signaling in normal colonic crypts. We also investigated p53 expression and mutations of p53 and K-ras genes. We further sought functional meaning of the phosphorylated Smad3-mediated signaling in vitro. As enterocytes in normal crypts migrated upward toward the lumen, cytostatic pSmad3C/p21(WAF1) tended to increase, while pSmad3L/c-Myc shown by progenitor cells gradually decreased. Colitis specimens showed prominence of pSmad3L/C/c-Myc, mediated by TGF-β and tumor necrosis factor (TNF)-α, in all enterocyte nuclei throughout entire crypts. In proportion with increases in frequency of p53 and K-ras mutations during progression from dysplasia to cancer, the oncogenic pSmad3L/c-Myc pathway came to be dominant with suppression of the pSmad3C/p21(WAF1) pathway. Oncogenic Smad3 signaling, altered by chronic inflammation and eventually somatic mutations, promotes UC-associated neoplastic progression by upregulating growth-related protein. Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

Antiproliferation effect of imatinib mesylate on MCF7, T-47D tumorigenic and MCF 10A nontumorigenic breast cell lines via PDGFR-β, PDGF-BB, c-Kit and SCF genes

PubMed Central

Kadivar, Ali; Kamalidehghan, Behnam; Akbari Javar, Hamid; Karimi, Benyamin; Sedghi, Reihaneh; Noordin, Mohamed Ibrahim

2017-01-01

Recent cancer molecular therapies are targeting main functional molecules to control applicable process of cancer cells. Attractive targets are established by receptor tyrosine kinases, such as platelet-derived growth factor receptors (PDGFRs) and c-Kit as mostly irregular signaling, which is due to either over expression or mutation that is associated with tumorigenesis and cell proliferation. Imatinib mesylate is a selective inhibitor of receptor tyrosine kinase, including PDGFR-β and c-Kit. In this research, we studied how imatinib mesylate would exert effect on MCF7 and T-47D breast cancer and MCF 10A epithelial cell lines, the gene and protein expression of PDGFR-β, c-Kit and their relevant ligands platelet-derived growth factor (PDGF)-BB and stem cell factor (SCF). The MTS assay was conducted in therapeutic relevant concentration of 2–10 µM for 96, 120 and 144 h treatment. In addition, apoptosis induction and cytostatic activity of imatinib mesylate were investigated with the terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL and cell cycle assays, respectively, in a time-dependent manner. Comparative real-time PCR and Western blot analysis were conducted to evaluate the expression and regulation of imatinib target genes and proteins. Our finding revealed that imatinib mesylate antiproliferation effect, apoptosis induction and cytostatic activity were significantly higher in breast cancer cell lines compared to MCF 10A. This effect might be due to the expression of PDGFR-β, PDGF-BB, c-Kit and SCF, which was expressed by all examined cell lines, except the T-47D cell line which was not expressed c-Kit. However, examined gene and proteins expressed more in cancer cell lines. Therefore, imatinib mesylate was more effective on them. It is concluded that imatinib has at least two potential targets in both examined breast cancer cell lines and can be a promising drug for targeted therapy to treat breast cancer. PMID:28260860

Comparative Analysis of the Antineoplastic Activity of C60 Fullerene with 5-Fluorouracil and Pyrrole Derivative In Vivo

NASA Astrophysics Data System (ADS)

Lynchak, O. V.; Prylutskyy, Yu I.; Rybalchenko, V. K.; Kyzyma, O. A.; Soloviov, D.; Kostjukov, V. V.; Evstigneev, M. P.; Ritter, U.; Scharff, P.

2017-01-01

The antitumor activity of pristine C60 fullerene aqueous solution (C60FAS) compared to 5-fluorouracil (5-FU) and pyrrole derivative 1-(4-Cl-benzyl)-3-Cl-4-(CF3-fenylamino)-1H-pyrrol-2.5-dione (MI-1) cytostatic drugs was investigated and analyzed in detail using the model of colorectal cancer induced by 1.2-dimethylhydrazine (DMH) in rats. The number, size, and location of the tumors were measured, and the pathology was examined. It was found that the number of tumors and total lesion area decreased significantly under the action of C60FAS and MI-1. Because these drugs have different mechanisms of action, their simultaneous administration can potentially increase the effectiveness and significantly reduce the side effects of antitumor therapy.

Karyological observations

NASA Technical Reports Server (NTRS)

Krikorian, A. D.; O'Connor, S. A.

1984-01-01

Root tips prepared for metaphase chromosome analysis from seedlings germinated under microgravity on the Space Shuttle (oats and mung bean) or which were exposed to space flight as very young seedlings (sunflower) have been examined. Experimental constraints did not permit pre-fixation in space with a cytostatic agent but arrest was achieved in the first division cycle on Earth after recovery. The number of cells in division was significantly depressed in all three species. Several chromosomal abnormalities were encountered in flight material. Bridge formation was seen in sunflower, as was aneuploidy. Breakage and fracture of chromosomes was prevalent in oats. No aberrant features could be detected in the chromosomes of mung bean. These results, although preliminary, should serve to alert investigators of the need to assess carefully as many aspects of cell division in higher plants exposed to space flight conditions as possible.

Multifunctional materials for bone cancer treatment

PubMed Central

Marques, Catarina; Ferreira, José MF; Andronescu, Ecaterina; Ficai, Denisa; Sonmez, Maria; Ficai, Anton

2014-01-01

The purpose of this review is to present the most recent findings in bone tissue engineering. Special attention is given to multifunctional materials based on collagen and collagen–hydroxyapatite composites used for skin and bone cancer treatments. The multi-functionality of these materials was obtained by adding to the base regenerative grafts proper components, such as ferrites (magnetite being the most important representative), cytostatics (cisplatin, carboplatin, vincristine, methotrexate, paclitaxel, doxorubicin), silver nanoparticles, antibiotics (anthracyclines, geldanamycin), and/or analgesics (ibuprofen, fentanyl). The suitability of complex systems for the intended applications was systematically analyzed. The developmental possibilities of multifunctional materials with regenerative and curative roles (antitumoral as well as pain management) in the field of skin and bone cancer treatment are discussed. It is worth mentioning that better materials are likely to be developed by combining conventional and unconventional experimental strategies. PMID:24920907

Comparative study of in vitro and in vivo drug effects on cell-mediated cytotoxicity.

PubMed Central

Borel, J F

1976-01-01

Cell-mediated cytolysis (CMC) was assayed in a system using spleen cells from mice (C57BL/6) sensitized with allogeneic tumour cells (DBA/2 mastocytoma P-815). Anti-inflammatory drugs, immunosuppressives, inhibitors of cell division and other agents were investigated for their capacity to inhibit CMC in three different ways. First, inhibition of CMC after in vitro addition of drug was observed with corticosteroids, some immunosuppressives and inhibitors of cell division. Secondly, suppression of CMC after a single drug administration to sensitized mice shortly before being killed was found with corticosteroids, several immunosuppressives and irradiation. Thirdly, prevention of development of CMC by repeated drug treatment (immunosuppressive schedule) was achieved with most immunosuppressives and cytostatic drugs. Non-steroidal anti-inflammatory drugs were inactive in these tests. Correlation of effects between the three procedures was very poor and it is suggested that various mechanisms may be involved in the different assays. PMID:824198

[Exudative enteropathy in congenital lymphedema-lymphangiectasia syndrome].

PubMed

Heruth, M; Müller, P; Liebscher, L; Kurze, G; Richter, T

2006-01-01

Congenital peripheral elephantiasiformic alterations are very rare in paediatric patients. In a patient with lymphangiectasia-lymphedema syndrome we demonstrate over a 8-year follow-up that not only cosmetic and social indications for surgical treatments but also internal care become important during the course. We report on a boy with congenital lymphedemas of the extremities and the genital region, which were several times surgically treated. The patient became symptomatic firstly with tetanic cramps caused by malabsorption syndrome due to intestinal lymphangiectasia at the age of 6 years. Synopsis of clinical and laboratory findings and the patient's course are pointing to a mild Hennekam syndrome with still unknown aetiology. The boy developed adequately with permanent oral substitution of electrolytes and vitamins, protein-rich diet, supplementation of medium-chain fatty acids and compressing bandages. Infusions of human albumin to correct persistent hypalbuminemia as well as cytostatic treatment with cyclophosphamide as a formal trial were ineffective and are not advisable, therefore.

Discovery of antitubulin agents with antiangiogenic activity as single entities with multitarget chemotherapy potential.

PubMed

Gangjee, Aleem; Pavana, Roheeth Kumar; Ihnat, Michael A; Thorpe, Jessica E; Disch, Bryan C; Bastian, Anja; Bailey-Downs, Lora C; Hamel, Ernest; Bai, Rouli

2014-05-08

Antiangiogenic agents (AA) are cytostatic, and their utility in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of vascular endothelial growth factor receptor-2 (VEGFR2) inhibitors with antitubulin agents have been particularly successful. We have discovered a novel, potentially important analogue, that combines potent VEGFR2 inhibitory activity (comparable to that of sunitinib) with potent antitubulin activity (comparable to that of combretastatin A-4 (CA)) in a single molecule, with GI50 values of 10(-7) M across the entire NCI 60 tumor cell panel. It potently inhibited tubulin assembly and circumvented the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to antimicrotubule agents. The compound is freely water-soluble as its HCl salt and afforded excellent antitumor activity in vivo, superior to docetaxel, sunitinib, or Temozolomide, without any toxicity.

Anthracycline antibiotics derivate mitoxantrone-Destructive sorption and photocatalytic degradation.

PubMed

Štenglová-Netíková, Irena R; Petruželka, Luboš; Šťastný, Martin; Štengl, Václav

2018-01-01

Nanostructured titanium(IV) oxide was used for the destructive adsorption and photocatalytic degradation of mitoxantrone (MTX), a cytostatic drug from the group of anthracycline antibiotics. During adsorption on a titania dioxide surface, four degradation products of MTX, mitoxantrone dicarboxylic acid, 1,4-dihydroxy-5-((2-((2-hydroxyethyl)amino)ethyl)amino)-8-((2-(methylamino)ethyl)amino)anthracene-9,10-dione, 1,4-dihydroxy-5,8-diiminoanthracene-9,10(5H,8H)-dione and 1,4-dihydroxy-5-imino-8-(methyleneamino)anthracene-9,10(5H,8H)-dione, were identified. In the case of photocatalytic degradation, only one degradation product after 15 min at m/z 472 was identified. This degradation product corresponded to mitoxantrone dicarboxylic acid, and complete mineralization was attained in one hour. Destructive adsorbent manganese(IV) oxide, MnO2, was used only for the destructive adsorption of MTX. Destructive adsorption occurred only for one degradation product, mitoxantrone dicarboxylic acid, against anatase TiO2.

Ganoderma lucidum for cancer treatment: we are close but still not there.

PubMed

Cheng, Shujie; Sliva, Daniel

2015-05-01

The medicinal fungus Ganoderma lucidum has been used in traditional Chinese medicine for millennia to improve health and promote longevity. The idea of using G. lucidum for cancer treatment is based on numerous laboratory and preclinical studies with cancer and immune cells as well as animal models demonstrating various biological activities in vitro and in vivo. For example, G. lucidum possesses cytotoxic, cytostatic, antimetastatic, anti-inflammatory, and immunomodulating activities. Limited clinical studies, including case reports and randomized controlled trials, suggest G. lucidum as an alternative adjunct therapy for stimulating the immune system in cancer patients. To confirm the efficacy of G. lucidum in cancer treatment, systematic translational research programs should be started worldwide. In addition, only standardized preclinically evaluated, biologically active G. lucidum extracts should be used in alternative treatments. This approach will lead to the development of standardized G. lucidum preparations with specific chemical fingerprint-associated anticancer activities. © The Author(s) 2015.

[The estimation of systemic chemotherapy treatment administered in breast cancer on lysozyme activity in tears--preliminary report].

PubMed

Wojciechowska, Katarzyna; Jurowski, Piotr; Wieckowska-Szakiel, Marzena; Rózalska, Barbara

2012-01-01

Estimation of cytostatics influence used in breast cancer treatment on lysozyme activity in human tears depend on time of treatment. 8 women were treated at the base of chemotherapy schema: docetaxel with doxorubicin and 4 women treated with schema CMF: cyclophosphamide, methotrexate, 5-fluorouracil. Lysozyme activity in tears was assessed by measurement of diameter zone of Micrococcus lysodeicticus growth inhibition. It was revealed that both chemotherapy schema caused statistically significant reduction of diameter zone of M. lysodeicticus growth inhibition, after first and second course of chemotherapy treatment. After second chemotherapy course CMF schema induced loss of lysozyme activity in patient's tears (zero mm of M. lysodeicticus diameter zone growth inhibition). Systemic chemotherapy administered in breast cancer induce reduction of lysozyme activity in tears, that may cause higher morbidity of ocular surface infections caused by Gram-positive bacteria.

[Demodicosis of dogs--a factorial disease?].

PubMed

Gothe, R

1989-09-01

Demodex canis is a normal resident of the intact canine skin, being present in small numbers in virtually every dog. Most animals are only carriers of the mites and do not develop clinical symptoms, therefore, demodectic mange has already to be considered as a factorial disease. The modus operandi of transition of clinically inapparent colonization of the mites into a disease may be explained according to investigations so far published multifactorially and thereby essentially as consequences of primary or secondary immunodepression. A primary immunodepression is initially based most probably on a hereditary defect of T-cells and is subsequently reinforced by substances, which are presumably synthesized and liberated not only by mites but also by secondary bacterial agents. A secondary immunodepression operates as trigger mechanism of a clinical manifestation after corticosteroid or cytostatic therapy or in course of underlying diseases of potentially immunodepressive nature, i.e., malignant neoplasia, hepatopathies, hyperadrenocorticism and lymphosarcoma.

[Total-body irradiation in non-Hodgkin's lymphomas as an alternative to chemotherapy].

PubMed

Rühl, U

1977-05-01

On the bases of previous experiences and present results it can be stated that total-body irradiation is an effective therapeutical technique for treatment of lymphocytic non-Hodkin's lymphomas including chronic lymphatic leukemia; first results from prospectively randomized studies even revealed a slight superiority of this method as compared to the scheme of combined cytostatical therapy (CVP) mostly applied at present. Particular advantages of total-body irradiation are the easy applicability, the relatively short time needed for treatment, and the lack of subjective secondary effects. Thus, ambulatory therapy can be performed without any difficulty. The only complication which may occur arises from myelotoxicity reaching its maximum not earlier than after the end of treatment. Careful follow-up of the patients, therefore, is indispensable. The indication of total-body irradiation for the treatment of non-Hodgkin's lymphomas depends on the objective findings, the stage of disease, and mainly on the histological classification.

Efficiency, costs and benefits of AOPs for removal of pharmaceuticals from the water cycle.

PubMed

Tuerk, J; Sayder, B; Boergers, A; Vitz, H; Kiffmeyer, T K; Kabasci, S

2010-01-01

Different advanced oxidation processes (AOP) were developed for the treatment of highly loaded wastewater streams. Optimisation of removal and improvement of efficiency were carried out on a laboratory, semiworks and pilot plant scale. The persistent cytostatic drug cyclophosphamide was selected as a reference substance regarding elimination and evaluation of the various oxidation processes because of its low degradability rate. The investigated processes are cost-efficient and suitable regarding the treatment of wastewater streams since they lead to efficient elimination of antibiotics and antineoplastics. A total reduction of toxicity was proven by means of the umuC-test. However, in order to reduce pharmaceuticals from the water cycle, it must be considered that the input of more than 80 % of the pharmaceuticals entering wastewater treatment systems results from private households. Therefore, advanced technologies should also be installed at wastewater treatment plants.

Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors.

PubMed

Shinji, Chihiro; Maeda, Satoko; Imai, Keisuke; Yoshida, Minoru; Hashimoto, Yuichi; Miyachi, Hiroyuki

2006-11-15

A series of hydroxamic acid derivatives bearing a cyclic amide/imide group as a linker and/or cap structure, prepared during our structural development studies based on thalidomide, showed class-selective potent histone deacetylase (HDAC)-inhibitory activity. Structure-activity relationship studies indicated that the steric character of the substituent introduced at the cyclic amide/imide nitrogen atom, the presence of the amide/imide carbonyl group, the hydroxamic acid structure, the shape of the linking group, and the distance between the zinc-binding hydroxamic acid group and the cap structure are all important for HDAC-inhibitory activity and class selectivity. A representative compound (30w) showed potent p21 promoter activity, comparable with that of trichostatin A (TSA), and its cytostatic activity against cells of the human prostate cell line LNCaP was more potent than that of the well-known HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA).

Exopolysaccharide from Ganoderma applanatum as a Promising Bioactive Compound with Cytostatic and Antibacterial Properties

PubMed Central

Osińska-Jaroszuk, Monika; Błachowicz, Adriana; Wydrych, Jerzy; Polak, Jolanta; Jarosz-Wilkołazka, Anna; Kandefer-Szerszeń, Martyna

2014-01-01

A new exopolysaccharide preparation isolated from stationary cultures of the white rot fungus Ganoderma applanatum (GpEPS) was tested in terms of its bioactive properties including its cytotoxic and immunostimulatory effect. The results indicate that the tested GpEPS (at concentrations above 22.85 µg/mL and 228.5 µg/mL) may exhibit selective activity against tumor cells (cell lines SiHa) and stimulate production of TNF-α THP-1-derived macrophages at the level of 752.17 pg/mL. The GpEPS showed antibacterial properties against Staphyloccoccus aureus and a toxic effect against Vibrio fischeri cells (82.8% cell damage). High cholesterol-binding capacity and triglycerides-binding capacity (57.9% and 41.6% after 24 h of incubation with the tested substances, resp.) were also detected for the investigated samples of GpEPS. PMID:25114920

Synthesis and conformational analysis of new arylated-diphenylurea derivatives related to sorafenib drug via Suzuki-Miyaura cross-coupling reaction

NASA Astrophysics Data System (ADS)

Al-Masoudi, Najim A.; Essa, Ali Hashem; Alwaaly, Ahmed A. S.; Saeed, Bahjat A.; Langer, Peter

2017-10-01

Sorafenib, is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. The development of new sorafenib analogues offers the possibility of generating structures of increased potency. To this end, a series of arylated-diphenylurea analogues 17-31 were synthesized via Suzuki-Miyaura coupling reaction, related to sorafenib by treatment of three diarylureas 2-4 having 3-bromo, 4-chloro and 2-iodo groups with various arylboronic acids. Conformational analysis of the new arylated urea analogues has been investigated using MOPAC 2016 of semi empirical PM7 Hamiltonian computational method. Our results showed that all compounds preferred the trans-trans conformations. Compound 17 has been selected to calculate the torsional energy profiles for rotation around the urea bonds and found to be existed predominantly in the trans-trans conformation with only very minimal fluctuation in conformation.

The dissociation constants of the cytostatic bosutinib by nonlinear least-squares regression of multiwavelength spectrophotometric and potentiometric pH-titration data.

PubMed

Meloun, Milan; Nečasová, Veronika; Javůrek, Milan; Pekárek, Tomáš

2016-02-20

Potentiometric and spectrophotometric pH-titration of the multiprotic cytostatics bosutinib for dissociation constants determination were compared. Bosutinib treats patients with positive chronic myeloid leukemia. Bosutinib exhibits four protonatable sites in a pH range from 2 to 11, where two pK are well separated (ΔpK>3), while the other two are near dissociation constants. In the neutral medium, bosutinib occurs in the slightly water soluble form LH that can be protonated to the soluble cation LH4(3+). The molecule LH can be dissociated to still difficultly soluble anion L(-). The set of spectra upon pH from 2 to 11 in the 239.3-375.0nm was divided into two absorption bands: the first one from 239.3 to 290.5nm and the second from 312.3 to 375.0nm, which differ in sensitivity of chromophores to a pH change. Estimates of pK of the entire set of spectra were compared with those of both absorption bands. Due to limited solubility of bosutinib the protonation in a mixed aqueous-methanolic medium was studied. In low methanol content of 3-6% three dissociation constants can be reliably determined with SPECFIT/32 and SQUAD(84) and after extrapolation to zero content of methanol they lead to pKc1=3.43(12), pKc2=4.54(10), pKc3=7.56(07) and pKc4=11.04(05) at 25°C and pKc1=3.44(06), pKc2=5.03(08) pKc3=7.33(05) and pKc4=10.92(06) at 37°C. With an increasing content of methanol in solvent the dissociation of bosutinib is suppressed and the percentage of LH3(2+) decreases and LH prevails. From the potentiometric pH-titration at 25°C the concentration dissociation constants were estimated with ESAB pKc1=3.51(02), pKc2=4.37(02), pKc3=7.97(02) and pKc4=11.05(03) and with HYPERQUAD: pKc1=3.29(12), pKc2=4.24(10), pKc3=7.95(07) and pKc4=11.29(05). Copyright © 2015 Elsevier B.V. All rights reserved.

Human ovarian cancer xenografts in nude mice: chemotherapy trials with paclitaxel, cisplatin, vinorelbine and titanocene dichloride.

PubMed

Villena-Heinsen, C; Friedrich, M; Ertan, A K; Farnhammer, C; Schmidt, W

1998-07-01

The new cytostatics titanocene dichloride and vinorelbine were compared to cisplatin and paclitaxel using a human ovarian cancer xenografts model. Biopsy material from a native human ovarian carcinoma was expanded and transplanted into 96 nude mice. The animals were divided into six treatment groups: cisplatin 3 x 4 mg/kg, paclitaxel 5 x 26 mg/kg, vinorelbine 1 x 20 mg/kg, titanocene dichloride 3 x 30 mg/kg, titanocene dichloride 3 x 40 mg/kg and a control group treated with 0.9% saline. Each experiment was repeated with eight mice in each treatment group. Treatment groups were evaluated in terms of average daily increase in tumor volume and average daily body weight increase of nude mice based on slopes of least-square regressions performed on individual animals. The slope factors alpha and beta of the body weight (alpha) and tumor volume changes (beta) within each group during the course of an experiment were calculated. Both a statistically significant decrease (p<0.05) in the body weight of the experimental animals (cisplatin: alpha = -0.5163, vinorelbine: alpha = -0.6598, paclitaxel: alpha = -0.6746, titanocene dichloride 3 x 30 mg/kg: alpha = -0.6259, titanocene dichloride 3 x 40 mg/kg: alpha = -0.7758) and a significant reduction (p<0.05) of the increase in tumor volume (cisplatin: beta = 12.049, vinorelbine: beta = 0.504, paclitaxel: beta = -1.636, titanocene dichloride 3 x 30 mg/kg: beta = 6.212, titanocene dichloride 3 x 40 mg/kg: beta= -0.685) was shown in all treated groups compared to the control group (alpha = -0.1398; beta = 23.056). No significant weight changes were observed between the individually treated groups. A statistically significant reduction of the tumor growth occured under paclitaxel (beta = -1.636), vinorelbine (beta = 0.504) and titanocene dichloride medication 3 x 40 mg/kg (beta = -0.685), as compared to the group treated with cisplatin (beta = 12.049). We found titanocene dichloride to be as effective as paclitaxel and more effective than cisplatin. Vinorelbine seems to be a very effective antineoplastic agent exhibiting a significant higher cytostatic effect than cisplatin. Both titanocene dichloride and vinorelbine provide new therapeutic options in women with ovarian carcinoma not responding to standard chemotherapy.

Chronic ecotoxic effects to Pseudomonas putida and Vibrio fischeri, and cytostatic and genotoxic effects to the hepatoma cell line (HepG2) of ofloxacin photo(cata)lytically treated solutions.

PubMed

Vasquez, M I; Garcia-Käufer, M; Hapeshi, E; Menz, J; Kostarelos, K; Fatta-Kassinos, D; Kümmerer, K

2013-04-15

Ofloxacin (OFL), a broad-spectrum and widespread-used photolabile fluoroquinolone, is frequently found in treated wastewaters, aquatic and terrestrial ecosystems leading to increasing concern during the past decades regarding its effects to the environment and human health. The elimination of OFL and other xenobiotics by the application of advanced oxidation processes using photolytic (PL) and photocatalytic (PC) treatments seems promising. However, an integrated assessment scheme is needed, in which, not only the removal of the parent compound, but also the effects of the photo-transformation products (PTPs) are investigated. For this purpose, in the present study, a chronic ecotoxic assessment using representative bacteria of marine and terrestrial ecosystems and a cytostatic and genotoxic evaluation using hepatoma cell line were performed. PL and PC treatments of OFL were applied using UV radiation. The photo-transformation of OFL during the treatments was monitored by DOC measurements and UPLC-MS/MS analysis. The chronic ecotoxicity of OFL and treated samples was evaluated using Pseudomonas putida and Vibrio fischeri; whereas the cytostasis and genotoxicity were estimated by the cytokinesis-block micronucleus assay (CBMN). The main results suggest that photo-transformation of OFL took place during these treatments since the concentration of OFL decreased when the irradiation time increased, as quantified by UPLC-MS/MS analysis, and this was not coupled with an analogous DOC removal. Furthermore, nine compounds were identified as probable PTPs formed through piperazinyl dealkylation and decarboxylation. The ecotoxicity of treated solutions to the bacteria studied decreased while the cytostasis to the hepatoma cell line remained at low levels during both treatments. However, the genotoxicity to the hepatoma cell line demonstrated a different pattern in which treated samples induced a greater number of MNi for the 4-16 min of irradiation (p<0.05) during both treatments. After 64 min of irradiation, the effects decreased to non genotoxic levels (p<0.05). These findings suggest that UV radiation for various treatment processes (catalytic or not), such as disinfection, may create genotoxic by-products. Therefore, in relevant technical applications, the residence time during treatment should receive special attention. Copyright © 2012. Published by Elsevier B.V.

Carbon nanotubes enhance the internalization of drugs by cancer cells and decrease their chemoresistance to cytostatics

NASA Astrophysics Data System (ADS)

Mahmood, M.; Xu, Y.; Dantuluri, V.; Mustafa, T.; Zhang, Y.; Karmakar, A.; Casciano, D.; Ali, S.; Biris, A.

2013-02-01

Etoposide is a semisynthetic, chemotherapeutic drug widely recommended to treat an extensive range of human cancers. Our studies indicate that, while etoposide is capable of killing human cancer cells, exposure to single-walled carbon nanotubes (SWCNTs) and etoposide results in enhanced cell death that appears to be synergistic and not merely additive. In this study, we used high pressure liquid chromatography and mass spectrometry to quantify the internal effective dose of etoposide when the human pancreatic cancer cell (PANC-1) was exposed to the combination of these agents. Our results unequivocally indicate that SWCNTs improve etoposide uptake and increase its capacity to kill cancer cells. We suggest that a combination of SWCNTs and etoposide may prove to be a more efficient chemotherapeutic protocol, especially because of the potential to lower toxic drug doses to levels that may be useful in decreasing adverse side effects, as well as in lowering the probability of inducing chemoresistance in exposed cancer cells.

Proliferation kinetics and cyclic AMP as prognostic factors in adult acute leukemia.

PubMed

Paietta, E; Mittermayer, K; Schwarzmeier, J

1980-07-01

In 41 adult patients with acute leukemia (myeloblastic, lymphoblastic, and undifferentiated), proliferation kinetics (as determined by double-label autoradiography) and cyclic adenosine 3',5'-monophosphate (cAMP) concentration were studied for their significance in the prediction of responsiveness to cytostatic therapy. Patients with good clinical response had significantly shorter turnover times and higher labeling indices in the bone marrow than did those who failed to respond to treatment. Cases for which cell kinetics did not correlate with clinical response were explained by variance in the distribution of leukemic blasts between the proliferative cell cycle and the resting pool. Good clinical response was also found to be associated with low levels of cAMP in leukemic cells prior to therapy, whereas high cAMP contents predicted failure. Low cAMP concentrations, however, did not necessarily correlate with short turnover times and vice versa. This might be due to fluctuations of the cAMP concentrations during the cell cycle.

Do cytostatic drugs reach drinking water? The case of mycophenolic acid.

PubMed

Franquet-Griell, Helena; Ventura, Francesc; Boleda, M Rosa; Lacorte, Silvia

2016-01-01

Mycophenolic acid (MPA) has been identified as a new river contaminant according to its wide use and high predicted concentration. The aim of this study was to monitor the impact of MPA in a drinking water treatment plant (DWTP) that collects water downstream Llobregat River (NE Spain) in a highly densified urban area. During a one week survey MPA was recurrently detected in the DWTP intake (17-56.2 ng L(-1)). The presence of this compound in river water was associated to its widespread consumption (>2 tons in 2012 in Catalonia), high excretion rates and low degradability. The fate of MPA in waters at each treatment step of the DWTP was analyzed and complete removal was observed after pretreatment with chlorine dioxide. So far, MPA has not been described as water contaminant and its presence associated with its consumption in anticancer treatments is of relevance to highlight the importance of monitoring this compound. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Antirheumatic therapy and reproduction. The influence on fertility, pregnancy and breast feeding].

PubMed

Ostensen, M

2006-05-01

Antirheumatic drugs can have a negative effect on reproduction in both men and women. Possible negative effects are impairment of fertility, harmful effects on the fetus and adverse effects on the breastfed child. In women non-steroidal antiinflammatory drugs (NSAID) and cyclophosphamide can impair fertility. In men infertility can result from the use of salazopyrine and cyclophosphamide. A desire for children should be taken into account before the start of disease modifying drugs (DMARD). Treatment with NSAID is possible at some stages of pregnancy as well as during lactation. A limited number of DMARD is compatible with pregnancy and is presented. Cytostatic drugs and leflunomide must be prophylactically withdrawn before a planned pregnancy. TNF alpha antagonists should be discontinued at the start of pregnancy. Safe birth control must be practised during therapy with drugs that are gonadotoxic or teratogenic. Treatment with immunosuppressive drugs during lactation is limited because of insufficient documentation of safety for the breastfed child.

Metallothionein as a Scavenger of Free Radicals - New Cardioprotective Therapeutic Agent or Initiator of Tumor Chemoresistance?

PubMed

Heger, Zbynek; Rodrigo, Miguel Angel Merlos; Krizkova, Sona; Ruttkay-Nedecky, Branislav; Zalewska, Marta; Del Pozo, Elena Maria Planells; Pelfrene, Aurelie; Pourrut, Bertrand; Stiborova, Marie; Eckschlager, Tomas; Emri, Gabriella; Kizek, Rene; Adam, Vojtech

2016-01-01

Cardiotoxicity is a serious complication of anticancer therapy by anthracycline antibiotics. Except for intercalation into DNA/RNA structure, inhibition of DNA-topoisomerase and histone eviction from chromatin, the main mechanism of their action is iron-mediated formation of various forms of free radicals, which leads to irreversible damage to cancer cells. The most serious adverse effect of anthracyclines is, thus, cardiomyopathy leading to congestive heart failure, which is caused by the same mechanisms. Here, we briefly summarize the basic types of free radicals formed by anthracyclines and the main processes how to scavenge them. From these, the main attention is paid to metallothioneins. These low-molecular cysteine-rich proteins are introduced and their functions and properties are reviewed. Further, their role in detoxification of metals and drugs is discussed. Based on these beneficial roles, their use as a new therapeutic agent against oxidative stress and for cardioprotection is critically evaluated with respect to their ability to increase chemoresistance against some types of commonly used cytostatics.

Fucoidan and Fucosylated Chondroitin Sulfate Stimulate Hematopoiesis in Cyclophosphamide-Induced Mice.

PubMed

Anisimova, Natalia; Ustyuzhanina, Nadezhda; Bilan, Maria; Donenko, Fedor; Usov, Anatolii; Kiselevskiy, Mikhail; Nifantiev, Nikolay

2017-09-30

Application of cytostatics in cancer patients' chemotherapy results in a number of side effects, including the inhibition of various parts of hematopoiesis. Two sulfated polysaccharides, fucoidan from the seaweed Chordaria flagelliformis ( PS-Fuc ) and fucosylated chondroitin sulfate from the sea cucumber Massinium magnum ( PS-FCS ), were studied as stimulators of hematopoiesis after cyclophosphamide immunosuppression in mice. Recombinant granulocyte colony-stimulating factor ( r G-CSF ) was applied as a reference. Both tested polysaccharides PS-Fuc and PS-FCS have a similar activity to r G-CSF , causing pronounced neutropoiesis stimulation in animals with myelosuppression induced by cyclophosphamide ( CPh ). Moreover, these compounds are also capable to enhance thrombopoiesis and erythropoiesis. It should be noted that PS-FCS demonstrated a greater activity than r G-CSF . The results indicate the perspective of further studies of PS-Fuc and PS-FCS , since these compounds can be considered as potentially promising stimulators of hematopoiesis. Such drugs are in demand for the accompanying treatment of cancer patients who suffer from hematological toxicity during chemo and/or radiation therapy.

Altruistic self-removal of health-compromised honey bee workers from their hive.

PubMed

Rueppell, O; Hayworth, M K; Ross, N P

2010-07-01

Social insect colonies represent distinct units of selection. Most individuals evolve by kin selection and forgo individual reproduction. Instead, they display altruistic food sharing, nest maintenance and self-sacrificial colony defence. Recently, altruistic self-removal of diseased worker ants from their colony was described as another important kin-selected behaviour. Here, we report corroborating experimental evidence from honey bee foragers and theoretical analyses. We challenged honey bee foragers with prolonged CO(2) narcosis or by feeding with the cytostatic drug hydroxyurea. Both treatments resulted in increased mortality but also caused the surviving foragers to abandon their social function and remove themselves from their colony, resulting in altruistic suicide. A simple model suggests that altruistic self-removal by sick social insect workers to prevent disease transmission is expected under most biologically plausible conditions. The combined theoretical and empirical support for altruistic self-removal suggests that it may be another important kin-selected behaviour and a potentially widespread mechanism of social immunity.

Chaetocin reactivates the lytic replication of Epstein-Barr virus from latency via reactive oxygen species.

PubMed

Zhang, Shilun; Yin, Juan; Zhong, Jiang

2017-01-01

Oxidative stress, regarded as a negative effect of free radicals in vivo, takes place when organisms suffer from harmful stimuli. Some viruses can induce the release of reactive oxygen species (ROS) in infected cells, which may be closely related with their pathogenicity. In this report, chaetocin, a fungal metabolite reported to have antimicrobial and cytostatic activity, was studied for its effect on the activation of latent Epstein-Barr virus (EBV) in B95-8 cells. We found that chaetocin remarkably up-regulated EBV lytic transcription and DNA replication at a low concentration (50 nmol L -1 ). The activation of latent EBV was accompanied by an increased cellular ROS level. N-acetyl-L-cysteine (NAC), an ROS inhibitor, suppressed chaetocin-induced EBV activation. Chaetocin had little effect on histone H3K9 methylation, while NAC also significantly reduced H3K9 methylation. These results suggested that chaetocin reactivates latent EBV primarily via ROS pathways.

Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport.

PubMed

Yang, Chendong; Ko, Bookyung; Hensley, Christopher T; Jiang, Lei; Wasti, Ajla T; Kim, Jiyeon; Sudderth, Jessica; Calvaruso, Maria Antonietta; Lumata, Lloyd; Mitsche, Matthew; Rutter, Jared; Merritt, Matthew E; DeBerardinis, Ralph J

2014-11-06

Alternative modes of metabolism enable cells to resist metabolic stress. Inhibiting these compensatory pathways may produce synthetic lethality. We previously demonstrated that glucose deprivation stimulated a pathway in which acetyl-CoA was formed from glutamine downstream of glutamate dehydrogenase (GDH). Here we show that import of pyruvate into the mitochondria suppresses GDH and glutamine-dependent acetyl-CoA formation. Inhibiting the mitochondrial pyruvate carrier (MPC) activates GDH and reroutes glutamine metabolism to generate both oxaloacetate and acetyl-CoA, enabling persistent tricarboxylic acid (TCA) cycle function. Pharmacological blockade of GDH elicited largely cytostatic effects in culture, but these effects became cytotoxic when combined with MPC inhibition. Concomitant administration of MPC and GDH inhibitors significantly impaired tumor growth compared to either inhibitor used as a single agent. Together, the data define a mechanism to induce glutaminolysis and uncover a survival pathway engaged during compromised supply of pyruvate to the mitochondria. Copyright © 2014 Elsevier Inc. All rights reserved.

Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport

PubMed Central

Yang, Chendong; Ko, Bookyung; Hensley, Christopher T.; Jiang, Lei; Wasti, Ajla T.; Kim, Jiyeon; Sudderth, Jessica; Calvaruso, Maria Antonietta; Lumata, Lloyd; Mitsche, Matthew; Rutter, Jared; Merritt, Matthew E.; DeBerardinis, Ralph J.

2014-01-01

Summary Alternative modes of metabolism enable cells to resist metabolic stress. Inhibiting these compensatory pathways may produce synthetic lethality. We previously demonstrated that glucose deprivation stimulated a pathway in which acetyl-CoA was formed from glutamine downstream of glutamate dehydrogenase (GDH). Here we show that import of pyruvate into the mitochondria suppresses GDH and glutamine-dependent acetyl-CoA formation. Inhibiting the mitochondrial pyruvate carrier (MPC) activates GDH and re-routes glutamine metabolism to generate both oxaloacetate and acetyl-CoA, enabling persistent tricarboxylic acid (TCA) cycle function. Pharmacological blockade of GDH elicited largely cytostatic effects in culture, but these effects became cytotoxic when combined with MPC inhibition. Concomitant administration of MPC and GDH inhibitors significantly impaired tumor growth compared to either inhibitor used as a single agent. Together, the data define a mechanism to induce glutaminolysis and uncover a survival pathway engaged during compromised supply of pyruvate to the mitochondria. PMID:25458842

[Hazardous material and safety conditions in veterinary practice. 2: Flammable liquid, disinfectants and cleansing media, cytostatics, pressurized gases, liquid nitrogen, narcotic gases, mailing of diagnostic samples, hazardous waste].

PubMed

Sliwinski-Korell, A; Lutz, F

1998-05-01

In the last years the standards for professional handling of hazardous material as well as health and safety in the veterinary practice became considerably more stringent. This is expressed in various safety regulations, particularly the decree of hazardous material and the legislative directives concerning health and safety at work. In part 1, a definition based on the law for hazardous material was given and the potential risks were mentioned. The correct documentation regarding the protection of personal and the purchase, storage, working conditions and removal of hazardous material was explained. General rules for the handling of hazardous material were described. In part 2, partial emphasis is put on the handling of flammable liquids, disinfectants, cytostatica, pressurised gases, liquid nitrogen, narcotics, mailing of potentially infectious material and safe disposal of hazardous waste. Advice about possible unrecognized hazards and references are also given.

Baicalin Scavenged Reactive Oxygen Species and Protected Human Keratinocytes Against UVB-induced Cytotoxicity.

PubMed

Chang, Wen-Shin; Lin, En-Yuan; Hsu, Shih-Wei; Hu, Pei-Shin; Chuang, Chin-Liang; Liao, Cheng-Hsi; Fu, Chun-Kai; Su, Chung-Hao; Gong, Chi-Li; Hsiao, Chieh-Lun; Bau, DA-Tian; Tsai, Chia-Wen

Ultraviolet B (UVB), with a wavelength of 280-320 nm, represents one of the most important environmental factors for skin disorders, including sunburn, hyperpigmentation, solar keratosis, solar elastosis and skin cancer. Therefore, protection against excessive UVA-induced damage is useful for prevention of sunburn and other human diseases. Baicalin, a major component of traditional Chinese medicine Scutellaria baicalensis, has been reported to possess antioxidant and cytostatic capacities. In this study, we examined whether baicalin is also capable of protecting human keratinocytes from UVB irradiation. The results showed that baicalin effectively scavenged reactive oxygen species (ROS) elevated within 4 h after UVB radiation and reversed the UVB-suppressed cell viability and UVB-induced apoptosis after 24 h. Our results demonstrated the utility of baicalin to complement the contributions of traditional Chinese medicine in UVB-induced damage to skin and suggested their potential application as pharmaceutical agents in long-term sun-shining injury prevention. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

The tumor suppressor cybL, a component of the respiratory chain, mediates apoptosis induction.

PubMed

Albayrak, Timur; Scherhammer, Volker; Schoenfeld, Nicole; Braziulis, Erik; Mund, Thomas; Bauer, Manuel K A; Scheffler, Immo E; Grimm, Stefan

2003-08-01

A genetic screen was established to clone apoptosis-inducing genes in a high-throughput format. It led to the isolation of several proapoptotic genes whose proteins are localized to mitochondria. One of the isolated genes is cytochrome bL (cybL also known as SDHC, CII-3, or QPs-1), a component of the respiratory chain complex II. It was further investigated because both cybL and another component of complex II, cybS, have recently been identified as tumor suppressor proteins, some of which act by controlling apoptosis. Our studies reveal that cell death induction by cybL expression is concomitant with a transient inhibition of complex II and the generation of reactive oxygen species. Importantly, cells that are constitutively deficient in cybL are resistant to a variety of proapoptotic cytostatic drugs and to the effects of the Fas receptor. Our results therefore identify complex II as a sensor for apoptosis induction and could explain the unexpected observation that complex II is inactivated in tumors.

The Tumor Suppressor cybL, a Component of the Respiratory Chain, Mediates Apoptosis Induction

PubMed Central

Albayrak, Timur; Scherhammer, Volker; Schoenfeld, Nicole; Braziulis, Erik; Mund, Thomas; Bauer, Manuel K.A.; Scheffler, Immo E.; Grimm, Stefan

2003-01-01

A genetic screen was established to clone apoptosis-inducing genes in a high-throughput format. It led to the isolation of several proapoptotic genes whose proteins are localized to mitochondria. One of the isolated genes is cytochrome bL (cybL also known as SDHC, CII-3, or QPs-1), a component of the respiratory chain complex II. It was further investigated because both cybL and another component of complex II, cybS, have recently been identified as tumor suppressor proteins, some of which act by controlling apoptosis. Our studies reveal that cell death induction by cybL expression is concomitant with a transient inhibition of complex II and the generation of reactive oxygen species. Importantly, cells that are constitutively deficient in cybL are resistant to a variety of proapoptotic cytostatic drugs and to the effects of the Fas receptor. Our results therefore identify complex II as a sensor for apoptosis induction and could explain the unexpected observation that complex II is inactivated in tumors. PMID:12925748

Liposomal Doxorubicin in the Treatment of Breast Cancer Patients: A Review

PubMed Central

Lao, Juan; Madani, Julia; Puértolas, Teresa; Álvarez, María; Hernández, Alba; Pazo-Cid, Roberto; Artal, Ángel; Antón Torres, Antonio

2013-01-01

Drug delivery systems can provide enhanced efficacy and/or reduced toxicity for anticancer agents. Liposome drug delivery systems are able to modify the pharmacokinetics and biodistribution of cytostatic agents, increasing the concentration of the drug released to neoplastic tissue and reducing the exposure of normal tissue. Anthracyclines are a key drug in the treatment of both metastatic and early breast cancer, but one of their major limitations is cardiotoxicity. One of the strategies designed to minimize this side effect is liposome encapsulation. Liposomal anthracyclines have achieved highly efficient drug encapsulation and they have proven to be effective and with reduced cardiotoxicity, as a single agent or in combination with other drugs for the treatment of either anthracyclines-treated or naïve metastatic breast cancer patients. Of particular interest is the use of the combination of liposomal anthracyclines and trastuzumab in patients with HER2-overexpressing breast cancer. In this paper, we discuss the different studies on liposomal doxorubicin in metastatic and early breast cancer therapy. PMID:23634302

Melatonin Synergizes the Chemotherapeutic Effect of Cisplatin in Ovarian Cancer Cells Independently of MT1 Melatonin Receptors.

PubMed

Zemła, Agata; Grzegorek, Irmina; Dzięgiel, Piotr; Jabłońska, Karolina

2017-01-01

Melatonin (MLT), through the interaction with membrane melatonin receptors MT1, can improve the effectiveness of cytostatic agents, including cisplatin (CP). The aim of this study was to examine the synergistic effect of MLT and CP in three cell lines: IOSE 364, SK-OV-3 and OVCAR-3, as well as to assess the role of MT1 receptors in this mechanism. Using the SRB assay we investigated the effect of different concentrations of CP and MLT on cell viability. Tests, using luzindole - MT1 inhibitor, allowed us to assess the potential involvement of MT1 in the mechanism of MLT action. MLT at certain concentrations demonstrated a synergistic effect in combination with CP. The addition of luzindole did not affect the action of MLT in combination with CP. In summary, the synergistic effect of MLT with CP seems to be independent of membrane MT1 receptors. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

[Small-cell lung cancer: epidemiology, diagnostics and therapy].

PubMed

Pešek, Miloš; Mužík, Jan

Authors present actual overview of information on diagnostic and therapeutic procedures in small-cell lung cancer (SCLC). This highly aggressive type of lung cancer is diagnosed in 14.8 % of Czech lung cancer patients. Vast majority of those patients (87 %) suffer from advanced and metastatic disease in the time of diagnosis. In this issue are presented prognostic factors, staging diagnostic procedures and therapeutic recommendations. The backbone of actual SCLC treatment is combined chemotherapy and radiotherapy and less frequently, carefully in selected cases, surgical procedures. SCLC should be have as chemosensitive, chemoresistent or chemorefractory disease. Actual cytostatic combinations used in 1st line treatment, different schedules of chemoradiotherapy, drugs used in second line treatment and schedules and timing of prophylactic brain irradiation are presented. In near future, perspectively, there are some promissible data on antitumour immunotherapy based on anti CTLA-4 and anti PD-1/PE-L1 antibodies also in SCLC patients.Key words: cancer immunotherapy - concomitant chemoradiotherapy - chemotherapy - chest radiotherapy - lung resections - prophylactic brain irradiation - small cell lung cancer.

The dopamine-somatostatin chimeric compound BIM-23A760 exerts antiproliferative and cytotoxic effects in human non-functioning pituitary tumors by activating ERK1/2 and p38 pathways.

PubMed

Peverelli, Erika; Olgiati, Luca; Locatelli, Marco; Magni, Paolo; Fustini, Marco Faustini; Frank, Giorgio; Mantovani, Giovanna; Beck-Peccoz, Paolo; Spada, Anna; Lania, Andrea

2010-02-28

The study investigated the effects of the dopamine-somatostatin chimeric compound BIM-23A760 on cell proliferation and apoptosis in cultured cells from human non-functioning pituitary tumors (NFPTs). Both BIM-23A760 and the dopaminergic agonist BIM-53097 induced a significant inhibition of cell proliferation associated with increased p27 expression, together with a significant increase in caspase-3 activity. Conversely, null or marginal effects were elicited by somatostatin analogs. Moreover, BIM-23A760 and BIM-53097 induced ERK1/2 and p38 phosphorylation and the blockade of these pathways prevented both the antiproliferative and the pro-apoptotic effects of these drugs. In conclusions the chimeric compound BIM-23A760 is able to exert cytostatic and cytotoxic effects in NFPTs, these phenomena being mainly mediated by DR2D and involving ERK1/2 and p38 pathways activation. 2009 Elsevier Ireland Ltd. All rights reserved.

Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

PubMed

Casey, Alison E; Sinha, Ankit; Singhania, Rajat; Livingstone, Julie; Waterhouse, Paul; Tharmapalan, Pirashaanthy; Cruickshank, Jennifer; Shehata, Mona; Drysdale, Erik; Fang, Hui; Kim, Hyeyeon; Isserlin, Ruth; Bailey, Swneke; Medina, Tiago; Deblois, Genevieve; Shiah, Yu-Jia; Barsyte-Lovejoy, Dalia; Hofer, Stefan; Bader, Gary; Lupien, Mathieu; Arrowsmith, Cheryl; Knapp, Stefan; De Carvalho, Daniel; Berman, Hal; Boutros, Paul C; Kislinger, Thomas; Khokha, Rama

2018-06-19

The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology. © 2018 Casey et al.

What do we know about canine osteosarcoma treatment? Review.

PubMed

Szewczyk, M; Lechowski, R; Zabielska, K

2015-03-01

Osteosarcoma (OSA) is the most common type of bone tumors in dogs, which has high metastasis ability. 80 % of dogs with OSA die due to lung metastasis. As a result its treatment is a challenge for veterinary practitioners. The authors discuss the etiology, pathogenesis and the possible risk factors of OSA. The article focuses on literature review and the study of recent advances in OSA treatment. The authors describe therapies which have significantly prolonged the lives of dogs, as well as those that have proven to be ineffective. Advantages and disadvantages of limb amputation and limb-sparing surgery have been described. Authors present also the results of both single agent's therapies with the most commonly used drugs as cisplatin, carboplatin and doxorubicin and compare them to the results obtained using combined chemotherapy. The use of nanotechnology as a new approach in OSA treatment in order to avoid multidrug resistance and reduce negative side effects of cytostatic drugs is presented. The main reasons of the therapies failure are also provided in this article.

[Identification of the functional activity of synthetic polyamine analogues using a biotest system based on highly proliferating cultured human cells].

PubMed

Lisitskaia, K V; Sokueva, N A; Malysheva, Iu G; Ivanov, A V; Shishkin, S S; Siatkin, S P

2013-01-01

A new biotest system was developed based on highly proliferating human cell cultures (lines LNCaP and PC-3). With the help of this system, two known synthetic polyamines--alpha-difluoromethylornithine (DFMO) and methylglioxalbis(guanylhydrason) (MGBG)--as well as four new synthetic analogues difenyl containing amines (DFCA-1-DFCA-4) with molecular weights of 725.5 (DFCA-1), 755.5 (DFCA-2), 655.5 (DFCA-3), and 681.5 Da (DFCA-4) were tested. In this biotest system, DFMO (0.1-400 microM) did not reveal functional activity, whereas for MGBG a cytotoxic effect was registered (100-200 microM). DFCA-1, DFCA-2, and DFCA-4 had a similar effect at concentrations of 10 microM and higher; DFCA-3, at a concentration of 50 microM and higher. Thus, DFCA-1 has a higher level of antiproliferating activity and may be considered as the most potent cytostatic agent.

Antitumoral materials with regenerative function obtained using a layer-by-layer technique

PubMed Central

Ficai, Denisa; Sonmez, Maria; Albu, Madalina Georgiana; Mihaiescu, Dan Eduard; Ficai, Anton; Bleotu, Coralia

2015-01-01

A layer-by layer technique was successfully used to obtain collagen/hydroxyapatite-magnetite-cisplatin (COLL/HAn-Fe3O4-CisPt, n=1–7) composite materials with a variable content of hydroxyapatite intended for use in the treatment of bone cancer. The main advantages of this system are the possibility of controlling the rate of delivery of cytostatic agents, the presence of collagen and hydroxyapatite to ensure more rapid healing of the injured bone tissue, and the potential for magnetite to be a passive antitumoral component that can be activated when an appropriate external electromagnetic field is applied. In vitro cytotoxicity assays performed on the COLL/HAn-Fe3O4-CisPt materials obtained using a layer-by layer method confirmed their antitumoral activity. Samples with a higher content of hydroxyapatite had more antitumoral activity because of their better absorption of cisplatin and consequently a higher amount of cisplatin being present in the matrices. PMID:25767374

Synthesis, characterization, and evaluation of paclitaxel loaded in six-arm star-shaped poly(lactic-co-glycolic acid)

PubMed Central

Chen, Yongxia; Yang, Ziying; Liu, Chao; Wang, Cuiwei; Zhao, Shunxin; Yang, Jing; Sun, Hongfan; Zhang, Zhengpu; Kong, Deling; Song, Cunxian

2013-01-01

Background Star-shaped polymers provide more terminal groups, and are promising for application in drug-delivery systems. Methods A new series of six-arm star-shaped poly(lactic-co-glycolic acid) (6-s-PLGA) was synthesized by ring-opening polymerization. The structure and properties of the 6-s-PLGA were characterized by carbon-13 nuclear magnetic resonance spectroscopy, infrared spectroscopy, gel permeation chromatography, and differential scanning calorimetry. Then, paclitaxel-loaded six-arm star-shaped poly(lactic-co-glycolic acid) nanoparticles (6-s-PLGA-PTX-NPs) were prepared under the conditions optimized by the orthogonal testing. High-performance liquid chromatography was used to analyze the nanoparticles’ encapsulation efficiency and drug-loading capacity, dynamic light scattering was used to determine their size and size distribution, and transmission electron microscopy was used to evaluate their morphology. The release performance of the 6-s-PLGA-PTX-NPs in vitro and the cytostatic effect of 6-s-PLGA-PTX-NPs were investigated in comparison with paclitaxel-loaded linear poly(lactic-co-glycolic acid) nanoparticles (L-PLGA-PTX-NPs). Results The results of carbon-13 nuclear magnetic resonance spectroscopy and infrared spectroscopy suggest that the polymerization was successfully initiated by inositol and confirm the structure of 6-s-PLGA. The molecular weights of a series of 6-s-PLGAs had a ratio corresponding to the molar ratio of raw materials to initiator. Differential scanning calorimetry revealed that the 6-s-PLGA had a low glass transition temperature of 40°C–50°C. The 6-s-PLGA-PTX-NPs were monodispersed with an average diameter of 240.4±6.9 nm in water, which was further confirmed by transmission electron microscopy. The encapsulation efficiency of the 6-s-PLGA-PTX-NPs was higher than that of the L-PLGA-PTX-NPs. In terms of the in vitro release of nanoparticles, paclitaxel (PTX) was released more slowly and more steadily from 6-s-PLGA than from linear poly(lactic-co-glycolic acid). In the cytostatic study, the 6-s-PLGA-PTX-NPs and L-PLGA-PTX-NPs were found to have a similar antiproliferative effect, which indicates durable efficacy due to the slower release of the PTX when loaded in 6-s-PLGA. Conclusion The results suggest that 6-s-PLGA may be promising for application in PTX delivery to enhance sustained antiproliferative therapy. PMID:24235829

[Acute Ph-negative lymphoblastic leukemias in adults: Risk factors in the use of the ALL-2009 protocol].

PubMed

Parovichnikova, E N; Sokolov, A N; Troitskaya, V V; Klyasova, G A; Rusinov, M A; Akhmerzaeva, Z Kh; Kuzmina, L A; Bondarenko, S N; Baranova, O Yu; Kaporskaya, T S; Zotina, E N; Zinina, E E; Samoilova, O S; Gavrilova, L V; Kaplanov, K D; Konstantinova, T S; Lapin, V A; Kravchenko, S K; Gribanova, E O; Zvonkov, E E; Gavrilina, O A; Baskhaeva, G A; Galstyan, G M; Obukhova, T N; Galtseva, I V; Kulikov, S M; Savchenko, V G

to analyze well-known risk factors (RFs), such as age, immunophenotype, baseline leukocytosis, enhanced lactate dehydrogenase (LDH) activity, time to achieve complete remission, a risk group, and cytogenetic abnormalities) in patients with acute lymphoblastic leukemia (ALL) in the use of the ALL-2009 protocol. The protocol covered 298 patients (137 women (including 13 pregnant women) and 161 men) aged 15 to 55 years (median age 28 years) with Ph-negative ALL. The phenotype was unknown in 6 patients. Three (1%) were ascertained to have a biphenotypic variant. 182 (62.4%) patients were found to have B-cell ALL (early pre-B ALL (n=51); common ALL (n=92), and pre-B ALL (n=39); 107 (36.6%) patients had T-cell ALL (early T-ALL (n=56); thymic T-ALL (n=41), and mature T-ALL (n=10). According to the baseline clinical and laboratory parameters (leukocytosis of 30·109/l and more for B-ALL; and that of 100·109/l and more for T-ALL; phenotype В-I for B-ALL, phenotype Т-I-II-IV for T-ALL; LDH activity was more than twice the normal values; the presence of translocation t(4;11)), the high-risk group included most patients with B-ALL (n=110 (72.8%)) and T-ALL (n=76 (76%)). Thirty-five patients with T-ALL underwent autologous bone marrow transplantation (BMT). Allogeneic BMT was performed in 18 (7%) of the 258 patients who had undergone an induction phase. Five-year overall survival for all the patients included in the investigation was 59%; relapse-free survival was 65%, which was significantly different in the patients with B-ALL and in those with T-ALL: the overall survival rates were 53.3 and 67.5% (p=0.1); the relapse-free survival was 56 and 79% (p=0.005), respectively. Multivariate analysis including the well-known RFs demonstrated that the latter for T-ALL were of no independent prognostic value and only the patient's age was identified for B-ALL (p=0.013). A lower chemotherapeutic load and a small number of allogeneic BMTs did not affect total positive treatment results in adult patients with ALL, by complying with the principle achieving the continuity of cytostatic effects and by preserving the total cytostatic loading dose. The results of the Russian investigation casts some doubt on the necessity of using very intensive consolidation cycles and performing a large number of allogeneic BMTs in adult patients with ALL.

Garcinia xanthochymus Benzophenones Promote Hyphal Apoptosis and Potentiate Activity of Fluconazole against Candida albicans Biofilms

PubMed Central

Jackson, Desmond N.; Yang, Lin; Wu, ShiBiao; Kennelly, Edward J.

2015-01-01

Xanthochymol and garcinol, isoprenylated benzophenones purified from Garcinia xanthochymus fruits, showed multiple activities against Candida albicans biofilms. Both compounds effectively prevented emergence of fungal germ tubes and were also cytostatic, with MICs of 1 to 3 μM. The compounds therefore inhibited development of hyphae and subsequent biofilm maturation. Xanthochymol treatment of developing and mature biofilms induced cell death. In early biofilm development, killing had the characteristics of apoptosis, including externalization of phosphatidyl serine and DNA fragmentation, as evidenced by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) fluorescence. These activities resulted in failure of biofilm maturation and hyphal death in mature biofilms. In mature biofilms, xanthochymol and garcinol caused the death of biofilm hyphae, with 50% effective concentrations (EC50s) of 30 to 50 μM. Additionally, xanthochymol-mediated killing was complementary with fluconazole against mature biofilms, reducing the fluconazole EC50 from >1,024 μg/ml to 13 μg/ml. Therefore, xanthochymol has potential as an adjuvant for antifungal treatments as well as in studies of fungal apoptosis. PMID:26195512

Targeting Metastasis with Snake Toxins: Molecular Mechanisms

PubMed Central

Urra, Félix A.

2017-01-01

Metastasis involves the migration of cancer cells from a primary tumor to invade and establish secondary tumors in distant organs, and it is the main cause for cancer-related deaths. Currently, the conventional cytostatic drugs target the proliferation of malignant cells, being ineffective in metastatic disease. This highlights the need to find new anti-metastatic drugs. Toxins isolated from snake venoms are a natural source of potentially useful molecular scaffolds to obtain agents with anti-migratory and anti-invasive effects in cancer cells. While there is greater evidence concerning the mechanisms of cell death induction of several snake toxin classes on cancer cells; only a reduced number of toxin classes have been reported (i.e., disintegrins/disintegrin-like proteins, C-type lectin-like proteins, C-type lectins, serinproteases, cardiotoxins, snake venom cystatins) as inhibitors of adhesion, migration, and invasion of cancer cells. Here, we discuss the anti-metastatic mechanisms of snake toxins, distinguishing three targets, which involve (1) inhibition of extracellular matrix components-dependent adhesion and migration, (2) inhibition of epithelial-mesenchymal transition, and (3) inhibition of migration by alterations in the actin/cytoskeleton network. PMID:29189742

A systemic literature review of neuroimaging studies in women with breast cancer treated with adjuvant chemotherapy

PubMed Central

Wiłkość, Monika; Izdebski, Paweł; Żurawski, Bogdan

2017-01-01

Chemotherapy-induced cognitive deficits in patients with breast cancer, predominantly in attention and verbal memory, have been observed in numerous studies. These neuropsychological findings are corroborated by the results of neuroimaging studies. The aim of this paper was to survey the reports on cerebral structural and functional alterations in women with breast cancer treated with chemotherapy (CTx). First, we discuss the host-related and disease-related mechanisms underlying cognitive impairment after CTx. We point out the direct and indirect neurotoxic effect of cytostatics, which may cause: a damage to neurons or glial cells, changes in neurotransmitter levels, deregulation of the immune system and/or cytokine release. Second, we focus on the results of neuroimaging studies on brain structure and function that revealed decreased: density of grey matter, integrity of white matter and volume of multiple brain regions, as well as their lower activation during cognitive task performance. Finally, we concentrate on compensatory mechanisms, which activate additional brain areas or neural connection to reach the premorbid cognitive efficiency. PMID:28435392

HPMA Copolymer-Drug Conjugates with Controlled Tumor-Specific Drug Release.

PubMed

Chytil, Petr; Koziolová, Eva; Etrych, Tomáš; Ulbrich, Karel

2018-01-01

Over the past few decades, numerous polymer drug carrier systems are designed and synthesized, and their properties are evaluated. Many of these systems are based on water-soluble polymer carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, or multidrug resistance inhibitors, all covalently bound to a carrier by a biodegradable spacer that enables controlled release of the active molecule to achieve the desired pharmacological effect. Among others, the synthetic polymer carriers based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers are some of the most promising carriers for this purpose. This review focuses on advances in the development of HPMA copolymer carriers and their conjugates with anticancer drugs, with triggered drug activation in tumor tissue and especially in tumor cells. Specifically, this review highlights the improvements in polymer drug carrier design with respect to the structure of a spacer to influence controlled drug release and activation, and its impact on the drug pharmacokinetics, enhanced tumor uptake, cellular trafficking, and in vivo antitumor activity. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

High content screening of defined chemical libraries using normal and glioma-derived neural stem cell lines.

PubMed

Danovi, Davide; Folarin, Amos A; Baranowski, Bart; Pollard, Steven M

2012-01-01

Small molecules with potent biological effects on the fate of normal and cancer-derived stem cells represent both useful research tools and new drug leads for regenerative medicine and oncology. Long-term expansion of mouse and human neural stem cells is possible using adherent monolayer culture. These cultures represent a useful cellular resource to carry out image-based high content screening of small chemical libraries. Improvements in automated microscopy, desktop computational power, and freely available image processing tools, now means that such chemical screens are realistic to undertake in individual academic laboratories. Here we outline a cost effective and versatile time lapse imaging strategy suitable for chemical screening. Protocols are described for the handling and screening of human fetal Neural Stem (NS) cell lines and their malignant counterparts, Glioblastoma-derived neural stem cells (GNS). We focus on identification of cytostatic and cytotoxic "hits" and discuss future possibilities and challenges for extending this approach to assay lineage commitment and differentiation. Copyright © 2012 Elsevier Inc. All rights reserved.

Anticancer and antioxidant activity of bread enriched with broccoli sprouts.

PubMed

Gawlik-Dziki, Urszula; Świeca, Michał; Dziki, Dariusz; Sęczyk, Łukasz; Złotek, Urszula; Różyło, Renata; Kaszuba, Kinga; Ryszawy, Damian; Czyż, Jarosław

2014-01-01

This study is focused on antioxidant and anticancer capacity of bread enriched with broccoli sprouts (BS) in the light of their potential bioaccessibility and bioavailability. Generally, bread supplementation elevated antioxidant potential of product (both nonenzymatic and enzymatic antioxidant capacities); however, the increase was not correlated with the percent of BS. A replacement up to 2% of BS gives satisfactory overall consumers acceptability and desirable elevation of antioxidant potential. High activity was especially found for extracts obtained after simulated digestion, which allows assuming their protective effect for upper gastrointestinal tract; thus, the anticancer activity against human stomach cancer cells (AGS) was evaluated. A prominent cytostatic response paralleled by the inhibition of AGS motility in the presence of potentially mastication-extractable phytochemicals indicates that phenolic compounds of BS retain their biological activity in bread. Importantly, the efficient phenolics concentration was about 12 μM for buffer extract, 13 μM for extracts after digestion in vitro, and 7 μM for extract after absorption in vitro. Our data confirm chemopreventive potential of bread enriched with BS and indicate that BS comprise valuable food supplement for stomach cancer chemoprevention.

Derivation of feline vaccine-associated fibrosarcoma cell line and its growth on chick embryo chorioallantoic membrane - a new in vivo model for veterinary oncological studies.

PubMed

Zabielska, K; Lechowski, R; Król, M; Pawłowski, K M; Motyl, T; Dolka, I; Zbikowski, A

2012-12-01

Feline vaccine associated fibrosarcomas are the second most common skin tumor in cats. Methods of treatment are: surgery, chemotherapy and radiotherapy. Nevertheless, the usage of cytostatics in feline vaccine associated sarcoma therapy is limited due to their adverse side effects, high toxicity and low biodistribution after i.v. injection. Therefore, much research on new therapeutic drugs is being conducted. In human medicine, the chick embryo chorioallantoic membrane (CAM) model is used as a cheap and easy to perform assay to assess new drug effectiveness in cancer treatment. Various human cell lines have different tumors growth on CAM. In veterinary medicine such model has not been described yet. In the present article derivation of feline vaccine associated fibrosarcoma cell line and its growth on CAM is described. The cell line and the tumor grown were confirmed by histopathological and immunohistochemical examination. As far as we believe, this is the first attempt to create such model, which may be used for further in vivo studies in veterinary oncology.

Prevention and treatment of hyperuricemia with rasburicase in children with leukemia and non-Hodgkin's lymphoma.

PubMed

Rényi, Imre; Bárdi, Edit; Udvardi, Erzsébet; Kovács, Gábor; Bartyik, Katalin; Kajtár, Pál; Masát, Péter; Nagy, Kálmán; Galántai, Ilona; Kiss, Csongor

2007-01-01

To prevent acute renal failure in children at risk for developing tumor lysis syndrome due to acute lymphoblastic leukemia or non-Hodgkin's lymphoma treated according to international BFM protocols, we investigated recombinant urate oxidase (rasburicase) in the first Central European openlabeled, prospective, multicenter phase IV trial. Rasburicase was administered intravenously, at 0.2 mg/kg for 5 consecutive days to 36 patients. Blood levels of uric acid, creatinine, phosphorus, calcium, lactate dehydrogenase and complete blood count were measured daily during rasburicase treatment and on days 6, 7 and 12. Initial uric acid level decreased significantly by 4 hours (from 343 micromol/L to 58 micromol/L, p<0.001), except for one steroid-resistant patient who required hemodialysis on day 14 after having introduced combined cytostatic treatment. Comparing the data of a subgroup of 12 patients receiving rasburicase with that of a historic cohort of 14 patients treated with allopurinol indicated the superiority of rasburicase over allopurinol in prophylaxis and treatment of hyperuricemia in children with leukemia and lymphoma.

MONITORING OF SYNERGISTIC ENHANCEMENT OF CAFFEIC ACID ON ESCHERICHIA COLI K-12 RECA::GFP STRAIN TREATED WITH DACARBAZINE.

PubMed

Matejczyk, Marzena; Swislocka, Renata; Kalinowska, Monika; Swidersk, Grzegorz; Lewandowsk, Wlodzimierz; Jablonska-Trypuo, Agata

2017-05-01

Caffeic acid and its derivatives because of its biological activities, including antioxidants, antithrombosis, antihypertensive, antifibrosis, antiviral, and anti-tumor properties are good candidates as adjuvants in anticancer therapy. The aim of this study was the examination of cyto- and genotoxic effect of caffeic acid on Escherichia coli K-12 recA::gfp strain treated with dacarbazine. Obtained results indicate that dacarbazine and caffeic acid influenced the reactivity of recA promoter and modulate the level of gfp expression in genetic construct rrcA::gfpmut2 in E. coli K-12. Simultaneuos administration of dacarbazine with caffeic acid caused the stronger inhibition of the bacteria growth than the dacarbazine and caffeic acid separated administration to bacteria cells. The simultaneous effect of the both tested chemicals - dacarbazine and caffeic acid indicated (cytostatic effect) anticancer activity in relation to bacteria cells. It suggests, that combination of known anticancer drug - dacarbazine w ith caffeic acid exerted synergistic cytotoxic and genotoxic effects toward E. coli K- 12 cells and indicated the possibility of usefulness of caffeic acid as a natural adjuvant in anticancer therapy.

Aggravation of cyclophosphamide-induced acute neurological disorders under conditions of artificial acidification of chyme in rats.

PubMed

Schaefer, T V; Rejuniuk, V L; Malakhovsky, V N; Ivnitsky, Ju Ju

2012-10-01

The effect of artificial acidification of the intestinal content on neurological manifestations of acute severe cyclophosphamide intoxication was studied in rats. The animals were gavaged with 20 ml/kg sulfuric (0.05 M), hydrochloric, boric, or lactic acids (0.1 M) 3 h before intraperitoneal injections of the cytostatic in doses of 0, 200, 600, or 1000 mg/kg. The decrease in pH (by.0) and ammonia-producing activity of the cecal chyme developed within 3 h after administration of acids. Cyclophosphamide caused hyperammonemia; glutamine/ammonia and urea/ammonia ratios in the blood decreased. These changes augmented after administration of acids (boric acid produced maximum and lactic acid minimum effects). Acid treatment resulted in greatest elevation of ammonia level in the portal venous blood and a lesser elevation in the vena cava posterior blood. Acid treatment promoted manifestation of cyclophosphamide neurotoxic effect and animal death. Hence, acidification of the chyme inhibited the formation of ammonia in it, while ammonia release from the gastrointestinal tract into the blood increased; the treatment augmented hyperammonemia and aggravated the neurological manifestations of cyclophosphamide intoxication.

Photochemical studies and nanomolar photodynamic activities of phthalocyanines functionalized with 1,4,7-trioxanonyl moieties at their non-peripheral positions.

PubMed

Sobotta, Lukasz; Wierzchowski, Marcin; Mierzwicki, Michal; Gdaniec, Zofia; Mielcarek, Jadwiga; Persoons, Leentje; Goslinski, Tomasz; Balzarini, Jan

2016-02-01

Manganese(III), cobalt(II), copper(II), magnesium(II), zinc(II) and metal-free phthalocyanines, possessing 1,4,7-trioxanonyl substituents, at their non-peripheral positions, were subjected to photochemical, photodynamic and biological activity studies. Demetallated phthalocyanine and its metallated d-block analogues, with copper(II), cobalt(II), manganese(III) chloride, were found to be less efficient singlet oxygen generators in comparison to the zinc(II) analogue and zinc(II) phthalocyanine reference. Irradiation of several phthalocyanines for short time periods resulted in a substantially increased cytostatic activity against both suspension (leukemic/lymphoma at 85nM) and solid (cervix carcinoma at 72nM and melanoma at 81nM) tumour cell lines (up to 200-fold). Noteworthy is that enveloped viruses, such as for herpesvirus and influenza A virus, but not, non-enveloped virus strains, such as Coxsackie B4 virus and reovirus-1, exposed to irradiation in the presence of the phthalocyanines, markedly lost their infectivity potential. Copyright © 2015 Elsevier Inc. All rights reserved.

Systemic administration of bevacizumab prolongs survival in an in vivo model of platinum pre-treated ovarian cancer

PubMed Central

REIN, DANIEL T.; VOLKMER, ANNE KATHRIN; VOLKMER, JENS; BEYER, INES M.; JANNI, WOLFGANG; FLEISCH, MARKUS C.; WELTER, ANNE KATHRIN; BAUERSCHLAG, DIRK; SCHÖNDORF, THOMAS; BREIDENBACH, MARTINA

2012-01-01

Ovarian cancer patients often suffer from malignant ascites and pleural effusion. Apart from worsening the outcome, this condition frequently impairs the quality of life in patients who are already distressed by ovarian cancer. This study investigated whether single intraperitoneal administration of the anti-VEGF antibody bevacizumab is capable of reducing the ascites-related body surface and prolonging survival. The study was performed in an orthotopic murine model of peritoneal disseminated platin-resistant ovarian cancer. Mice were treated with bevacizumab and/or paclitaxel or buffer (control). Reduction of body surface and increased survival rates were assessed as therapeutic success. Survival of mice in all treatment groups was significantly enhanced when compared to the non-treatment control group. The combination of paclitaxel plus bevacizumab significantly improved body surface as well as overall survival in comparison to a treatment with only one of the drugs. Treatment of malignant effusion with a single dose of bevacizumab as an intraperitoneal application, with or without cytostatic co-medication, may be a powerful alternative to systemic treatment. PMID:22740945

New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells.

PubMed

Heinrich, Jörg C; Donakonda, Sainitin; Haupt, V Joachim; Lennig, Petra; Zhang, Yixin; Schroeder, Michael

2016-10-18

Drug resistance is an important open problem in cancer treatment. In recent years, the heat shock protein HSP27 (HSPB1) was identified as a key player driving resistance development. HSP27 is overexpressed in many cancer types and influences cellular processes such as apoptosis, DNA repair, recombination, and formation of metastases. As a result cancer cells are able to suppress apoptosis and develop resistance to cytostatic drugs. To identify HSP27 inhibitors we follow a novel computational drug repositioning approach. We exploit a similarity between a predicted HSP27 binding site to a viral thymidine kinase to generate lead inhibitors for HSP27. Six of these leads were verified experimentally. They bind HSP27 and down-regulate its chaperone activity. Most importantly, all six compounds inhibit development of drug resistance in cellular assays. One of the leads - chlorpromazine - is an antipsychotic, which has a positive effect on survival time in human breast cancer. In summary, we make two important contributions: First, we put forward six novel leads, which inhibit HSP27 and tackle drug resistance. Second, we demonstrate the power of computational drug repositioning.

Antiproliferative Effect of Synadenium grantii Hook f. stems (Euphorbiaceae) and a Rare Phorbol Diterpene Ester.

PubMed

Campos, Adriana; Vendramini-Costa, Débora Barbosa; Longato, Giovanna Barbarini; Zermiani, Tailyn; Ruiz, Ana Lúcia Tasca Gois; de Carvalho, João Ernesto; Pandiella, Atanasio; Cechinel Filho, Valdir

2016-11-01

Synadenium grantii is frequently used for the treatment of various diseases such as allergies, gastric disorders, and especially cancer. The aim of this study was to evaluate the possible antiproliferative potential of the methanol extract, fractions, and pure compounds from the stems of S grantii Phytochemical analysis was carried out by conventional chromatographic techniques, and the antiproliferative activity was analyzed using the sulforhodamine B assay and an MTT-based assay. Nonpolar fraction and its subfractions from the stems of S grantii exhibited promising cytostatic effect against several human tumor cell lines (glioma, breast, kidney, and lung), with total grown inhibition values ranging from 0.37 to 2.9 μg/mL. One of the active principles of this plant was identified as a rare phorbol diterpene ester, denoted as 3,4,12,13-tetraacetylphorbol-20-phenylacetate. This compound demonstrated antiproliferative activity against glioma, kidney, lung, and triple-negative breast cancer cell lines. These results demonstrate that S grantii stems produce active principles with relevant antiproliferative potential. © The Author(s) 2016.

[Update on soft tissue sarcomas].

PubMed

Bui, Binh Nguyen; Tabrizi, Reza; Dagada, Corinne; Trufflandier, Nathalie; St ckle, Eberhard; Coindre, Jean-Michel

2002-01-01

Important refinements have taken place in the diagnosis of soft tissue sarcoma with extensive use of immuno-histochemistry. New entities have been described, while malignant histiocytofibroma, the most diagnosed sarcoma type during the last two decades, has been dismembered. As for prognosis, the new UICC classification is effectively more discriminating in the definition of prognostic groups; but the usefullness of new biological or genetic markers remains to be assessed. Several breakthrough have taken place in the last years in the treatment of soft tissue sarcoma. Isolated limb perfusion with TNF, hyperthermia and melphalan have proven its efficacy, and is now an alternative to preoperative chemotherapy and/or radiotherapy for limb sparing treatment of the primary tumor site or to amputation. For systemic treatments, novel cytostatic drugs have been shown to be active in sarcomas, including ecteinascidine (ET743) and Glivec (STI571). This last drug has been shown to be remarkably active in c-kit+ stromal sarcoma of the gastro-intestinal tract. It can hopefully regarded as an example for targeted therapies, which may come with a better understanding of the molecular mechanisms triggered by the fundamental, specific genetic alterations shown in sarcoma.

Identification & Characterization of lactobacillus salavarius bacteriocins and its relevance in cancer therapeutics.

PubMed

Shaikh, Faraz; Abhinand, Pa; Ragunath, Pk

2012-01-01

Therapeutic agents with a goal to eradicate cancer needs to capable of inhibiting the growth and kill, any preformed tumor and should also inhibit oncogenic transformation of normal cells to cancer cells. Bacteriocins are bacterial proteins produced to prevent the growth of competing microorganisms in a particular biological niche and have been proved to possess antineoplastic activity. The entire genome of Lactobacillus salavarius was scanned for putative bacteriocins and subsequently these bacteriocins were characterized by subjecting them as functional annotation algorithms. Azurin is a well characterized bacteriocins with proven cytostatic and apoptotic effect against human cancer cell and was taken as control. Functional characterization revealed that the three bacteriocins Lsl_003, Lsl_0510, Lsl_0554 possessed functional properties very similar to that of Azurin. Molecular screening of these bacteriocins against the common cancer targets p53, Rb1 and AR revealed that Lsl_0510 possessed highest binding affinity towards the all the three receptors making it to ideal candidate for future cancer therapeutics. P53 - Protein 53, Rb1 - Retinoblastoma 1, AR - Androgen Receptor, Lsl - Lactobacillus salavarius.

[Anti-epidermal growth factor receptor treatment: a new paradigm for conducting therapeutic trials].

PubMed

Marty, Michel; Bedairia, Naima; Armand, Jean-Pierre

2003-11-01

Agents which modify biological properties of tumour tissue can target many tenths of functions over- or underexpressed in human tumours. In general these agents are cytostatic rather than cytotoxic and will affect only that fraction of human tumours where the target plays and important and unique role for the viability of the tumour tissue. Alternatively it is expected that acute toxicity will not be observed at active dose-time exposure; rather subacute or chronic toxicity can be observed with these agents. Clinical studies will have to follow the following rules: characterisation of the pharmacological target and of its functional role on tumour tissue; definition of an optimal biological dose rather than a maximum tolerated dose; importance of validated pharmacodynamic endpoints; importance and thus need for early studies of combination regimens. It is still too early to define general guidelines for the study of these different therapeutic families. Nevertheless, studies already conducted with agents interfering with EGF mediated signalization have already permitted preliminary indications on pharmacodynamics, target assessment, level of activity and conduct of clinical trials with combination regimens.

A New and Fast Technique to Generate Offspring after Germ Cells Transplantation in Adult Fish: The Nile Tilapia (Oreochromis niloticus) Model

PubMed Central

Lacerda, Samyra M. S. N.; Batlouni, Sergio R.; Costa, Guilherme M. J.; Segatelli, Tânia M.; Quirino, Bruno R.; Queiroz, Bruno M.; Kalapothakis, Evanguedes; França, Luiz R.

2010-01-01

Background Germ cell transplantation results in fertile recipients and is the only available approach to functionally investigate the spermatogonial stem cell biology in mammals and probably in other vertebrates. In the current study, we describe a novel non-surgical methodology for efficient spermatogonial transplantation into the testes of adult tilapia (O. niloticus), in which endogenous spermatogenesis had been depleted with the cytostatic drug busulfan. Methodology/Principal Findings Using two different tilapia strains, the production of fertile spermatozoa with donor characteristics was demonstrated in adult recipient, which also sired progeny with the donor genotype. Also, after cryopreservation tilapia spermatogonial cells were able to differentiate to spermatozoa in the testes of recipient fishes. These findings indicate that injecting germ cells directly into adult testis facilitates and enable fast generation of donor spermatogenesis and offspring compared to previously described methods. Conclusion Therefore, a new suitable methodology for biotechnological investigations in aquaculture was established, with a high potential to improve the production of commercially valuable fish, generate transgenic animals and preserve endangered fish species. PMID:20505774

Gold-Containing Indoles as Anti-Cancer Agents that Potentiate the Cytotoxic Effects of Ionizing Radiation

PubMed Central

Craig, Sandra; Gao, Lei; Lee, Irene; Gray, Thomas; Berdis, Anthony J.

2012-01-01

This report describes the design and application of several distinct gold-containing indoles as anti-cancer agents. When used individually, all gold-bearing compounds display cytostatic effects against leukemia and adherent cancer cell lines. However, two gold-bearing indoles show unique behavior by increasing the cytotoxic effects of clinically relevant levels of ionizing radiation. Quantifying the amount of DNA damage demonstrates that each gold-indole enhances apoptosis by inhibiting DNA repair. Both Au(I)-indoles were tested for inhibitory effects against various cellular targets including thioredoxin reductase, a known target of several gold compounds, and various ATP-dependent kinases. While neither compound significantly inhibits the activity of thioreoxin reductase, both showed inhibitory effects against several kinases associated with cancer initiation and progression. The inhibition of these kinases provides a possible mechanism for the ability of these Au(I)-indoles potentiate the cytotoxic effects of ionizing radiation. Clinical applications of combining Au(I)-indoles with ionizing radiation are discussed as a new strategy to achieve chemosensitization of cancer cells. PMID:22289037

Selenitetriglicerydes affect CYP1A1 and QR activity by involvement of reactive oxygen species and Nrf2 transcription factor.

PubMed

Suchocki, Piotr; Misiewicz-Krzemińska, Irena; Skupińska, Katarzyna; Niedźwiecka, Katarzyna; Lubelska, Katarzyna; Fijałek, Zbigniew; Kasprzycka-Guttman, Teresa

2010-01-01

Selenitetriglycerides are a group of compounds that contain selenium (Se) (IV). In this paper, we present the results of examinations of three structurally-related selenitetriglicerydes that contain various Se concentrations: 2%, 5% and 7% Selol. The present study concentrates on the effect of Selol on phase 1 and 2 enzyme activity and the implications of free radicals and the nuclear erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway in the activity of this compound. The cytotoxic and cytostatic activities of the three kinds of Selol were evaluated; however, the cytotoxic effect was observed only for 7% Selol. Our results show that 2% Selol acts as a monofunctional inducer of phase 2 enzyme activity, and the induction is mediated by the Nrf2 transcription factor. Selol 7% acts in an opposite manner and induces phase 1 with simultaneous inhibition of phase 2 enzyme activity. The differential effect can be associated with the increase in Se content, leading to a change in the structure of the compound.

[Alternative medicine: really an alternative to academic medicine?].

PubMed

Happle, R

2000-06-01

Numerous courses on alternative medicine are regularly advertised in Deutsches Arzteblatt, the organ of the German Medical Association. The present German legislation likewise supports this form of medicine, and this explains why Iscador, an extract of the mistletoe, is found in the Rote Liste, a directory of commercially available medical drugs, under the heading "cytostatic and antimetastatic drugs" although such beneficial effect is unproven. To give another example, a German health insurance fund was sentenced to pay for acupuncture as a treatment for hepatic failure. This judgement is characteristic of the present German judicial system and represents a victory of "oracling irrationalism" (Popper). The astonishing popularity of alternative medicine can be explained by a revival of romanticism. An intellectually fair opposite position has been delineated by Karl Popper in the form of critical rationalism. It is important to realize, however, that our decision to adhere to rational thinking is made in the innermost depth of our heart but not on the basis of rational arguing. Rather, the decision in favor of reason has a moral dimension.

Relation of polymorphism C1236T and C3435T in ABCB1 gene with bone marrow suppression in chemotherapy-treated breast cancer patients

NASA Astrophysics Data System (ADS)

Syarifah, S.; Hamdi, T.; Widyawati, T.; Sari, M. I.; Anggraini, D. R.

2018-03-01

ABCB1 is agene that encoded P-glycoprotein (P-gp), a transmembrane active efflux pump for a variety of carcinogens and cytostatics.ABCB1 polymorphisms C1236T and C3435T contribute to the variability oftherapeutic outcome and side effects.The present study was conducted to investigatethe relation of C1236T and C3435T polymorphisms in ABCB1 gene with bone marrow suppression in breast cancer patients treated withchemotherapy72 Indonesian womens isolated DNA sampleswere amplified using the PCR method. The analysis process of ABCB1 C1236T and C3435T polymorphism was by using thePCR-RFLP method. The frequencies of ABCB1 C1236T genotype for homozygous CC,heterozygous CT and variant TT was 11(15.28%), 42(58.33%), 19(26.39%), respectively. No associationwas between ABCB1 C1236T and C3435T polymorphisms in both individually and haplotypes with bone marrow suppression event (p > 0.05). There was no specific deviation of allele and genotype frequency from Hardy-Weinberg Equilibrium. There was a linkage between heterozygous CT-heterozygous CT in position 1236 and 3435 within 25 people (35%).

Achiral Mannich-Base Curcumin Analogs Induce Unfolded Protein Response and Mitochondrial Membrane Depolarization in PANC-1 Cells.

PubMed

Szebeni, Gábor J; Balázs, Árpád; Madarász, Ildikó; Pócz, Gábor; Ayaydin, Ferhan; Kanizsai, Iván; Fajka-Boja, Roberta; Alföldi, Róbert; Hackler, László; Puskás, László G

2017-10-07

Achiral Mannich-type curcumin analogs have been synthetized and assayed for their cytotoxic activity. The anti-proliferative and cytotoxic activity of curcuminoids has been tested on human non-small-cell lung carcinoma (A549), hepatocellular carcinoma (HepG2) and pancreatic cancer cell line (PANC-1). Based on the highest anti-proliferative activity nine drug candidates were further tested and proved to cause phosphatidylserine exposure as an early sign of apoptosis. Curcumin analogs with the highest apoptotic activity were selected for mechanistic studies in the most sensitive PANC-1 cells. Cytotoxic activity was accompanied by cytostatic effect since curcumin and analogs treatment led to G₀/G₁ cell cycle arrest. Moreover, cytotoxic effect could be also detected via the accumulation of curcuminoids in the endoplasmic reticulum (ER) and the up-regulation of ER stress-related unfolded protein response (UPR) genes: HSPA5 , ATF4, XBP1 , and DDIT3 . The activated UPR induced mitochondrial membrane depolarization, caspase-3 activation and subsequent DNA breakdown in PANC-1 cells. Achiral curcumin analogs, C509, C521 and C524 possessed superior, 40-times more potent cytotoxic activity compared to natural dihydroxy-dimetoxycurcumin in PANC-1 cells.

New Poly(3-hydroxybutyrate) Microparticles with Paclitaxel Sustained Release for Intraperitoneal Administration.

PubMed

Bonartsev, Anton P; Zernov, Anton L; Yakovlev, Sergey G; Zharkova, Irina I; Myshkina, Vera L; Mahina, Tatiana K; Bonartseva, Garina A; Andronova, Natalia V; Smirnova, Galina B; Borisova, Juliya A; Kalishjan, Mikhail S; Shaitan, Konstantin V; Treshalina, Helena M

2017-01-01

Poly(hydroxyalkanoates) (PHA) have recently attracted increasing attention due to their biodegradability and high biocompatibility, which makes them suitable for the development of new prolong drug formulations. This study was conducted to develop new prolong paclitaxel (PTX) formulation based on poly(3- hydroxybutyrate) (PHB) microparticles. PHB microparticles loaded with antitumor cytostatic drug PTX were obtained by spray-drying method using Nano Spray Dryer B-90. The PTX release kinetics in vitro from PHB microparticles and their cytotoxity on murine hepatoma cell line MH-22a were studied. Microparticles antitumor activity in vivo was studied using intraperitoneally (i.p.) transplanted tumor models: murine Lewis lung carcinoma and xenografts of human breast cancer RMG1. Uniform PTX release from PHB-microparticles during 2 months was observed. PTX-loaded PHB microparticles have demonstrated a significant antitumor activity versus pure drug both in vitro in murine hepatoma cells and in vivo when administered i.p. to mice with murine Lewis lung carcinoma and xenografts of human breast cancer RMG1. The developed technique of PTX sustained delivery from PHB-microparticles has therapeutic potential as prolong anticancer drug formulation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Efficacy of a ketogenic diet in urological cancers patients : A systematic review].

PubMed

Maisch, P; Gschwend, J E; Retz, M

2018-03-01

Beside the classical anticancer treatment tumor patients try to find proactive alternative therapies to fight their disease. Lifestyle changes such as introducing a ketogenic diet is one of the most popular among them. The German Association of Urological Oncology (AUO, Arbeitsgemeinschaft Urologische Onkologie) presents a systematic review investigating the evidence of ketogenic diet in cancer patients. A systematic literature research was conducted in the databases Medline, Livivo, and the Cochrane Library. Only clinical studies of tumor patients receiving chemotherapy while on a ketogenic diet were included. The assessment of the results was performed according to the predefined primary endpoints overall survival and progression-free survival and secondary endpoints quality of life and reduction of adverse effects induced by cytostatics. Nine studies met the inclusion criteria: eight prospective and one retrospective study case series respectively cohort-studies, with a total of 107 patients. Currently there is no evidence of a therapeutic effect of a ketogenic diet in patients with malignant tumors regarding the clinical outcome or quality of life. Based on the current data, a ketogenic diet can not be recommended to cancer patients because prospective, randomized trials are missing.

[Transient myeloproliferation and acute myeloid leukemia in infants with Down's syndrome].

PubMed

Creutzig, U; Ritter, J; Vormoor, J; Eschenbach, C; Dickerhoff, R; Burdach, S; Scheel-Walter, H G; Kühl, J; Schellong, G

1990-01-01

Transient neonatal myeloproliferative disorders (TMD's) indistinguishable from acute leukaemia by clinical and morphological criteria have been described in neonates with Down's syndrome. To analyse its clinical significance, 10 infants under 1 year of age presenting with Down's syndrome and the morphological picture of acute myelogenous leukaemia were reviewed. 3 of these children had true AML leading to death after 2, 8 and 11 months. In the other 7 children the diagnosis TMD was suggested as spontaneous or in one case interferon-induced remission occurred within 4 to 25 weeks after diagnosis. The interferon-treated patient died of SIDS at the age of 11 months. Another one of the TMD children developed fatal erythroleukaemia at the age of 2 years. Regarding initial clinical and haematological parameters, TMD was indistinguishable from true congenital leukaemie. In all patients classification according to the FAB criteria was difficult, as mainly undifferentiated or poorly differentiated myeloid blasts were seen, sometimes with erythro- or megakaryocytic features. Because of the difficulties in the differential diagnosis of TMD and true AML it is recommended to delay specific cytostatic therapy in neonates with Down's syndrome, until definite progression of the leukaemic process is observed or cytogenetic analyses suggesting true AML are available.

The antineoplastic agent α-bisabolol promotes cell death by inducing pores in mitochondria and lysosomes.

PubMed

Rigo, Antonella; Vinante, Fabrizio

2016-08-01

The sesquiterpene α-bisabolol (α-BSB) has been shown to be an effective cytotoxic agent for a variety of human cancer cells in culture and animal models. However, much of its intracellular action remains elusive. We evaluated the cytotoxic action of α-BSB against CML-T1, Jurkat and HeLa cell lines, as preclinical models for myeloid, lymphoid and epithelial neoplasias. The approach included single cell analysis (flow cytometry, immunocytology) combined with cytotoxicity and proliferation assays to characterize organelle damage, autophagy, cytostatic effect, and apoptosis. The study focuses on the relevant steps in the cytotoxic cascade triggered by α-BSB: (1) the lipid rafts through which α-BSB enters the cells, (2) the opening of pores in the mitochondria and lysosomes, (3) the activation of both caspase-dependent and caspase-independent cell death pathways, (4) the induction of autophagy and (5) apoptosis. The effectiveness of α-BSB as an agent against tumor cells is grounded on its capability to act on different layers of cell regulation to elicit different concurrent death signals, thereby neutralizing a variety of aberrant survival mechanisms leading to treatment resistance in neoplastic cell.

The preclinical evaluation of TIC10/ONC201 as an anti-pancreatic cancer agent.

PubMed

Zhang, Qiangbo; Wang, Hong; Ran, Lin; Zhang, Zongli; Jiang, Runde

2016-08-05

Here we evaluated the potential anti-pancreatic cancer activity by TIC10/ONC201, a first-in-class small-molecule inducer of tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL). The in vitro results showed that TIC10 induced potent cytotoxic and cytostatic activities in several human pancreatic cancer cell lines (Panc-1, Mia-PaCa2, AsPC-1 or L3.6). TIC10 activated both extrinsic (TRAIL-caspase-8-dependent) and endogenous/mitochondrial (caspase-9-dependent) apoptosis pathways in the pancreatic cancer cells. Molecularly, we showed that TIC10 inhibited Akt-Erk activation, yet induced TRAIL expression in pancreatic cancer cells. Significantly, TIC10, at a relatively low concentration, sensitized gemcitabine-induced growth inhibition and apoptosis against pancreatic cancer cells. Further, TIC10 and gemcitabine synergistically inhibited Panc-1 xenograft growth in SCID mice. The combination treatment also significantly improved mice survival. In addition, Akt-Erk in-activation and TRAIL/cleaved-caspase-8 induction were observed in TIC10-treated Panc-1 xenografts. Together, the preclinical results of the study demonstrate the potent anti-pancreatic cancer activity by TIC10, or with gemcitabine. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of a cyclic combination chemotherapeutic protocol on primary haemostasis in dogs suffering from malignant lymphoma.

PubMed

Eberle, N; Mischke, R

2010-03-01

The purpose of this study was to examine the influence of cyclic combination chemotherapy on primary haemostasis in dogs with malignant lymphoma. Seventeen dogs receiving cytostatic treatment for high-grade lymphoma were included in the study. The dogs were treated with a Madison-Wisconsin derived protocol, which included asparaginase, vincristine, doxorubicin and prednisolone. At different time points during the first 4 weeks of induction, platelet count, capillary bleeding time, analysis of the platelet function using the platelet function analyser PFA-100, and platelet aggregation by the Born-method were measured. The most obvious changes were found for median values of the platelet count, which increased significantly from 210,000/microL before induction to 349,000/microL during the second week of induction (P=0.0010). Median platelet count subsequently decreased by the fourth week of treatment (Friedman-test: P<0.0001). None of the parameters of platelet function (capillary bleeding time, automatic platelet function analysis, aggregation maximum) showed significant changes with time (P>0.05, Friedman-test). The results did not suggest that significant platelet dysfunction was induced by the chemotherapeutic protocol used in the study. 2009 Elsevier Ltd. All rights reserved.

The effect of Lychnis chalcedonica L. flavonoids on the development of tumors in mice and the effectiveness of treatment with cyclophosphamide

NASA Astrophysics Data System (ADS)

Zibareva, L. N.; Zueva, E. P.; Razina, T. G.; Amosova, E. N.; Krylova, S. G.; Lopatina, K. A.; Rybalkina, O. Y.; Badulina, A. A.; Safonova, E. A.; Babushkina, M. S.; Filonenko, E. S.; Galiulina, A. V.

2015-11-01

A complex of biologically active substances was obtained from Lychnis chalcedonica L. introduced in culture at the Siberian botanical garden of Tomsk State University. Earlier, bioactivities such as radioprotective, gemoreologic and antifungal, were identified, which were determined by the presence of phytoecdysteroids whose composition was studied. The antitumor action of flavonoids extracted from ethanol extract of Lychnis chalcedonica was identified in this study. They were partially identified using the HPLC method. A major component of this complex was detected, which likely determines the effect on the tumor. The influence of these polyphenol compounds was studied on three models of tumors: Lewis lung carcinoma, melanoma - B16 and cancer light - 67. As a result of experiments conducted on female mice of the C57BL/6 line it was discovered that the Lychnis chalcedonica flavonoids complex inhibits tumor growth in mice with melanoma B-16, and together with cyclophosphamide enhances the antitumor effect of cytostatic. Lychnis chalcedonica flavonoids, when given as an isolated injection to mice with Lewis lung carcinomas, prevent a deterioration of the level of gematocrit and hemoglobin in the peripheral blood.

Anticancer and Antioxidant Activity of Bread Enriched with Broccoli Sprouts

PubMed Central

Gawlik-Dziki, Urszula; Świeca, Michał; Dziki, Dariusz; Sęczyk, Łukasz; Złotek, Urszula; Różyło, Renata; Kaszuba, Kinga; Ryszawy, Damian; Czyż, Jarosław

2014-01-01

This study is focused on antioxidant and anticancer capacity of bread enriched with broccoli sprouts (BS) in the light of their potential bioaccessibility and bioavailability. Generally, bread supplementation elevated antioxidant potential of product (both nonenzymatic and enzymatic antioxidant capacities); however, the increase was not correlated with the percent of BS. A replacement up to 2% of BS gives satisfactory overall consumers acceptability and desirable elevation of antioxidant potential. High activity was especially found for extracts obtained after simulated digestion, which allows assuming their protective effect for upper gastrointestinal tract; thus, the anticancer activity against human stomach cancer cells (AGS) was evaluated. A prominent cytostatic response paralleled by the inhibition of AGS motility in the presence of potentially mastication-extractable phytochemicals indicates that phenolic compounds of BS retain their biological activity in bread. Importantly, the efficient phenolics concentration was about 12 μM for buffer extract, 13 μM for extracts after digestion in vitro, and 7 μM for extract after absorption in vitro. Our data confirm chemopreventive potential of bread enriched with BS and indicate that BS comprise valuable food supplement for stomach cancer chemoprevention. PMID:25050366

Premature aging and cancer in nucleotide excision repair-disorders

PubMed Central

Diderich, K.; Alanazi, M.; Hoeijmakers, J.H.J.

2014-01-01

During past decades the major impact of DNA damage on cancer as ‘disease of the genes’ has become abundantly apparent. In addition to cancer recent years have also uncovered a very strong association of DNA damage with many features of (premature) aging. The notion that DNA repair systems not only protect against cancer but equally against too fast aging has become evident from a systematic, integral analysis of a variety of mouse mutants carrying defects in e.g. transcription-coupled repair with or without an additional impairment of global genome nucleotide excision repair and the corresponding segmental premature aging syndromes in man. A striking correlation between the degree of the DNA repair deficiency and the acceleration of specific progeroid symptoms has been discovered for those repair systems that primarily protect from the cytotoxic and cytostatic effects of DNA damage. These observations are explained from the perspective of nucleotide excision repair mouse mutant and human syndromes. However, similar principles likely apply to other DNA repair pathways including interstrand crosslink repair and double strand break repair and genome maintenance systems in general, supporting the notion that DNA damage constitutes an important intermediate in the process of aging. PMID:21680258

Tangeretin inhibits high glucose-induced extracellular matrix accumulation in human glomerular mesangial cells.

PubMed

Chen, Fang; Ma, Yali; Sun, Zhiqiang; Zhu, Xiaoguang

2018-06-01

Tangeretin (5, 6, 7, 8, 4'-pentamethoxyflavone), a natural compound extracted from citrus plants, has been shown to possess a variety of pharmacological activities, including anti-oxidant, anti-tumor, cytostatic and anti-diabetic properties. However, the role of tangeretin in diabetic nephropathy (DN) has not yet been investigated. This study was undertaken to elucidate the effects of tangeretin on high glucose (HG)-induced oxidative stress and extracellular matrix (ECM) accumulation in human glomerular mesangial cells (MCs) and explore the underlying mechanisms. Our results showed that tangeretin significantly inhibited HG-induced the proliferation of MCs. In addition, tangeretin dramatically reduced the levels of reactive oxygen species (ROS) and malondialdhyde (MDA), and induced SOD activity, as well as inhibited the expression of fibronectin (FN) and collagen IV in HG-stimulated MCs. Furthermore, tangeretin efficiently prevented the activation of ERK signaling pathway in HG-stimulated MCs. Taken together, these data indicated that tangeretin inhibits HG-induced cell proliferation, oxidative stress and ECM expression in glomerular MCs, at least in part, through the inactivation of ERK signaling pathway. Therefore, tangeretin may be a potential agent in the treatment of DN. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Photothermal monitoring of interaction of carcinoma cells with cytostatic drugs in vitro

NASA Astrophysics Data System (ADS)

Lapotko, Dmitri; Hanna, Ehab; Cannon, Martin

2003-06-01

Background/problem. Monitoring of tumor response to cancer chemotherapy and dose optimization for specific patients are the key factors for successful application of anti-tumor drugs. Using patient's tumor cells for preliminary in vitro drug screening may allow optimal selection of drug type and dose. Method. Single cell state was studied with photothermal microscope. Carcinoma cells were irradiated at 427 nm with 8 ns laser pulse with energy 30 - 40 μJ. Cell photothermal (PT) response amplitude and shape from each cell were analyzed and amount of cells that produced specific PT response was used as PT parameter. Parallel experiment included cell viability control. Results were obtained for two cytotoxic chemotherapy agents -- Platinol-aq and Adrucil. Incubation of cell suspensions for 90 min at 20 and 37°C caused changes in cell PT parameters. Reaction of carcinoma cells to the drug was very similar to reaction of hepatocytes to respiratory chain inhibition and reaction of RBC to osmotic pressure decrease. PT effect was found to be dose-dependent. PT method allows detecting drug-induced changes before cell death or morphological changes and therefore can be fast and sensitive modality for control of chemotherapy.

A high-content image-based method for quantitatively studying context-dependent cell population dynamics

PubMed Central

Garvey, Colleen M.; Spiller, Erin; Lindsay, Danika; Chiang, Chun-Te; Choi, Nathan C.; Agus, David B.; Mallick, Parag; Foo, Jasmine; Mumenthaler, Shannon M.

2016-01-01

Tumor progression results from a complex interplay between cellular heterogeneity, treatment response, microenvironment and heterocellular interactions. Existing approaches to characterize this interplay suffer from an inability to distinguish between multiple cell types, often lack environmental context, and are unable to perform multiplex phenotypic profiling of cell populations. Here we present a high-throughput platform for characterizing, with single-cell resolution, the dynamic phenotypic responses (i.e. morphology changes, proliferation, apoptosis) of heterogeneous cell populations both during standard growth and in response to multiple, co-occurring selective pressures. The speed of this platform enables a thorough investigation of the impacts of diverse selective pressures including genetic alterations, therapeutic interventions, heterocellular components and microenvironmental factors. The platform has been applied to both 2D and 3D culture systems and readily distinguishes between (1) cytotoxic versus cytostatic cellular responses; and (2) changes in morphological features over time and in response to perturbation. These important features can directly influence tumor evolution and clinical outcome. Our image-based approach provides a deeper insight into the cellular dynamics and heterogeneity of tumors (or other complex systems), with reduced reagents and time, offering advantages over traditional biological assays. PMID:27452732

Bimodal regulation of p21waf1 protein as function of DNA damage levels

PubMed Central

Buscemi, G; Ricci, C; Zannini, L; Fontanella, E; Plevani, P; Delia, D

2014-01-01

Human p21Waf1 protein is well known for being transcriptionally induced by p53 and activating the cell cycle checkpoint arrest in response to DNA breaks. Here we report that p21Waf1 protein undergoes a bimodal regulation, being upregulated in response to low doses of DNA damage but rapidly and transiently degraded in response to high doses of DNA lesions. Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21Waf1 on T145 and S146 residues and induces its proteasome-dependent proteolysis. The initial p21Waf1 degradation is then counteracted by the ATM-Chk2 pathway, which promotes the p53-dependent accumulation of p21Waf1 at any dose of damage. We also found that p21Waf1 ablation favors the activation of an apoptotic program to eliminate otherwise irreparable cells. These findings support a model in which in human cells a balance between ATM-Chk2-p53 and the ATR-Chk1 pathways modulates p21Waf1 protein levels in relation to cytostatic and cytotoxic doses of DNA damage. PMID:25486478

Evaluation of genotoxic potential of avarol, avarone, and its methoxy and methylamino derivatives in prokaryotic and eukaryotic test models.

PubMed

Kolarević, Stoimir; Milovanović, Dragana; Kračun-Kolarević, Margareta; Kostić, Jovana; Sunjog, Karolina; Martinović, Rajko; Đorđević, Jelena; Novaković, Irena; Sladić, Dušan; Vuković-Gačić, Branka

2018-01-04

In this study, mutagenic and genotoxic potential of anti-tumor compounds avarol, avarone, and its derivatives 3'-methoxyavarone, 4'-(methylamino)avarone and 3'-(methylamino)avarone was evaluated and compared to cytostatics commonly used in chemotherapy (5-fluorouracil, etoposid, and cisplatin). Mutagenic potential of selected hydroquinone and quinones was assessed in prokaryotic model by the SOS/umuC assay in Salmonella typhimurium TA1535/pSK1002. Genotoxic potential was also assessed in eukaryotic models using comet assay in human fetal lung cell line (MRC-5), human adenocarcinoma epithelial cell line (A549), and in human peripheral blood cells (HPBC). The results indicated that avarol and avarone do not exert mutagenic/genotoxic potential. Among the studied avarone derivatives, mutagenic potential was detected by SOS/umuC test for 3'-(methylamino)avarone, but only after metabolic activation. The results of comet assay indicated that 3'-methoxyavarone and 3'-(methylamino)avarone have a significant impact on the level of DNA damage in the MRC-5 cell line. Genotoxic potential was not observed in A549 cells or HPBC probably due to a different uptake rate for the compounds and lower in metabolism rate within these cells.

Related factors with extravasation of non-cytostatic agents in peripheral vein catheters.

PubMed

Fernández-García, Cristina; Mata-Peón, Esther; Avanzas-Fernández, Sara

To know the independent variables related to the occurrence of extravasation in patients with peripheral vein catheters (PVC). Retrospective study carried out in 6 longitudinal cuts between July 2013 an January 2014. A total of 1,442 PVC were reviewed, of which 730 met the inclusion criteria, and were divided into 2 groups: extravasation and not extravasation, with 365 cases each. The variables of age, gender, admission unit, catheter gauge, insertion site, previous insertion into the same limb, hospital unit where the insertion took place, communication difficulties, personal health history and analyzed parenterally drug administered were considered. Risk factors to develop extravasation were: female gender, with previous insertion in the same limb, <72h PVC of insertion, communication difficulties, personal health history of neoplasia and KCl, gentamicin or beta lactam treatment. Our study allows to know the variables that are related to the emergence of extravasations in patients with non-cancer treatments (gender, medical service of admission, catheter gauge, elapsed time since the insertion, patient communication difficulties, personal health history, and intravenous treatments), as well as the factors that may be considered protective. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Anticancer potential of benzothiazolic derivative (E)-2-((2-(benzo[d]thiazol-2-yl)hydrazono)methyl)-4-nitrophenol against melanoma cells.

PubMed

Vasconcelos, Zanair Soares; Ralph, Ana Carolina Lima; Calcagno, Danielle Queiroz; Dos Santos Barbosa, Gleyce; do Nascimento Pedrosa, Tatiana; Antony, Lucas Pio; de Arruda Cardoso Smith, Marília; de Lucas Chazin, Eliza; Vasconcelos, Thatyana Rocha Alves; Montenegro, Raquel Carvalho; de Vasconcellos, Marne Carvalho

2018-08-01

Malignant melanoma is an important type of cancer worldwide due to its aggressiveness and poor survival rate. Significant efforts to understand the biology of melanoma and approaches to treat the advanced disease are focused on targeted gene inhibitors. Frequently mutated genes, such as NRAS, B-RAF and TP53, significantly exceed the frequency of mutations of other genes, emphasizing their importance for future targeted therapies. Considering the antitumor activity of benzothiazolic derivatives, this study aimed to demonstrate the action of benzothiazolic (E)-2-((2-(benzo[d]thiazol-2-yl)hydrazono)methyl)-4-nitrophenol (AFN01) against three established human melanoma cell lines that recapitulate the molecular landscape of the disease in terms of its genetic alterations and mutations, such as the TP53, NRAS and B-RAF genes. The results presented here indicate that AFN01, as a significant cytostatic and cytotoxic drug due to its induction of DNA fragmentation, causes single and double DNA strand breaks, consequently inhibiting cell proliferation, migration and invasion by promoting apoptosis. Our data suggest that AFN01 might be considered as a future therapeutic option for managing melanoma. Copyright © 2018 Elsevier Ltd. All rights reserved.

New estradiol-linked nitrosoureas: can the pharmacokinetic properties help to explain the pharmacodynamic activities?

PubMed

Betsch, B; Berger, M R; Spiegelhalder, B; Eisenbrand, G; Schmähl, D

1989-01-01

The pharmacokinetics of 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) a new estradiol-linked anticancer drug and the unlinked DNA-crosslinking agent 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine (CNC-alanine) have been studied in methylnitrosourea-induced female Sprague-Dawley rats after equimolar intravenous and oral administration. In comparison with the unlinked single agent, the CNC-alanine-estradiol-17-ester showed a 3-fold longer halflife in plasma and a three times larger volume of distribution. The distribution after intravenous administration was nearly three times faster. The absorption after peroral administration was likewise two times faster. The bioavailability of the estradiol-linked drug was determined to be 52%. After application of CNC-alanine-estradiol-17-ester the cytostatic metabolite CNC-alanine was found, indicating the cleavage of the ester bond. CNC-alanine generated from CNC-alanine-estradiol-17-ester showed a 50% longer halflife than when applied directly. The results indicate that linking 2-chloroethyl-nitrosoureas to estradiol can result in new anticancer agents with modified properties in comparison to the unlinked single agent. The higher antineoplastic activity of the hormone-linked drug can mainly be attributed to differences in the pharmacokinetic behaviour.

Effects of Corynebacterium parvum treatment and Toxoplasma gondii infection on macrophage-mediated cytostasis of tumour target cells.

PubMed Central

Krahenbuhl, J L; Lambert, L H; Remington, J S

1976-01-01

Injection of mice with Corynebacterium parvum or living or killed Toxoplasma gondii was studied to determine the efficacy of these treatments in activating peritoneal macrophages to inhibit the uptake of [3H]TdR (cytostasis) by tumour target cells in vitro. In the presence of activated macrophages from mice treated i.p. with a wide dose range of either C. parvum or living Toxoplasma, cytostasis was usually greater than 99%. This population of activated macrophages was transient in C. parvum-treated mice, but persists, probably for life, in Toxoplasma-infected mice. Whereas the i.p. route of administration of C. parvum was more efficient in activating macrophages than the i.v. route, the s.c. route appeared to be relatively ineffective. Treatment with killed Toxoplasma by any route was also relatively ineffective in activating macrophages. In contrast Toxoplasma infection resulted in highly activated peritoneal macrophages, regardless of the route of administration. Depending upon the route of initial treatment, the route of readministration of C. parvum had either no appreciable effect or resulted in a marked alteration in the cytostatic capacity of peritoneal macrophages. PMID:992714

The short and long term effects of docetaxel chemotherapy on rodent object recognition and spatial reference memory.

PubMed

Fardell, Joanna E; Vardy, Janette; Johnston, Ian N

2013-10-17

Previous animal studies have examined the potential for cytostatic drugs to induce learning and memory deficits in laboratory animals but, to date, there is no pre-clinical evidence that taxanes have the potential to cause cognitive impairment. Therefore our aim was to explore the short- and long-term cognitive effects of different dosing schedules of the taxane docetaxel (DTX) on laboratory rodents. Healthy male hooded Wistar rats were treated with DTX (6 mg/kg, 10mg/kg) or physiological saline (control), once a week for 3 weeks (Experiment 1) or once only (10mg/kg; Experiment 2). Cognitive function was assessed using the novel object recognition (NOR) task and spatial water maze (WM) task 1 to 3 weeks after treatment and again 4 months after treatment. Shortly after DTX treatment, rats perform poorly on NOR regardless of treatment regimen. Treatment with a single injection of 10mg/kg DTX does not appear to induce sustained deficits in object recognition or peripheral neuropathy. Overall these findings show that treatment with the taxane DTX in the absence of cancer and other anti-cancer treatments causes cognitive impairment in healthy rodents. Copyright © 2013 Elsevier Inc. All rights reserved.

New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells

PubMed Central

Lennig, Petra; Zhang, Yixin; Schroeder, Michael

2016-01-01

Drug resistance is an important open problem in cancer treatment. In recent years, the heat shock protein HSP27 (HSPB1) was identified as a key player driving resistance development. HSP27 is overexpressed in many cancer types and influences cellular processes such as apoptosis, DNA repair, recombination, and formation of metastases. As a result cancer cells are able to suppress apoptosis and develop resistance to cytostatic drugs. To identify HSP27 inhibitors we follow a novel computational drug repositioning approach. We exploit a similarity between a predicted HSP27 binding site to a viral thymidine kinase to generate lead inhibitors for HSP27. Six of these leads were verified experimentally. They bind HSP27 and down-regulate its chaperone activity. Most importantly, all six compounds inhibit development of drug resistance in cellular assays. One of the leads – chlorpromazine – is an antipsychotic, which has a positive effect on survival time in human breast cancer. In summary, we make two important contributions: First, we put forward six novel leads, which inhibit HSP27 and tackle drug resistance. Second, we demonstrate the power of computational drug repositioning. PMID:27626687

A high-content image-based method for quantitatively studying context-dependent cell population dynamics

NASA Astrophysics Data System (ADS)

Garvey, Colleen M.; Spiller, Erin; Lindsay, Danika; Chiang, Chun-Te; Choi, Nathan C.; Agus, David B.; Mallick, Parag; Foo, Jasmine; Mumenthaler, Shannon M.

2016-07-01

Tumor progression results from a complex interplay between cellular heterogeneity, treatment response, microenvironment and heterocellular interactions. Existing approaches to characterize this interplay suffer from an inability to distinguish between multiple cell types, often lack environmental context, and are unable to perform multiplex phenotypic profiling of cell populations. Here we present a high-throughput platform for characterizing, with single-cell resolution, the dynamic phenotypic responses (i.e. morphology changes, proliferation, apoptosis) of heterogeneous cell populations both during standard growth and in response to multiple, co-occurring selective pressures. The speed of this platform enables a thorough investigation of the impacts of diverse selective pressures including genetic alterations, therapeutic interventions, heterocellular components and microenvironmental factors. The platform has been applied to both 2D and 3D culture systems and readily distinguishes between (1) cytotoxic versus cytostatic cellular responses; and (2) changes in morphological features over time and in response to perturbation. These important features can directly influence tumor evolution and clinical outcome. Our image-based approach provides a deeper insight into the cellular dynamics and heterogeneity of tumors (or other complex systems), with reduced reagents and time, offering advantages over traditional biological assays.

Hormesis does not make sense except in the light of TOR-driven aging

PubMed Central

Blagosklonny, Mikhail V.

2011-01-01

Weak stresses (including weak oxidative stress, cytostatic agents, heat shock, hypoxia, calorie restriction) may extend lifespan. Known as hormesis, this is the most controversial notion in gerontology. For one, it is believed that aging is caused by accumulation of molecular damage. If so, hormetic stresses (by causing damage) must shorten lifespan. To solve the paradox, it was suggested that, by activating repair, hormetic stresses eventually decrease damage. Similarly, Baron Munchausen escaped from a swamp by pulling himself up by his own hair. Instead, I discuss that aging is not caused by accumulation of molecular damage. Although molecular damage accumulates, organisms do not live long enough to age from this accumulation. Instead, aging is driven by overactivated signal-transduction pathways including the TOR (Target of Rapamycin) pathway. A diverse group of hormetic conditions can be divided into two groups. “Hormesis A” inhibits the TOR pathway. “Hormesis B” increases aging-tolerance, defined as the ability to survive catastrophic complications of aging. Hormesis A includes calorie restriction, resveratrol, rapamycin, p53-inducing agents and, in part, physical exercise, heat shock and hypoxia. Hormesis B includes ischemic preconditioning and, in part, physical exercise, heat shock, hypoxia and medical interventions. PMID:22166724

In vitro exposure to 0.57-MHz electric currents exerts cytostatic effects in HepG2 human hepatocarcinoma cells.

PubMed

Hernández-Bule, María Luisa; Trillo, María Angeles; Cid, María Antonia; Leal, Jocelyne; Ubeda, Alejandro

2007-03-01

Capacitive-resistive electric transfer (CRET) therapy is a non-invasive technique currently applied to the treatment of skin, muscle and tendon injuries that uses 0.45-0.6 MHz electric currents to transdermically and focally increase the internal temperature of targeted tissues. Because CRET electrothermal treatment has been reported to be more effective than other thermal therapies, it has been proposed that the electric stimulus could induce responses in exposed tissues that are cooperative or synergic with the thermal effects of the treatment. Previous studies by our group, investigating the nature of the alleged electric response, have shown that short, repeated stimuli with 0.57-MHz currents at subthermal levels could provoke partial, cytotoxic effects on human neuroblastoma cells in vitro. The aim of the present study was to investigate the response from another human cell type, the human hepatocarcinoma HepG2 line, during and after the exposure to 0.57-MHz CRET currents at subthermal densities. The electric stimuli provoked a decrease in the proliferation rate of the cultures, possibly due to an electrically-induced blocking of the cell cycle in a fraction of the cellular population.

Evaluation of the “Steal” Phenomenon on the Efficacy of Hypoxia Activated Prodrug TH-302 in Pancreatic Cancer

PubMed Central

Ibrahim-Hashim, Arig; Wojtkowiak, Jonathan W.; Hart, Charles P.; Zhang, Xiaomeng; Leos, Rafael; Martinez, Gary V.; Baker, Amanda F.; Gillies, Robert J.

2014-01-01

Pancreatic ductal adenocarcinomas are desmoplastic and hypoxic, both of which are associated with poor prognosis. Hypoxia-activated prodrugs (HAPs) are specifically activated in hypoxic environments to release cytotoxic or cytostatic effectors. TH-302 is a HAP that is currently being evaluated in a Phase III clinical trial in pancreatic cancer. Using animal models, we show that tumor hypoxia can be exacerbated using a vasodilator, hydralazine, improving TH-302 efficacy. Hydralazine reduces tumor blood flow through the “steal” phenomenon, in which atonal immature tumor vasculature fails to dilate in coordination with normal vasculature. We show that MIA PaCa-2 tumors exhibit a “steal” effect in response to hydralazine, resulting in decreased tumor blood flow and subsequent tumor pH reduction. The effect is not observed in SU.86.86 tumors with mature tumor vasculature, as measured by CD31 and smooth muscle actin (SMA) immunohistochemistry staining. Combination therapy of hydralazine and TH-302 resulted in a reduction in MIA PaCa-2 tumor volume growth after 18 days of treatment. These studies support a combination mechanism of action for TH-302 with a vasodilator that transiently increases tumor hypoxia. PMID:25532146

A study of the effects of citrate-coated silver nanoparticles on RAW 264.7 cells using a toolbox of cytotoxic endpoints

NASA Astrophysics Data System (ADS)

Bastos, V.; Duarte, I. F.; Santos, C.; Oliveira, H.

2017-05-01

Citrate-coated silver nanoparticles (citrate-AgNPs) are among the most commonly used nanomaterials, widely present in industrial and biomedical products. In this study, the cytotoxicity of 30-nm citrate-AgNPs on the macrophage cell line RAW 264.7 was evaluated, using a battery of cytotoxicity endpoints (viability, oxidative stress, and cytostaticity/clastogenicity), at 24 and 48 h of exposure. Citrate-AgNPs decreased cell proliferation and viability only at 75 μg/mL, suggesting a low sensitivity of RAW cells to lower doses of these AgNPs. After 24 h of exposure, ROS content decreased in cells exposed to 60 μg/mL AgNPs (IC20 value), corroborating the high tolerance of these cells to citrate-AgNPs. However, these cells suffered an impairment of the cell cycle, shown by an increase at the sub-G1 phase. This increase of the sub-G1 population was correlated with an increase of DNA fragmentation, suggesting an increase of apoptosis. Thus, our data are important to understand the effects of low concentrations (IC20) of citrate-AgNPs on in vitro vital macrophage functions.

Synthesis and evaluation of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.

PubMed

Zaware, Nilesh; Kisliuk, Roy; Bastian, Anja; Ihnat, Michael A; Gangjee, Aleem

2017-04-01

In an effort to optimize the structural requirements for combined cytostatic and cytotoxic effects in single agents, a series of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines 3-7 were synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs) as well as thymidylate synthase (TS). The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-bromo/5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate aryl thiols. A novel four step synthetic scheme to the common intermediate was developed which is more efficient relative to the previously reported six-step sequence. Biological evaluation of these compounds indicated dual activity in RTKs and human TS (hTS). In the VEGFR-2 assay, compound 5 was equipotent to the standard compound semaxanib and was better than standard TS inhibitor pemetrexed, in the hTS assay. Compounds 3, 6 and 7 were nanomolar inhibitors of hTS and were several fold better than pemetrexed. Copyright © 2017 Elsevier Ltd. All rights reserved.

New Tirucallane-Type Triterpenoids from Guarea guidonia.

PubMed

Hernandez, Vanessa; De Leo, Marinella; Cotugno, Roberta; Braca, Alessandra; De Tommasi, Nunziatina; Severino, Lorella

2018-01-16

The aerial parts of Guarea guidonia afforded three new tirucallane-type triterpenoids: 3,4- seco -tirucalla-4(28),8(9),24(25)-trien-7α,11α-dihydroxy-21,23-epoxy-3,11-olide, named guareolide (1: ), 3,4- seco -tirucalla-4(28),7(8),24(25)-trien-21-hydroxy-21,23-epoxy-3-oic acid, named guareoic acid A (2: ), and 3,4- seco -tirucalla-4(28),7(8),24(25)-trien-21,23-epoxy-3-oic acid, named guareoic acid B (3: ), of which 1: possessed an unusual seven-membered lactone ring. Seven known terpenes were also isolated and characterized as flindissone, 7-acetyldihydronomilin, picroquassin E, boscartol C, and cneorubins A, B, and X. Their structures were determined by spectroscopic methods including one-dimensional and two-dimensional nuclear magnetic resonance analysis and high-resolution mass spectrometry. The isolates were investigated for their potential cytotoxic activity on Jurkat, HeLa, and MCF7 cancer cell lines. Flindissone and compound 2: showed an antiproliferative activity in all cell lines. Further studies revealed that flindissone, the most active compound, induced in Jurkat and HeLa cells both cytostatic and cytotoxic responses. Georg Thieme Verlag KG Stuttgart · New York.

Agmatine: at the crossroads of the arginine pathways.

PubMed

Satriano, Joseph

2003-12-01

In acute inflammatory responses, such as wound healing and glomerulonephritis, arginine is the precursor for production of the cytostatic molecule nitric oxide (NO) and the pro-proliferative polyamines. NO is an early phase response whereas increased generation of polyamines is requisite for the later, repair phase response. The temporal switch of arginine as a substrate for the inducible nitric oxide synthase (iNOS)/NO axis to arginase/ornithine decarboxylase (ODC)/polyamine axis is subject to regulation by inflammatory cytokines as well as interregulation by the arginine metabolites themselves. Herein we describe the capacity of another arginine pathway, the metabolism of arginine to agmatine by arginine decarboxylase (ADC), to aid in this interregulation. Agmatine is an antiproliferative molecule due to its suppressive effects on intracellular polyamine levels, whereas the aldehyde metabolite of agmatine is a potent inhibitor of iNOS. We propose that the catabolism of agmatine to its aldehyde metabolite may act as a gating mechanism at the transition from the iNOS/NO axis to the arginase/ODC/polyamine axis. Thus, agmatine has the potential to serve in the coordination of the early and repair phase pathways of arginine in inflammation.

Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells.

PubMed

Proietti, Sara; Cucina, Alessandra; D'Anselmi, Fabrizio; Dinicola, Simona; Pasqualato, Alessia; Lisi, Elisabetta; Bizzarri, Mariano

2011-03-01

Melatonin and vitamin D3 inhibit breast cancer cell growth and induce apoptosis, but they have never been combined as a breast cancer treatment. Therefore, we investigated whether their association could lead to an enhanced anticancer activity. In MCF-7 breast cancer cells, melatonin together with vitamin D3, induced a synergistic proliferative inhibition, with an almost complete cell growth arrest at 144 hr. Cell growth blockade is associated to an activation of the TGFβ-1 pathway, leading to increased TGFβ-1, Smad4 and phosphorylated-Smad3 levels. Concomitantly, melatonin and D3, alone or in combination, caused a significant reduction in Akt phosphorylation and MDM2 values, with a consequent increase of p53/MDM2 ratio. These effects were completely suppressed by adding a monoclonal anti-TGFβ-1 antibody to the culture medium. Taken together, these results indicate that cytostatic effects triggered by melatonin and D3 are likely related to a complex TGFβ-1-dependent mechanism, involving down-regulation of both MDM2 and Akt-phosphorylation. © 2010 The Authors. Journal of Pineal Research © 2010 John Wiley & Sons A/S.

Protein Profiling Identifies mTOR Pathway Modulation and Cytostatic Effects of Pim Kinase Inhibitor, AZD1208, in Acute Myeloid Leukemia

PubMed Central

Chen, Lisa S.; Yang, Ji-Yeon; Liang, Han; Cortes, Jorge E.; Gandhi, Varsha

2017-01-01

Pim kinases phosphorylate and regulate a number of key AML cell survival proteins, and Pim inhibitors have recently entered clinical trial for hematological malignancies. AZD1208 is a small molecule pan-Pim kinase inhibitor and AZD1208 treatment resulted in growth inhibition and cell size reduction in AML cell lines including FLT3-WT (OCI-AML-3, KG-1a, MOLM-16) and FLT3-ITD mutated (MOLM-13, MV-4-11). There was limited apoptosis induction (<10% increase) in the AML cell lines evaluated with up to 3 μM AZD1208 for 24h, suggesting that growth inhibition is not through apoptosis induction. Using reverse phase protein array (RPPA) and immunoblot analysis, we identified that AZD1208 resulted in suppression of mTOR signaling, including inhibition of protein phosphorylation of mTOR(Ser2448), p70S6K(Thr389), S6(Ser235/236) and 4E-BP1(Ser65). Consistent with mTOR inhibition, there was also a reduction in protein synthesis that correlated with cell size reduction and growth inhibition with AZD1208; our study provide insights into the mechanism of AZD1208. PMID:27054578

Antimicrobial and Antiproliferative Potential of Anadenanthera colubrina (Vell.) Brenan

PubMed Central

Lima, Rennaly de Freitas; Alves, Érika Ponchet; Rosalen, Pedro Luiz; Ruiz, Ana Lúcia Tasca Gois; Teixeira Duarte, Marta Cristina; Góes, Vivian Fernandes Furletti; de Medeiros, Ana Cláudia Dantas; Pereira, Jozinete Vieira; Godoy, Gustavo Pina; Melo de Brito Costa, Edja Maria

2014-01-01

The aim of the present study was to perform an in vitro analysis of the antimicrobial and antiproliferative potential of an extract from Anadenanthera colubrina (Vell.) Brenan (angico) and chemically characterize the crude extract. Antimicrobial action was evaluated based on the minimum inhibitory concentration (MIC), minimum bactericidal/fungicidal concentration, and the inhibition of formation to oral biofilm. Cell morphology was determined through scanning electron microscopy (SEM). Six strains of tumor cells were used for the determination of antiproliferative potential. The extract demonstrated strong antifungal activity against Candida albicans ATCC 18804 (MIC = 0.031 mg/mL), with similar activity found regarding the ethyl acetate fraction. The extract and active fraction also demonstrated the capacity to inhibit the formation of Candida albicans to oral biofilm after 48 hours, with median values equal to or greater than the control group, but the difference did not achieve statistical significance (P > 0.05). SEM revealed alterations in the cell morphology of the yeast. Regarding antiproliferative activity, the extract demonstrated cytostatic potential in all strains tested. The present findings suggest strong antifungal potential for Anadenanthera colubrina (Vell.) Brenan as well as a tendency toward diminishing the growth of human tumor cells. PMID:25093029

Affecting of aquatic vascular plant Lemna minor by cisplatin revealed by voltammetry.

PubMed

Supalkova, Veronika; Beklova, Miroslava; Baloun, Jiri; Singer, Christoph; Sures, Bernd; Adam, Vojtech; Huska, Dalibor; Pikula, Jiri; Rauscherova, Libuse; Havel, Ladislav; Zehnalek, Josef; Kizek, Rene

2008-02-01

Within the context of application of platinum derivates based effective cytostatics, we can suppose that these risk metals can get into aquatic ecosystems where they can show biologic availability for food chain. In the present work we report on investigation of affecting of duckweed (Lemna minor) by various doses of cisplatin (0, 5, 10, 20, 40, 80 and 160 microM) for 4 days. The toxic influence of cisplatin was evaluated on the basis of growth inhibition expressed as number of leaves, growth rate, and total amount of biomass. The result value of 96hEC50, calculated from growth inhibition with comparison of growth rates, was 6.93 microM. Moreover we aimed on determination of cisplatin content using differential pulse voltammetry. The highest content of cisplatin (320 ng g(-1) of fresh weight) was determined in plants treated by 80 microM at the second day of treatment. Plants protect themselves against heavy metals by means of synthesis of cysteine-rich peptides such as glutathione and phytochelatins. Thus thiol determination in the treated plants by means of Brdicka reaction followed. The marked increase in thiol concentration detected is associated with defence reaction of the plant against stress caused by cisplatin.

Lack of genotoxicity in medical oncology nurses handling antineoplastic drugs: effect of work environment and protective equipment.

PubMed

Gulten, Tuna; Evke, Elif; Ercan, Ilker; Evrensel, Turkkan; Kurt, Ender; Manavoglu, Osman

2011-01-01

In this study we aimed to investigate the genotoxic effects of antineoplastic agents in occupationally exposed oncology nurses. Genotoxic effects mean the disruptive effects in the integrity of DNA and they are associated with cancer development. Biomonitoring of health care workers handling antineoplastic agents is helpful for the evaluation of exposure to cytostatics. The study included an exposed and two control groups. The exposed group (n=9) was comprised of oncology nurses. The first (n=9) and second (n=10) control groups were comprised of subjects who did not come into contact with antineoplastic drugs working respectively in the same department with oncology nurses and in different departments. Genotoxicity evaluation was performed using SCE analysis. After applying culture, harvest and chromosome staining procedures, a total of 25 metaphases were analyzed per person. Kruskal Wallis test was used to perform statistical analysis. A statistically significant difference of sister chromatid exchange frequencies was not observed between the exposed and control groups. Lack of genotoxicity in medical oncology nurses might be due to good working conditions with high standards of technical equipment and improved personal protection.

Carbon materials as new nanovehicles in hot-melt drug deposition

NASA Astrophysics Data System (ADS)

Bielicka, Agnieszka; Wiśniewski, Marek; Terzyk, Artur P.; Gauden, Piotr A.; Furmaniak, Sylwester; Roszek, Katarzyna; Kowalczyk, Piotr; Bieniek, A.

2013-09-01

The application of commercially available carbon materials (nanotubes and porous carbons) for the preparation of drug delivery systems is studied. We used two types of carbon nanotubes (CNT) and two activated carbons as potential materials in so-called hot-melt drug deposition (HMDD). The materials were first studied using Raman spectroscopy. Paracetamol was chosen as a model drug. The performed thermal analysis, kinetics, and adsorption-desorption studies revealed that nanoaggregates are formed between carbon nanotubes. In contrast, in pores of activated carbon we do not observe this process and the drug adsorption phenomenon mechanism is simply the filling of small pores. The formation of nanoaggregates was confirmed by the results of GCMC (grand canonical Monte Carlo) simulations and the study of the surface area on nitrogen adsorption-desorption isotherms. The application of carbon nanotubes in HMDD offers the possibility of controlling the rate of drug delivery. Performed MTT tests of nanotubes and drug-loaded nanotubes show that the observed decrease in cell viability number is caused by the influence of the cytostatic properties of nanotubes—they inhibit the proliferation of cells. The carbon nanotubes studied in this paper are essentially nontoxic.

Molecular evolution of Theta-class glutathione transferase for enhanced activity with the anticancer drug 1,3-bis-(2-chloroethyl)-1-nitrosourea and other alkylating agents.

PubMed

Larsson, Anna-Karin; Shokeer, Abeer; Mannervik, Bengt

2010-05-01

Glutathione transferase (GST) displaying enhanced activity with the cytostatic drug 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) and structurally related alkylating agents was obtained by molecular evolution. Mutant libraries created by recursive recombination of cDNA coding for human and rodent Theta-class GSTs were heterologously expressed in Escherichia coli and screened with the surrogate substrate 4-nitrophenethyl bromide (NPB) for enhanced alkyltransferase activity. A mutant with a 70-fold increased catalytic efficiency with NPB, compared to human GST T1-1, was isolated. The efficiency in degrading BCNU had improved 170-fold, significantly more than with the model substrate NPB. The enhanced catalytic activity of the mutant GST was also 2-fold higher with BCNU than wild-type mouse GST T1-1, which is 80-fold more efficient than wild-type human GST T1-1. We propose that GSTs catalyzing inactivation of anticancer drugs may find clinical use in protecting sensitive normal tissues to toxic side-effects in treated patients, and as selectable markers in gene therapy. Copyright 2010 Elsevier Inc. All rights reserved.

Redox mechanism of levobupivacaine cytostatic effect on human prostate cancer cells.

PubMed

Jose, Caroline; Hebert-Chatelain, Etienne; Dias Amoedo, Nivea; Roche, Emmanuel; Obre, Emilie; Lacombe, Didier; Rezvani, Hamid Reza; Pourquier, Philippe; Nouette-Gaulain, Karine; Rossignol, Rodrigue

2018-05-31

Anti-cancer effects of local anesthetics have been reported but the mode of action remains elusive. Here, we examined the bioenergetic and REDOX impact of levobupivacaine on human prostate cancer cells (DU145) and corresponding non-cancer primary human prostate cells (BHP). Levobupivacaine induced a combined inhibition of glycolysis and oxidative phosphorylation in cancer cells, resulting in a reduced cellular ATP production and consecutive bioenergetic crisis, along with reactive oxygen species generation. The dose-dependent inhibition of respiratory chain complex I activity by levobupivacaine explained the alteration of mitochondrial energy fluxes. Furthermore, the potency of levobupivacaine varied with glucose and oxygen availability as well as the cellular energy demand, in accordance with a bioenergetic anti-cancer mechanism. The levobupivacaine-induced bioenergetic crisis triggered cytostasis in prostate cancer cells as evidenced by a S-phase cell cycle arrest, without apoptosis induction. In DU145 cells, levobupivacaine also triggered the induction of autophagy and blockade of this process potentialized the anti-cancer effect of the local anesthetic. Therefore, our findings provide a better characterization of the REDOX mechanisms underpinning the anti-effect of levobupivacaine against human prostate cancer cells. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Effects of curcumin in pediatric epithelial liver tumors: inhibition of tumor growth and alpha-fetoprotein in vitro and in vivo involving the NFkappaB- and the beta-catenin pathways

PubMed Central

Bortel, Nicola; Armeanu-Ebinger, Sorin; Schmid, Evi; Kirchner, Bettina; Frank, Jan; Kocher, Alexa; Schiborr, Christina; Warmann, Steven; Fuchs, Jörg; Ellerkamp, Verena

2015-01-01

In children with hepatocellular carcinoma (pHCC) the 5-year overall survival rate is poor. Effects of cytostatic therapies such as cisplatin and doxorubicin are limited due to chemoresistance and tumor relapse. In adult HCC, several antitumor properties are described for the use of curcumin. Curcumin is one of the best-investigated phytochemicals in complementary oncology without relevant side effects. Its use is limited by low bioavailability. Little is known about the influence of curcumin on pediatric epithelial hepatic malignancies. We investigated the effects of curcumin in combination with cisplatin on two pediatric epithelial liver tumor cell lines. As mechanisms of action inhibition of NFkappaB, beta-catenin, and decrease of cyclin D were identified. Using a mouse xenograft model we could show a significant decrease of alpha-fetoprotein after combination therapy of oral micellar curcumin and cisplatin. Significant concentrations of curcuminoids were found in blood samples, organ lysates, and tumor tissue after oral micellar curcumin administration. Micellar curcumin in combination with cisplatin can be a promising strategy for treatment of pediatric HCC. PMID:26515460

The biotransformation of soil biocenosis by micromycetes under introduction of Fagus sylvatica L. to oak-hornbeam forest

NASA Astrophysics Data System (ADS)

Likhanov, Artur; Bilyera, Nataliya; Sedykh, Olena; Melnychuk, Maksym

2017-04-01

Keywords: micromycetes, beech, soil enzymes, illuminance, Penicillium canescens. European beech (Fagus sylvatica L.) is a commercially valuable tree species. As the potential distribution area for beech forest is restricted by Europe, planting of artificial stands is adopted in this region. Beech introduction can alter ecosystem considerably, but the mechanism of this transformation is not clear. We aimed to define abiotic and biotic parameters affecting floor development in beech stands introduced to the oak-hornbeam forest ecosystem ca.50 years ago in Eastern Europe (Ukraine). The daylight illuminace level was similar (2.9-6.5 klx) for both stands. However, grass cover in beech stands did not exceed 0.1-0.5 % even on sites with illuminace level 7.5-8.3 klx. It does not comply with the commonly used suggestion that shading is the main factor causes forest floor absence in the beech stands. We indicated predominantly biotic factors influencing forest floor formation. Thus, particular edaphon represented by micromycetes was able to inhibit plants and microorganisms. We isolated Penicillium canescens strains from soil under beech stands. These fungi utilized beech root exudates and phenol compounds of leaf litter, and produced biologically active substances caused cytostatic and mutagenic effects. They also accelerated (in 2-3.2 times) soil β-glucosidase activity, but had no effect on phosphatase. The biomass of fungi varied under cultivation of Penicillium canescens strains on Czapek medium with the addition of aqueous extracts of beech leaf litter. The biomass of micromycetes increased on 10-15 % at plant phenols concentrations up to 1 mg mL-1. On the contrary, increasing the concentration of phenols up to 4 mg mL-1resulted in a biomass decrease to 40%. The relationship between the concentration of plant phenols and rate of fungal biomass formation indicates that there is probably seasonal regulation of micromycetes activity in the forest biocenosis. The highest biological activity of soil fungi was observed in spring under the optimum phenol level for them. It was found experimentally that the cellulose addition to the Czapek medium at the amount of 100 mg L-1 leads to an increase in the synthesis of substances with a pronounced herbicidal action. Medium- and low polar fungi metabolites (curvularin, griseofulvin, polyacetylen) significantly inhibited root growth of test plants. They provided a cytostatic effect and caused numerous irregularities in cell division (formation of chromosome bridges and micronuclei). Thus, the introduction of Fagus sylvatica L. in Kyiv Polissya leads to the formation of unique environmental conditions in the forest soils. They contributed to the dominance of micromycetes (mainly genus Penicillium) in the soil. Soil fungi transformed leaf litter and inhibited the growth and development of plants of the lower tier by producing exudates. This led to a significant reduction in the biodiversity of the forest biocenosis.

Experimental results using 3-bromopyruvate in mesothelioma: in vitro and in vivo studies.

PubMed

Icard, Philippe; Philippe, Icard; Zhang, Xiao-Dong; Xiao-Dong, Zhang; Lemoisson, Edwige; Edwige, Lemoisson; Louis, Marie-Hélène; Marie-Hélène, Louis; Allouche, Stéphane; Stéphane, Allouche; Lincet, Hubert; Hubert, Lincet; Poulain, Laurent; Laurent, Poulain

2012-02-01

Over many years we have taken advantage of the special metabolism of cancer cells involving an increased consumption of glucose associated with lactic acid production even in the presence of oxygen, a phenomenon referred to as the "Warburg effect", to counteract cancer cell growth. We have tested 3-bromopyruvate (3-BrPA), an inhibitor of pyruvate-associated reactions. Firstly, we tested this agent, in vitro, in two mesothelioma cell lines. Cellular response would appear to depend on the mode of administration (immediately or 24 h after seeding). Depending on the line, 3-BrPA induced a cytostatic or cytotoxic effect. This effect was accompanied by cell death induction even in cells highly refractory to cisplatin. Mitochondrial apoptotic death appeared to involve both lines; however, a different death pathway such as necrosis cannot be excluded. Interestingly, 3-BrPA leads to a diminution of the expression of the anti-apotptoic protein Mcl-1. We then tested 3-BrPA in vivo. Survival of nude mice bearing human mesothelioma was significantly prolonged (p < 0.0001). Toxicity and clinical studies should be performed to test 3- BrPA as local therapy for patients suffering from pleural or peritoneal mesothelioma. Association with cisplatin should be particularly considered.

Peripheral arteriovenous fistula as vascular access for long-term chemotherapy.

PubMed

Kovalyov, Oleksiy O; Kostyuk, Oleksandr G; Tkachuk, Tetyana V

To provide long-term vascular access in clinical oncology peripheral forearm veins (up to 95% of patients in Ukraine), central venous access and "complete implanted vascular systems" are used most often. Many oncology patients have contraindications to catheterization of superior vena cava. Besides, exploitation of central veins is associated with potential technical and infectious complications. The aim - to study short-term and long-term results of arteriovenous fistula exploitation as vascular access for continuous anticancer therapy. Peripheral venous bed status in 41 oncology patients taking long-term chemotherapy treatment is analyzed in the article. Doppler sonography, morphologic and immune histochemical analyses were used in the study. Doppler sonography found qualitative and quantitative changes in forearm veins at different time periods after initiation of chemotherapy in the majority of patients. The major morphologic manifestations of venous wall damage were chemical phlebitis, local or extended hardening of venous wall, venous thrombosis and extravasations with necrosis and subsequent paravasal tissue sclerosis. Alternative vascular access created in 12 patients completely met the adequacy criteria (safety, multiple use, longevity, realization of the designed therapy program). The conclusion was made about inapplicability of forearm veins for long-term administration of cytostatic agents. If it is impossible to use central veins, arteriovenous fistula can become an alternative vascular access.

Temozolomide-induced increase of tumorigenicity can be diminished by targeting of mitochondria in in vitro models of patient individual glioblastoma

PubMed Central

Walther, Madlin; Schneider, Björn; Linnebacher, Michael; Classen, Carl Friedrich

2018-01-01

Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumor with a dismal prognosis. Development of resistance towards cytostatic drugs like the GBM standard drug temozolomide is a severe problem in GBM treatment. One potential source of GBM relapse could be so called cancer stem like cells (CSCs). These represent an undifferentiated subpopulation of cells with high potential for tumor initiation. Furthermore, it has been shown that differentiated GBM cells can regain CSC properties when exposed to continuous temozolomide treatment in vitro. In this study, treatment of several primary GBM cell lines with clinically relevant doses of temozolomide increased their tumorigenicity as determined by colony formation assays in soft agar. Increased tumorigenicity is a known property of CSCs. Hence, therapy options that specifically target CSCs are under investigation. CSCs appear to be particularly dependent on mitochondria biogenesis which may represent a useful target for CSC elimination. Toxicity towards mitochondria is a known side effect of several antibiotics. Thus, addition of antibiotics like doxycycline may represent a useful tool to inhibit CSCs in GBM. Here, we show that combining temozolomide treatment of primary GBM cells with doxycycline could counteract the increase of tumorigenicity induced by temozolomide treatment. PMID:29352318

Murine Macrophages Use Oxygen- and Nitric Oxide-Dependent Mechanisms To Synthesize S-Nitroso-Albumin and To Kill Extracellular Trypanosomes

PubMed Central

Gobert, Alain P.; Semballa, Silla; Daulouede, Sylvie; Lesthelle, Sophie; Taxile, Murielle; Veyret, Bernard; Vincendeau, Philippe

1998-01-01

Reactive nitrogen intermediates were synthesized spontaneously in cultures of macrophages from Trypanosoma brucei brucei-infected mice by an inducible nitric oxide (NO) synthase. This was inhibited by the addition of nitro-l-arginine. In this paper, we report the kinetics of the fixation of macrophage-derived NO on bovine serum albumin by using an enzyme-linked immunosorbent assay. S nitrosylation was confirmed by the Saville reaction, using mercuric chloride. It is known that reactive oxygen intermediates (ROI) are also synthesized by stimulated macrophages. The fact that NO is able to bind cysteine only under aerobic conditions led us to investigate the role of macrophage-derived ROI in the formation of S-nitrosylated proteins by activated macrophages. The immunoenzymatic signal decreased by 66 and 30% when superoxide dismutase and catalase, respectively, were added to the culture medium of macrophages from infected mice. In addition, the decrease in S-nitrosylated albumin formation correlated with the protection of extracellular trypanosomes from the cytostatic and cytotoxic activity of NO. Melatonin, a hydroxyl radical scavenger resulting from the decomposition of peroxynitrous acid, had no effect. All these data support the concept that an interaction between NO and ROI promoted the production of S-nitroso-albumin by activated macrophages from infected mice. PMID:9712749

A single-blind study of the efficacy and safety of intravenous granisetron compared with alizapride plus dexamethasone in the prophylaxis and control of emesis in patients receiving 5-day cytostatic therapy. The Granisetron Study Group.

PubMed

Bremer, K

1992-01-01

200 cancer patients who were due to receive fractionated chemotherapy (cisplatin greater than or equal to 15, ifosfamide greater than or equal to 1.2 or etoposide greater than or equal to 120, all mg/m2 per day) for 5 days, entered a multicentre study. Patients were randomised single-blind to receive either prophylactic intravenous granisetron (40 micrograms/kg) or alizapride (4 mg/kg followed by 4 mg/kg at 4 and 8 h post-treatment) plus dexamethasone 8 mg. Granistron was superior to the combination in preventing nausea and vomiting (54% vs. 43% complete responders). The differences were in the cisplatin-treated group. The time to first episode of moderate to severe nausea was significantly longer in the granisetron group (P = 0.03). Dosing with granisetron was more simple, with over 85% of patients requiring only a single prophylactic dose. Fewer patients receiving granisetron experienced adverse events (48% vs. 62%, P = 0.047). The frequency of constipation was, as expected, significantly higher in the granisetron group. Extrapyramidal effects, which were not noted by any granisetron patient, occurred in 5.3% of comparator patients.

Implementation of a pharmaceutical care programme for patients receiving new molecular-targeted agents in a clinical trial unit.

PubMed

Riu, G; Gaba, L; Victoria, I; Molas, G; do Pazo, F; Gómez, B; Creus, N; Vidal, L

2018-01-01

A pharmaceutical care programme was implemented at our hospital in early 2013. The main objectives were to analyse and describe the pharmaceutical interventions made, to calculate adherence, interventions and to evaluate patient satisfaction with the care programme. We performed a single-centre descriptive and prospective intervention in cancer patients who received oral chemotherapy as part of a clinical trial in 2013. Eighty-three patients were included. Median age was 58 years (range, 31-80) and 42 patients (50.6%) were men. We recorded 23 interventions, 13 of which were associated with drug interactions. The mean percentage of adherence was 98.9%. The interview with the pharmacist was considered to be very important by 84.6% of the respondents. A total of 92.3% said that they would like to speak to the pharmacist at subsequent visits. The doubts detected during the visits enable us to conclude that the information patients receive with respect to their study medication is usually incomplete. An integrated pharmaceutical care programme for cancer patients participating in clinical trials with oral cytostatic drugs was successful in terms of adherence and patient satisfaction and makes it possible to guarantee the safety and effectiveness of treatment on an individual basis. © 2016 John Wiley & Sons Ltd.

Hepcidin as a possible marker in determination of malignancy degree and sensitivity of breast cancer cells to cytostatic drugs.

PubMed

Yalovenko, T M; Todor, I M; Lukianova, N Y; Chekhun, V F

2016-06-01

To investigate the role of hepcidin (Hepc) in the formation of cells malignant phenotype in vitro and its expression in the dyna-mics of growth of Walker-256 carcinosarcoma with different sensitivity to doxorubicin (Dox). The cell lines used in the analysis included T47D, MCF-7, MDA-MB-231, MDA-MB-468, MCF/CP, and MCF/Dox. Hepc expression was studied by immunocytochemical method. "Free" iron content was determined by EPR spectroscopy. Determination of Hepc expression in homogenates of tumor tissue and in blood serum of rats with Dox-sensitive and -resistant Walker-256 carcinosarcoma was performed. It was found that Hepc levels in breast cancer (BC) cells with high degree of malignancy (MDA-MB-231, MDA-MB-468) and drug-resistant phenotype (MCF/CP, MCF/Dox) were by 1.5-2 times higher (p < 0.05) in comparison with sensitive and less malignant BC cells. The development of drug-resistant phenotype in Walker-256 carcinosarcoma cells was accompanied by increasing of Hepc and "free" iron content (by 2.4 and 1.2 times, respectively). The data of in vitro and in vivo research evidenced on involvement of Hepc in formation of BC cells malignant phenotype and their resistance to Dox.

RNase MC2: a new Momordica charantia ribonuclease that induces apoptosis in breast cancer cells associated with activation of MAPKs and induction of caspase pathways.

PubMed

Fang, Evandro Fei; Zhang, Chris Zhi Yi; Fong, Wing Ping; Ng, Tzi Bun

2012-04-01

Ribonucleases (RNases) are ubiquitously distributed nucleases that cleave RNA into smaller pieces. They are promising drugs for different cancers based on their concrete antitumor activities in vitro and in vivo. Here we report for the first time purification and characterization of a 14-kDa RNase, designated as RNase MC2, in the seeds of bitter gourd (Momordica charantia). RNase MC2 manifested potent RNA-cleavage activity toward baker's yeast tRNA, tumor cell rRNA, and an absolute specificity for uridine. RNase MC2 demonstrated both cytostatic and cytotoxic activities against MCF-7 breast cancer cells. Treatment of MCF-7 cells with RNase MC2 caused nuclear damage (karyorrhexis, chromatin condensation, and DNA fragmentation), ultimately resulting in early/late apoptosis. Further molecular studies unveiled that RNase MC2 induced differential activation of MAPKs (p38, JNK and ERK) and Akt. On the other hand, RNase MC2 exposure activated caspase-8, caspase-9, caspase-7, increased the production of Bak and cleaved PARP, which in turn contributed to the apoptotic response. In conclusion, RNase MC2 is a potential agent which can be exploited in the worldwide fight against breast cancer.

Snake Venom As An Effective Tool Against Colorectal Cancer.

PubMed

Uzair, Bushra; Atlas, Nagina; Malik, Sidra Batool; Jamil, Nazia; Salaam, Temitope Ojuolape; Rehman, Mujaddad Ur; Khan, Barkat Ali

2018-06-13

Cancer is considered one of the most predominant causes of morbidity and mortality all over the world and colorectal cancer is the most common fatal cancers, triggering the second cancer related death. Despite progress in understanding carcinogenesis and development in chemotherapeutics, there is an essential need to search for improved treatment. More than the half a century, cytotoxic and cytostatic agents have been examined as a potential treatment of cancer, among these agents; remarkable progresses have been reported by the use of the snake venom. Snake venoms are secreting materials of lethal snakes are store in venomous glands. Venoms are composite combinations of various protein, peptides, enzymes, toxins and non proteinaceous secretions. Snake venom possesses immense valuable mixtures of proteins and enzymes. Venoms have potential to combat with the cancerous cells and produce positive effect. Besides the toxicological effects of venoms, several proteins of snake venom e.g. disintegrins, phospholipases A2, metalloproteinases, and L-amino acid oxidases and peptides e.g. bradykinin potentiators, natriuretic, and analgesic peptides have shown potential as pharmaceutical agents, including areas of diagnosis and cancer treatment. In this review we have discussed recent remarkable research that has involved the dynamic snake venoms compounds, having anticancer bustle especially in case of colorectal cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Curcumin in combined cancer therapy.

PubMed

Troselj, Koraljka Gall; Kujundzic, Renata Novak

2014-01-01

The mechanisms of beneficial preventive and therapeutic effects achieved by traditional and complementary medicine are currently being deciphered in molecular medicine. Curcumin, a yellow-colored polyphenol derived from the rhizome of turmeric (Curcuma longa), influences a wide variety of cellular processes through the reshaping of many molecular targets. One of them, nuclear factor kappa B (NF-κB), represents a strong mediator of inflammation and, in a majority of systems, supports the pro-proliferative features of cancer cells. The application of various anticancer drugs, cytostatics, triggers signals which lead to an increase in cellular NF-κB activity. As a consequence, cancer cells often reshape their survival signaling pathways and, over time, become resistant to applied therapy. Curcumin was shown to be a strong inhibitor of NF-κB activity and its inhibitory effect on NF-κB related pathways often leads to cellular apoptotic response. All these facts, tested and confirmed in many different biological systems, have paved the way for research aimed to elucidate the potential beneficial effects of combining curcumin and various anti-cancer drugs in order to establish more efficient and less toxic cancer treatment modalities. This review addresses certain aspects of NF-κB-related inflammatory response, its role in carcinogenesis and therapy benefits that may be gained through silencing NF-κB by selectively combining curcumin and various anticancer drugs.

Discovery of Phylloseptins that Defense against Gram-Positive Bacteria and Inhibit the Proliferation of the Non-Small Cell Lung Cancer Cell Line, from the Skin Secretions of Phyllomedusa Frogs.

PubMed

Liu, Jia; Wu, Qing; Li, Lei; Xi, Xinping; Wu, Di; Zhou, Mei; Chen, Tianbao; Shaw, Chris; Wang, Lei

2017-08-29

The growing occurrence of bacterial resistance to conventional antibiotics has called for the development of new classes of antimicrobial agents. Antimicrobial peptides (AMPs) with broad antimicrobial spectrum derived from frog skin secretions have been demonstrated to be promising candidates for new antibiotic development. A proven rich source of these compounds are the skin secretions of the frogs in the Phyllomedusa genus. In this study, two novel phylloseptin peptides-phylloseptin-PTa and phylloseptin-PHa-were isolated from the skin secretions of the South American frogs, Phyllomedusa tarsius ( P. tarsius ) and Phyllomedusa hypochondrialis ( P. hypochondrialis ) through parallel transcriptomic and peptidomic studies. Replicates obtained by chemical synthesis were structurally analysed and shown to adopt an α-helix configuration in an amphiphilic environment. Both peptides demonstrated antimicrobial activities against planktonic Gram-positive bacteria strains, including Staphylococcus aureus , Enterococcus faecalis and methicillin-resistant Staphylococcus aureus , biofilms, as well as cytostatic effects on the non-small cell lung cancer cell line, NCI-H157, with relatively low haemolysis on horse erythrocytes and low cytotoxicity on the human microvascular endothelial cell line, HMEC-1. The discovery of phylloseptin peptides may further inspire the development of new types of antibiotics.

Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, modulates the E-cadherin/beta-catenin system in a human pancreatic cancer cell line, BxPC-3.

PubMed

Ohta, Tetsuo; Elnemr, Ayman; Yamamoto, Miyuki; Ninomiya, Itasu; Fushida, Sachio; Nishimura, Gen-Ichi; Fujimura, Takashi; Kitagawa, Hirohisa; Kayahara, Masato; Shimizu, Koichi; Yi, Shuangqin; Miwa, Koichi

2002-07-01

Activation of peroxisome proliferator-activated receptor (PPAR)-gamma induces terminal differentiation and growth inhibition associated with G1 cell cycle arrest in some cancer cells. The multifunctional molecule beta-catenin performs important roles in intercellular adhesion and signal transduction. However, no report has focused on actions of PPAR-gamma in regulating the E-cadherin/beta-catenin system. We examined whether thiazolidinedione (TZD), a potent PPAR-gamma ligand, could modulate the E-cadherin/beta-catenin system in a human pancreatic cancer cell line, BxPC-3, that has been found to express PPAR-gamma. According to Western blotting, TZD markedly increased differentiation markers including E-cadherin and carcinoembryonic antigen, while beta-catenin did not change significantly. In untreated cells, fluorescence immunostaining demonstrated beta-catenin predominantly in the cytoplasm and/or nucleus; in TZD-treated cells, beta-catenin localization had dramatically shifted to the plasma membrane, in association with increased E-cadherin at this site. Thus, a PPAR-gamma ligand appears to participate not only in induction of differentiation in pancreatic cancer cells, but also in the regulation of the E-cadherin/beta-catenin system. Such ligands may prove clinically useful as cytostatic anticancer agents.

Effects of an Anticarcinogenic Bowman-Birk Protease Inhibitor on Purified 20S Proteasome and MCF-7 Breast Cancer Cells

PubMed Central

Souza, Larissa da Costa; Camargo, Ricardo; Demasi, Marilene; Santana, Jaime Martins; de Freitas, Sonia Maria

2014-01-01

Proteasome inhibitors have been described as an important target for cancer therapy due to their potential to regulate the ubiquitin-proteasome system in the degradation pathway of cellular proteins. Here, we reported the effects of a Bowman-Birk-type protease inhibitor, the Black-eyed pea Trypsin/Chymotrypsin Inhibitor (BTCI), on proteasome 20S in MCF-7 breast cancer cells and on catalytic activity of the purified 20S proteasome from horse erythrocytes, as well as the structural analysis of the BTCI-20S proteasome complex. In vitro experiments and confocal microscopy showed that BTCI readily crosses the membrane of the breast cancer cells and co-localizes with the proteasome in cytoplasm and mainly in nucleus. Indeed, as indicated by dynamic light scattering, BTCI and 20S proteasome form a stable complex at temperatures up to 55°C and at neutral and alkaline pHs. In complexed form, BTCI strongly inhibits the proteolytic chymotrypsin-, trypsin- and caspase-like activities of 20S proteasome, indicated by inhibition constants of 10−7 M magnitude order. Besides other mechanisms, this feature can be associated with previously reported cytostatic and cytotoxic effects of BTCI in MCF-7 breast cancer cells by means of apoptosis. PMID:24475156

Synthesis, cytotoxicity, cellular uptake and influence on eicosanoid metabolism of cobalt-alkyne modified fructoses in comparison to auranofin and the cytotoxic COX inhibitor Co-ASS.

PubMed

Ott, Ingo; Koch, Thao; Shorafa, Hashem; Bai, Zhenlin; Poeckel, Daniel; Steinhilber, Dieter; Gust, Ronald

2005-06-21

Propargylhexacarbonyldicobalt complexes with fructopyranose ligands were prepared and investigated for cytotoxicity in the MCF-7 human breast cancer cell line. The antiproliferative effects depended on the presence of isopropylidene protecting groups in the carbohydrate ligand and correlated with the cellular concentration of the complexes. IC(50) values of > 20 microM demonstrated that the fructose derivatives were only moderately active compared to the references auranofin and the aspirin (ASS) derivative [2-acetoxy(2-propynyl)benzoate]hexacarbonyldicobalt (Co-ASS). In continuation of our studies on the mode of action of cobalt-alkyne complexes we studied the influence of the compounds on the formation of 12-HHT (COX-1 product) and 12-HETE (12-LOX product) by human platelets as an indication of the interference in the eicosanoid metabolism, which is discussed as a target system of cytostatics. Co-ASS was an efficient COX-1 inhibitor without LOX inhibitory activity and auranofin inhibited both COX-1 and 12-LOX eicosanoid production. The missing activity of the fructopyranose complexes at the 12-LOX and the only moderate effects at COX-1 indicate that COX/LOX inhibition may be in part responsible for the pharmacological effects of auranofin and Co-ASS but not for those of the fructopyranose complexes.

A lentiviral vector with expression controlled by E2F-1: A potential tool for the study and treatment of proliferative diseases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strauss, Bryan E.; Patricio, Juliana Rotelli; Program in Biotechnology, University of Sao Paulo

2006-10-06

We have constructed a lentiviral vector with expression limited to cells presenting active E2F-1 protein, a potential advantage for gene therapy of proliferative diseases. For the FE2FLW vector, the promoter region of the human E2F-1 gene was utilized to drive expression of luciferase cDNA, included as a reporter of viral expression. Primary, immortalized, and transformed cells were transduced with the FE2FLW vector and cell cycle alterations were induced with serum starvation/replacement, contact inhibition or drug treatment, revealing cell cycle-dependent changes in reporter activity. Forced E2F-1 expression, but not E2F-2 or E2F-3, increased reporter activity, indicating a major role for thismore » factor in controlling expression from the FE2FLW virus. We show the utility of this vector as a reporter of E2F-1 and proliferation-dependent cellular alterations upon cytotoxic/cytostatic treatment, such as the introduction of tumor suppressor genes. We propose that the FE2FLW vector may be a starting point for the development of gene therapy strategies for proliferative diseases, such as cancer or restinosis.« less

Antiradical and cytotoxic activity of different Helichrysum plicatum flower extracts.

PubMed

Bigović, Dubravka; Savikin, Katarina; Janković, Teodora; Menković, Nebojsa; Zdunić, Gordana; Stanojković, Tatjana; Djurić, Zorica

2011-06-01

Flowers of Helichrysum plicatum were extracted under different experimental conditions, and their antioxidant activity was determined by DPPH radical scavenging assay. Extracts obtained with higher concentration of ethyl acetate (90% or 100%) were found to contain the greatest amount of total phenolics (> 250 mg gallic acid equivalents/g of dried extract), and high correlation between total phenolic content and antiradical activity was observed (r = -0.79). Based on the total phenolic content and antiradical activity, some extracts were selected for investigation of cytotoxic activity toward PC3, HeLa and K562 human cancer cell lines in vitro. All tested extracts exhibited moderate activity against HeLa cells (41.9-42.1 microg/mL), whereas the extract obtained with 100% ethyl acetate was the most active against K562 and PC3 cell lines (25.9 and 39.2 microg/mL, respectively). Statistical analysis revealed significant correlation between total phenolic content and cytotoxic activity against PC3 and K562 cells. HPLC identification of phenolic compounds from the extracts indicated the presence of apigenin, naringenin and kaempferol as free aglycones, and glycosides of apigenin, naringenin, quercetin and kaempferol. Among aglycones, kaempferol displayed moderate cytostatic activity against all cell lines (24.8-64.7 microM).

Radio-protective effect of cinnamic acid, a phenolic phytochemical, on genomic instability induced by X-rays in human blood lymphocytes in vitro.

PubMed

Cinkilic, Nilufer; Tüzün, Ece; Çetintaş, Sibel Kahraman; Vatan, Özgür; Yılmaz, Dilek; Çavaş, Tolga; Tunç, Sema; Özkan, Lütfi; Bilaloğlu, Rahmi

2014-08-01

The present study was designed to determine the protective activity of cinnamic acid against induction by X-rays of genomic instability in normal human blood lymphocytes. This radio-protective activity was assessed by use of the cytokinesis-block micronucleus test and the alkaline comet assay, with human blood lymphocytes isolated from two healthy donors. A Siemens Mevatron MD2 (Siemens AG, USA, 1994) linear accelerator was used for the irradiation with 1 or 2 Gy. Treatment of the lymphocytes with cinnamic acid prior to irradiation reduced the number of micronuclei when compared with that in control samples. Treatment with cinnamic acid without irradiation did not increase the number of micronuclei and did not show a cytostatic effect in the lymphocytes. The results of the alkaline comet assay revealed that cinnamic acid reduces the DNA damage induced by X-rays, showing a significant radio-protective effect. Cinnamic acid decreased the frequency of irradiation-induced micronuclei by 16-55% and reduced DNA breakage by 17-50%, as determined by the alkaline comet assay. Cinnamic acid may thus act as a radio-protective compound, and future studies may focus on elucidating the mechanism by which cinnamic acid offers radioprotection. Copyright © 2014 Elsevier B.V. All rights reserved.

Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells

PubMed Central

Monti, Paolo; Scirpoli, Miriam; Maffi, Paola; Ghidoli, Nadia; De Taddeo, Francesca; Bertuzzi, Federico; Piemonti, Lorenzo; Falcone, Marika; Secchi, Antonio; Bonifacio, Ezio

2008-01-01

Successful transplantation requires the prevention of allograft rejection and, in the case of transplantation to treat autoimmune disease, the suppression of autoimmune responses. The standard immunosuppressive treatment regimen given to patients with autoimmune type 1 diabetes who have received an islet transplant results in the loss of T cells. In many other situations, the immune system responds to T cell loss through cytokine-dependant homeostatic proliferation of any remaining T cells. Here we show that T cell loss after islet transplantation in patients with autoimmune type 1 diabetes was associated with both increased serum concentrations of IL-7 and IL-15 and in vivo proliferation of memory CD45RO+ T cells, highly enriched in autoreactive glutamic acid decarboxylase 65–specific T cell clones. Immunosuppression with FK506 and rapamycin after transplantation resulted in a chronic homeostatic expansion of T cells, which acquired effector function after immunosuppression was removed. In contrast, the cytostatic drug mycophenolate mofetil efficiently blocked homeostatic T cell expansion. We propose that the increased production of cytokines that induce homeostatic expansion could contribute to recurrent autoimmunity in transplanted patients with autoimmune disease and that therapy that prevents the expansion of autoreactive T cells will improve the outcome of islet transplantation. PMID:18431516

Modelling of temperature and perfusion during scalp cooling

NASA Astrophysics Data System (ADS)

Janssen, F. E. M.; Van Leeuwen, G. M. J.; Van Steenhoven, A. A.

2005-09-01

Hair loss is a feared side effect of chemotherapy treatment. It may be prevented by cooling the scalp during administration of cytostatics. The supposed mechanism is that by cooling the scalp, both temperature and perfusion are diminished, affecting drug supply and drug uptake in the hair follicle. However, the effect of scalp cooling varies strongly. To gain more insight into the effect of cooling, a computer model has been developed that describes heat transfer in the human head during scalp cooling. Of main interest in this study are the mutual influences of scalp temperature and perfusion during cooling. Results of the standard head model show that the temperature of the scalp skin is reduced from 34.4 °C to 18.3 °C, reducing tissue blood flow to 25%. Based upon variations in both thermal properties and head anatomies found in the literature, a parameter study was performed. The results of this parameter study show that the most important parameters affecting both temperature and perfusion are the perfusion coefficient Q10 and the thermal resistances of both the fat and the hair layer. The variations in the parameter study led to skin temperature ranging from 10.1 °C to 21.8 °C, which in turn reduced relative perfusion to 13% and 33%, respectively.

Study of DT-diaphorase in pigment-producing cells.

PubMed

Smit, N P; Hoogduijn, M J; Riley, P A; Pavel, S

1999-11-01

DT-diaphorase is an FAD-containing enzyme capable of a two-electron reduction of ortho- and paraquinones. Nicotinamide coenzymes (NADH + H+ and NADPH + H+) serve as hydrogen sources in these reactions. The role of DT-diaphorase has been thoroughly investigated in situations when the enzyme is able to reduce exogenous and endogenous quinones, hence protecting the cells against these reactive intermediates. The enzyme has also been studied in connection with its ability to activate some quinoid cytostatics. It is surprising that DT-diaphorase has never been investigated in pigment-producing cells that are known to generate considerable amounts of ortho-quinones. Using a spectrophotometric method we could readily measure the activity of DT-diaphorase in epidermis and various cultured pigment cells. The melanocytes isolated from dark skin showed generally higher DT-diaphorase activity than those from fair skin samples. Also, darkly pigmented congenital naevus cells exhibited higher activity of this enzyme. The most striking was the high DT-diaphorase activity in melanoma cell cultures. In these cells DT-diaphorase activity could be induced by incubation of the cells with 4-hydroxyanisole. A similar effect was seen when a catechol-O-methyltransferase (COMT) inhibitor (3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione (OR-462) was utilised. The induction was inhibited by cyclohexidine.

Antidepressant drugs can modify cytotoxic action of temozolomide.

PubMed

Bielecka, A M; Obuchowicz, E

2017-09-01

Cancer patients often require antidepressant treatment due to comorbid depressive disorder. However, recent studies have demonstrated that antidepressant drugs affect the efficacy of chemotherapy and promote progression of cancer. Apart from the main mood-improving effect, antidepressant drugs also produce analgesic, anxiolytic, hypnotic and pro-cognitive actions. Patients suffering from brain cancer constitute the greatest percentage of depressive cancer patients. However, vital safety and efficacy issues related to combined therapy with temozolomide, the first-line cytostatic in patients diagnosed with glioblastoma multiforme, and antidepressant drugs have yet to be addressed. The aim of the present studies was to evaluate the effect of three antidepressant drugs (imipramine, fluoxetine and tranylcypromine) on the cytotoxic efficacy of temozolomide on T98G cells, a human glioblastoma cell line. In our experiments, we used a complex experimental in vitro system to mimic the instability of a tumour's oxygen supply, thereby reproducing conditions that occur inside the tumour. The effect of the interaction between temozolomide and antidepressant drugs on viability, apoptosis and intensity of divisions of glioblastoma cells was evaluated under different oxygen conditions. The results of our studies demonstrated that imipramine and tranylcypromine reduced the cytotoxic efficacy of temozolomide under some oxygen conditions while fluoxetine did not demonstrate such effects. © 2016 John Wiley & Sons Ltd.

Peptide hormones and lung cancer.

PubMed

Moody, T W

2006-03-01

Several peptide hormones have been identified which alter the proliferation of lung cancer. Small cell lung cancer (SCLC), which is a neuroendocrine cancer, produces and secretes gastrin releasing peptide (GRP), neurotensin (NT) and adrenomedullin (AM) as autocrine growth factors. GRP, NT and AM bind to G-protein coupled receptors causing phosphatidylinositol turnover or elevated cAMP in SCLC cells. Addition of GRP, NT or AM to SCLC cells causes altered expression of nuclear oncogenes, such as c-fos, and stimulation of growth. Antagonists have been developed for GRP, NT and AM receptors which function as cytostatic agents and inhibit SCLC growth. Growth factor antagonists, such as the NT1 receptor antagonist SR48692, facilitate the ability of chemotherapeutic drugs to kill lung cancer cells. It remains to be determined if GRP, NT and AM receptors will served as molecular targets, for development of new therapies for the treatment of SCLC patients. Non-small cell lung cancer (NSCLC) cells also have a high density of GRP, NT, AM and epidermal growth factor (EGF) receptors. Several NSCLC patients with EGF receptor mutations respond to gefitinib, a tyrosine kinase inhibitor. Gefitinib relieves NSCLC symptoms, maintaining stable disease in patients who are not eligible for systemic chemotherapy. It is important to develop new therapeutic approaches using translational research techniques for the treatment of lung cancer patients.

Functioning of Fluorescent Proteins in Aggregates in Anthozoa Species and in Recombinant Artificial Models

PubMed Central

Povarova, Natalia V.; Petri, Natalia D.; Blokhina, Anna E.; Bogdanov, Alexey M.; Lukyanov, Konstantin A.

2017-01-01

Despite great advances in practical applications of fluorescent proteins (FPs), their natural function is poorly understood. FPs display complex spatio-temporal expression patterns in living Anthozoa coral polyps. Here we applied confocal microscopy, specifically, the fluorescence recovery after photobleaching (FRAP) technique to analyze intracellular localization and mobility of endogenous FPs in live tissues. We observed three distinct types of protein distributions in living tissues. One type of distribution, characteristic for Anemonia, Discosoma and Zoanthus, is free, highly mobile cytoplasmic localization. Another pattern is seen in FPs localized to numerous intracellular vesicles, observed in Clavularia. The third most intriguing type of intracellular localization is with respect to the spindle-shaped aggregates and lozenge crystals several micrometers in size observed in Zoanthus samples. No protein mobility within those structures was detected by FRAP. This finding encouraged us to develop artificial aggregating FPs. We constructed “trio-FPs” consisting of three tandem copies of tetrameric FPs and demonstrated that they form multiple bright foci upon expression in mammalian cells. High brightness of the aggregates is advantageous for early detection of weak promoter activities. Simultaneously, larger aggregates can induce significant cytostatic and cytotoxic effects and thus such tags are not suitable for long-term and high-level expression. PMID:28704934

Antitumoral Activity of Snake Venom Proteins: New Trends in Cancer Therapy

PubMed Central

Calderon, Leonardo A.; Sobrinho, Juliana C.; Zaqueo, Kayena D.; de Moura, Andrea A.; Grabner, Amy N.; Mazzi, Maurício V.; Marcussi, Silvana; Fernandes, Carla F. C.; Zuliani, Juliana P.; Carvalho, Bruna M. A.; da Silva, Saulo L.; Stábeli, Rodrigo G.; Soares, Andreimar M.

2014-01-01

For more than half a century, cytotoxic agents have been investigated as a possible treatment for cancer. Research on animal venoms has revealed their high toxicity on tissues and cell cultures, both normal and tumoral. Snake venoms show the highest cytotoxic potential, since ophidian accidents cause a large amount of tissue damage, suggesting a promising utilization of these venoms or their components as antitumoral agents. Over the last few years, we have studied the effects of snake venoms and their isolated enzymes on tumor cell cultures. Some in vivo assays showed antineoplastic activity against induced tumors in mice. In human beings, both the crude venom and isolated enzymes revealed antitumor activities in preliminary assays, with measurable clinical responses in the advanced treatment phase. These enzymes include metalloproteases (MP), disintegrins, L-amino acid oxidases (LAAOs), C-type lectins, and phospholipases A2 (PLA2s). Their mechanisms of action include direct toxic action (PLA2s), free radical generation (LAAOs), apoptosis induction (PLA2s, MP, and LAAOs), and antiangiogenesis (disintegrins and lectins). Higher cytotoxic and cytostatic activities upon tumor cells than normal cells suggest the possibility for clinical applications. Further studies should be conducted to ensure the efficacy and safety of different snake venom compounds for cancer drug development. PMID:24683541

Proteasome expression and activity in cancer and cancer stem cells.

PubMed

Voutsadakis, Ioannis A

2017-03-01

Proteasome is a multi-protein organelle that participates in cellular proteostasis by destroying damaged or short-lived proteins in an organized manner guided by the ubiquitination signal. By being in a central place in the cellular protein complement homeostasis, proteasome is involved in virtually all cell processes including decisions on cell survival or death, cell cycle, and differentiation. These processes are important also in cancer, and thus, the proteasome is an important regulator of carcinogenesis. Cancers include a variety of cells which, according to the cancer stem cell theory, descend from a small percentage of cancer stem cells, alternatively termed tumor-initiating cells. These cells constitute the subsets that have the ability to propagate the whole variety of cancer and repopulate tumors after cytostatic therapies. Proteasome plays a role in cellular processes in cancer stem cells, but it has been found to have a decreased function in them compared to the rest of cancer cells. This article will discuss the transcriptional regulation of proteasome sub-unit proteins in cancer and in particular cancer stem cells and the relationship of the proteasome with the pluripotency that is the defining characteristic of stem cells. Therapeutic opportunities that present from the understanding of the proteasome role will also be discussed.

Antimicrobial and Antiproliferative Activity of Bauhinia forficata Link and Cnidoscolus quercifolius Extracts commonly Used in Folk Medicine.

PubMed

Alves, Erika P; de F Lima, Rennaly; de Almeida, Carolina M; Freires, Irlan A; Rosalen, Pedro L; Ruiz, Ana Ltg; Granville-Garcia, Ana F; Godoy, Gustavo P; Pereira, Jozinete V; de Brito Costa, Edja Mm

2017-08-01

Bauhinia forficata and Cnidoscolus quercifolius plants are commonly used in folk medicine. However, few studies have investigated their therapeutic potential. Herein, we evaluated the antimicrobial activity of B. forficata and C. quercifolius extracts against microorganisms of clinical relevance and their antiproliferative potential against tumor cells. The following tests were performed: Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)/minimum fungicidal concentration (MFC), inhibition of biofilm adhesion, and effects on cell morphology. Antiproliferative tests were carried out with human keratinocytes and six tumor lines. Bauhinia forficata showed antimicrobial activity only against C. albicans with MIC of 15.62 ug/mL and MFC higher than 2000 ug/mL. It also inhibited biofilm adhesion and caused alterations in cell morphology. Cnidoscolus quercifolius showed no significant activity (MIC > 2.0 mg/mL) against the strains. Bauhinia forficata and C. quercifolius extracts showed cytostatic activity against the tumor cells. Bauhinia forficata has promising anti-Cand/da activity and should be further investigated for its therapeutic potential. The use of medicinal plants in the treatment of infectious processes has an important function nowadays, due to the limitations of the use of synthetic antibiotics available, related specifically to the microbial resistance emergence.

Inhibition effects of protein-conjugated amorphous zinc sulfide nanoparticles on tumor cells growth

NASA Astrophysics Data System (ADS)

Cao, Ying; Wang, Hua-Jie; Cao, Cui; Sun, Yuan-Yuan; Yang, Lin; Wang, Bao-Qing; Zhou, Jian-Guo

2011-07-01

In this article, a facile and environmentally friendly method was applied to fabricate BSA-conjugated amorphous zinc sulfide (ZnS) nanoparticles using bovine serum albumin (BSA) as the matrix. Transmission electron microscopy analysis indicated that the stable and well-dispersed nanoparticles with the diameter of 15.9 ± 2.1 nm were successfully prepared. The energy dispersive X-ray, X-ray powder diffraction, Fourier transform infrared spectrograph, high resolution transmission electron microscope, and selected area electron diffraction measurements showed that the obtained nanoparticles had the amorphous structure and the coordination occurred between zinc sulfide surfaces and BSA in the nanoparticles. In addition, the inhibition effects of BSA-conjugated amorphous zinc sulfide nanoparticles on tumor cells growth were described in detail by cell viability analysis, optical and electron microscopy methods. The results showed that BSA-conjugated amorphous zinc sulfide nanoparticles could inhibit the metabolism and proliferation of human hepatocellular carcinoma cells, and the inhibition was dose dependent. The half maximal inhibitory concentration (IC50) was 0.36 mg/mL. Overall, this study suggested that BSA-conjugated amorphous zinc sulfide nanoparticles had the application potential as cytostatic agents and BSA in the nanoparticles could provide the modifiable site for the nanoparticles to improve their bioactivity or to endow them with the target function.

The Effect of Lycopene Preexposure on UV-B-Irradiated Human Keratinocytes

PubMed Central

Ascenso, Andreia; Pedrosa, Tiago; Pinho, Sónia; Pinho, Francisco; de Oliveira, José Miguel P. Ferreira; Cabral Marques, Helena; Oliveira, Helena; Simões, Sandra; Santos, Conceição

2016-01-01

Lycopene has been reported as the antioxidant most quickly depleted in skin upon UV irradiation, and thus it might play a protective role. Our goal was to investigate the effects of preexposure to lycopene on UV-B-irradiated skin cells. Cells were exposed for 24 h to 10 M lycopene, and subsequently irradiated and left to recover for another 24 h period. Thereafter, several parameters were analyzed by FCM and RT-PCR: genotoxicity/clastogenicity by assessing the cell cycle distribution; apoptosis by performing the Annexin-V assay and analyzing gene expression of apoptosis biomarkers; and oxidative stress by ROS quantification. Lycopene did not significantly affect the profile of apoptotic, necrotic and viable cells in nonirradiated cells neither showed cytostatic effects. However, irradiated cells previously treated with lycopene showed an increase in both dead and viable subpopulations compared to nonexposed irradiated cells. In irradiated cells, lycopene preexposure resulted in overexpression of BAX gene compared to nonexposed irradiated cells. This was accompanied by a cell cycle delay at S-phase transition and consequent decrease of cells in G0/G1 phase. Thus, lycopene seems to play a corrective role in irradiated cells depending on the level of photodamage. Thus, our findings may have implications for the management of skin cancer. PMID:26664697

Relationship between the adjuvant and cytotoxic effects of the positive charges and polymerization in liposomes.

PubMed

Gasparri, Julieta; Speroni, Lucía; Chiaramoni, Nadia Silvia; del Valle Alonso, Silvia

2011-06-01

Vaccine development today encounters a main obstacle, which is the need for effective adjuvants suitable for clinical trials. Aluminum salts, discovered 70 years ago and, very recently, MF59, are the only types of adjuvants currently used in vaccines licensed by the U.S. Food and Drug Administration. Liposomes represent an alternative approach to vaccine adjuvants. In this article, we describe the inflammatory response and biological effect of polymerization and the addition of positive charges in liposome formulations. Nonpolymerized cationic (NP(+)) liposomes significantly reduce metabolism in Vero cells after 24 hours. Correspondingly, both NP(+) and polymerized cationic (P(+)) liposomes reduce cell viability following a 48-hour incubation. Similar results were obtained with cells from the peritoneal cavities of mice. Paradoxically, those liposomes that presented clearly cytostatic or cytotoxic effects in vitro stimulated metabolism and had a mitogenic effect in vivo. Finally, the adjuvant effect was tested by immunization in BALB/c mice. The major effect was obtained with NP(+) liposomes. Accordingly, we also demonstrated that NP(+) liposomes injected into the dermis produced an outstanding inflammatory reaction, showing the histopathological characteristics of an inoculation granuloma. Thus, positive charge would play an important role in the immunoadjuvant effect of liposomes by conferring them cytotoxic capacity.

Genotoxic effects of styrene-7,8-oxide in human white blood cells: comet assay in relation to the induction of sister-chromatid exchanges and micronuclei.

PubMed

Laffon, B; Pásaro, E; Méndez, J

2001-04-05

Styrene is used in the production of plastics, resins and rubber. The highest human exposures to styrene take place by inhalation during the production of fiberglass reinforced plastics. Styrene is metabolized mainly in the liver to styrene-7,8-oxide (SO), its principal in vivo mutagenic metabolite. In this study, human peripheral white blood cells were exposed to several SO concentrations (10-200 microM) in order to evaluate its genotoxic properties by means of comet assay, sister-chromatid exchanges (SCE) and cytokinesis-blocked micronucleus (MN) test, in addition to determine its clastogenic or aneugenic properties by combining MN with fluorescence in situ hybridization (FISH) procedures. Our results show that SO induces DNA damage, SCE and MN in human leukocytes in vitro at concentrations above 50 microM, and that there is a strong relationship between DNA damage, as measured by the comet assay, and cytogenetic damage induced by SO at the doses employed. SO shows preferentially a clastogenic activity and produces a cytostatic effect at high doses, reflected by the significant decrease of the calculated proliferation indices. A good dose-effect relationship is obtained in the three tests performed at the concentration range assayed.

Preclinical Evaluation of Vemurafenib as Therapy for BRAFV600E Mutated Sarcomas.

PubMed

Gouravan, Sarina; Meza-Zepeda, Leonardo A; Myklebost, Ola; Stratford, Eva W; Munthe, Else

2018-03-23

The BRAF V600E mutation, which in melanoma is targetable with vemurafenib, is also found in sarcomas and we here evaluate the therapeutic potential in sarcoma cell lines. Four sarcoma cell lines harboring the BRAFV600E mutation, representing liposarcomas (SA-4 and SW872), Ewing sarcoma (A673) and atypical synovial sarcoma (SW982), were treated with vemurafenib and the effects on cell growth, apoptosis, cell cycle progression and cell signaling were determined. Vemurafenib induced a strong cytostatic effect in SA-4 cells, mainly due to cell cycle arrest, whereas only moderate levels of apoptosis were observed. However, a high dose was required compared to BRAF V600E mutated melanoma cells, and removal of vemurafenib demonstrated that the continuous presence of drug was required for sustained growth inhibition. A limited growth inhibition was observed in the other three cell lines. Protein analyses demonstrated reduced phosphorylation of ERK during treatment with vemurafenib in all the four sarcoma cell lines confirming that the MAPK pathway is active in these cell lines, and that the pathway can be inhibited by vemurafenib, but also that these cells can proliferate despite this. These findings indicate that vemurafenib alone would not be an efficient therapy against BRAF V600E mutated sarcomas. However, further investigations of combination with other drugs are warranted.

BKM-120 (Buparlisib): A Phosphatidyl-Inositol-3 Kinase Inhibitor with Anti-Invasive Properties in Glioblastoma.

PubMed

Speranza, Maria-Carmela; Nowicki, Michal O; Behera, Prajna; Cho, Choi-Fong; Chiocca, E Antonio; Lawler, Sean E

2016-02-05

Glioblastoma is an aggressive, invasive tumor of the central nervous system (CNS). There is a widely acknowledged need for anti-invasive therapeutics to limit glioblastoma invasion. BKM-120 is a CNS-penetrant pan-class I phosphatidyl-inositol-3 kinase (PI3K) inhibitor in clinical trials for solid tumors, including glioblastoma. We observed that BKM-120 has potent anti-invasive effects in glioblastoma cell lines and patient-derived glioma cells in vitro. These anti-migratory effects were clearly distinguishable from cytostatic and cytotoxic effects at higher drug concentrations and longer durations of drug exposure. The effects were reversible and accompanied by changes in cell morphology and pronounced reduction in both cell/cell and cell/substrate adhesion. In vivo studies showed that a short period of treatment with BKM-120 slowed tumor spread in an intracranial xenografts. GDC-0941, a similar potent and selective PI3K inhibitor, only caused a moderate reduction in glioblastoma cell migration. The effects of BKM-120 and GDC-0941 were indistinguishable by in vitro kinase selectivity screening and phospho-protein arrays. BKM-120 reduced the numbers of focal adhesions and the velocity of microtubule treadmilling compared with GDC-0941, suggesting that mechanisms in addition to PI3K inhibition contribute to the anti-invasive effects of BKM-120. Our data suggest the CNS-penetrant PI3K inhibitor BKM-120 may have anti-invasive properties in glioblastoma.

Loss of antibodies and response to (re-)vaccination in children after treatment for acute lymphocytic leukemia: a systematic review.

PubMed

van Tilburg, C M; Sanders, E A M; Rovers, M M; Wolfs, T F W; Bierings, M B

2006-10-01

Intensified chemotherapy regimens resulting in improved survival of children with acute lymphocytic leukemia (ALL) lead to concerns about therapy-induced immune damage reflected by the loss of protection of previous immunizations and the efficacy of (re-)vaccination. The severity of secondary immunodeficiency, however, is not clear and knowledge is based on a limited number of studies. We performed a systematic review on literature concerning vaccination data of children with ALL published since 1980. Eight studies fulfilled the inclusion criteria. Regarding antibody titers after treatment, the number of children who had preserved the defined protection level for antibodies differed widely, ranging from 17 to 98% for diphtheria, 27 to 82% for Bordetella pertussis, 20 to 98% for tetanus, 62 to 100% for poliomyelitis, 35 to 100% for Haemophilus influenzae type B (HiB), 29 to 92% for mumps, 29 to 60% for measles and 72 to 92% for rubella. Most patients however responded to revaccination, demonstrating immunological recovery. Although the designs and results of the included studies varied widely, it can be concluded that cytostatic therapy for ALL in children results in a temporarily reduction of specific antibody levels. Memory is preserved but revaccination may be warranted. This is the first systematic review and the best possible current approximation of chemotherapy-induced immune damage in children after ALL treatment.

Targeting Histone Deacetylases in Diseases: Where Are We?

PubMed Central

Benedetti, Rosaria; Conte, Mariarosaria

2015-01-01

Abstract Significance: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death. Recent Advances: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy. Critical Issues: (i) Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. (ii) Advantages/disadvantages of non-selective or isoform-directed HDACi. (iii) Limited number of response-predictive biomarkers. (iv) Toxicity leading to dysfunction of critical biological processes. Future Directions: Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers, enabling better patient stratification and prediction of response to treatment. Antioxid. Redox Signal. 23, 99–126. PMID:24382114

Effects of the ACTH(4-9) analogue, ORG 2766, on vincristine cytotoxicity in two human lymphoma cell lines, U937 and U715.

PubMed Central

Kiburg, B.; van de Loosdrecht, A. A.; Schweitzer, K. M.; Ossenkoppele, G. J.; Müller, L. J.; Heimans, J. J.; Huijgens, P. C.

1994-01-01

The use of cytotoxic drug vincristine (VCR) is limited by the occurrence of peripheral neuropathy. A neurotrophic ACTH(4-9) analogue, ORG 2766, is being studied for its protective effect. Possible modulatory effects of ORG 2766 on tumour cell growth and interference with the cytotoxic efficacy of VCR were studied in two human lymphoma cell lines, U937 and U715. The effects of ORG 2766 on cell growth and survival and on VCR-mediated cytotoxicity were investigated using two MTT-based assays to study direct cytotoxic effects and to assess residual growth after pretreatment. Treatment with ORG 2766 alone had no effect on cell growth and survival. Neither did this drug affect VCR cytotoxicity. However, after 96 h pretreatment with ORG 2766 and a culture period of 7 days, a reduction in residual growth and a potentiation of VCR-induced inhibition of growth capacity was observed in U715 cells, and to some extent also in U937 cells. It is concluded that ORG 2766 has no stimulatory effects on tumour growth and does not negatively interfere with VCR-mediated cytotoxicity. Rather it enhances the cytostatic effect of VCR. It is suggested that ORG 2766 can safely be used in clinical trials investigating the ability of ORG 2766 to counteract VCR-induced neurotoxicity. PMID:8123480

To the Large Nucleolar Bodies in Apoptotic Leukaemic Granulocytic Progenitors without Further Differentiation. Are Large Nucleoli Always Present in Proliferating Cells?

PubMed

Smetana, K; Kuželová, K; Zápotocký, M; Hrkal, Z

2017-01-01

Large nucleoli have generally been believed to be present in less differentiated and proliferating cells including the malignant ones. Such nucleoli have also been considered to be active in the biosynthetic process and major cell developmental activities. In contrast, after cytostatic treatment, apoptotic leukaemic progenitors still containing nuclei did not exhibit substantial reduction of the nucleolar size but displayed decreased nucleolar biosynthetic activity. The present study was undertaken to provide more information on the large nucleoli in spontaneously occurring apoptotic leukaemic progenitors without further differentiation. Leukaemic progenitors of established cell lineages originating from leukaemic patients represented a very convenient model for such study. Some of them exhibit morphological signs of the spontaneously occurring apoptotic process. Since such signs are expressed by nuclear and cytoplasmic morphological variability, the present study dealt with spontaneously occurring apoptotic progenitors with preserved nuclei characterized by heavy chromatin condensation and occasional fragmentation. Based of nucleolar body and nuclear maximal diameter measurements it seems to be clear that the nucleolar size in these cells was not substantially reduced, contrary to that of the nucleus. However, large nucleolar bodies in spontaneously occurring apoptotic cells were characterized by markedly reduced biosynthetic activity, as expressed by the decreased number of nucleolar transcription markers such as nucleolar fibrillar centres. In conclusion, large nucleoli may be present not only in proliferating, but also in spontaneously occurring apoptotic cells.

Reversion of multidrug resistance in the P-glycoprotein-positive human pancreatic cell line (EPP85-181RDB) by introduction of a hammerhead ribozyme.

PubMed Central

Holm, P. S.; Scanlon, K. J.; Dietel, M.

1994-01-01

A major problem in cytostatic treatment of many tumours is the development of multidrug resistance (MDR4). This is most often accompanied by the overexpression of a membrane transport protein, P-glycoprotein, and its encoding mRNA. In order to reverse the resistant phenotype in cell cultures, we constructed a specific hammerhead ribozyme possessing catalytic activity that cleaves the 3'-end of the GUC sequence in codon 880 of the mdr1 mRNA. We demonstrated that the constructed ribozyme is able to cleave a reduced substrate mdr1 mRNA at the GUC position under physiological conditions in a cell-free system. A DNA sequence encoding the ribozyme gene was then incorporated into a mammalian expression vector (pH beta APr-1 neo) and transfected into the human pancreatic carcinoma cell line EPP85-181RDB, which is resistant to daunorubicin and expresses the MDR phenotype. The expressed ribozyme decreased the level of mdr1 mRNA expression, inhibited the formation of P-glycoprotein and reduced the cell's resistance to daunorubicin dramatically; this means that the resistant cells were 1,600-fold more resistant than the parental cell line (EPP85-181P), whereas those cell clones that showed ribozyme expression were only 5.3-fold more resistant than the parental cell line. Images Figure 1 Figure 3 Figure 2 PMID:7914421

Elimination of pharmaceutical residues in biologically pre-treated hospital wastewater using advanced UV irradiation technology: a comparative assessment.

PubMed

Köhler, C; Venditti, S; Igos, E; Klepiszewski, K; Benetto, E; Cornelissen, A

2012-11-15

UV irradiation technology as a membrane bioreactor (MBR) post-treatment was investigated and assessed. Both UV low pressure (LP) and medium pressure (MP) lamps were examined. The technology was installed in a pilot plant treating hospital wastewater to provide the study with adequate field data. The effect of the UV irradiation was enhanced with varying dosages of H2O2 to establish an advanced oxidation process (AOP). The efficiency of the pharmaceutical removal process was assessed by examining 14 micropollutants (antibiotics, analgesics, anticonvulsants, beta-blockers, cytostatics and X-ray contrast media) which are typically released by hospitals and detected with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS). While the MBR treatment generally showed only a low degradation capacity for persistent pharmaceuticals, much better degradation was obtained by applying UV irradiation and H2O2 as AOP. The "conventional" cost-benefit analysis of the different technology options taking into account both electrical energy consumption and pharmaceutical removal efficiency, revealed clearly better performance of low pressure UV lamps as AOP. However, a holistic comparison between the different scenarios was carried out by evaluating their environmental impacts using the life cycle assessment (LCA) methodology. Decisive advantages were highlighted to include this approach in the decision making process. Copyright © 2012 Elsevier B.V. All rights reserved.

Increasing Antiproliferative Properties of Endocannabinoids in N1E-115 Neuroblastoma Cells through Inhibition of Their Metabolism

PubMed Central

Hamtiaux, Laurie; Hansoulle, Laurie; Dauguet, Nicolas; Muccioli, Giulio G.; Gallez, Bernard; Lambert, Didier M.

2011-01-01

The antitumoral properties of endocannabinoids received a particular attention these last few years. Indeed, these endogenous molecules have been reported to exert cytostatic, apoptotic and antiangiogenic effects in different tumor cell lines and tumor xenografts. Therefore, we investigated the cytotoxicity of three N-acylethanolamines – N-arachidonoylethanolamine (anandamide, AEA), N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA) - which were all able to time- and dose-dependently reduce the viability of murine N1E-115 neuroblastoma cells. Moreover, several inhibitors of FAAH and NAAA, whose presence was confirmed by RT-PCR in the cell line, induced cell cytotoxicity and favored the decrease in cell viability caused by N-acylethanolamines. The most cytotoxic treatment was achieved by the co-incubation of AEA with the selective FAAH inhibitor URB597, which drastically reduced cell viability partly by inhibiting AEA hydrolysis and consequently increasing AEA levels. This combination of molecules synergistically decreased cell proliferation without inducing cell apoptosis or necrosis. We found that these effects are independent of cannabinoid, TRPV1, PPARα, PPARγ or GPR55 receptors activation but seem to occur through a lipid raft-dependent mechanism. These findings further highlight the interest of targeting the endocannabinoid system to treat cancer. More particularly, this emphasizes the great potential benefit of designing novel anti-cancerous therapies based on the association of endocannabinoids and inhibitors of their hydrolysis. PMID:22046372

Bioactive Secondary Metabolites from a Thai Collection of Soil and Marine-Derived Fungi of the Genera Neosartorya and Aspergillus.

PubMed

Zin, War War May; Prompanya, Chadaporn; Buttachon, Suradet; Kijjoa, Anake

2016-01-01

Fungi are microorganisms which can produce interesting secondary metabolites with structural diversity. Although terrestrial fungi have been extensively investigated for their bioactive secondary metabolites such as antibiotics, marine-derived fungi have only recently attracted attention of Natural Products chemists. Our group has been working on the secondary metabolites produced by the cultures of the fungi of the genera Neosartorya and Aspergillus, collected from soil and marine environments from the tropical region for the purpose of finding new leads for anticancer and antibacterial drugs. This review covers only the secondary metabolites of four soil and six marine-derived species of Neosarorya as well as a new species of marine-derived Aspergillus, investigated by our group. In total, we have isolated fifty three secondary metabolites which can be categorized as polyketides (two), isocoumarins (six), terpenoids (two), meroterpenes (fourteen), alkaloids (twenty eight) and cyclic peptide (one). The anticancer and antibacterial activities of these fungal metabolites are also discussed. Among fifty three secondary metabolites isolated, only the alkaloid eurochevalierine and the cadinene sesquiterpene, isolated from the soil fungus N. pseudofisheri, showed relevant in vitro cytostatic activity against glioblastoma (U373) and non-small cell lung cancer (A549) cell lines while the meroditerpene aszonapyrone A exhibited strong antibacterial activity against multidrug-resistant Gram-positive bacteria and also strong antibiofilm activity in these isolates.

Prevention of myelosuppression by combined treatment with enterosorbent and granulocyte colony-stimulating factor.

PubMed

Shevchuk, O O; Posokhova, К А; Todor, I N; Lukianova, N Yu; Nikolaev, V G; Chekhun, V F

2015-06-01

Hematotoxicity and its complication are the prominent limiting factors for rational treatment of malignancies. Granulocyte colony-stimulating factor (G-CSF) is used to increase granulocyte production. It has been shown previously that enterosorption causes prominent myeloprotective activity also. Still, no trial was performed to combine both of them. To study the influence of combination of enterosorption and pharmaceutical analogue of naturally occurring G-CSF (filgrastim) on bone marrow protection and the growth of grafted tumor in a case of injection of melphalan (Mel). Mel injections were used for promotion of bone marrow suppression in rats. Carbon granulated enterosorbent C2 (IEPOR) was used for providing of enteral sorption detoxifying therapy. Filgrastim was used to increase white blood cells (WBC) count. The simultaneous usage of enterosorption and filgrastim had maximum effectiveness for restoring of all types of blood cells. WBC count was higher by 138.3% compared with the Mel group. The increase of platelets count by 98.5% was also observed. In the group (Mel + C2 + filgrastim) the absolute neutrophils count was twofold higher, in comparison with rats of Mel group. Simultaneous administration of G-CSF-analogue and carbonic enterosorbent C2 is a perspective approach for bone marrow protection, when the cytostatic drug melphalan is used. Such combination demonstrates prominent positive impact on restoring of all types of blood cells and had no influence on the antitumor efficacy.

Cycles of Transient High-Dose Cyclophosphamide Administration and Oncolytic Adenovirus Vector Intratumoral Injection for Long Term Tumor Suppression in Syrian Hamsters

PubMed Central

Dhar, Debanjan; Toth, Karoly; Wold, William S.M.

2014-01-01

Immune responses against oncolytic adenovirus (Ad) vectors are thought to limit vector anti-tumor efficacy. In Syrian hamsters, which are immunocompetent and whose tumors and normal tissues are permissive for replication of Ad5-based oncolytic Ad vectors, treating with high-dose cyclophosphamide to suppress the immune system and exert chemotherapeutic effects enhances Ad vector anti-tumor efficacy. However, long term cyclophosphamide treatment and immunosuppression can lead to anemia and vector spread to normal tissues. Here we employed three cycles of transient high-dose cyclophosphamide administration plus intratumoral injection of the oncolytic Ad vector VRX-007 followed by withdrawal from cyclophosphamide. Each cycle lasted 4-6 weeks. This protocol allowed the hamsters to remain healthy so the study could be continued for ~100 days. The tumors were very well suppressed throughout the study. With immunocompetent hamsters, the vector retarded tumor growth initially, but after 3-4 weeks the tumors resumed rapid growth and further injections of vector were ineffective. Preimmunization of the hamsters with Ad5 prevented vector spillover from the tumor to the liver yet still allowed for effective long term anti-tumor efficacy. Our results suggest that a clinical protocol might be developed with cycles of transient chemotherapy plus intratumoral vector injection to achieve significant anti-tumor efficacy while minimizing the side effects of cytostatic treatment. PMID:24722357

Cycles of transient high-dose cyclophosphamide administration and intratumoral oncolytic adenovirus vector injection for long-term tumor suppression in Syrian hamsters.

PubMed

Dhar, D; Toth, K; Wold, W S M

2014-04-01

Immune responses against oncolytic adenovirus (Ad) vectors are thought to limit vector anti-tumor efficacy. With Syrian hamsters, which are immunocompetent and whose tumors and normal tissues are permissive for replication of Ad5-based oncolytic Ad vectors, treating with high-dose cyclophosphamide (CP) to suppress the immune system and exert chemotherapeutic effects enhances Ad vector anti-tumor efficacy. However, long-term CP treatment and immunosuppression can lead to anemia and vector spread to normal tissues. Here, we employed three cycles of transient high-dose CP administration plus intratumoral injection of the oncolytic Ad vector VRX-007 followed by withdrawal of CP. Each cycle lasted 4-6 weeks. This protocol allowed the hamsters to remain healthy so the study could be continued for ~100 days. The tumors were very well suppressed throughout the study. With immunocompetent hamsters, the vector retarded tumor growth initially, but after 3-4 weeks the tumors resumed rapid growth and further injections of vector were ineffective. Preimmunization of the hamsters with Ad5 prevented vector spillover from the tumor to the liver yet still allowed for effective long-term anti-tumor efficacy. Our results suggest that a clinical protocol might be developed with cycles of transient chemotherapy plus intratumoral vector injection to achieve significant anti-tumor efficacy while minimizing the side effects of cytostatic treatment.

Co-delivery of cisplatin and doxorubicin from calcium phosphate beads/matrix scaffolds for osteosarcoma therapy.

PubMed

Hess, Ulrike; Shahabi, Shakiba; Treccani, Laura; Streckbein, Philipp; Heiss, Christian; Rezwan, Kurosch

2017-08-01

Bone substitute materials with a controlled drug release ability can fill cavities caused by the resection of bone tumours and thereby combat any leftover bone cancer cells. The combined release of different cytostatics seems to enhance their toxicity. In this study, calcium phosphate beads and matrix scaffolds are combined for a long-term co-delivery of cis-diamminedichloroplatinum (cisplatin, CDDP) and doxorubicin hydrochloride (DOX) as clinical relevant model drugs. Tricalcium phosphate/alginate beads as additional drug carrier are produced by droplet extrusion with ionotropic gelation and incorporated in scaffold matrix by freeze gelation without sintering. CDDP shows a short burst release while DOX has a continuous release measurable over the entire study period of 40days. Drug release from matrix is decreased by ~30% compared to release from beads. Nevertheless, all formulations follow the Korsmeyer-Peppas release kinetic model and show Fickian diffusion. Cytotoxic activity was conducted on MG-63 osteosarcoma cells after 1, 4, and 7days with WST-1 cell viability assay. Co-loaded composites enhance activity towards MG-63 cells up to ~75% toxicity while reducing the released drug quantity. The results suggest that co-loaded beads/matrix scaffolds are highly promising for osteosarcoma therapy due to synergistic effects over a long period of more than a month. Copyright © 2017 Elsevier B.V. All rights reserved.

[Augmentation with PMMA cement].

PubMed

Kühn, K-D; Höntzsch, D

2015-09-01

Cements based on polymethyl methacrylate (PMMA) can be used without any problem in a variety of clinical augmentations. Cement-related complications in surgical procedures involving PMMA cements, such as embolism, thermal necrosis, toxicity and hypersensitivity, are often due to other causes. Knowledge about the properties of the cement helps the user to safely employ PMMA cements in augmentations. High radio-opacity is required in vertebral body augmentations and this is provided in particular by zirconium dioxide. In vertebral body augmentations, a low benzoyl peroxide (BPO) content can considerably prolong the liquid dough phase. In augmentations with cement fillings in the region of a tumor, a high BPO content can specifically increase the peak temperature of the PMMA cement. In osteosynthetic augmentations with PMMA, necrosis is rare because heat development in the presence of metallic implants is low due to heat conduction via the implant. Larger cement fillings where there is no heat conduction via metal implants can exhibit substantially higher peak temperatures. The flow properties of PMMA cements are of particular importance for the user to allow optimum handling of PMMA cements. In patients with hypersensitivity to antibiotics, there is no need to avoid the use of PMMA as there are sufficient PMMA-based alternatives. The PMMA cements are local drug delivery systems and antibiotics, antiseptics, antimycotics and also cytostatics can be mixed with the cement. Attention must be paid to antagonistic and synergistic effects.

Iro/IRX transcription factors negatively regulate Dpp/TGF-β pathway activity during intestinal tumorigenesis.

PubMed

Martorell, Òscar; Barriga, Francisco M; Merlos-Suárez, Anna; Stephan-Otto Attolini, Camille; Casanova, Jordi; Batlle, Eduard; Sancho, Elena; Casali, Andreu

2014-11-01

Activating mutations in Wnt and EGFR/Ras signaling pathways are common in colorectal cancer (CRC). Remarkably, clonal co-activation of these pathways in the adult Drosophila midgut induces "tumor-like" overgrowths. Here, we show that, in these clones and in CRC cell lines, Dpp/TGF-β acts as a tumor suppressor. Moreover, we discover that the Iroquois/IRX-family-protein Mirror downregulates the transcription of core components of the Dpp pathway, reducing its tumor suppressor activity. We also show that this genetic interaction is conserved in human CRC cells, where the Iro/IRX proteins IRX3 and IRX5 diminish the response to TGF-β. IRX3 and IRX5 are upregulated in human adenomas, and their levels correlate inversely with the gene expression signature of response to TGF-β. In addition, Irx5 expression confers a growth advantage in the presence of TGF-β, but is selected against in its absence. Together, our results identify a set of Iro/IRX proteins as conserved negative regulators of Dpp/TGF-β activity. We propose that during the characteristic adenoma-to-carcinoma transition of human CRC, the activity of IRX proteins could reduce the sensitivity to the cytostatic effect of TGF-β, conferring a growth advantage to tumor cells prior to the acquisition of mutations in TGF-β pathway components. © 2014 The Authors.

Discrepancy between body surface area and body composition in cancer.

PubMed

Stobäus, Nicole; Küpferling, Susanne; Lorenz, Marie-Luise; Norman, Kristina

2013-01-01

Calculation of cytostatic dose is typically based on body surface area (BSA) regardless of body composition. The aim of this study was to assess the discrepancy between BSA and low fat-free mass (FFM) by investigating the prevalence of low FFM with regard to BSA in 630 cancer patients. First, BSA was calculated according to DuBois and DuBois. Patients were divided into 6 categories with respect to their BSA. Each BSA category was further divided into 3 groups according to FFM: low (<-1 SD of mean FFM), normal (-0.99 and 0.99 SD of mean FFM) or high (>1 SD of mean FFM), which was derived through bioelectric impedance analysis. FFM was reduced in 15.7% of patients, 69% had normal and 15.2% had high FFM. In patients with low FFM (i.e., more than-1 SD lower than the mean FFM within their BSA group), body mass index and fatigue were higher whereas functional status was reduced. Moreover, in the subcohort of patients receiving chemotherapy, absolute FFM [Hazard ratio (HR) = 0.970, P = 0.026] as well as the allocation to the low FFM group (HR = 1.644, P = 0.025) emerged as predictors of increased 1-yr mortality. In conclusion, there was a large discrepancy between FFM and BSA. Particularly women were affected by low FFM.

Induction of cytogenetic damage in human lymphocytes in vitro and of antineoplastic effects in Ehrlich ascites tumor cells in vivo treated by methotrexate, hyperthermia and/or caffeine.

PubMed

Maskaleris, T; Lialiaris, T; Triantaphyllidis, C

1998-12-03

The synergistic effect of methotrexate (at concentrations between 3. 1 and 100 nM) and its combinations with caffeine (618 microM) and/or hyperthermia (42 degreesC for 2 h) on the frequency of sister chromatid exchanges (SCEs), the proliferating rate index and the mitotic index in cultured human lymphocytes, was examined. Also, the in vivo antineoplastic effects of methotrexate (at a concentration of 0.45 microg/g body weight) and its combination with caffeine (120 microg/g body weight), both on the survival time and the increase of the weight of tumor of BALB/c mice inoculated with Ehrlich ascites tumor cells was examined in the present study. The results indicated that: (a) the triple combination of methotrexate, caffeine and hyperthermia synergistically increased the levels of SCEs and exerted cytostatic and cytotoxic action and (b) the combination of methotrexate and caffeine significantly increased the survival span of the mice inoculated with Ehrlich ascites tumor cells and reduced the increase of the weight of their tumors at rates higher than in the case of methotrexate by itself. It is suggested that the above triple combination (methotrexate plus caffeine plus hyperthermia) could achieve increased effectiveness of methotrexate, better therapy results, and could be successfully applied in the treatment of various types of cancer. Copyright 1998 Elsevier Science B.V.

Estimation of dynamic treatment strategies for maintenance therapy of children with acute lymphoblastic leukaemia: an application of history-adjusted marginal structural models.

PubMed

Rosthøj, S; Keiding, N; Schmiegelow, K

2012-02-28

Childhood acute lymphoblastic leukaemia is treated with long-term intensive chemotherapy. During the latter part of the treatment, the maintenance therapy, the patients receive oral doses of two cytostatics. The doses are tailored to blood counts measured on a weekly basis, and the treatment is therefore highly dynamic. In 1992-1996, the Nordic Society of Paediatric Haematology and Oncology (NOPHO) conducted a randomised study (NOPHO-ALL-92) to investigate the effect of a new and more sophisticated dynamic treatment strategy. Unexpectedly, the new strategy worsened the outcome for the girls, whereas there were no treatment differences for the boys. There are as yet no general guidelines for optimising the treatment. On basis of the data from this study, our goal is to formulate an alternative dosing strategy. We use recently developed methods proposed by van der Laan et al. to obtain statistical models that may be used in the guidance of how the physicians should assign the doses to the patients to obtain the target of the treatment. We present a possible strategy and discuss the reliability of this strategy. The implementation is complicated, and we touch upon the limitations of the methods in relation to the formulation of alternative dosing strategies for the maintenance therapy. Copyright © 2011 John Wiley & Sons, Ltd.

FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma.

PubMed

Suryo Rahmanto, Aldwin; Savov, Vasil; Brunner, Andrä; Bolin, Sara; Weishaupt, Holger; Malyukova, Alena; Rosén, Gabriela; Čančer, Matko; Hutter, Sonja; Sundström, Anders; Kawauchi, Daisuke; Jones, David Tw; Spruck, Charles; Taylor, Michael D; Cho, Yoon-Jae; Pfister, Stefan M; Kool, Marcel; Korshunov, Andrey; Swartling, Fredrik J; Sangfelt, Olle

2016-10-17

SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here, we show that SOX9 is a substrate of FBW7, a tumor suppressor, and a SCF (SKP1/CUL1/F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase and consequently degraded by SCF FBW 7α Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. FBW7 is either mutated or downregulated in medulloblastoma, and in cases where FBW7 mRNA levels are low, SOX9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Transcriptional profiling of medulloblastoma cells expressing a degradation-resistant SOX9 mutant reveals activation of pro-metastatic genes and genes linked to cisplatin resistance. Finally, we show that pharmacological inhibition of PI3K/AKT/mTOR pathway activity destabilizes SOX9 in a GSK3/FBW7-dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Charomers—Interleukin-6 Receptor Specific Aptamers for Cellular Internalization and Targeted Drug Delivery

PubMed Central

2017-01-01

Interleukin-6 (IL-6) is a key player in inflammation and the main factor for the induction of acute phase protein biosynthesis. Further to its central role in many aspects of the immune system, IL-6 regulates a variety of homeostatic processes. To interfere with IL-6 dependent diseases, such as various autoimmune diseases or certain cancers like multiple myeloma or hepatocellular carcinoma associated with chronic inflammation, it might be a sensible strategy to target human IL-6 receptor (hIL-6R) presenting cells with aptamers. We therefore have selected and characterized different DNA and RNA aptamers specifically binding IL-6R. These IL-6R aptamers, however, do not interfere with the IL-6 signaling pathway but are internalized with the receptor and thus can serve as vehicles for the delivery of different cargo molecules like therapeutics. We succeeded in the construction of a chlorin e6 derivatized aptamer to be delivered for targeted photodynamic therapy (PDT). Furthermore, we were able to synthesize an aptamer intrinsically comprising the cytostatic 5-Fluoro-2′-deoxy-uridine for targeted chemotherapy. The α6β4 integrin specific DNA aptamer IDA, also selected in our laboratory is internalized, too. All these aptamers can serve as vehicles for targeted drug delivery into cells. We call them charomers—in memory of Charon, the ferryman in Greek mythology, who ferried the deceased into the underworld. PMID:29211023

The Dual Role of TGFβ in Human Cancer: From Tumor Suppression to Cancer Metastasis

PubMed Central

Lebrun, Jean-Jacques

2012-01-01

The transforming growth factor-beta (TGFβ) superfamily encompasses widespread and evolutionarily conserved polypeptide growth factors that regulate and orchestrate growth and differentiation in all cell types and tissues. While they regulate asymmetric cell division and cell fate determination during early development and embryogenesis, TGFβ family members play a major regulatory role in hormonal and immune responses, cell growth, cell death and cell immortalization, bone formation, tissue remodeling and repair, and erythropoiesis throughout adult life. The biological and physiological functions of TGFβ, the founding member of this family, and its receptors are of central importance to human diseases, particularly cancer. By regulating cell growth, death, and immortalization, TGFβ signaling pathways exert tumor suppressor effects in normal cells and early carcinomas. Thus, it is not surprising that a high number of human tumors arise due to mutations or deletions in the genes coding for the various TGFβ signaling components. As tumors develop and progress, these protective and cytostatic effects of TGFβ are often lost. TGFβ signaling then switches to promote cancer progression, invasion, and tumor metastasis. The molecular mechanisms underlying this dual role of TGFβ in human cancer will be discussed in depth in this paper, and it will highlight the challenge and importance of developing novel therapeutic strategies specifically aimed at blocking the prometastatic arm of the TGFβ signaling pathway without affecting its tumor suppressive effects. PMID:27340590

Cytokine gene expression in intestine of rat during the postnatal developmental period: increased IL-1 expression at weaning.

PubMed

Mengheri, E; Ciapponi, L; Vignolini, F; Nobili, F

1996-01-01

In the present study we have investigate whether cytokines are constitutively and differently expressed in intestine during the differentiative processes that take place at weaning. We have analyzed the expression of IL-1 beta, IL-2, IL-4 and IFN gamma by polymerase chain reaction in Peyer's patches (PP) and in intestine deprived of PP (I-PP) of rats from 16 to 30 days of age. The results showed a constitutive and marked expression of the cytokines already before weaning, with the exception of IL-2 in PP and IFN gamma in I-PP. IL-beta was the only cytokine to show a different expression at various ages with an initial increase at 19 days and a further elevation at 21 days when intestinal epithelium passes through major differentiative stages, suggesting an involvement of this cytokine in intestinal development. We have also tested whether treatment of rats with the immunosuppressor cyclosporin A (CsA) could affect intestinal differentiation. The results showed that only some markers of differentiation were affected (proliferation of staminal crypt cells and length of crypts). This was probably due to a direct effect rather than an immunomediated effect of CsA, since treatment of three intestinal cell lines (Caco-2, HT-29, FRIC) with CsA indicated that this drug can exert a cytostatic activity on intestinal cells.

Cytotoxic and genotoxic effects of silver nanoparticles in testicular cells.

PubMed

Asare, Nana; Instanes, Christine; Sandberg, Wiggo J; Refsnes, Magne; Schwarze, Per; Kruszewski, Marcin; Brunborg, Gunnar

2012-01-27

Serious concerns have been expressed about potential risks of engineered nanoparticles. Regulatory health risk assessment of such particles has become mandatory for the safe use of nanomaterials in consumer products and medicines; including the potential effects on reproduction and fertility, are relevant for this risk evaluation. In this study, we examined effects of silver particles of nano- (20nm) and submicron- (200nm) size, and titanium dioxide nanoparticles (TiO(2)-NPs; 21nm), with emphasis on reproductive cellular- and genotoxicity. Ntera2 (NT2, human testicular embryonic carcinoma cell line), and primary testicular cells from C57BL6 mice of wild type (WT) and 8-oxoguanine DNA glycosylase knock-out (KO, mOgg1(-/-)) genotype were exposed to the particles. The latter mimics the repair status of human testicular cells vs oxidative damage and is thus a suitable model for human male reproductive toxicity studies. The results suggest that silver nano- and submicron-particles (AgNPs) are more cytotoxic and cytostatic compared to TiO(2)-NPs, causing apoptosis, necrosis and decreased proliferation in a concentration- and time-dependent manner. The 200nm AgNPs in particular appeared to cause a concentration-dependent increase in DNA-strand breaks in NT2 cells, whereas the latter response did not seem to occur with respect to oxidative purine base damage analysed with any of the particles tested. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Role of Anthocyanin-enriched Purple-fleshed Sweet Potato P40 in Colorectal Cancer Prevention

PubMed Central

Lim, Soyoung; Xu, Jianteng; Kim, Jaeyong; Chen, Tzu-Yu; Su, Xiaoyu; Standard, Joseph; Carey, Edward; Griffin, Jason; Herndon, Betty; Katz, Benjamin; Tomich, John; Wang, Weiqun

2013-01-01

Scope Anthocyanins, the natural pigments in plant foods, have been associated with cancer prevention. However, the content of anthocyanins in staple foods is typically low and the mechanisms by which they exert anti-cancer activity is not yet fully defined. Methods and results We selected an anthocyanin-enriched purple-fleshed sweet potato clone, P40, and investigated its potential anti-cancer effect in both in vitro cell culture and in vivo animal model. In addition to a high level of total phenolics and antioxidant capacity, P40 possesses a high content of anthocyanins at 7.5 mg/g dry matter. Treatment of human colonic SW480 cancer cells with P40 anthocyanin extracts at 0–40 μM of peonidin-3-glucoside equivalent resulted in a dose-dependent decrease in cell number due to cytostatic arrest of cell cycle at G1 phase but not cytotoxicity. Furthermore, dietary P40 at 10–30% significantly suppressed azoxymethane-induced formation of aberrant crypt foci in the colons of CF-1 mice in conjunction with, at least in part, a lesser proliferative PCNA and a greater apoptotic caspase-3 expression in the colon mucosal epithelial cells. Conclusion These observations, coupled with both in vitro and in vivo studies reported here, suggest anthocyanin-enriched sweet potato P40 may protect against colorectal cancer by inducing cell cycle arrest, anti-proliferative and apoptotic mechanisms. PMID:23784800

Phytometabolite Dehydroleucodine Induces Cell Cycle Arrest, Apoptosis, and DNA Damage in Human Astrocytoma Cells through p73/p53 Regulation.

PubMed

Bailon-Moscoso, Natalia; González-Arévalo, Gabriela; Velásquez-Rojas, Gabriela; Malagon, Omar; Vidari, Giovanni; Zentella-Dehesa, Alejandro; Ratovitski, Edward A; Ostrosky-Wegman, Patricia

2015-01-01

Accumulating evidence supports the idea that secondary metabolites obtained from medicinal plants (phytometabolites) may be important contributors in the development of new chemotherapeutic agents to reduce the occurrence or recurrence of cancer. Our study focused on Dehydroleucodine (DhL), a sesquiterpene found in the provinces of Loja and Zamora-Chinchipe. In this study, we showed that DhL displayed cytostatic and cytotoxic activities on the human cerebral astrocytoma D384 cell line. With lactone isolated from Gynoxys verrucosa Wedd, a medicinal plant from Ecuador, we found that DhL induced cell death in D384 cells by triggering cell cycle arrest and inducing apoptosis and DNA damage. We further found that the cell death resulted in the increased expression of CDKN1A and BAX proteins. A marked induction of the levels of total TP73 and phosphorylated TP53, TP73, and γ-H2AX proteins was observed in D384 cells exposed to DhL, but no increase in total TP53 levels was detected. Overall these studies demonstrated the marked effect of DhL on the diminished survival of human astrocytoma cells through the induced expression of TP73 and phosphorylation of TP73 and TP53, suggesting their key roles in the tumor cell response to DhL treatment.

Phytometabolite Dehydroleucodine Induces Cell Cycle Arrest, Apoptosis, and DNA Damage in Human Astrocytoma Cells through p73/p53 Regulation

PubMed Central

Bailon-Moscoso, Natalia; González-Arévalo, Gabriela; Velásquez-Rojas, Gabriela; Malagon, Omar; Vidari, Giovanni; Zentella-Dehesa, Alejandro; Ratovitski, Edward A.; Ostrosky-Wegman, Patricia

2015-01-01

Accumulating evidence supports the idea that secondary metabolites obtained from medicinal plants (phytometabolites) may be important contributors in the development of new chemotherapeutic agents to reduce the occurrence or recurrence of cancer. Our study focused on Dehydroleucodine (DhL), a sesquiterpene found in the provinces of Loja and Zamora-Chinchipe. In this study, we showed that DhL displayed cytostatic and cytotoxic activities on the human cerebral astrocytoma D384 cell line. With lactone isolated from Gynoxys verrucosa Wedd, a medicinal plant from Ecuador, we found that DhL induced cell death in D384 cells by triggering cell cycle arrest and inducing apoptosis and DNA damage. We further found that the cell death resulted in the increased expression of CDKN1A and BAX proteins. A marked induction of the levels of total TP73 and phosphorylated TP53, TP73, and γ-H2AX proteins was observed in D384 cells exposed to DhL, but no increase in total TP53 levels was detected. Overall these studies demonstrated the marked effect of DhL on the diminished survival of human astrocytoma cells through the induced expression of TP73 and phosphorylation of TP73 and TP53, suggesting their key roles in the tumor cell response to DhL treatment. PMID:26309132

The anti-tumor effect of bee honey in Ehrlich ascite tumor model of mice is coincided with stimulation of the immune cells.

PubMed

Attia, W Y; Gabry, M S; El-Shaikh, K A; Othman, G A

2008-01-01

Honey is thought to exhibit a broad spectrum of therapeutic properties including antibacterial, antifungal, cytostatic and anti-inflammatory activity and has been used for the treatment of gastric ulcers, burns, and for storage of skin grafts. The present study investigated the antitumor effect of bee honey against Ehrlich ascites tumor in mice and the possible mode of antitumor action. Peroral administration of mice with honey (10, 100 or 1000 mg/ 100 g BW) every other day for 4 weeks before intraperitoneal inoculation with Ehrlich ascites tumor (EAT, 1 x 10(6) cells) increased the number bone marrow cells as well as peritoneal macrophages, but not peripheral blood leukocytes nor splenocytes. The phagocytic function of macrophages as well as the T- and B-cell functions were also increased. Honey pre-treatment also recovered the total lipids, total proteins, as well as liver and kidney enzyme activities in EAT-bearing mice. In vitro studies on EAT cells demonstrated inhibitory effect of honey on tumor cell proliferation, viability % of tumor cells as well as the size of solid tumor. The present results indicate that the preventive treatment with honey is considerably effective against EAT in mice both in vivo and in vitro. The antitumor activity of honey may occur through the activation of macrophages, T-cells and B-cells.

HPV-16 E7 expression up-regulates phospholipase D activity and promotes rapamycin resistance in a pRB-dependent manner.

PubMed

Rabachini, Tatiana; Boccardo, Enrique; Andrade, Rubiana; Perez, Katia Regina; Nonogaki, Suely; Cuccovia, Iolanda Midea; Villa, Luisa Lina

2018-04-27

Human Papillomavirus (HPV) infection is the main risk factor for the development and progression of cervical cancer. HPV-16 E6 and E7 expression is essential for induction and maintenance of the transformed phenotype. These oncoproteins interfere with the function of several intracellular proteins, including those controlling the PI3K/AKT/mTOR pathway in which Phospolipase D (PLD) and Phosphatidic acid (PA) play a critical role. PLD activity was measured in primary human keratinocytes transduced with retroviruses expressing HPV-16 E6, E7 or E7 mutants. The cytostatic effect of rapamycin, a well-known mTOR inhibitor with potential clinical applications, was evaluated in monolayer and organotypic cultures. HPV-16 E7 expression in primary human keratinocytes leads to an increase in PLD expression and activity. Moreover, this activation is dependent on the ability of HPV-16 E7 to induce retinoblastoma protein (pRb) degradation. We also show that cells expressing HPV-16 E7 or silenced for pRb acquire resistance to the antiproliferative effect of rapamycin. This is the first indication that HPV oncoproteins can affect PLD activity. Since PA can interfere with the ability of rapamycin to bind mTOR, the use of combined strategies to target mTOR and PLD activity might be considered to treat HPV-related malignancies.

Ferulic acid reverses ABCB1-mediated paclitaxel resistance in MDR cell lines.

PubMed

Muthusamy, Ganesan; Balupillai, Agilan; Ramasamy, Karthikeyan; Shanmugam, Mohana; Gunaseelan, Srithar; Mary, Beaulah; Prasad, N Rajendra

2016-09-05

Multidrug resistance (MDR) remains a major obstacle in cancer chemotherapy. The use of the dietary phytochemicals as chemosensitizing agents to enhance the efficacy of conventional cytostatic drugs has recently gained the attention as a plausible approach for overcoming the drug resistance. The aim of this study was to investigate whether a naturally occurring diet-based phenolic acid, ferulic acid, could sensitize paclitaxel efficacy in ABCB1 overexpressing (P-glycoprotein) colchicine selected KB Ch(R)8-5 cell line. In vitro drug efflux assays demonstrated that ferulic acid inhibits P-glycoprotein transport function in drug resistant KB Ch(R)8-5 cell lines. However, ferulic acid significantly downregulates ABCB1 expression in a concentration dependent manner. Cytotoxicity assay reveals that ferulic acid decreased paclitaxel resistance in KBCh(R)8-5 and HEK293/ABCB1 cells, which indicates its chemosensitizing potential. Clonogenic cell survival assay and apoptotic morphological staining further confirm the chemosensitizing potential of ferulic acid in drug resistant KB Ch(R)8-5 cell lines. Ferulic acid treatment enhances paclitaxel mediated cell cycle arrest and upregulates paclitaxel-induced apoptotic signaling in KB resistant cells. Hence, it has been concluded that downregulation of ABCB1 and subsequent induction of paclitaxel-mediated cell cycle arrest and apoptotic signaling may be the cause for the chemosensitizing potential of ferulic acid in P-gp overexpressing cell lines. Copyright © 2016 Elsevier B.V. All rights reserved.

FK-3000 isolated from Stephania delavayi Diels. inhibits MDA-MB-231 cell proliferation by decreasing NF-κB phosphorylation and COX-2 expression.

PubMed

Xu, Hong De; Cho, Soon-Chang; Bang, Mi-Ae; Bae, Chun-Sik; Choi, Yeonshik; Li, Yong-Chun; Lim, Seung-Kil; Shim, Jaegal; Park, Dae-Hun

2015-01-01

The World Health Organization (WHO) has reported that cancer is one of the most prevalent diseases and a leading cause of death worldwide. Many anticancer drug development studies have been pursued over the last few decades and several viable drugs have been discovered, such as paclitaxel, topotecan and irinotecan. Previously, our research group uncovered the cytocidal and cytostatic effects of the plant Stephania delavayi Diels. In this study, we determined the active chemical to be 6,7-di-O-acetylsinococuline (FK-3000). The FK-3000 half maximal inhibitory concentration (IC50) in MDA-MB-231 breast carcinoma cells at 48 h was 0.52 µg/ml and it induced apoptosis in a dose- and time-dependent manner. FK-3000 suppressed NF-κB nuclear translocation, decreased NF-κB phosphorylation, and decreased COX-2 protein expression. MDA-MB-231 xenografted mice were treated with FK-3000, Taxol, or their combination for 21 days. The tumor size was smallest in the co-treatment group, indicating that FK-3000 may have a synergistic effect with Taxol. FK-3000 treatment showed no adverse effects on blood cell counts, serum protein levels, or pathology. These studies demonstrate that FK-3000, isolated from S. delavayi Diels., is a promising, pathway-specific anticancer agent that exhibits low toxicity.

Study of the influence of platinum, palladium and rhodium on duckweed (Lemna minor).

PubMed

Bednarova, Ivana; Mikulaskova, Hana; Havelkova, Barbora; Strakova, Lenka; Beklova, Miroslava; Sochor, Jiri; Hynek, David; Adam, Vojtech; Kizek, Rene

2014-01-01

Road traffic pollutants and the residues of cytostatics that are widely used in anti-cancer therapy are a significant sources of platinum group elements (PGE; Pt, Pd and Rh) in environment. These metals can migrate into sewage and thus pollute surface waters. The purpose of our study was to evaluate the effect of PtCl4 on the antioxidant and enzymatic activity of duckweed (Lemna minor), a bioindicator of the aquatic environment. The study was performed using a 7-day conventional test based on the OECD 221 (CSN EN ISO 20079)--Lemna sp. Growth Inhibition Test. We also conducted a microbiotest to analyse the effects of PtC4, PdCl2 and RhCl3 on the morphology and vegetative growth of colonies of this plant and compared their inhibitory effects during the microbiotest. We observed inhibition of colony growth and clear morphological changes. Antioxidant and enzymatic activities increased with platinum doses increased. The 168hEC50 of PtCl4 was 12.16 μM (95% confidence interval = 9.88-14.44) and the 168hEC50 of PdCl2 was 50.39 (95% confidence interval = 23.83-76.96). The greatest inhibition of growth by RhCl3 was observed at 25 μM. The obtained results suggest that L. minor phytotoxicity tests should be widely used in the biomonitoring.

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

PubMed

Hessmann, Elisabeth; Johnsen, Steven A; Siveke, Jens T; Ellenrieder, Volker

2017-01-01

Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies with a 5-year survival rate of <7%. Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Although intensified cytostatic combinations, particularly gemcitabine plus nab-paclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) protocol, provide some improvement in efficacy and survival compared with gemcitabine alone, a breakthrough in the treatment of metastatic pancreatic cancer remains out of sight. Nevertheless, recent translational research activities propose that either modulation of the immune response or pharmacological targeting of epigenetic modifications alone, or in combination with chemotherapy, might open highly powerful therapeutic avenues in GI cancer entities, including pancreatic cancer. Deregulation of key epigenetic factors and chromatin-modifying proteins, particularly those responsible for the addition, removal or recognition of post-translational histone modifications, are frequently found in human pancreatic cancer and hence constitute particularly exciting treatment opportunities. This review summarises both current clinical trial activities and discovery programmes initiated throughout the biopharma landscape, and critically discusses the chances, hurdles and limitations of epigenetic-based therapy in future PDAC treatment. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Mycoplasmas and cancer: focus on nucleoside metabolism

PubMed Central

Vande Voorde, Johan; Balzarini, Jan; Liekens, Sandra

2014-01-01

The standard of care for patients suffering cancer often includes treatment with nucleoside analogues (NAs). NAs are internalized by cell-specific nucleobase/nucleoside transporters and, after enzymatic activation (often one or more phosphorylation steps), interfere with cellular nucleo(s)(t)ide metabolism and DNA/RNA synthesis. Therefore, their efficacy is highly dependent on the expression and activity of nucleo(s)(t)ide-metabolizing enzymes, and alterations thereof (e.g. by down/upregulated expression or mutations) may change the susceptibility to NA-based therapy and/or confer drug resistance. Apart from host cell factors, several other variables including microbial presence may determine the metabolome (i.e. metabolite concentrations) of human tissues. Studying the diversity of microorganisms that are associated with the human body has already provided new insights in several diseases (e.g. diabetes and inflammatory bowel disease) and the metabolic exchange between tissues and their specific microbiota was found to affect the bioavailability and toxicity of certain anticancer drugs, including NAs. Several studies report a preferential colonization of tumor tissues with some mycoplasma species (mostly Mycoplasma hyorhinis). These prokaryotes are also a common source of cell culture contamination and alter the cytostatic activity of some NAs in vitro due to the expression of nucleoside-catabolizing enzymes. Mycoplasma infection may therefore bias experimental work with NAs, and their presence in the tumor microenvironment could be of significance when optimizing nucleoside-based cancer treatment. PMID:26417262

Osmolyte Type and the Osmolarity Level Affect Chondrogenesis of Mesenchymal Stem Cells.

PubMed

Ahmadyan, Sorour; Kabiri, Mahboubeh; Hanaee-Ahvaz, Hana; Farazmand, Ali

2018-06-01

The inductive effects of increased osmolarity on chondrogenesis are well approved. However, the effects of the osmolyte agent invoked to induce hyperosmolarity are largely neglected. Herein, we scrutinized how hyperosmotic conditions acquired by addition of different osmolytes would impact chondrogenesis. We briefly assessed whether such conditions would differentially affect hypertrophy and angiogenesis during MSC chondrogenesis. Chondrogenic and hypertrophic marker expression along with VEGF secretion during adipose-derived (AD)-MSC chondrogenesis under three osmolarity levels (350, 450, and 550 mOsm) using three different osmolytes (NaCl, sorbitol, and PEG) were assessed. MTT assay, qRT-PCR, immunocytochemistry, Alcian Blue staining, ELISA, and ALP assays proved osmolyte-type dependent effects of hyperosmolarity on chondrogenesis, hypertrophy, and angiogenesis. At same osmolarity level, PEG had least cytotoxic/cytostatic effect and most prohibitive effects on angiogenesis. As expected, all hyperosmolar conditions led to enhanced chondrogenesis with slightly varying degrees. PEG and sorbitol had higher chondro-promotive and hypertrophy-suppressive effects compared to NaCl, while NaCl had exacerbated hypertrophy. We observed that TonEBP was involved in osmoadaptation of all treatments in varying degrees. Of importance, we highlighted differential effects of hyperosmolarity obtained by different osmolytes on the efficacy of chondrogenesis and more remarkably on the induction/suppression of cartilage pathologic markers. Our study underlies the need for a more vigilant exploitation of physicobiochemical inducers in order to maximize chondrogenesis while restraining unwanted hypertrophy and angiogenesis.

[The drop in toxicity and the rise in the effectiveness of antineoplastic chemotherapy by correcting the activity of liver monooxygenases: from the experiment to the clinical practice].

PubMed

Bogush, T A; Bogush, E A; Durnov, L A; Syrkin, A B

2002-01-01

The paper reviews both the data available in the literature and the authors' own results of long-term experimental and clinical investigations of the involvement of hepatic monooxygenases (HMO) in the biological activity of antitumor drugs. It reports data of evaluation of HMO activity in pediatric and adult cancer patients, which has shown a decrease in HMO activity in one third of patients without clinical signs of hepatopathy and two thirds of those with toxic hepatic damages after prior chemotherapy. Decreased HMO activity has been found to be stimulated with the enzyme inductor zyxorin. Altered biochemical parameters, such as total bilirubin, ALT and AST, can be corrected with HNO, even if they show a 10-fold deviation from the normal physiological level. The efficacy of zyxorin was tested in patients with advanced cancer and concomitant toxic or viral hepatic disorders (grades II-IV by the WHO classification). Stimulation of inhibited HMO activity allows both decrease and prevention of the manifestations of hepatic toxicity due to anticancer chemotherapy providing a beneficial effect, the dose of cytostatics being not reduced. The authors concluded that the findings provide strong evidence for their assumption that the efficiency of antitumor chemotherapy can be enhanced in patients with concurrent hepatic abnormality by stimulating monooxygenases whose activity is diminished in the majority of these patients.

Charomers-Interleukin-6 Receptor Specific Aptamers for Cellular Internalization and Targeted Drug Delivery.

PubMed

Hahn, Ulrich

2017-12-06

Interleukin-6 (IL-6) is a key player in inflammation and the main factor for the induction of acute phase protein biosynthesis. Further to its central role in many aspects of the immune system, IL-6 regulates a variety of homeostatic processes. To interfere with IL-6 dependent diseases, such as various autoimmune diseases or certain cancers like multiple myeloma or hepatocellular carcinoma associated with chronic inflammation, it might be a sensible strategy to target human IL-6 receptor (hIL-6R) presenting cells with aptamers. We therefore have selected and characterized different DNA and RNA aptamers specifically binding IL-6R. These IL-6R aptamers, however, do not interfere with the IL-6 signaling pathway but are internalized with the receptor and thus can serve as vehicles for the delivery of different cargo molecules like therapeutics. We succeeded in the construction of a chlorin e6 derivatized aptamer to be delivered for targeted photodynamic therapy (PDT). Furthermore, we were able to synthesize an aptamer intrinsically comprising the cytostatic 5-Fluoro-2'-deoxy-uridine for targeted chemotherapy. The α6β4 integrin specific DNA aptamer IDA, also selected in our laboratory is internalized, too. All these aptamers can serve as vehicles for targeted drug delivery into cells. We call them charomers-in memory of Charon, the ferryman in Greek mythology, who ferried the deceased into the underworld.

Neurofilament light chain as disease biomarker in a rodent model of chemotherapy induced peripheral neuropathy.

PubMed

Meregalli, Cristina; Fumagalli, Giulia; Alberti, Paola; Canta, Annalisa; Carozzi, Valentina Alda; Chiorazzi, Alessia; Monza, Laura; Pozzi, Eleonora; Sandelius, Åsa; Blennow, Kaj; Zetterberg, Henrik; Marmiroli, Paola; Cavaletti, Guido

2018-06-13

The objective of this study is to test the feasibility of using serum neurofilament light chain (NfL) as a disease biomarker in Chemotherapy Induced Peripheral Neuropathy (CIPN) since this easy accessible biological test may have a large impact on clinical management and safety of cancer patients. We performed this preclinical study using a well-characterized rat model based on repeated administration of the cytostatic drug vincristine (VCR, 0.2 mg/kg intravenously via the tail vein once/week for 4 times). Serial NfL serum concentration measured using the in-house Simoa NfL assay and peripheral neuropathy onset was measured by sensory and motor nerve conduction studies. Serum NfL measure in untreated and VCR-treated rats demonstrated a steady, and significant increase during the course of VCR administration, with a final 4-fold increase with respect to controls (p < .001) when sign of axonopathy and loss of intraepidermal nerve fibers were clearly evident and verified by behavioral, neurophysiological and pathological examination. This simple monitoring approach based on serum NfL concentration measures may be easily translated to clinical practice and should be considered as a putative marker of CIPN severity in a typical oncology outpatient setting. Further studies are needed to validate it's utility in cancer patients treated with different neurotoxic drugs. Copyright © 2017. Published by Elsevier Inc.

Peritoneal metastases of colorectal origin - cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). The financial aspect.

PubMed

Jastrzębski, Tomasz; Bębenek, Marek

2017-12-30

The incidence of peritoneal carcinomatosis of colorectal cancer amounts to 5%-15% for synchronous metastases and as much as 40% in cases of local recurrence. Best results are obtained for cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment offers much better outcomes, leading to 5-year survival rates of as much as 30%-50%. The procedures require significant experience in abdominal surgery, are time-consuming (mean duration of the procedure ranging from 6 to 8 hours) and are burdened by complications that are due not only to the procedure itself but also to the intraperitoneal administration of the cytostatic drug at elevated temperature (41.5 °C). After the procedure, patients are required to be admitted to intensive care units due to potential complications associated with the extent and duration of the procedure as well as chemotherapy administered in hyperthermia. Postoperative management of these patients requires appropriate experience of the entire medical and nursing team. Cytoreductive surgeries combined with HIPEC as highly specialized medical procedures should be assessed for their potential long-term benefits and their costs should be appropriately calculated with consideration to realistic reimbursement rates. Realistic valuation and reimbursement covering the overall average cost of the procedure is recommended by the National Consultant in Surgical Oncology as well as the ESMO consensus guidelines.

Pharmaceutically active secondary metabolites of marine actinobacteria.

PubMed

Manivasagan, Panchanathan; Venkatesan, Jayachandran; Sivakumar, Kannan; Kim, Se-Kwon

2014-04-01

Marine actinobacteria are one of the most efficient groups of secondary metabolite producers and are very important from an industrial point of view. Many representatives of the order Actinomycetales are prolific producers of thousands of biologically active secondary metabolites. Actinobacteria from terrestrial sources have been studied and screened since the 1950s, for many important antibiotics, anticancer, antitumor and immunosuppressive agents. However, frequent rediscovery of the same compounds from the terrestrial actinobacteria has made them less attractive for screening programs in the recent years. At the same time, actinobacteria isolated from the marine environment have currently received considerable attention due to the structural diversity and unique biological activities of their secondary metabolites. They are efficient producers of new secondary metabolites that show a range of biological activities including antibacterial, antifungal, anticancer, antitumor, cytotoxic, cytostatic, anti-inflammatory, anti-parasitic, anti-malaria, antiviral, antioxidant, anti-angiogenesis, etc. In this review, an evaluation is made on the current status of research on marine actinobacteria yielding pharmaceutically active secondary metabolites. Bioactive compounds from marine actinobacteria possess distinct chemical structures that may form the basis for synthesis of new drugs that could be used to combat resistant pathogens. With the increasing advancement in science and technology, there would be a greater demand for new bioactive compounds synthesized by actinobacteria from various marine sources in future. Copyright © 2013 Elsevier GmbH. All rights reserved.

5-Benzylglycinyl-Amiloride Kills Proliferating and Nonproliferating Malignant Glioma Cells through Caspase-Independent Necroptosis Mediated by Apoptosis-Inducing Factor

PubMed Central

Pasupuleti, Nagarekha; Leon, Leonardo; Carraway, Kermit L.

2013-01-01

5′–Βenzylglycinyl-amiloride (UCD38B) and glycinyl-amiloride (UCD74A) are cell-permeant and cell-impermeant derivatives of amiloride, respectively, and used here to identify the cellular mechanisms of action underlying their antiglioma effects. UCD38B comparably kills proliferating and nonproliferating gliomas cells when cell cycle progression is arrested either by cyclin D1 siRNA or by acidification. Cell impermeant UCD74A inhibits plasmalemmal urokinase plasminogen activator (uPA) and the type 1 sodium-proton exchanger with potencies analogous to UCD38B, but is cytostatic. In contrast, UCD38B targets intracellular uPA causing mistrafficking of uPA into perinuclear mitochondria, reducing the mitochondrial membrane potential, and followed by the release of apoptotic inducible factor (AIF). AIF nuclear translocation is followed by a caspase-independent necroptotic cell death. Reduction in AIF expression by siRNA reduces the antiglioma cytotoxic effects of UCD38B, while not activating the caspase pathway. Ultrastructural changes shortly following treatment with UCD38B demonstrate dilation of endoplasmic reticulum (ER) and mitochondrial swelling followed by nuclear condensation within hours consistent with a necroptotic cell death differing from apoptosis and from autophagy. These drug mechanism of action studies demonstrate that UCD38B induces a cell cycle-independent, caspase-independent necroptotic glioma cell death that is mediated by AIF and independent of poly (ADP-ribose) polymerase and H2AX activation. PMID:23241369

Guidelines for safe handling of hazardous drugs: A systematic review

PubMed Central

Bernabeu-Martínez, Mari A.; Ramos Merino, Mateo; Santos Gago, Juan M.; Álvarez Sabucedo, Luis M.; Wanden-Berghe, Carmina

2018-01-01

Objective To review the scientific literature related to the safe handling of hazardous drugs (HDs). Method Critical analysis of works retrieved from MEDLINE, the Cochrane Library, Scopus, CINHAL, Web of Science and LILACS using the terms "Hazardous Substances", "Antineoplastic Agents" and "Cytostatic Agents", applying "Humans" and "Guidelines" as filters. Date of search: January 2017. Results In total, 1100 references were retrieved, and from those, 61 documents were selected based on the inclusion and exclusion criteria: 24 (39.3%) documents related to recommendations about HDs; 27 (44.3%) about antineoplastic agents, and 10 (33.3%) about other types of substances (monoclonal antibodies, gene medicine and other chemical and biological agents). In 14 (23.3%) guides, all the stages in the manipulation process involving a risk due to exposure were considered. Only one guide addressed all stages of the handling process of HDs (including stages with and without the risk of exposure). The most described stages were drug preparation (41 guides, 67.2%), staff training and/or patient education (38 guides, 62.3%), and administration (37 guides, 60.7%). No standardized informatics system was found that ensured quality management, traceability and minimization of the risks associated with these drugs. Conclusions Most of the analysed guidelines limit their recommendations to the manipulation of antineoplastics. The most frequently described activities were preparation, training, and administration. It would be convenient to apply ICTs (Information and Communications Technologies) to manage processes involving HDs in a more complete and simpler fashion. PMID:29750798

Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

PubMed Central

Kawata, S; Yamasaki, E; Nagase, T; Inui, Y; Ito, N; Matsuda, Y; Inada, M; Tamura, S; Noda, S; Imai, Y; Matsuzawa, Y

2001-01-01

Chemotherapy is not effective for hepatocellular carcinoma (HCC). HMG-CoA redutase inhibitors have cytostatic activity for cancer cells, but their clinical usefulness is unknown. To investigate whether pravastatin, a potent HMG-CoA reductase inhibitor, prolongs survival in patients with advanced HCC, this randomized controlled trial was conducted between February 1990 and February 1998 at Osaka University Hospital. 91 consecutive patients <71 years old (mean age 62) with unresectable HCC were enroled in this study. 8 patients were withdrawn because of progressive liver dysfunction; 83 patients were randomized to standard treatment with or without pravastatin. All patients underwent transcatheter arterial embolization (TAE) followed by oral 5-FU 200 mg−1d for 2 months. Patients were then randomly assigned to control (n = 42) and pravastatin (n = 41) groups. Pravastatin was administered at a daily dose of 40 mg. The effect of pravastatin on tumour growth was assessed by ultrasonography. Primary endpoint was death due to progression of HCC. The duration of pravastatin administration was 16.5 ± 9.8 months (mean ± SD). No patients in either group were lost to follow-up. Median survival was 18 months in the pravastatin group versus 9 months in controls (P = 0.006). The Cox proportional hazards model showed that pravastatin was a significant factor contributing to survival. Pravastatin prolonged the survival of patients with advanced HCC, suggesting its value for adjuvant treatment. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11286466

Smad phospho-isoforms direct context-dependent TGF-β signaling.

PubMed

Matsuzaki, Koichi

2013-08-01

Better understanding of TGF-β signaling has deepened our appreciation of normal epithelial cell homeostasis and its dysfunction in such human disorders as cancer and fibrosis. Smad proteins, which convey signals from TGF-β receptors to the nucleus, possess intermediate linker regions connecting Mad homology domains. Membrane-bound, cytoplasmic, and nuclear protein kinases differentially phosphorylate Smad2 and Smad3 to create C-tail (C), the linker (L), or dually (L/C) phosphorylated (p, phospho-) isoforms. According to domain-specific phosphorylation, distinct transcriptional responses, and selective metabolism, Smad phospho-isoform pathways can be grouped into 4 types: cytostatic pSmad3C signaling, mitogenic pSmad3L (Ser-213) signaling, invasive/fibrogenic pSmad2L (Ser-245/250/255)/C or pSmad3L (Ser-204)/C signaling, and mitogenic/migratory pSmad2/3L (Thr-220/179)/C signaling. We outline how responses to TGF-β change through the multiple Smad phospho-isoforms as normal epithelial cells mature from stem cells through progenitors to differentiated cells, and further reflect upon how constitutive Ras-activating mutants favor the Smad phospho-isoform pathway promoting tumor progression. Finally, clinical analyses of reversible Smad phospho-isoform signaling during human carcinogenesis could assess effectiveness of interventions aimed at reducing human cancer risk. Spatiotemporally separate, functionally different Smad phospho-isoforms have been identified in specific cells and tissues, answering long-standing questions about context-dependent TGF-β signaling. Copyright © 2013 Elsevier Ltd. All rights reserved.

A karyometric note on nucleoli in human early granulocytic precursors.

PubMed

Smetana, K; Mikulenková, D; Jirásková, I; Klamová, H

2006-01-01

The diameter of nucleoli was measured in human bone marrow early granulocytic precursors after visualization by a simple cytochemical method for demonstration of RNA. Such method facilitated to clearly see nucleolar bodies without perinucleolar chromatin, including those of micronucleoli. The bone marrow of patients suffering from chronic myeloid leukaemia (untreated with cytostatics) provided a satisfactory number of both myeloblasts and promyelocytes for nucleolar measurements because of prevailing granulopoiesis. The direct nucleolar measurement was carried out on digitized and processed images on the screen at magnification 4,300x. It seems to be likely that the nucleolar size is directly related to the number of nucleoli per cell. The largest nucleoli were present in both myeloblasts and promyelocytes that possessed a single nucleolus. In contrast, the nucleolar diameter was significantly smaller in cells with multiple nucleoli. However, in cells with small multiple nucleoli, one of them was always larger and dominant with a large number of AgNORs. Such large nucleoli are possibly visible in specimens stained with panoptic procedures or methods staining nuclear chromatin or DNA. It should also be mentioned that both myeloblasts and promyelocytes mostly possessed two nucleoli with the mean diameter close to 1.5 microm. The incidence of early granulocytic precursors classified according to the nucleolar number and size strongly suggested that the various nucleolar number and nucleolar size in these cells might be related to the different stage of the cell cycle and might also explain their heterogeneity.

Occurrence of cyclophosphamide and ifosfamide in aqueous environment and their removal by biological and abiotic wastewater treatment processes.

PubMed

Česen, Marjeta; Kosjek, Tina; Laimou-Geraniou, Maria; Kompare, Boris; Širok, Brane; Lambropolou, Dimitra; Heath, Ester

2015-09-15

Cytostatic drug residues in the aqueous environment are of concern due to their possible adverse effects on non-target organisms. Here we report the occurrence and removal efficiency of cyclophosphamide (CP) and ifosfamide (IF) by biological and abiotic treatments including advanced oxidation processes (AOPs). Cyclophosphamide was detected in hospital wastewaters (14-22,000 ng L(-1)), wastewater treatment plant influents (19-27 ng L(-1)) and effluent (17 ng L(-1)), whereas IF was detected only in hospital wastewaters (48-6800 ng L(-1)). The highest removal efficiency during biological treatment (attached growth biomass in a flow through bioreactor) was 59 ± 15% and 35 ± 9.3% for CP and IF, respectively. Also reported are the removal efficiencies of both compounds from wastewater using hydrodynamic cavitation (HC), ozonation (O3) and/or UV, either individually or in combination with hydrogen peroxide (H2O2). Hydrodynamic cavitation did not remove CP and IF to any significant degree. The highest removal efficiencies: 99 ± 0.71% for CP and 94 ± 2.4% for IF, were achieved using UV/O3/H2O2 at 5 g L(-1) for 120 min. When combined with biological treatment, removal efficiencies were >99% for both compounds. This is the first report of combined biological and AOP treatment of CP and IF from wastewater with a removal efficiency >99%. Copyright © 2015 Elsevier B.V. All rights reserved.

Simultaneous determination of clofarabine and cytarabine in human plasma by LC-MS/MS.

PubMed

Büttner, Božena; Oertel, Reinhard; Schetelig, Johannes; Middeke, Jan Moritz; Bornhäuser, Martin; Seeling, Andreas; Knoth, Holger

2016-06-05

Combination of cytostatic agents is a basic principle in the treatment of cancer. For the treatment of acute myeloid leukemia (AML), purine analogs, like clofarabine and cytarabine act synergistically. Little is known, however, on their interaction in vivo. We developed a method for the simultaneous determination of clofarabine and cytarabine in human plasma. The substances were extracted from plasma samples by protein precipitation with acetonitrile. Cladribine was the internal standard (IS). The analytes were separated on Synergi HydroRP column (150mm×2.0mm, 4μm) and a triple-quadrupole mass spectrometry with an electrospray ionisation (ESI) source was applied for detection. The mobile phase consisted of acetonitrile, ammonium acetate 2mM and 0.5% formic acid in a gradient mode at a flow rate of 0.5ml/min. The injection volume was 10μl and the total run time was 6.0min. Retention times were 2.46min for clofarabine, 0.97min for cytarabine and 2.43min for the IS. Calibration ranges were 8-1000ng/ml for clofarabine and 20-2500ng/ml for cytarabine. The intra-day and inter-day precision was less than 15% and the relative standard deviation was all within ±15%. This new method allows a rapid and simple determination of both clofarabine and cytarabine in human plasma. It was applied to a pharmacokinetic investigation within a hematological trial in adult patients with AML. Copyright © 2016 Elsevier B.V. All rights reserved.

Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages

PubMed Central

Xia, Yong; Zweier, Jay L.

1997-01-01

Superoxide (O2⨪) and nitric oxide (NO) act to kill invading microbes in phagocytes. In macrophages NO is synthesized by inducible nitric oxide synthase (iNOS, NOS 2) from l-arginine (l-Arg) and oxygen; however, O2⨪ was thought to be produced mainly by NADPH oxidase. Electron paramagnetic resonance (EPR) spin trapping experiments performed in murine macrophages demonstrate a novel pathway of O2⨪ generation. It was observed that depletion of cytosolic l-Arg triggers O2⨪ generation from iNOS. This iNOS-mediated O2⨪ generation was blocked by the NOS inhibitor N-nitro-l-arginine methyl ester or by l-Arg, but not by the noninhibitory enantiomer N-nitro-d-arginine methyl ester. In l-Arg-depleted macrophages iNOS generates both O2⨪ and NO that interact to form the potent oxidant peroxynitrite (ONOO−), which was detected by luminol luminescence and whose formation was blocked by superoxide dismutase, urate, or l-Arg. This iNOS-derived ONOO− resulted in nitrotyrosine formation, and this was inhibited by iNOS blockade. iNOS-mediated O2⨪ and ONOO− increased the antibacterial activity of macrophages. Thus, with reduced l-Arg availability iNOS produces O2⨪ and ONOO− that modulate macrophage function. Due to the existence of l-Arg depletion in inflammation, iNOS-mediated O2⨪ and ONOO− may occur and contribute to cytostatic/cytotoxic actions of macrophages. PMID:9192673

Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology).

PubMed

Soffietti, Riccardo; Trevisan, Elisa; Bertero, Luca; Cassoni, Paola; Morra, Isabella; Fabrini, Maria Grazia; Pasqualetti, Francesco; Lolli, Ivan; Castiglione, Anna; Ciccone, Giovannino; Rudà, Roberta

2014-02-01

The optimal combination of bevacizumab with cytotoxic or cytostatic drugs in recurrent glioblastoma is unknown. We performed a phase 2 trial of combined bevacizumab and fotemustine for patients with glioblastoma at first relapse after radiotherapy and temozolomide. The primary endpoint was 6-month progression-free survival (PFS), while secondary endpoints were overall survival (OS), response rate based on RANO criteria and toxicity. Fifty-four patients with recurrent GBM were enrolled. The authors observed a 6-month PFS rate of 42.6% (95% CI 29.3-55.2) and a median PFS of 5.2 months (95% CI 3.8-6.6). The median OS was 9.1 months (95% CI 7.3-10.3). Twenty-eight patients (52%) had a radiographic response, and a significant neurological improvement with steroid reduction was observed in 25/42 symptomatic patients (60%). MGMT promoter methylation was significantly associated with improved PFS in univariate analysis. Most unifocal tumors at baseline had a focal enhancing progression (76%), while the diffuse non-enhancing progression accounted for 9.5%. Response or survival were not associated with any pattern of progression. Survival after failure of treatment was short. Twelve out of 54 patients (22%) discontinued fotemustine for grade 3/4 myelotoxicity, while 4/54 (7.4%) discontinued bevacizumab. This study failed to demonstrate a superiority of the combination of bevacizumab and fotemustine over either bevacizumab or fotemustine alone as historical controls. Future studies should explore alternative regimens of combination of the two drugs.

Polyamine uptake by the intraerythrocytic malaria parasite, Plasmodium falciparum.

PubMed

Niemand, J; Louw, A I; Birkholtz, L; Kirk, K

2012-09-01

Polyamines and the enzymes involved in their biosynthesis are present at high levels in rapidly proliferating cells, including cancer cells and protozoan parasites. Inhibition of polyamine biosynthesis in asexual blood-stage malaria parasites causes cytostatic arrest of parasite development under in vitro conditions, but does not cure infections in vivo. This may be due to replenishment of the parasite's intracellular polyamine pool via salvage of exogenous polyamines from the host. However, the mechanism(s) of polyamine uptake by the intraerythrocytic parasite are not well understood. In this study, the uptake of the polyamines, putrescine and spermidine, into Plasmodium falciparum parasites functionally isolated from their host erythrocyte was investigated using radioisotope flux techniques. Both putrescine and spermidine were taken up into isolated parasites via a temperature-dependent process that showed cross-competition between different polyamines. There was also some inhibition of polyamine uptake by basic amino acids. Inhibition of polyamine biosynthesis led to an increase in the total amount of putrescine and spermidine taken up from the extracellular medium. The uptake of putrescine and spermidine by isolated parasites was independent of extracellular Na(+) but increased with increasing external pH. Uptake also showed a marked dependence on the parasite's membrane potential, decreasing with membrane depolarization and increasing with membrane hyperpolarization. The data are consistent with polyamines being taken up into the parasite via an electrogenic uptake process, energised by the parasite's inwardly negative membrane potential. Copyright © 2012 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Multidrug resistance characterization in multicellular tumour spheroids from two human lung cancer cell lines.

PubMed

Barrera-Rodríguez, Raúl; Fuentes, Jorge Morales

2015-01-01

Most of the knowledge about the mechanisms of multidrug resistance in lung cancer has been achieved through the use of cell lines isolated from tumours cultivated either in suspensions of isolated cells or in monolayers and following exposition to different cytostatic agents. However, tumour cell lines growing as multicellular tumour spheroids (MTS) frequently develop multicellular resistance in a drug-independent form. The aim of this study was to characterize the phenotypic and functional differences between two human NSCLC cell lines (INER-37 and INER-51) grown as traditional monolayer cultures versus as MTS. After 72 hours treatment with anticancer drugs, chemosensitivity in monolayers and tumour spheroids cultures was assessed using MTT assay. Reverse transcription-polymerase chain reaction was employed to detect the mRNAs of multidrug resistance-related genes. The expression of P-gp was analyzed by immunohistochemical staining and cell cycle profiles were analyzed using FACS. The results indicate that when grown as MTS each lung cancer cell line had different morphologies as well as and abrogation of cell proliferation with decrease of the G2/M phase. Also, MTS acquired multicellular resistance to several chemotherapeutic agents in only a few days of culture which were accomplished by significant changes in the expression of MDR-related genes. Overall, the MTS culture changed the cellular response to drugs nevertheless each of the cell lines studied seems to implement different mechanisms to acquire multicellular resistance.

Ganglionic adrenergic action modulates ovarian steroids and nitric oxide in prepubertal rat.

PubMed

Delgado, Silvia Marcela; Casais, Marilina; Sosa, Zulema; Rastrilla, Ana María

2006-08-01

Both peripheral innervation and nitric oxide (NO) participate in ovarian steroidogenesis. The purpose of this work was to analyse the ganglionic adrenergic influence on the ovarian release of steroids and NO and the possible steroids/NO relationship. The experiments were carried out in the ex vivo coeliac ganglion-superior ovarian nerve (SON)-ovary system of prepubertal rats. The coeliac ganglion-SON-ovary system was incubated in Krebs Ringer-bicarbonate buffer in presence of adrenergic agents in the ganglionic compartment. The accumulation of progesterone, androstenedione, oestradiol and NO in the ovarian incubation liquid was measured. Norepinephrine in coeliac ganglion inhibited the liberation of progesterone and increased androstenedione, oestradiol and NO in ovary. The addition of alpha and beta adrenergic antagonists also showed different responses in the liberation of the substances mentioned before, which, from a physiological point of view, reveals the presence of adrenergic receptors in coeliac ganglion. In relation to propranolol, it does not revert the effect of noradrenaline on the liberation of progesterone, which leads us to think that it might also have a "per se" effect on the ganglion, responsible for the ovarian response observed for progesterone. Finally, we can conclude that the ganglionic adrenergic action via SON participates on the regulation of the prepubertal ovary in one of two ways: either increasing the NO, a gaseous neurotransmitter with cytostatic characteristics, to favour the immature follicles to remain dormant or increasing the liberation of androstenedione and oestradiol, the steroids necessary for the beginning of the near first estral cycle.

Clostridium difficile Infection: Associations with Chemotherapy, Radiation Therapy, and Targeting Therapy Treatments.

PubMed

Peretz, Avi; Shlomo, Izhar Ben; Nitzan, Orna; Bonavina, Luigi; Schaffer, Pmela M; Schaffer, Moshe

2016-01-01

Although mucositis, diarrhea, and constipation as well as immunosuppression are well recognized side-effects of cancer treatment, the underlying mechanisms including changes in the composition of gut microbiota and Clostridium difficile infection have not yet been thoroughly reviewed. We herein set out to review the literature regarding the relations between cancer chemotherapy, radiation treatment, and Clostridium difficile-associated colitis. Review of the English language literature published from 2008 to 2015 on the association between cancer chemotherapy, radiation treatment, and C. difficile-associated colitis. Certain chemotherapeutic combinations, mainly those containing paclitaxel, are more likely to be followed by C. difficile infection (CDI), while some tumor types are more likely to be complicated by CDI following chemotherapy. CDI following irradiation occurs mostly in patients who were treated for cancer in the head and neck area. Risk factors found were proton pump inhibitors, antibiotics, cytostatic agents, and tube feeding. The drug of choice for an initial episode of mild-to-moderate CDI is metronidazole, whereas vancomycin is reserved for an initial episode of severe CDI. Fidaxomycin is another option for treatment of severe CDI, with fewer recurrences. The influence of CDI on the treatment of oncological patients is not fully acknowledged. Infection with C. difficile is more frequent in those patients treated by antibiotics simultaneously with chemotherapy. Aggressive supportive care with intravenous hydration, antibiotics, and close surgical monitoring for selective intervention can significantly decrease the morbidity and life-threatening complications associated with this infection.

Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells.

PubMed

Bruno, Silvia; Ledda, Bernardetta; Tenca, Claudya; Ravera, Silvia; Orengo, Anna Maria; Mazzarello, Andrea Nicola; Pesenti, Elisa; Casciaro, Salvatore; Racchi, Omar; Ghiotto, Fabio; Marini, Cecilia; Sambuceti, Gianmario; DeCensi, Andrea; Fais, Franco

2015-09-08

B-cell chronic lymphocytic leukemia (CLL) was believed to result from clonal accumulation of resting apoptosis-resistant malignant B lymphocytes. However, it became increasingly clear that CLL cells undergo, during their life, iterative cycles of re-activation and subsequent clonal expansion. Drugs interfering with CLL cell cycle entry would be greatly beneficial in the treatment of this disease. 1, 1-Dimethylbiguanide hydrochloride (metformin), the most widely prescribed oral hypoglycemic agent, inexpensive and well tolerated, has recently received increased attention for its potential antitumor activity. We wondered whether metformin has apoptotic and anti-proliferative activity on leukemic cells derived from CLL patients. Metformin was administered in vitro either to quiescent cells or during CLL cell activation stimuli, provided by classical co-culturing with CD40L-expressing fibroblasts. At doses that were totally ineffective on normal lymphocytes, metformin induced apoptosis of quiescent CLL cells and inhibition of cell cycle entry when CLL were stimulated by CD40-CD40L ligation. This cytostatic effect was accompanied by decreased expression of survival- and proliferation-associated proteins, inhibition of signaling pathways involved in CLL disease progression and decreased intracellular glucose available for glycolysis. In drug combination experiments, metformin lowered the apoptotic threshold and potentiated the cytotoxic effects of classical and novel antitumor molecules. Our results indicate that, while CLL cells after stimulation are in the process of building their full survival and cycling armamentarium, the presence of metformin affects this process.

Cytostatic response of HepG2 to 0.57 MHz electric currents mediated by changes in cell cycle control proteins.

PubMed

Hernández-Bule, María Luisa; Cid, María Antonia; Trillo, María Angeles; Leal, Jocelyne; Ubeda, Alejandro

2010-12-01

The capacitive-resistive electric transfer (CRet) therapy is a non-invasive technique that applies electrical currents of 0.4-0.6 MHz to the treatment of musculoskeletal injuries. Although this therapy has proved effective in clinical studies, its interaction mechanisms at the cellular level still are insufficiently investigated. Results from previous studies have shown that the application of CRet currents at subthermal doses causes alterations in cell cycle progression and decreased proliferation in hepatocarcinoma (HepG2) and neuroblastoma (NB69) human cell lines. The aim of the present study was to investigate the antiproliferative response of HepG2 to CRet currents. The results showed that 24-h intermittent treatment with 50 µA/mm(2) current density induced in HepG2 statistically significant changes in expression and activation of cell cycle control proteins p27Kip1 and cyclins D1, A and B1. The chronology of these changes is coherent with that of the alterations reported in the cell cycle of HepG2 when exposed to the same electric treatment. We propose that the antiproliferative effect exerted by the electric stimulus would be primarily mediated by changes in the expression and activation of proteins intervening in cell cycle regulation, which are among the targets of emerging chemical therapies. The capability to arrest the cell cycle through electrically-induced changes in cell cycle control proteins might open new possibilities in the field of oncology.

Management of oxidative stress by heme oxygenase-1 in cisplatin-induced toxicity in renal tubular cells.

PubMed

Schaaf, G J; Maas, R F M; de Groene, E M; Fink-Gremmels, J

2002-08-01

Induction of heme oxygenase-1 (HO-1) may serve as an immediate protective response during treatment with the cytostatic drug cisplatin (CDDP). Oxidative pathways participate in the characteristic nephrotoxicity of CDDP. In the present study, cultured tubular cells (LLC-PK1) were used to investigate whether induction of HO provided protection against CDDP by maintaining the cellular redox balance. The antioxidants, alpha-tocopherol (TOCO) and N-acetylcysteine (NAC), were used to demonstrate that elevation of ROS levels contribute to the development of CDDP-induced cytotoxicity. Chemical modulators of HO activity were used to investigate the role of HO herein. Hemin was used to specifically induce HO-1, while exposure of the cells to tin-protoporphyrin (SnPP) was shown to inhibit HO activity. Hemin treatment prior to CDDP-exposure significantly decreased the generation of ROS to control levels, while inhibition of HO increased the ROS levels beyond the levels measured in cells treated with CDDP alone. Furthermore, HO induction protected significantly against the cytotoxicity of CDDP, although this protection was limited. Similar results were obtained when the cells were preincubated with TOCO, suggesting that mechanisms other than impairment of the redox ratio are important in CDDP-induced loss of cell viability in vitro. In addition, SnPP treatment exacerbated the oxidative response and cytotoxicity of CDDP, especially at low CDDP concentrations. We therefore conclude that HO is able to directly limit the CDDP-induced oxidative stress response and thus serves as safeguard of the cellular redox balance.

Poly(2-ethyl-2-oxazoline) conjugates with doxorubicin for cancer therapy: In vitro and in vivo evaluation and direct comparison to poly[N-(2-hydroxypropyl)methacrylamide] analogues.

PubMed

Sedlacek, Ondrej; Monnery, Bryn D; Mattova, Jana; Kucka, Jan; Panek, Jiri; Janouskova, Olga; Hocherl, Anita; Verbraeken, Bart; Vergaelen, Maarten; Zadinova, Marie; Hoogenboom, Richard; Hruby, Martin

2017-11-01

We designed and synthesized a new delivery system for the anticancer drug doxorubicin based on a biocompatible hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx) carrier with linear architecture and narrow molar mass distribution. The drug is connected to the polymer backbone via an acid-sensitive hydrazone linker, which allows its triggered release in the tumor. The in vitro studies demonstrate successful cellular uptake of conjugates followed by release of the cytostatic cargo. In vivo experiments in EL4 lymphoma bearing mice revealed prolonged blood circulation, increased tumor accumulation and enhanced antitumor efficacy of the PEtOx conjugate having higher molecular weight (40 kDa) compared to the lower molecular weight (20 kDa) polymer. Finally, the in vitro and in vivo anti-cancer properties of the prepared PEtOx conjugates were critically compared with those of the analogous system based on the well-established PHPMA carrier. Despite the relatively slower intracellular uptake of PEtOx conjugates, resulting also in their lower cytotoxicity, there are no substantial differences in in vivo biodistribution and anti-cancer efficacy of both classes of polymer-Dox conjugates. Considering the synthetic advantages of poly(2-alkyl-2-oxazoline)s, the presented study demonstrates their potential as a versatile alternative to well-known PEO- or PHPMA-based materials for construction of drug delivery systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

Antiproliferative and apoptotic effects triggered by Grape Seed Extract (GSE) versus epigallocatechin and procyanidins on colon cancer cell lines.

PubMed

Dinicola, Simona; Cucina, Alessandra; Pasqualato, Alessia; D'Anselmi, Fabrizio; Proietti, Sara; Lisi, Elisabetta; Pasqua, Gabriella; Antonacci, Donato; Bizzarri, Mariano

2012-01-01

Grape seed extract has been proven to exert anticancer effects on different tumors. These effects are mainly ascribed to catechin and procyanidin content. Analytical studies demonstrated that grape seed extract composition is complex and it is likely other components could exert biological activities. Using cell count and flow cytometry assays, we evaluated the cytostatic and apoptotic effects produced by three different grape seed extracts from Italia, Palieri and Red Globe cultivars, on Caco2 and HCT-8 colon cancer cells. These effects were compared to those induced by epigallocatechin and procyanidins, alone or in association, on the same cell lines. All the extracts induced growth inhibition and apoptosis in Caco2 and HCT-8 cells, along the intrinsic apoptotic pathway. On both cell lines, growth inhibition induced by Italia and Palieri grape seed extracts was significantly higher than that it has been recorded with epigallocatechin, procyanidins and their association. In Caco2 cells, the extract from Red Globe cultivar was less effective in inducing growth inhibition than procyanidins alone and in association with epigallocatechin, whereas, in HCT-8 cells, only the association of epigallocatechin and procyanidins triggers a significant proliferation decrease. On both cell lines, apoptosis induced by Italia, Palieri and Red Globe grape seed extracts was considerably higher than has been recorded with epigallocatechin, procyanidins and their association. These data support the hypothesis by which other compounds, present in the grape seed extracts, are likely to enhance the anticancer effects.

The Diterpene Sclareol Vascular Effect in Normotensive and Hypertensive Rats

PubMed Central

Campos, Debora Ribeiro; Celotto, Andrea Carla; Albuquerque, Agnes Afrodite S.; Ferreira, Luciana Garros; Monteiro, Ariadne Santana e Neves; Coelho, Eduardo Barbosa; Evora, Paulo Roberto Barbosa

2017-01-01

Background The diterpene Sclareol has antimicrobial action, cytotoxic and cytostatic effects and anti-tumor activities. However, researches on the cardiovascular system are scarce. Objective This study was designed to investigate the mechanisms involved in the Sclareol cardiovascular effect in normotensive and hypertensive rats. Methods The arterial hypertension was promoted using 2-kidneys 1-clip model in rats. The effect of sclareol on blood pressure was performed by using three dose (10, 20 and 40 mg/kg). Cumulative dose-response curves for Sclareol were determined for endothelium-intact and endothelium-denuded aortic rings in presence or absence of L-NAME and ODQ. The NOx levels were measure in the plasma sample. Results The Sclareol administration in vivo caused a significant reduction in blood pressure in both groups. In vitro the sclareol promoted relaxation in aorta, with endothelium, pre-contracted to Phe. The inhibitors of the nitric oxide synthase and soluble guanylate cyclase were as efficient as the removal of endothelium, in inhibiting the Sclareol-induced relaxation. Otherwise, it was no change of NOx. Also, for unknown reasons, the Sclareol is not selective for hypertensive animals. Conclusion The diterpene Sclareol showed in vivo hypotensive and in-vitro vasodilator effects;The chemiluminescence plasmatic NO analysis showed no significant difference between groups andThe Sclareol exhibit better effect on normotensive than hypertensive animals to reduce blood pressure. It is concluded that the diterpenes metabolites would be a promising source prototype for the development of new agents in the cardiovascular therapy. PMID:28678928

Guidelines for safe handling of hazardous drugs: A systematic review.

PubMed

Bernabeu-Martínez, Mari A; Ramos Merino, Mateo; Santos Gago, Juan M; Álvarez Sabucedo, Luis M; Wanden-Berghe, Carmina; Sanz-Valero, Javier

2018-01-01

To review the scientific literature related to the safe handling of hazardous drugs (HDs). Critical analysis of works retrieved from MEDLINE, the Cochrane Library, Scopus, CINHAL, Web of Science and LILACS using the terms "Hazardous Substances", "Antineoplastic Agents" and "Cytostatic Agents", applying "Humans" and "Guidelines" as filters. Date of search: January 2017. In total, 1100 references were retrieved, and from those, 61 documents were selected based on the inclusion and exclusion criteria: 24 (39.3%) documents related to recommendations about HDs; 27 (44.3%) about antineoplastic agents, and 10 (33.3%) about other types of substances (monoclonal antibodies, gene medicine and other chemical and biological agents). In 14 (23.3%) guides, all the stages in the manipulation process involving a risk due to exposure were considered. Only one guide addressed all stages of the handling process of HDs (including stages with and without the risk of exposure). The most described stages were drug preparation (41 guides, 67.2%), staff training and/or patient education (38 guides, 62.3%), and administration (37 guides, 60.7%). No standardized informatics system was found that ensured quality management, traceability and minimization of the risks associated with these drugs. Most of the analysed guidelines limit their recommendations to the manipulation of antineoplastics. The most frequently described activities were preparation, training, and administration. It would be convenient to apply ICTs (Information and Communications Technologies) to manage processes involving HDs in a more complete and simpler fashion.

Antiproliferative and Apoptotic Effects Triggered by Grape Seed Extract (GSE) versus Epigallocatechin and Procyanidins on Colon Cancer Cell Lines

PubMed Central

Dinicola, Simona; Cucina, Alessandra; Pasqualato, Alessia; D’Anselmi, Fabrizio; Proietti, Sara; Lisi, Elisabetta; Pasqua, Gabriella; Antonacci, Donato; Bizzarri, Mariano

2012-01-01

Grape seed extract has been proven to exert anticancer effects on different tumors. These effects are mainly ascribed to catechin and procyanidin content. Analytical studies demonstrated that grape seed extract composition is complex and it is likely other components could exert biological activities. Using cell count and flow cytometry assays, we evaluated the cytostatic and apoptotic effects produced by three different grape seed extracts from Italia, Palieri and Red Globe cultivars, on Caco2 and HCT-8 colon cancer cells. These effects were compared to those induced by epigallocatechin and procyanidins, alone or in association, on the same cell lines. All the extracts induced growth inhibition and apoptosis in Caco2 and HCT-8 cells, along the intrinsic apoptotic pathway. On both cell lines, growth inhibition induced by Italia and Palieri grape seed extracts was significantly higher than that it has been recorded with epigallocatechin, procyanidins and their association. In Caco2 cells, the extract from Red Globe cultivar was less effective in inducing growth inhibition than procyanidins alone and in association with epigallocatechin, whereas, in HCT-8 cells, only the association of epigallocatechin and procyanidins triggers a significant proliferation decrease. On both cell lines, apoptosis induced by Italia, Palieri and Red Globe grape seed extracts was considerably higher than has been recorded with epigallocatechin, procyanidins and their association. These data support the hypothesis by which other compounds, present in the grape seed extracts, are likely to enhance the anticancer effects. PMID:22312277

Long-term effect of rituximab in a case with late-onset Rasmussen´s encephalitis with anti-ganglioside IgGQ1b and anti-GAD antibodies positivity. Case Report.

PubMed

Timarova, Gabriela; Lisa, Iveta; Kukumberg, Peter

2016-07-01

Rasmussen's encephalitis is a rare autoimmune encephalitis usually involving one brain hemisphere, presenting with refractory epileptic seizures, and neurological and cognitive decline. Only 10% of cases start later in adolescence/adulthood. The only effective treatment for refractory seizures in childhood is hemispherectomy. For late-onset cases with mild neurological deficit the hemispherectomy is usually postponed because of its severe consequences. Immunotherapy shows some temporal effect for seizure control and slowing the brain atrophy, mainly in late onset Rasmussen's encephalitis. We report a patient with late onset Rasmussen´s encephalitis with anti-ganglioside IgGQ1b and anti-GAD antibodies positivity, who failed immunotherapy with cytostatics, immunoglobulins and steroids. Anti-ganglioside IgGQ1b antibodies are typically associated with a Miller-Fisher variant of Guillain-Barre syndrome and Bickerstaff's brainstem encephalitis. The association with Rasmussen´s encephalitis was not described before. Patient´s neurological deficit was mild and hemispherectomy was refused. The treatment with rituximab, an anti-CD20+ monoclonal antibody, led to 36-month control of seizures without any signs of progression of neurological deficit and MRI brain atrophy. Although the treatment is associated with long term B-cells depletion, patient doesn´t suffer from any clinically relevant infection. The biological treatment with monoclonal antibodies might be the way to stabilize patients with Rasmussen´s encephalitis, mainly late-onset, to prevent them from harmful and devastating hemispherectomy.

Platinum nanoparticles induce damage to DNA and inhibit DNA replication

PubMed Central

Nejdl, Lukas; Kudr, Jiri; Moulick, Amitava; Hegerova, Dagmar; Ruttkay-Nedecky, Branislav; Gumulec, Jaromir; Cihalova, Kristyna; Smerkova, Kristyna; Dostalova, Simona; Krizkova, Sona; Novotna, Marie; Kopel, Pavel

2017-01-01

Sparsely tested group of platinum nanoparticles (PtNPs) may have a comparable effect as complex platinum compounds. The aim of this study was to observe the effect of PtNPs in in vitro amplification of DNA fragment of phage λ, on the bacterial cultures (Staphylococcus aureus), human foreskin fibroblasts and erythrocytes. In vitro synthesized PtNPs were characterized by dynamic light scattering (PtNPs size range 4.8–11.7 nm), zeta potential measurements (-15 mV at pH 7.4), X-ray fluorescence, UV/vis spectrophotometry and atomic absorption spectrometry. The PtNPs inhibited the DNA replication and affected the secondary structure of DNA at higher concentrations, which was confirmed by polymerase chain reaction, DNA sequencing and DNA denaturation experiments. Further, cisplatin (CisPt), as traditional chemotherapy agent, was used in all parallel experiments. Moreover, the encapsulation of PtNPs in liposomes (LipoPtNPs) caused an approximately 2.4x higher of DNA damage in comparison with CisPt, LipoCisPt and PtNPs. The encapsulation of PtNPs in liposomes also increased their antibacterial, cytostatic and cytotoxic effect, which was determined by the method of growth curves on S. aureus and HFF cells. In addition, both the bare and encapsulated PtNPs caused lower oxidative stress (determined by GSH/GSSG ratio) in the human erythrocytes compared to the bare and encapsulated CisPt. CisPt was used in all parallel experiments as traditional chemotherapy agent. PMID:28704436

Biological activity of Ganoderma lucidum basidiocarps cultivated on alternative and commercial substrate.

PubMed

Cilerdžić, Jasmina; Vukojević, Jelena; Stajić, Mirjana; Stanojković, Tatjana; Glamočlija, Jasmina

2014-08-08

Ganoderma lucidum (W. Curt.:Fr.) P. Karst. has been used for several thousand years in traditional medicine of the Far East for the treatment of a various diseases including: cancer, immunological disorders, hepatitis, arthritis, nephritis, bronchitis, asthma etc. Ganoderma species are natural sources of various antimicrobial, antioxidant and antitumor active compounds which can be alternative to commercial antibiotics, antimycotics, antioxidants and cytostatics. As the amount of wild Ganoderma lucidum basidiocarps is not sufficient, the aim of this study was to compare the bioactivity of basidiaocarps obtained on alternative substrate (wheat straw) with commercially cultivated ones. Antimicrobial potential of the tested Ganoderma lucidum extracts was studied by disc-diffusion and microdilution method. Cytotoxic effect of tested extracts on two cancer cell lines was determined by microculture tetrazolium test. DPPH scavenging ability, total phenols and flavonoids content were measured in order to determine the antioxidative potential of Ganoderma lucidum extracts. Ganoderma lucidum BEOFB 434 extract was the most effective antibacterial agent, while commercial strain was the weakest. DPPH· scavenging activity of extracts of basidiocarps from alternative substrate was also significantly higher than that of commercially obtained basidiocarps. The extracts of Ganoderma lucidum BEOFB 431 exhibited the strongest cytotoxic activity significantly higher than those in commercial strain. The study showed that fruiting bodies produced on one of the most accessible and cheapest crop residue, wheat straw, are better antimicrobial, antioxidant and cytotoxic agents than those obtained on conventional substrate, oak sawdust. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

In vitro safety assessment of the strawberry tree (Arbutus unedo L.) water leaf extract and arbutin in human peripheral blood lymphocytes.

PubMed

Jurica, K; Brčić Karačonji, I; Mikolić, A; Milojković-Opsenica, D; Benković, V; Kopjar, N

2018-04-25

Strawberry tree (Arbutus unedo L.) leaves have long been used in the traditional medicine of the Mediterranean region. One of their most bioactive constituents is the glycoside arbutin, whose presence makes A. unedo suitable as a potential substitute for bearberry [Arctostaphylos uva ursi (L.) Spreng] leaves, an herbal preparation widely used for treating urinary tract infections. The safety and biocompatibility of strawberry tree water leaf extract have not yet been documented well. This study estimated arbutin content in strawberry tree water leaf extract (STE) using high performance liquid chromatography. Furthermore, we performed an in vitro safety assessment of the 24 h exposure to three presumably non-toxic concentrations of standardized STE and arbutin in human peripheral blood lymphocytes using the apoptosis/necrosis assay, the alkaline comet assay, and the cytokinesis-block micronucleus cytome assay. The STE was also tested for total antioxidant capacity and lipid peroxidation. At a concentration corresponding to the maximum allowable daily intake of arbutin, the tested extract was not cytotoxic, had a negligible potential for causing primary DNA damage and even hindered micronuclei formation in lymphocytes. It also showed a valuable antioxidant capacity, and did not exert marked lipid peroxidation. These promising results represent a solid frame for further development of STE-based herbal preparations. Although arbutin generally had a low DNA damaging potential, the slowing down of lymphocyte proliferation observed after 24 h of exposure points to a cytostatic effect, which merits further research.

Cannabinoids - a new weapon against cancer?

PubMed

Pokrywka, Małgorzata; Góralska, Joanna; Solnica, Bogdan

2016-12-29

Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis - Δ9 - tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine. Many scientific studies indicate the potential use of cannabinoids in the fight against cancer. Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize. The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors. Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.

Vero/BC-F: an efficient packaging cell line stably expressing F protein to generate single round-infectious human parainfluenza virus type 2 vector.

PubMed

Ohtsuka, J; Fukumura, M; Tsurudome, M; Hara, K; Nishio, M; Kawano, M; Nosaka, T

2014-08-01

A stable packaging cell line (Vero/BC-F) constitutively expressing fusion (F) protein of the human parainfluenza virus type 2 (hPIV2) was established for production of the F-defective and single round-infectious hPIV2 vector in a strategy for recombinant vaccine development. The F gene expression has not evoked cytostatic or cytotoxic effects on the Vero/BC-F cells and the F protein was physiologically active to induce syncytial formation with giant polykaryocytes when transfected with a plasmid expressing hPIV2 hemagglutinin-neuraminidase (HN). Transduction of the F-defective replicon RNA into the Vero/BC-F cells led to the release of the infectious particles that packaged the replicon RNA (named as hPIV2ΔF) without detectable mutations, limiting the infectivity to a single round. The maximal titer of the hPIV2ΔF was 6.0 × 10(8) median tissue culture infections dose per ml. The influenza A virus M2 gene was inserted into hPIV2ΔF, and the M2 protein was found to be highly expressed in a human lung cancer cell line after transduction. Furthermore, in vivo airway infection experiments revealed that the hPIV2ΔF was capable of delivering transgenes to hamster tracheal cells. Thus, non-transmissible or single round-infectious hPIV2 vector will be potentially applicable to human gene therapy or recombinant vaccine development.

The role of metallothionein in oncogenesis and cancer treatment.

PubMed

Bizoń, Anna; Jędryczko, Kinga; Milnerowicz, Halina

2017-02-14

Metallothionein is cysteine-rich low molecular mass protein. The involvement of MT in many physiological and pathophysiological processes such as apoptosis, proliferation, angiogenesis, and the detoxification of heavy metals suggested participation of this protein in carcinogenesis and tumor therapy. Depending on the type of tissue and classification of carcinoma various it was observed relation between MT expression and tumor type, stage, grade, poor prognosis and body resistance to radiotherapy and chemotherapy. MT in tumor cell plays important role in defense mechanism against the effect of radiation by inhibiting the processes that lead to the apoptosis. A number of studies have shown an increased expression of MT in various human tumors of larynx, pancreas, kidney, uterus and breast, whereas lower MT expression was detected in liver tumors. Variable MT expression was detected in case of thyroid, prostate, lung, stomach and central nervous system tumors. Also MT plays crucial role in the cytostatics treatment. MT can bind cis-platinum compounds and removes them from the cells, which may lead to multidrug resistance. However, the same functions of MT protect against the negative effects of chemotherapeutic treatment. It is especially important in case of heart cells. Analysis of MT expression in tumor cells may be useful in choosing method of treatment. It is difficult to determine whether increased expression of MT is only a inducing factor of the development of the carcinogenesis, its malignances and multidrug resistance, or it is a factor inhibiting the induction and development of cancer.

Platinum nanoparticles induce damage to DNA and inhibit DNA replication.

PubMed

Nejdl, Lukas; Kudr, Jiri; Moulick, Amitava; Hegerova, Dagmar; Ruttkay-Nedecky, Branislav; Gumulec, Jaromir; Cihalova, Kristyna; Smerkova, Kristyna; Dostalova, Simona; Krizkova, Sona; Novotna, Marie; Kopel, Pavel; Adam, Vojtech

2017-01-01

Sparsely tested group of platinum nanoparticles (PtNPs) may have a comparable effect as complex platinum compounds. The aim of this study was to observe the effect of PtNPs in in vitro amplification of DNA fragment of phage λ, on the bacterial cultures (Staphylococcus aureus), human foreskin fibroblasts and erythrocytes. In vitro synthesized PtNPs were characterized by dynamic light scattering (PtNPs size range 4.8-11.7 nm), zeta potential measurements (-15 mV at pH 7.4), X-ray fluorescence, UV/vis spectrophotometry and atomic absorption spectrometry. The PtNPs inhibited the DNA replication and affected the secondary structure of DNA at higher concentrations, which was confirmed by polymerase chain reaction, DNA sequencing and DNA denaturation experiments. Further, cisplatin (CisPt), as traditional chemotherapy agent, was used in all parallel experiments. Moreover, the encapsulation of PtNPs in liposomes (LipoPtNPs) caused an approximately 2.4x higher of DNA damage in comparison with CisPt, LipoCisPt and PtNPs. The encapsulation of PtNPs in liposomes also increased their antibacterial, cytostatic and cytotoxic effect, which was determined by the method of growth curves on S. aureus and HFF cells. In addition, both the bare and encapsulated PtNPs caused lower oxidative stress (determined by GSH/GSSG ratio) in the human erythrocytes compared to the bare and encapsulated CisPt. CisPt was used in all parallel experiments as traditional chemotherapy agent.

In vitro and in vivo efficacy of non-psychoactive cannabidiol in neuroblastoma.

PubMed

Fisher, T; Golan, H; Schiby, G; PriChen, S; Smoum, R; Moshe, I; Peshes-Yaloz, N; Castiel, A; Waldman, D; Gallily, R; Mechoulam, R; Toren, A

2016-03-01

Neuroblastoma (nbl) is one of the most common solid cancers in children. Prognosis in advanced nbl is still poor despite aggressive multimodality therapy. Furthermore, survivors experience severe long-term multi-organ sequelae. Hence, the identification of new therapeutic strategies is of utmost importance. Cannabinoids and their derivatives have been used for years in folk medicine and later in the field of palliative care. Recently, they were found to show pharmacologic activity in cancer, including cytostatic, apoptotic, and antiangiogenic effects. We investigated, in vitro and in vivo, the anti-nbl effect of the most active compounds in Cannabis, Δ(9)-tetrahydrocannabinol (thc) and cannabidiol (cbd). We set out to experimentally determine the effects of those compounds on viability, invasiveness, cell cycle distribution, and programmed cell death in human nbl SK-N-SH cells. Both compounds have antitumourigenic activity in vitro and impeded the growth of tumour xenografts in vivo. Of the two cannabinoids tested, cbd was the more active. Treatment with cbd reduced the viability and invasiveness of treated tumour cells in vitro and induced apoptosis (as demonstrated by morphology changes, sub-G1 cell accumulation, and annexin V assay). Moreover, cbd elicited an increase in activated caspase 3 in treated cells and tumour xenografts. Our results demonstrate the antitumourigenic action of cbd on nbl cells. Because cbd is a nonpsychoactive cannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anticancer drug in the management of nbl.

In vitro and in vivo efficacy of non-psychoactive cannabidiol in neuroblastoma

PubMed Central

Fisher, T.; Golan, H.; Schiby, G.; PriChen, S.; Smoum, R.; Moshe, I.; Peshes-Yaloz, N.; Castiel, A.; Waldman, D.; Gallily, R.; Mechoulam, R.; Toren, A.

2016-01-01

Background Neuroblastoma (nbl) is one of the most common solid cancers in children. Prognosis in advanced nbl is still poor despite aggressive multimodality therapy. Furthermore, survivors experience severe long-term multi-organ sequelae. Hence, the identification of new therapeutic strategies is of utmost importance. Cannabinoids and their derivatives have been used for years in folk medicine and later in the field of palliative care. Recently, they were found to show pharmacologic activity in cancer, including cytostatic, apoptotic, and antiangiogenic effects. Methods We investigated, in vitro and in vivo, the anti-nbl effect of the most active compounds in Cannabis, Δ9-tetrahydrocannabinol (thc) and cannabidiol (cbd). We set out to experimentally determine the effects of those compounds on viability, invasiveness, cell cycle distribution, and programmed cell death in human nbl SK-N-SH cells. Results Both compounds have antitumourigenic activity in vitro and impeded the growth of tumour xenografts in vivo. Of the two cannabinoids tested, cbd was the more active. Treatment with cbd reduced the viability and invasiveness of treated tumour cells in vitro and induced apoptosis (as demonstrated by morphology changes, sub-G1 cell accumulation, and annexin V assay). Moreover, cbd elicited an increase in activated caspase 3 in treated cells and tumour xenografts. Conclusions Our results demonstrate the antitumourigenic action of cbd on nbl cells. Because cbd is a nonpsychoactive cannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anticancer drug in the management of nbl. PMID:27022310

Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone.

PubMed Central

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-01-01

Metal complexes related to the cytotoxic complexes cisplatin [cis-diamminedichloroplatinum(II)] and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. For instance, SB-40, a PtCl2-containing metallopeptide in which platinum is coordinated to an N epsilon-(DL-2,3-diaminopropionyl)-D-lysine residue [D-Lys(DL-A2pr] at position 6, showed 50 times higher LH-releasing potency than the native hormone. SB-95, [Ac-D-Nal(2)1,D-Phe(pCl)2, D-Pal(3)2, Arg5,D-Lys[DL-A2pr(Sal2Cu)]6,D-Ala10]LH-RH, where Nal(2) is 3-(2-naphthyl)alanine, Pal(3) is 3-(3-pyridyl)alanine, and copper(II) is coordinated to the salicylideneimino moieties resulting from condensation of salicylaldehyde with D-Lys(DL-A2pr)6, caused 100% inhibition of ovulation at a dose of 3 micrograms in rats. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer cell lines in vitro (this will be the subject of a separate paper on cytotoxicity evaluation). Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides. PMID:2548206

Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone.

PubMed

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-08-01

Metal complexes related to the cytotoxic complexes cisplatin [cis-diamminedichloroplatinum(II)] and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. For instance, SB-40, a PtCl2-containing metallopeptide in which platinum is coordinated to an N epsilon-(DL-2,3-diaminopropionyl)-D-lysine residue [D-Lys(DL-A2pr] at position 6, showed 50 times higher LH-releasing potency than the native hormone. SB-95, [Ac-D-Nal(2)1,D-Phe(pCl)2, D-Pal(3)2, Arg5,D-Lys[DL-A2pr(Sal2Cu)]6,D-Ala10]LH-RH, where Nal(2) is 3-(2-naphthyl)alanine, Pal(3) is 3-(3-pyridyl)alanine, and copper(II) is coordinated to the salicylideneimino moieties resulting from condensation of salicylaldehyde with D-Lys(DL-A2pr)6, caused 100% inhibition of ovulation at a dose of 3 micrograms in rats. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer cell lines in vitro (this will be the subject of a separate paper on cytotoxicity evaluation). Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.

A Potential Bone-Targeting Hypotoxic Platinum(II) Complex with an Unusual Cytostatic Mechanism toward Osteosarcoma Cells.

PubMed

Zhang, Zhenqin; Zhu, Zhenzhu; Luo, Cheng; Zhu, Chengcheng; Zhang, Changli; Guo, Zijian; Wang, Xiaoyong

2018-03-19

Osteosarcoma (OS) is the most common primary pediatric bone tumor lethal to children and adolescents. Chemotherapeutic agents such as cisplatin are not effective for OS because of their poor accessibility to this cancer and severe systemic toxicity. In this study, a lipophilic platinum(II) complex bearing a bisphosphonate bone-targeting moiety, cis-[PtL(NH 3 ) 2 Cl]NO 3 {BPP; L = tetraethyl [2-(pyridin-2-yl)ethane-1,1-diyl]bisphosphonate}, was prepared and characterized by NMR, electrospray ionization mass spectrometry, and single-crystal X-ray crystallography. The cytotoxicity of BPP toward OS cell lines U2OS and MG-63 was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. BPP exhibits moderate inhibition against U2OS cells through a mechanism involving both DNA binding and a mevalonate pathway. The acute toxicity of BPP to mice is 7-fold lower than that of cisplatin. The relative low systemic toxicity may result from the steric hindrance of the ligand, which blocks BPP approaching the bases of DNA. The results suggest that incorporating bisphosphonates into a platinum complex not only enhances its bone-targeting property but also minimizes its reactivity toward DNA and thereby lowers the systematic toxicity of the complex. The diminished cytotoxicity of BPP could be compensated for by increasing the therapeutic dose with marginal harm. This strategy provides a new possibility for overcoming the ineffectiveness and systemic toxicity of platinum drugs in the treatment of OS.

The activation of the G protein-coupled estrogen receptor (GPER) inhibits the proliferation of mouse melanoma K1735-M2 cells.

PubMed

Ribeiro, Mariana P C; Santos, Armanda E; Custódio, José B A

2017-11-01

The activation of the G protein-coupled estrogen receptor (GPER) by its specific agonist G-1 inhibits prostate cancer and 17β-estradiol-stimulated breast cancer cell proliferation. Tamoxifen (TAM), which also activates the GPER, decreases melanoma cell proliferation, but its action mechanism remains controversial. Here we investigated the expression and the effects of GPER activation by G-1, TAM and its key metabolite endoxifen (EDX) on melanoma cells. Mouse melanoma K1735-M2 cells expressed GPER and G-1 reduced cell biomass, and the number of viable cells, without increasing cell death. Rather, G-1 decreased cell division by blocking cell cycle progression in G2. Likewise, TAM and EDX exhibited an antiproliferative activity in melanoma cells due to decreased cell division. Both G-1 and the antiestrogens showed a trend to decrease the levels of phosphorylated ERK 1/2 after 1 h treatment, although only EDX, the most potent antiproliferative antiestrogen, induced significant effects. Importantly, the targeting of GPER with siRNA abolished the cytostatic activity of both G-1 and antiestrogens, suggesting that the antitumor actions of antiestrogens in melanoma cells involve GPER activation. Our results unveil a new target for melanoma therapy and identify GPER as a key mediator of antiestrogen antiproliferative effects, which may contribute to select the patients that benefit from an antiestrogen-containing regimen. Copyright © 2017 Elsevier B.V. All rights reserved.

Pb low doses induced genotoxicity in Lactuca sativa plants.

PubMed

Silva, S; Silva, P; Oliveira, H; Gaivão, I; Matos, M; Pinto-Carnide, O; Santos, C

2017-03-01

Soil and water contamination by lead (Pb) remains a topic of great concern, particularly regarding crop production. The admissible Pb values in irrigation water in several countries range from ≈0.1 to ≈5 mg L -1 . In order to evaluate putative effects of Pb within legal doses on crops growth, we exposed Lactuca sativa seeds and seedlings to increasing doses of Pb(NO 3 ) 2 up to 20 mg L -1 . The OECD parameter seed germination and seedling/plant growth were not affected by any of the Pb-concentrations used. However, for doses higher than 5 mg L -1 significant DNA damage was detected: Comet assay detected DNA fragmentation at ≥ 5 mg L -1 and presence of micronuclei (MN) were detected for 20 mg L -1 . Also, cell cycle impairment was observed for doses as low as 0.05 mg L -1 and 0.5 mg L -1 (mostly G 2 arrest). Our data show that for the low doses of Pb used, the OECD endpoints were not able to detect toxicity, while more sensitive endpoints (related with DNA damage and mitotic/interphase disorders) identified genotoxic and cytostatic effects. Furthermore, the nature of the genotoxic effect was dependent on the concentration. Finally, we recommend that MN test and the comet assay should be included as sensitive endpoints in (eco)toxicological assays. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

New Perspectives in the Pharmacological Treatment of Non-Melanoma Skin Cancer.

PubMed

Savoia, Paola; Cremona, Ottavio; Fava, Paolo

2016-01-01

Non-melanoma skin cancers are the most common malignancy in humans, with a basal/squamous cell carcinoma incidence ratio of 4:1 in immunocompetent patients. Basal cell carcinoma rarely metastasizes but commonly causes significant local tissue destruction and disfigurement, whereas squamous cell carcinoma is associated with a substantial risk of recurrence and metastasis; the prognosis in metastatic patients is poor. Surgical approaches give a cure rate greater than 90% if appropriately applied, on the basis of the characteristics of the primary tumors and of the patients, but in selected cases, medical treatment (5-fluorouracil, imiquimod, diclofenac and, more recently, ingenol mebutate) is preferable to invasive procedures and provides a good chance of cure, with generally excellent cosmetic outcomes. In case of advanced and metastatic non-melanoma skin cancer, newly developed molecularly targeted therapy represents a reasonably promising alternative to classical cytostatics. In particular, the monoclonal antibody cetuximab, directed against the epidermal growth factor receptor, is effective and well-tolerated in squamous cell carcinoma patients. Moreover, the recent identification of mutations in the Hedgehog signaling pathway in basal cell carcinoma lead to the development of the smoothened Hedgehog pathway inhibitor vismodegib, that was recently approved for the treatment of locally advanced or metastatic basal cell carcinoma. In this review we provide an overview of the molecular pathways involved in NMSC pathogenesis, focusing on the mechanisms of action, indications, efficacy, side effects and contraindications of new medical treatments that specifically tackle molecular targets of these pathways.

The modification of spectral characteristics of cytostatics by optical beams

NASA Astrophysics Data System (ADS)

Pascu, Mihail Lucian; Brezeanu, Mihail; Carstocea, Benone D.; Voicu, Letitia; Gazdaru, Doina M.; Smarandache, Adriana A.

2004-10-01

Besides the biochemical action of methotrexate (MTX) and 5-fluorouracil (FU) their effect in destroying cancer tumours could be enhanced by exposure to light at different doses. Absorption, excitation and emission spectra of 10-4M - 10-5M MTX solutions in natural saline and sodium hydroxide at pH = 8.4 were measured, while their exposure to coherent and uncoherent light in the visible and near ultraviolet (UV) spectral ranges was made (Hg lamps and Nitrogen pulsed laser radiation were used). Absorption spectra exhibit spectral bands in the range 200 nm - 450 nm. The 200 - 450 nm excitation spectra were measured with emission centered on 470 nm; MTX fluorescence excitation was measured at 390 nm and the emission was detected between 400 nm and 600 nm showing a maximum at 470 nm. Spectra modifications, nonlinearly depending on exposure time (varying from 1 min to 20 min), evidenced MTX photo-dissociation to the fluorescent compound 2,4 diamino-formylpteridine. In the 5-FU case the absorption spectra exhibit bands between 200 nm and 450 nm. The emission fluorescence spectra were measured between 400 nm and 600 nm, with λex = 350 nm for UV Hg lamp and with λex = 360 nm for laser irradiated samples; at irradiation with N2 laser emitted radiation the excitation spectra were measured in the range of 200 nm - 400 nm, with λem = 440 nm. New vascularity rapid destruction was observed for conjunctive impregnated with 5-FU solution whilst exposed to incoherent UV and visible light.

Purification of a factor from the granules of a rat natural killer cell line (RNK) that reduces tumor cell growth and changes tumor morphology. Molecular identity with a granule serine protease (RNKP-1).

PubMed

Sayers, T J; Wiltrout, T A; Sowder, R; Munger, W L; Smyth, M J; Henderson, L E

1992-01-01

We have purified a protein from the granules of the rat NK leukemia cell line (RNK) that is cytostatic to a variety of tumor cells. This protein shows no species specificity because certain tumor cell lines of mouse, rat, and human origin were equally sensitive to its growth inhibitory effects. Treatment of sensitive cells resulted in a rounding of the cells followed by homotypic aggregation into large aggregates. The granule protein was distinct from cytolysin, Na-Cbz-Lys-thiobenzylester-esterase, or leukolexin. It had a molecular mass of 29 to 31 kDa, bound strongly to heparin, was inactivated by heating at 70 degrees C for 5 min or reduction, but was stable to trypsin treatment. By using molecular sieve chromatography, heparin agarose chromatography, and reverse phase HPLC, this protein was purified to homogeneity. The first 33 amino acids of the N-terminal amino acid sequence showed complete identity to the sequence predicted from a rat serine protease gene recently cloned and designated RNKP-1. Therefore we have purified a novel serine protease and demonstrated that it has effects on the growth and morphology of certain tumor cells. Other serine proteases that were structurally related and have substantial homology with RNKP-1 at the amino acid level showed neither growth inhibitory properties nor affected the morphology of the tumor target cells we used.

Synthesis of sulfadimethoxine based surfactants and their evaluation as antitumor agents.

PubMed

Khowdiary, Manal Mohmed; Mostafa, Nashwa S

2016-01-01

Synthesized CO (II) and Pt (II) of sulfadimethoxine. These compounds were tested for potential antitumor activity against two of human tumor cell lines, colon carcinoma cell line [Hct116], and breast carcinoma cell line MCF7. The structures of the resulting compounds have been investigated by elemental, FT-IR and H 1 NMR analyzes to insure the purity and confirmed the structures of them. The surface properties studies and octanol/water partition coefficients, Po/w were measured. The synthesized compounds exhibit biological activities with the lowest log Po/w and critical micelle concentration (CMC) values. In addition, in this article we provide an insight into this subject in order to increase the drug bioavailability. Inhibitory activity against colon carcinoma cells was detected for Pt and cobalt ion complex with IC50 = 4.5, 2.2 µg and against breast carcinoma cells IC50 = 18.2, 5.7 µg, respectively. The main goal of cancer therapy is to attain the maximum therapeutic damage of tumor cells in combination with a minimum concentration of the drug. This can be achieved in principle via selective antitumor preparations, the cytostatic effects of which would be restricted within tumor tissue. While 100% selectivity may be impractical, the achievement of reasonably high selectivity seems to be a feasible aim. Platinum and cobalt complex surfactants in our research affect tumor tissue at a very low concentration at values lower than their CMC values; this indicate that the sulfadimethoxine complexes merit further investigation as potential antitumor drugs.

The role of plant processing for the cancer preventive potential of Ethiopian kale (Brassica carinata).

PubMed

Odongo, Grace Akinyi; Schlotz, Nina; Herz, Corinna; Hanschen, Franziska S; Baldermann, Susanne; Neugart, Susanne; Trierweiler, Bernhard; Frommherz, Lara; Franz, Charles M A P; Ngwene, Benard; Luvonga, Abraham Wahid; Schreiner, Monika; Rohn, Sascha; Lamy, Evelyn

2017-01-01

Background : Ethiopian kale ( Brassica carinata ) is a horticulturally important crop used as leafy vegetable in large parts of East and Southern Africa. The leaves are reported to contain high concentrations of health-promoting secondary plant metabolites. However, scientific knowledge on their health benefits is scarce. Objective : This study aimed to determine the cancer preventive potential of B. carinata using a human liver in vitro model focusing on processing effects on the pattern of secondary plant metabolites and bioactivity. Design : B. carinata was cultivated under controlled conditions and differentially processed (raw, fermented, or cooked) after harvesting. Human liver cancer cells (HepG2) were treated with ethanolic extracts of raw or processed B. carinata leaves and analyzed for their anti-genotoxic, anti-oxidant, and cytostatic potential. Chemical analyses were carried out on glucosinolates including breakdown products, phenolic compounds, carotenoids, and chlorophyll content. Results : Pre-treatment with B. carinata extracts concentration dependently reduced aflatoxin-induced DNA damage in the Comet assay, reduced the production of reactive oxygen species as determined by electron paramagnetic resonance spectroscopy, and induced Nrf2-mediated gene expression. Increasing extract concentrations also promoted cytostasis. Processing had a significant effect on the content of secondary plant metabolites. However, different processing methodologies did not dramatically decrease bioactivity, but enhanced the protective effect in some of the endpoints studied. Conclusion : Our findings highlight the cancer preventive potential of B. carinata as indicated by the protection of human liver cells against aflatoxin in vitro . In general, consumption of B. carinata should be encouraged as part of chemopreventive measures to combat prevalence of aflatoxin-induced diseases.

Feasibility of therapeutic pneumoperitoneum in a large animal model using a microvaporisator.

PubMed

Reymond, M A; Hu, B; Garcia, A; Reck, T; Köckerling, F; Hess, J; Morel, P

2000-01-01

Multimodal therapy is used increasingly in advanced gastrointestinal tumors. Potential benefits of using an intraoperative adjuvant therapy during laparoscopy for cancer have been documented in animal studies. The aim of this study was to develop a device that could deliver such an intraoperative drug therapy. We developed a micropump suitable for minimally invasive surgery procedures that allowed microdroplets of therapeutic substance to be distributed into the pneumoperitoneum (CO2), creating a "therapeutic pneumoperitoneum." A closed-loop control system regulates drug delivery according to the gas flow. In vitro, the micropump is able to aerosolize various aqueous and ethanol solutions, including cytostatic and bacteriostatic drugs and adhesion-modulating agents. The size of the microdroplets has been optimized to prevent visual artifacts. The micropump was tested in an animal model (pig). The system was inserted into a 5-mm trocar. After insufflation of a 12-mm CO2 pneumoperitoneum, laparoscopic sigmoid colon resections could be performed with no special difficulties. No fog developed, and no system-related complication was observed. At autopsy, the active principle was distributed to all exposed peritoneal surfaces. As opposed to conventional peritoneal washing, therapeutic pneumoperitoneum reaches the entire peritoneal surface, allowing an optimal drug distribution. Drug diffusion into the tissues is enhanced by the intraperitoneal pressure. Precise determination of the instantaneous and total drug quantity is possible. Therefore, this drug delivery system has several advantages over conventional irrigation. Its potential domains of application are locoregional cancer therapy, prevention of port-site recurrences, immunomodulation, analgesia, peritonitis, and prevention of postoperative adhesions.

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

PubMed Central

Wang, Huaijun; Marchal, Guy; Ni, Yicheng

2011-01-01

Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis; a process known as tumor angiogenesis. Angiogenesis is largely involved in tumor survival, progression and spread, which are known to be significantly attributed to treatment failures. Over the past decades, efforts have been made to understand the difference between normal and tumor vessels. It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes, which provides opportunities for developing novel anticancer strategies. Targeting tumor vasculature is not only a unique therapeutic intervention to starve neoplastic cells, but also enhances the efficacy of conventional cancer treatments. Vascular disrupting agents (VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors, cause catastrophic vascular shutdown within short time, and induce secondary tumor necrosis. VDAs are cytostatic; they can only inhibit tumor growth, but not eradicate the tumor. This novel drug mechanism has urged us to develop multiparametric imaging biomarkers to monitor early hemodynamic alterations, cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected. In this article, we review the characteristics of tumor vessels, tubulin-destabilizing mechanisms of VDAs, and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials. We also compare the different tumor models adopted in the preclinical studies on VDAs. Multiparametric imaging biomarkers, mainly diffusion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging, are evaluated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs. PMID:21286490

Synthesis, anti-inflammatory, bactericidal activities and docking studies of novel 1,2,3-triazoles derived from ibuprofen using click chemistry.

PubMed

Angajala, Kishore Kumar; Vianala, Sunitha; Macha, Ramesh; Raghavender, M; Thupurani, Murali Krishna; Pathi, P J

2016-01-01

Nonsteroidal anti-inflammatory drugs are of vast therapeutic benefit in the treatment of different types of inflammatory conditions. 1,2,3-Triazoles and their derivatives have a wide range of applications as anti-bacterial, anti-fungal, anti-tubercular, cytostatic, anti-HIV, anti-allergic, anti-neoplastic and anti-inflammatory (AI) agents. Considering the individual biological and medicinal importance of ibuprofen and 1,2,3-triazoles, we wanted to explore novel chemical entities based on ibuprofen and triazole moieties towards their biological significance. Click chemistry has utilized as an ideal strategy to prepare novel ibuprofen-based 1,4-disubstituted 1,2,3-triazole containing molecules. These compounds were screened for their in vivo AI activity, among all the synthesized analogues 13o was shown potent effect than the reference AI drug ibuprofen at the same concentration (10 mg/kg body weight). Compounds 13l, 13g, 13c, 13k, 13i, 13n, 13m and 13j were shown significant AI activity. These triazole analogues were also screened for their bactericidal profile. Compounds 13c, 13i, 13l and 13o exhibited considerable bactericidal activity against gram positive and gram negative strains. In addition to this, molecular docking studies were also carried out into cyclooxygenase-2 active site to predict the affinity and orientation of these novel compounds (13a-q). In summary, we have designed and synthesized 1,2,3-triazole analogues of ibuprofen in good yields using Click chemistry approach. AI and bactericidal activities of these compounds were evaluated and shown remarkable results.

[Turmeric - not only spice].

PubMed

Zdrojewicz, Zygmunt; Szyca, Marta; Popowicz, Ewa; Michalik, Tomasz; Śmieszniak, Bartłomiej

2017-06-23

The purpose of this article is to introduce the role of turmeric in medicine and summarize the current state of research on its applications. Turmeric (Curcuma longa) has had a wide range of uses in middle eastern and orietnal traditional medicine. Currently, however, its use has been truncated to a common cooking spice, despite numerous studies pointing to its healing properties and possible use in the treatment of many diseases. The main focus is on curcumin, a polyphenol which serves as the biologically active component of turmeric. Curcumin's anti-inflammatory effects have been well documented in medical studies, with wide ranging applications from the treatment of rheumatologic diseases such as arthritis to dermatology, with significant effects in the treatment of psoriasis, acne and in relieving of itching. In addition to the effect of pro-inflammatory cytokines, curcumin can also accelerate healing of skin wounds. Apart from controlling the body's inflammatory response, curcumin has a bacteriostatic effect, which has been shown to be an important factor in the treatment of diseases with complex etiology. Additionally, studies show that curcumin's effects on oncogenesis, the process of metastasis, angiogenesis, apoptosis or response to cytostatic drugs have yielded promising results. It has been confirmed that its antioxidant effect correlates with a decrease in LDL levels in blood and to a reduced risk of atherosclerosis. Curcumin consumption has also been shown to have a vasodilating effect through its indirect impact on prostacyclins and directly on vascular endothelium. Many of the mention medicinal properties of turmeric are still the subject of research and debate; as such, only some of them have entered the phase of clinical trials.

Management of high risk metastatic prostate cancer: the case for novel therapies.

PubMed

Brand, Timothy C; Tolcher, Anthony W

2006-12-01

We reviewed the results of preliminary studies of select novel agents for metastatic prostate cancer and discuss the potential benefit of these agents for earlier stage disease, eg biochemically recurrent prostate cancer with high risk features. Available data on select investigational immunotherapies as well as endothelin-A receptor antagonists and survivin inhibitors were obtained and reviewed through PubMed searches, conference proceedings and unpublished proprietary information, when available. A large number of promising agents are in varying stages of development. Phase III results have been reported for the endothelin-A receptor antagonist atrasentan. Several immunotherapies are currently in phase II/III trials, namely the GM-CSF transduced tumor cell vaccine GVAX, the prostatic acid phosphatase loaded dendritic cell vaccine Provenge and the prostate specific antigen expressing poxvirus vaccine PROSTVAC-VF. Another immunotherapy, the prostate specific membrane antigen immunoconjugate MLN2704 (Millennium Pharmaceuticals, Cambridge, Massachusetts), is in phase I/II study. The first clinical inhibitors of survivin are in early phase I studies. Several of these agents, including atrasentan, have shown statistically significant but modest effects in the advanced disease setting in which they have been studied. Clinical trial design with these novel therapies presents particular challenges since most of these agents may induce disease stabilization rather than disease regression. There is a risk of false-negative results and failure to recognize a potentially efficacious agent if these cytostatic agents are studied only in men with advanced, heavily pretreated disease in whom life expectancy is measured in months. We advocate the early referral and enrollment of men with high risk prostate cancer in clinical trials.

Human tumour xenografts in nude mice: chemotherapy trials with titanocene dichloride in different dosages.

PubMed

Villena-Heinsen, C; Friedrich, M; Ertan, A K; Schmidt, W

1998-01-01

In this study new cytostatic therapies with titanocene dichloride in different dosages for the treatment of ovarian cancer are analyzed on human tumour xenografts in nude mice. The aim was to compare the effects of different dosages of titanocene dichloride on the growth of human tumour xenografts and nude mice body weight. Biopsy material from one human ovarian carcinoma was expanded and transplanted into 52 nude mice. The treatment protocol included one experiment that consisted of the following six treatment groups: titanocene dichloride 3 x 10 mg/kg, titanocene dichloride 3 x 20 mg/kg, titanocene dichloride 3 x 30 mg/kg, titanocene dichloride 1 x 30 mg/kg, titanocene dichloride 1 x 40 mg/kg and a control group treated with 0.9% saline. Treatment groups were evaluated in terms of average daily increase in tumour volume and average daily body weight increase on nude mice. The slope factors alpha and beta of the body weight and tumour volume changes were calculated. Titanocene dichloride in the dosage of 3 x 30 mg/kg and 3 x 20 mg/kg brought about a significant reduction in tumour volume (p < 0.05) compared to the control group and to the treatment group under medication with titanocene dichloride 1 x 30 mg/kg. There were no significant changes in the body weight of nude mice. We found titanocene dichloride to be effective in the reduction of tumour volume increase in nude mice. Titanocene dichloride could be an active chemotherapeutic drug in women with ovarian carcinoma not responding to standard therapies.

How do I deal with the axilla in patients with a positive sentinel lymph node?

PubMed

Falkson, Conrad B

2011-12-01

Optimal management of the axilla in a patient with a positive sentinel node biopsy is not yet defined.These patients usually have Breast Conserving Surgery and receive adjuvant systemic therapy and whole breast radiation.Treatment options for the axilla include: no further surgery with or without radiation completion axillary nodal dissection with or without radiation Radiation options in addition to whole breast radiation include axillary and supraclavicular nodal irradiation regional nodal irradiationincludes supraclavicular and internal mammary nodes Completion axillary dissection has been standard practice in patients with positive sentinel nodes. the number of involved nodes provides prognostic information. theoretically improves local control, but may be obviated by systemic chemotherapy. but avoidance of dissection may not adversely affect locoregional control or survival. dissection has significant morbidity so safe avoidance is desirable. There is little worldwide concordance on the use of radiation: whole breast radiation (commonly used after breast conserving surgery) may radiate the lower axilla supraclavicular radiation is most commonly recommended for patients with four or more nodes but may confer a survival benefit on patients with lower risk disease. adding nodal irradiation reduces local recurrence with only modest toxicity. Adjuvant systemic therapy provides a survival benefit for patients with nodal disease. Most will receive cytostatic chemotherapy containing an anthracycline and a taxane. Hormone therapy is appropriate for estrogen receptor positive disease. The extent to which systemic therapy controls microscopic nodal disease is unknown. Node positive patients should generally receive adjuvant chemotherapy.A small group of patients benefit from specific nodal therapy. Further studies are needed to better identify these patients.

Combination of etoposide and fisetin results in anti-cancer efficiency against osteosarcoma cell models.

PubMed

Ferreira de Oliveira, José Miguel P; Pacheco, Ana Rita; Coutinho, Laura; Oliveira, Helena; Pinho, Sónia; Almeida, Luis; Fernandes, Eduarda; Santos, Conceição

2018-03-01

Osteosarcoma chemotherapy is often limited by chemoresistance, resulting in poor prognosis. Combined chemotherapy could, therefore, be used to prevent resistance to chemotherapeutics. Here, the effects of fisetin on osteosarcoma cells were investigated, as well as cytostatic potential in combination with the anti-cancer drug etoposide. For this, different osteosarcoma cell lines were treated with fisetin, with etoposide and with respective combinations. Fisetin was associated with decrease in colony formation in Saos-2 and in U2OS cells but not in MG-63 cells. Notwithstanding, upon evaluation of cellular growth by crystal violet assay, MG-63 and Saos-2 cells showed decreased cell proliferation at 40 and 20 µM fisetin, respectively. Depending on the relative concentrations, fisetin:etoposide combinations showed negative-to-positive interactions on the inhibition of cell proliferation. In addition, fisetin treatment up to 50 µM for 48 h resulted in G2-phase cell cycle arrest. Regardless of the combination, fisetin:etoposide increased % cells in G2-phase and decreased % cells in G1-phase. In addition, mixtures with more positive combined effects induced increased % cells in S-phase. Compared to etoposide treatment, these combinations resulted in decreased levels of cyclins B1 and E1, pointing to the role of these regulators in fisetin-induced cell cycle arrest. In conclusion, these results show that the combination of fisetin with etoposide has higher anti-proliferative effects in osteosarcoma associated with cell cycle arrest, allowing the use of lower doses of the chemotherapeutic agent, which has important implications for osteosarcoma treatment.

Cytomics in predictive medicine

NASA Astrophysics Data System (ADS)

Tarnok, Attila; Valet, Guenther K.

2004-07-01

Predictive Medicine aims at the detection of changes in patient's disease state prior to the manifestation of deterioration or improvement of the current status. Patient-specific, disease-course predictions with >95% or >99% accuracy during therapy would be highly valuable for everyday medicine. If these predictors were available, disease aggravation or progression, frequently accompanied by irreversible tissue damage or therapeutic side effects, could then potentially be avoided by early preventive therapy. The molecular analysis of heterogeneous cellular systems (Cytomics) by cytometry in conjunction with pattern-oriented bioinformatic analysis of the multiparametric cytometric and other data provides a promising approach to individualized or personalized medical treatment or disease management. Predictive medicine is best implemented by cell oriented measurements e.g. by flow or image cytometry. Cell oriented gene or protein arrays as well as bead arrays for the capture of solute molecules form serum, plasma, urine or liquor are equally of high value. Clinical applications of predictive medicine by Cytomics will include multi organ failure in sepsis or non infectious posttraumatic shock in intensive care, or the pretherapeutic identification of high risk patients in cancer cytostatic. Early individualized therapy may provide better survival chances for individual patient at concomitant cost containment. Predictive medicine guided early reduction or stop of therapy may lower or abrogate potential therapeutic side effects. Further important aspects of predictive medicine concern the preoperative identification of patients with a tendency for postoperative complications or coronary artery disease patients with an increased tendency for restenosis. As a consequence, better patient care and new forms of inductive scientific hypothesis development based on the interpretation of predictive data patterns are at reach.

Gefitinib targets EGFR dimerization and ERK1/2 phosphorylation to inhibit pleural mesothelioma cell proliferation.

PubMed

Favoni, Roberto E; Pattarozzi, Alessandra; Lo Casto, Michele; Barbieri, Federica; Gatti, Monica; Paleari, Laura; Bajetto, Adriana; Porcile, Carola; Gaudino, Giovanni; Mutti, Luciano; Corte, Giorgio; Florio, Tullio

2010-03-01

Altered EGFR activity is a causal factor for human tumor development, including malignant pleural mesotheliomas. The aim of the present study was the evaluation of the effects of Gefitinib on EGF-induced mesothelioma cell proliferation and the intracellular mechanisms involved. Cell proliferation, DNA synthesis and apoptosis were measured by MTT, thymidine incorporation and FACS analysis; EGFR, ERK1/2 and Akt expression and phosphorylation by Western blot, whereas receptor sites were analyzed by binding studies. Gefitinib inhibited EGF-induced proliferation in two mesothelioma cell lines, derived from pleural effusion (IST-Mes2) or tumor biopsy (ZL55). The treatment with Gefitinib induced cell cycle arrest in both cell lines, while apoptosis was observed only for high concentrations and prolonged drug exposure. EGF-dependent mesothelioma cell proliferation was mediated by EGFR and ERK1/2 phosphorylation, while Akt was not affected. Gefitinib inhibited both EGFR and ERK1/2 activation, being maximal at drug concentrations that induce cytostatic effects, suggesting that the proapoptotic activity of Gefitinib is independent from EGFR inhibition. Gefitinib treatment increased EGFR Bmax, possibly through membrane stabilization of inactive receptor dimers that we show to be induced by the drug also in the absence of EGF. EGFR activation of ERK1/2 represents a key pathway for pleural mesothelioma cell proliferation. Low concentrations of Gefitinib cause mesothelioma cell cycle arrest through the blockade of EGFR activity while high concentrations induce apoptosis. Finally, we propose that the formation of inactive EGFR dimers may contribute to the antitumoral activity of Gefitinib.

Increased expression of annexin I and thioredoxin detected by two-dimensional gel electrophoresis of drug resistant human stomach cancer cells.

PubMed

Sinha, P; Hütter, G; Köttgen, E; Dietel, M; Schadendorf, D; Lage, H

1998-11-18

The therapy of advanced cancer using chemotherapy alone or in combination with radiation or hyperthermia yields an overall response rate of about 20-50%. This success is often marred by the development of resistance to cytostatic drugs. Our aim was to study the global analysis of protein expression in the development of chemoresistance in vitro. We therefore used a cell culture model derived from the gastric carcinoma cell line EPG 85-257P. A classical multidrug-resistant subline EPG85-257RDB selected to daunorubicin and an atypical multidrug-resistant cell variant EPG85-257RNOV selected to mitoxantrone, were analysed using two-dimensional electrophoresis in immobilized pH-gradients (pH 4.0-8.0) in the first dimension and linear polyacrylamide gels (12%) in the second dimension. After staining with coomassie brilliant blue, image analysis was performed using the PDQuest system. Spots of interest were isolated using preparative two-dimensional electrophoresis and subjected to microsequencing. A total of 241 spots from the EPG85-257RDB-standard and 289 spots from the EPG85-257RNOV-standard could be matched to the EPG85-257P-standard. Microsequencing after enzymatic hydrolysis in gel, mass spectrometric data and sequencing of the peptides after their fractionation using microbore HPLC identified that two proteins annexin I and thioredoxin were overexpressed in chemoresistant cell lines. Annexin I was present in both the classical and the atypical multidrug-resistant cells. Thioredoxin was found to be overexpressed only in the atypical multidrug-resistant cell line.

Pharmacological effect of aminoferrocene in mice with L1210 leukemia.

PubMed

Chekhun, V F; Mokhir, A; Daum, S; Todor, I N; Lukianova, N Yu; Shvets, Yu V; Burlaka, A P

2015-06-01

To study the cytostatic and some biological effects of aminoferrocene using mice with L1210 lymphoid leukemia. Experiments were performed on BDF1 male mice (DBA/2, female × C57Bl/6, male) with transplantable L1210 lymphoid leukemia. Determination of antitumor activity of Benzyl-Fc Boron (Bn), it was injected intraperitoneally 6 times daily, starting on day 2 after L1210 leukemia cell transplantation. Doses of Bn such as 26; 260 and 2600 μg/kg were used. The determination of intracellular content of cardiolipin, thiols, reactive oxygen species (ROS) and also analysis of Annexin V positivity and mitochondrial transmembrane potential (JC-1 staining) were performed with use of flow cytometry. The levels of "free iron" complexes, transferrin active forms and the rate of NO generation were measured by EPR-specroscopy. Six daily injections of Bn at a dose of 26 μg/kg resulted in an increased survival of mice with L1210 leukemia by 28% (p < 0.05). Bn led to an increase of apoptotic cells number and ROS amount in leukemia cells. Besides, Bn caused a decrease of cardiolipin and nonprotein thiol compounds content. The membrane electrochemical potential of cell mitochondria was decreased also after Bn administration. Studies using EPR-spectroscopy revealed a significant increase in a level of "free iron", content of transferrin active species and generation rate of NO by inducible NO-synthase in L1210 cells after aminoferrocene administration. Our data indicate that Benzyl-Fc Boron can be promising candidate for realizing a new strategy of anticancer therapy with the use of ROS-inducing agents.

Characterization and cytotoxicity of ions released from stainless steel and nickel-titanium orthodontic alloys.

PubMed

Eliades, Theodore; Pratsinis, Harris; Kletsas, Dimitris; Eliades, George; Makou, Margarita

2004-01-01

The purpose of this study was to qualitatively and quantitatively characterize the substances released from orthodontic brackets and nickel-titanium wires and to comparatively assess the cytotoxicity of the ions released from these orthodontic alloys. Two full sets of stainless steel brackets of 20 brackets each (weight 2.1 g) and 2 groups of 0.018 x 0.025 Ni-Ti archwires of 10 wires each (weight 2.0 g) were immersed in 0.9% saline solution for a month. The immersion media were analyzed with inductively coupled plasma-atomic emission spectroscopy (ICP-AES), and the ionic content was statistically analyzed with 1-way analysis of variance (ANOVA). Human periodontal ligament fibroblasts and gingival fibroblasts were exposed to various concentrations of the 2 immersion media; nickel chloride was used as a positive control for comparison purposes. The cytotoxic or cytostatic activity of the media was investigated with the MTT and the DNA synthesis assays. The results of the cytotoxicity assay were analyzed with 2-way ANOVA and the Tukey test with solution and concentration variants as discriminating variables (alpha=0.05). The results indicated no ionic release for the nickel-titanium alloy aging solution, whereas measurable nickel and traces of chromium were found in the stainless steel bracket-aging medium. Concentrations of the nickel chloride solution greater then 2 mM were found to reduce by more than 50% the viability and DNA synthesis of fibroblasts; however, neither orthodontic materials-derived media had any effect on the survival and DNA synthesis of either cells.

Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.

PubMed

Tsen, Andrew R; Long, Patrick M; Driscoll, Heather E; Davies, Matthew T; Teasdale, Benjamin A; Penar, Paul L; Pendlebury, William W; Spees, Jeffrey L; Lawler, Sean E; Viapiano, Mariano S; Jaworski, Diane M

2014-03-15

Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors. © 2013 UICC.

Essential Oil from Myrica rubra Leaves Potentiated Antiproliferative and Prooxidative Effect of Doxorubicin and its Accumulation in Intestinal Cancer Cells.

PubMed

Ambrož, Martin; Hanušová, Veronika; Skarka, Adam; Boušová, Iva; Králová, Věra; Langhasová, Lenka; Skálová, Lenka

2016-01-01

Essential oil from the leaves of Myrica rubra, a subtropical Asian fruit tree traditionally used in folk medicines, has a significant antiproliferative effect in several intestinal cancer cell lines. Doxorubicin belongs to the most important cytostatics used in cancer therapy. The present study was designed to evaluate the effects of defined essential oil from M. rubra leaves on efficacy, prooxidative effect, and accumulation of doxorubicin in cancer cell lines and in non-cancerous cells. For this purpose, intestinal adenocarcinoma CaCo2 cells were used. Human fibroblasts (periodontal ligament) and a primary culture of rat hepatocytes served as models of non-cancerous cells. The results showed that the sole essential oil from M. rubra has a strong prooxidative effect in cancer cells while it acts as a mild antioxidant in hepatocytes. Combined with doxorubicin, the essential oil enhanced the antiproliferative and prooxidative effects of doxorubicin in cancer cells. At higher concentrations, synergism of doxorubicin and essential oil from M. rubra was proved. In non-cancerous cells, the essential oil did not affect the toxicity of doxorubicin and the doxorubicin-mediated reactive oxygen species formation. The essential oil increased the intracellular concentration of doxorubicin and enhanced selectively the doxorubicin accumulation in nuclei of cancer cells. Taken together, essential oil from M. rubra leaves could be able to improve the doxorubicin efficacy in cancer cells due to an increased reactive oxygen species production, and the doxorubicin accumulation in nuclei of cancer cells. Georg Thieme Verlag KG Stuttgart · New York.

Development of a UPLC-MS/MS method for the determination of ten anticancer drugs in hospital and urban wastewaters, and its application for the screening of human metabolites assisted by information-dependent acquisition tool (IDA) in sewage samples.

PubMed

Ferrando-Climent, L; Rodriguez-Mozaz, S; Barceló, D

2013-07-01

In the present work, the development, optimization, and validation (including a whole stability study) of a fast, reliable, and comprehensive method for the analysis of ten anticancer drugs in hospital and urban wastewater is described. Extraction of these pharmaceutical compounds was performed using automated off-line solid-phase extraction followed by their determination by ultra-performance liquid chromatography coupled to a triple quadrupole-linear ion trap mass spectrometer. Target compounds include nine cytotoxic agents: cyclophosphamide, ifosfamide, docetaxel, paclitaxel, etoposide, vincristine, tamoxifen, methotrexate, and azathioprine; and the cytotoxic quinolone, ciprofloxacin. Method detection limits (MDL) ranged from 0.8 to 24 ng/L. Levels found of cytostatic agents in the hospital and wastewater influents did not differ significantly, and therefore, hospitals cannot be considered as the primary source of this type of contaminants. All the target compounds were detected in at least one of the influent samples analyzed: Ciprofloxacin, cyclophosphamide, tamoxifen, and azathioprine were found in most of them and achieving maximum levels of 14.725, 0.201, 0.133, and 0.188 μg/L, respectively. The rest of target cancer drugs were less frequently detected and at values ranging between MDL and 0.406 μg/L. Furthermore, a feasible, useful, and advantageous approach based on information acquisition tool (information-dependent acquisition) was used for the screening of human metabolites in hospital effluents, where the hydroxy tamoxifen, endoxifen, and carboxyphosphamide were detected.

Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: A Four-Arm Randomized Trial on the Effectiveness of Electroacupuncture

PubMed Central

Rostock, M.; Jaroslawski, K.; Guethlin, C.; Ludtke, R.; Schröder, S.; Bartsch, H. H.

2013-01-01

Purpose. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting side effect of cytostatic drugs. Since there are no proven therapeutic procedures against CIPN, we were interested to define the role of electroacupuncture (EA) from which preliminary data showed promising results. Methods. In a randomized trial with a group sequential adaptive design in patients with CIPN, we compared EA (LV3, SP9, GB41, GB34, LI4, LI11, SI3, and HT3; n = 14) with hydroelectric baths (HB, n = 14), vitamin B1/B6 capsules (300/300 mg daily; VitB, n = 15), and placebo capsules (n = 17). The statistical power in this trial was primarily calculated for proving EA only, so results of HB and VitB are pilot data. Results. CIPN complaints improved by 0.8 ± 1.2 (EA), 1.7 ± 1.7 (HB), 1.6 ± 2.0 (VitB), and 1.3 ± 1.3 points (placebo) on a 10-point numeric rating scale without significant difference between treatment groups or placebo. In addition no significant differences in sensory nerve conduction studies or quality of life (EORTC QLQ-C30) were found. Conclusions. The used EA concept, HB, and VitB were not superior to placebo. Since, contrary to our results, studies with different acupuncture concepts showed a positive effect on CIPN, the effect of acupuncture on CIPN remains unclear. Further randomized, placebo controlled studies seem necessary. This trial is registered with DRKS00004448. PMID:24066010

When all you have is a dermatoscope— start looking at the nails

PubMed Central

Haenssle, Holger A.; Blum, Andreas; Hofmann-Wellenhof, Rainer; Kreusch, Juergen; Stolz, Wilhelm; Argenziano, Giuseppe; Zalaudek, Iris; Brehmer, Franziska

2014-01-01

Pigmented and non-pigmented nail alterations are a frequent challenge for dermatologists. A profound knowledge of clinical and dermatoscopic features of nail disorders is crucial because a range of differential diagnoses and even potentially life-threatening diseases are possible underlying causes. Nail matrix melanocytes of unaffected individuals are in a dormant state, and, therefore, fingernails and toenails physiologically are non-pigmented. The formation of continuous, longitudinal pigmented streaks (longitudinal melanonychia) may either be caused by a benign activation of matrix melanocytes (e.g., as a result of trauma, inflammation, or adverse drug reactions) or by a true melanocytic proliferation (e.g., in a nevus or melanoma). In general, non-continuous nail alterations, affecting only limited parts of the nail apparatus, are most frequently of non-melanocytic origin. Important and common differential diagnoses in these cases are subungual hemorrhage or onychomycosis. In addition, foreign bodies, bacterial infections, traumatic injuries, or artificial discolorations of the nail unit may less frequently cause non-continuous nail alterations. Many systemic diseases that may also show involvement of the nails (e.g., psoriasis, atopic dermatitis, lichen planus, alopecia areata) tend to induce alterations in numerous if not all nails of the hands and feet. A similar extensive and generalized alteration of nails has been reported after treatment with a number of systemic drugs, especially antibiotics and cytostatics. Benign or malignant neoplasms that may also affect the nail unit include glomus tumor, Bowen’s disease, squamous cell carcinoma, and rare collision tumors. This review aims to assist clinicians in correctly evaluating and diagnosing nail disorders with the help of dermatoscopy. PMID:25396079

Melatonin: an Inhibitor of Breast Cancer

PubMed Central

Hill, Steven M.; Belancio, Victoria P.; Dauchy, Robert T.; Xiang, Shulin; Brimer, Samantha; Mao, Lulu; Hauch, Adam; Lundberg, Peter W.; Summers, Whitney; Yuan, Lin; Frasch, Tripp; Blask, David E.

2015-01-01

This review discusses recent work on melatonin-mediated circadian regulation and metabolic and molecular signaling mechanisms involved in human breast cancer growth and associated consequences of circadian disruption by exposure to light at night (LEN). The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin, via the MT1 receptor, suppresses ERα mRNA expression and ERα transcriptional activity. As well, melatonin regulates the transactivation of other members of the nuclear receptor super-family, estrogen metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (Warburg effect), and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways including inhibition of p38 MAPK and repression of epithelial-to-mesenchymal transition. Studies demonstrate that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models indicate that LEN induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer to drive breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms underpinning the epidemiologic demonstration of elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LEN. PMID:25876649

Intact LKB1 activity is required for survival of dormant ovarian cancer spheroids.

PubMed

Peart, Teresa; Ramos Valdes, Yudith; Correa, Rohann J M; Fazio, Elena; Bertrand, Monique; McGee, Jacob; Préfontaine, Michel; Sugimoto, Akira; DiMattia, Gabriel E; Shepherd, Trevor G

2015-09-08

Metastatic epithelial ovarian cancer (EOC) cells can form multicellular spheroids while in suspension and disperse directly throughout the peritoneum to seed secondary lesions. There is growing evidence that EOC spheroids are key mediators of metastasis, and they use specific intracellular signalling pathways to control cancer cell growth and metabolism for increased survival. Our laboratory discovered that AKT signalling is reduced during spheroid formation leading to cellular quiescence and autophagy, and these may be defining features of tumour cell dormancy. To further define the phenotype of EOC spheroids, we have initiated studies of the Liver kinase B1 (LKB1)-5'-AMP-activated protein kinase (AMPK) pathway as a master controller of the metabolic stress response. We demonstrate that activity of AMPK and its upstream kinase LKB1 are increased in quiescent EOC spheroids as compared with proliferating adherent EOC cells. We also show elevated AMPK activity in spheroids isolated directly from patient ascites. Functional studies reveal that treatment with the AMP mimetic AICAR or allosteric AMPK activator A-769662 led to a cytostatic response in proliferative adherent ovarian cancer cells, but they fail to elicit an effect in spheroids. Targeted knockdown of STK11 by RNAi to reduce LKB1 expression led to reduced viability and increased sensitivity to carboplatin treatment in spheroids only, a phenomenon which was AMPK-independent. Thus, our results demonstrate a direct impact of altered LKB1-AMPK signalling function in EOC. In addition, this is the first evidence in cancer cells demonstrating a pro-survival function for LKB1, a kinase traditionally thought to act as a tumour suppressor.

Heat-shock protein 27 (HSP27, HSPB1) is synthetic lethal to cells with oncogenic activation of MET, EGFR and BRAF.

PubMed

Konda, John D; Olivero, Martina; Musiani, Daniele; Lamba, Simona; Di Renzo, Maria F

2017-06-01

The small heat-shock protein of 27 kDa (HSP27) is highly expressed in many cancers and is associated with aggressive tumour behaviour, metastasis, poor prognosis and resistance to chemotherapy. We aimed at assessing the role of HSP27 in modulating responses to target therapies. We selected several oncogene-addicted cancer cell lines, which undergo either cell cycle blockade or cell death in response to agents that target the specific oncogene. Surprisingly, HSP27 suppression alone resulted in the apoptotic death of MET-addicted EBC-1 lung cancer cells, epidermal growth factor receptor (EGFR)-addicted colorectal carcinoma (CRC) DiFi cells and BRAF-addicted CRC COLO205 and OXCO-1 and melanoma COLO741 cells, all of which also undergo death when treated with the specific targeted agent. In other cell lines, such as MET-addicted gastric carcinoma MKN45 and EGFR-addicted CRC SW48 lines, where oncogene inhibition only blocked proliferation, HSP27 knockdown made targeted agents switch from cytostatic to cytotoxic activity. Mechanistically, the more the cells were susceptible to HSP27 suppression, the more they were primed for death, as demonstrated by increased levels of mitochondrial outer membrane permeabilization. Priming for death was accompanied by the increase in pro-apoptotic proteins of the BCL2 family and of active caspase-3 and lamin B. Together, these data suggest that oncogene-addicted cells require HSP27 for survival and that HSP27 might interfere with the effectiveness of targeted agents. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Comparative analysis of success of psoriasis treatment with standard therapeutic modalities and balneotherapy.

PubMed

Baros, Duka Ninković; Gajanin, Vesna S; Gajanin, Radoslav B; Zrnić, Bogdan

2014-01-01

Psoriasis is a chronic, inflammatory, immune-mediated skin disease. In addition to standard therapeutic modalities (antibiotics, cytostatics, phototherapy, photochemotherapy and retinoids), nonstandard methods can be used in the treatment of psoriasis. This includes balneotherapy which is most commonly used in combination with therapeutic resources. The aim of this research was to determine the length of remission of psoriasis in patients treated with standard therapeutic modalities, balneotherapy, and combined treatment (standard therapeutic modalities and balneotherapy). The study analyzed 60 adult patients, of both sexes, with different clinical forms of psoriasis, who were divided into three groups according to the applied therapeutic modalities: the first group (treated with standard therapeutic modalities), the second group (treated with balneotherapy) and the third group (treated with combined therapy-standard methods therapy and balneotherapy). The Psoriasis Area and Severity Index was determined in first, third and sixth week of treatment for all patients. The following laboratory analysis were performed and monitored: C reactive protein, iron with total iron binding capacity, unsaturated iron binding capacity and ferritin, uric acid, rheumatoid factors and antibodies to streptolysin O in the first and sixth week of treatment. The average length of remission in patients treated with standard therapeutic modalities and in those treated with balneotherapy was 1.77 +/- 0.951 months and 1.79 +/- 0.918 months, respectively. There was a statistically significant difference in the duration of remission between the patients treated with combination therapy and patients treated with standard therapeutic modalities (p = 0.019) and balneotherapy (p = 0.032). The best results have been achieved when the combination therapy was administered.

Curcumin and Viscum album Extract Decrease Proliferation and Cell Viability of Soft-Tissue Sarcoma Cells: An In Vitro Analysis of Eight Cell Lines Using Real-Time Monitoring and Colorimetric Assays.

PubMed

Harati, K; Behr, B; Daigeler, A; Hirsch, T; Jacobsen, F; Renner, M; Harati, A; Wallner, C; Lehnhardt, M; Becerikli, M

2017-01-01

The cytostatic effects of the polyphenol curcumin and Viscum album extract (VAE) were assessed in soft-tissue sarcoma (STS) cells. Eight human STS cell lines were used: fibrosarcoma (HT1080), liposarcoma (SW872, T778, MLS-402), synovial sarcoma (SW982, SYO1, 1273), and malignant fibrous histiocytoma (U2197). Primary human fibroblasts served as control cells. Cell proliferation, viability, and cell index (CI) were analyzed by BrdU assay, MTT assay, and real-time cell analysis (RTCA). As indicated by BrdU and MTT, curcumin significantly decreased the cell proliferation of five cell lines (HT1080, SW872, SYO1, 1273, and U2197) and the viability of two cell lines (SW872 and SW982). VAE led to significant decreases of proliferation in eight cell lines (HT1080, SW872, T778, MLS-402, SW982, SYO1, 1293, and U2197) and reduced viability in seven STS lines (HT1080, SW872, T778, MLS-402, SW982, SYO1, and 1273). As indicated by RTCA for 160 h, curcumin decreased the CI of all synovial sarcoma cell lines as well as T778 and HT1080. VAE diminished the CI in most of the synovial sarcoma (SW982, SYO1) and liposarcoma (SW872, T778) cell lines as well as HT1080. Primary fibroblasts were not affected adversely by the two compounds in RTCA. Curcumin and VAE can inhibit the proliferation and viability of STS cells.

Polyaminoquinoline iron chelators for vectorization of antiproliferative agents: design, synthesis, and validation.

PubMed

Corcé, Vincent; Morin, Emmanuelle; Guihéneuf, Solène; Renault, Eric; Renaud, Stéphanie; Cannie, Isabelle; Tripier, Raphaël; Lima, Luís M P; Julienne, Karine; Gouin, Sébastien G; Loréal, Olivier; Deniaud, David; Gaboriau, François

2012-09-19

Iron chelation in tumoral cells has been reported as potentially useful during antitumoral treatment. Our aim was to develop new polyaminoquinoline iron chelators targeting tumoral cells. For this purpose, we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, which we named Quilamines, based on an 8-hydroxyquinoline (8-HQ) scaffold linked to linear polyamine vectors. These were designed to target tumor cells expressing an overactive polyamine transport system (PTS). A set of Quilamines bearing variable polyamine chains was designed and assessed for their ability to interact with iron. Quilamines were also screened for their cytostatic/cytotoxic effects and their selective uptake by the PTS in the CHO cell line. Our results show that both the 8-HQ moiety and the polyamine part participate in the iron coordination. HQ1-44, the most promising Quilamine identified, presents a homospermidine moiety and was shown to be highly taken up by the PTS and to display an efficient antiproliferative activity that occurred in the micromolar range. In addition, cytotoxicity was only observed at concentrations higher than 100 μM. We also demonstrated the high complexation capacity of HQ1-44 with iron while much weaker complexes were formed with other cations, indicative of a high selectivity. We applied the density functional theory to study the binding energy and the electronic structure of prototypical iron(III)-Quilamine complexes. On the basis of these calculations, Quilamine HQ1-44 is a strong tridentate ligand for iron(III) especially in the form of a 1:2 complex.

Induced pluripotent stem cells reveal functional differences between drugs currently investigated in patients with hutchinson-gilford progeria syndrome.

PubMed

Blondel, Sophie; Jaskowiak, Anne-Laure; Egesipe, Anne-Laure; Le Corf, Amelie; Navarro, Claire; Cordette, Véronique; Martinat, Cécile; Laabi, Yacine; Djabali, Karima; de Sandre-Giovannoli, Annachiara; Levy, Nicolas; Peschanski, Marc; Nissan, Xavier

2014-04-01

Hutchinson-Gilford progeria syndrome is a rare congenital disease characterized by premature aging in children. Identification of the mutation and related molecular mechanisms has rapidly led to independent clinical trials testing different marketed drugs with a preclinically documented impact on those mechanisms. However, the extensive functional effects of those drugs remain essentially unexplored. We have undertaken a systematic comparative study of the three main treatments currently administered or proposed to progeria-affected children, namely, a farnesyltransferase inhibitor, the combination of an aminobisphosphonate and a statin (zoledronate and pravastatin), and the macrolide antibiotic rapamycin. This work was based on the assumption that mesodermal stem cells, which are derived from Hutchinson-Gilford progeria syndrome-induced pluripotent stem cells expressing major defects associated with the disease, may be instrumental to revealing such effects. Whereas all three treatments significantly improved misshapen cell nuclei typically associated with progeria, differences were observed in terms of functional improvement in prelamin A farnesylation, progerin expression, defective cell proliferation, premature osteogenic differentiation, and ATP production. Finally, we have evaluated the effect of the different drug combinations on this cellular model. This study revealed no additional benefit compared with single-drug treatments, whereas a cytostatic effect equivalent to that of a farnesyltransferase inhibitor alone was systematically observed. Altogether, these results reveal the complexity of the modes of action of different drugs, even when they have been selected on the basis of a similar mechanistic hypothesis, and underscore the use of induced pluripotent stem cell derivatives as a critical and powerful tool for standardized, comparative pharmacological studies.

Induced Pluripotent Stem Cells Reveal Functional Differences Between Drugs Currently Investigated in Patients With Hutchinson-Gilford Progeria Syndrome

PubMed Central

Blondel, Sophie; Jaskowiak, Anne-Laure; Egesipe, Anne-Laure; Le Corf, Amelie; Navarro, Claire; Cordette, Véronique; Martinat, Cécile; Laabi, Yacine; Djabali, Karima; de Sandre-Giovannoli, Annachiara; Levy, Nicolas; Peschanski, Marc

2014-01-01

Hutchinson-Gilford progeria syndrome is a rare congenital disease characterized by premature aging in children. Identification of the mutation and related molecular mechanisms has rapidly led to independent clinical trials testing different marketed drugs with a preclinically documented impact on those mechanisms. However, the extensive functional effects of those drugs remain essentially unexplored. We have undertaken a systematic comparative study of the three main treatments currently administered or proposed to progeria-affected children, namely, a farnesyltransferase inhibitor, the combination of an aminobisphosphonate and a statin (zoledronate and pravastatin), and the macrolide antibiotic rapamycin. This work was based on the assumption that mesodermal stem cells, which are derived from Hutchinson-Gilford progeria syndrome-induced pluripotent stem cells expressing major defects associated with the disease, may be instrumental to revealing such effects. Whereas all three treatments significantly improved misshapen cell nuclei typically associated with progeria, differences were observed in terms of functional improvement in prelamin A farnesylation, progerin expression, defective cell proliferation, premature osteogenic differentiation, and ATP production. Finally, we have evaluated the effect of the different drug combinations on this cellular model. This study revealed no additional benefit compared with single-drug treatments, whereas a cytostatic effect equivalent to that of a farnesyltransferase inhibitor alone was systematically observed. Altogether, these results reveal the complexity of the modes of action of different drugs, even when they have been selected on the basis of a similar mechanistic hypothesis, and underscore the use of induced pluripotent stem cell derivatives as a critical and powerful tool for standardized, comparative pharmacological studies. PMID:24598781

Breast carcinoma and the role of iron metabolism. A cytochemical, tissue culture, and ultrastructural study.

PubMed

Elliott, R L; Elliott, M C; Wang, F; Head, J F

1993-11-30

Transferrin receptors on proliferating and malignant cells are well documented. Iron is an essential micronutrient for cell growth that plays an important role in energy metabolism and DNA synthesis. Malignant cells requiring more iron modulate a transferrin receptor. Iron-bound transferrin interacts with this receptor, facilitating the transport of iron across the cell membrane. Transferrin is a glycoprotein and is the chief iron transport protein in mammalian blood. The more aggressive the tumor, the higher the transferrin receptor levels and the greater the proliferative index. We have found by cytochemical and ultrastructural studies that ferritin, an iron storage protein, is increased in breast cancer tissue. Anaplastic tumors have higher tissue ferritin levels. Tissue ferritin concentration may be an indirect method of measuring transferrin receptors and thus might be an index of proliferation and a prognostic indicator. Transferrin may be used as a carrier to target toxic therapy selectively to tumor tissue. A platinum transferrin complex (MPTC-63) has been developed and shown to be cytostatic in tissue culture, animal, and human studies. It also sensitizes tissue to agents that produce free radicals, such as adriamycin, and thus is synergistic with other drugs and radiation. Other transferrin complexes and conjugates of gallium, indium, and daunorubicin have also shown growth inhibition in tissue culture and animals. Human studies are in progress. By studying iron metabolism in breast cancer, we may be able to selectively inhibit tumor growth without toxic effects, and with other tumor biologic data be better able to select the stage I patient for adjuvant therapy.

Role for DUSP1 (dual-specificity protein phosphatase 1) in the regulation of autophagy.

PubMed

Wang, Juan; Zhou, Jun-Ying; Kho, Dhonghyo; Reiners, John J; Wu, Gen Sheng

2016-10-02

Accumulating evidence suggests that mitogen-activated protein kinases (MAPKs) regulate macroautophagy/autophagy. However, the involvement of dual-specificity protein phosphatases (DUSPs), endogenous inhibitors for MAPKs, in autophagy remains to be determined. Here we report that DUSP1/MKP-1, the founding member of the DUSP family, plays a critical role in regulating autophagy. Specifically, we demonstrate that DUSP1 knockdown by shRNA in human ovarian cancer CAOV3 cells and knockout in murine embryonic fibroblasts, increases both basal and rapamycin-increased autophagic flux. Overexpression of DUSP1 had the opposite effect. Importantly, knockout of Dusp1 promoted phosphorylation of ULK1 at Ser555, and BECN1/Beclin 1 at Ser15, and the association of PIK3C3/VPS34, ATG14, BECN1 and MAPK, leading to the activation of the autophagosome-initiating class III phosphatidylinositol 3-kinase (PtdIns3K) complex. Furthermore, knockdown and pharmacological inhibitor studies indicated that DUSP1-mediated suppression of autophagy reflected inactivation of the MAPK1-MAPK3 members of the MAPK family. Knockdown of DUSP1 sensitized CAOV3 cells to rapamycin-induced antigrowth activity. Moreover, CAOV3-CR cells, a line that had acquired cisplatin resistance, exhibited an elevated DUSP1 level and were refractory to rapamycin-induced autophagy and cytostatic effects. Knockdown of DUSP1 in CAOV3-CR cells restored sensitivity to rapamycin. Collectively, this work identifies a previously unrecognized role for DUSP1 in regulating autophagy and suggests that suppression of DUSP1 may enhance the therapeutic activity of rapamycin.

Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma

PubMed Central

Tsen, Andrew R.; Long, Patrick M.; Driscoll, Heather E.; Davies, Matthew T.; Teasdale, Benjamin A.; Penar, Paul L.; Pendlebury, William W.; Spees, Jeffrey L.; Lawler, Sean E.; Viapiano, Mariano S.; Jaworski, Diane M.

2013-01-01

Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic, and hypoacetylated mesenchymal glioma tumors. PMID:23996800

Roles for insulin and ecdysteroids in differentiation of an insect cell line of epidermal origin.

PubMed

Hatt, P J; Moriniere, M; Oberlander, H; Porcheron, P

1994-10-01

During postembryonic development of insects, molting cycles affect epidermal cells with alternate periods of proliferation and differentiation. Cells of the cell line established from imaginal discs of the Indian meal moth (IAL-PID2) differentiate under the action of the molting hormone, 20-hydroxyecdysone, in a manner that is meaningful in terms of the development of the tissue from which they were derived. In particular, the hormone caused an accumulation of the cells in the G2 phase of their cycle and induced the formation of epithelial-like aggregates and the synthesis of specific proteoglycans. Recent discovery of members of the insulin superfamily in insects and the role of growth factors played by this family of molecules in vertebrates led us to check for their potential effects on IAL-PID2 cell cycle regulation. On the one hand, our results showed that insulin was involved in partial resumption of the cell cycle after an arrest caused by serum deprivation, but that other growth factors present in fetal calf serum were needed for full completion of mitosis. On the other hand, the cytostatic effect of 20-hydroxyecdysone was reversible, and, prior exposure of the cells to the hormone allowed the cells to complete one cell cycle in serum-free medium. These results suggest that the production of autocrine growth factors induced by ecdysteroids could circumvent the absence of serum. This cell culture model provides potential for further study of interactions between ecdysteroids and growth factor homologs during differentiation of insect epidermal cells.

Synthesis of Novel Chiral Sulfonamide-Bearing 1,2,4-Triazole-3-thione Analogs Derived from D- and L-Phenylalanine Esters as Potential Anti-Influenza Agents.

PubMed

Başaran, Eyüp; Karaküçük-Iyidoğan, Ayşegül; Schols, Dominique; Oruç-Emre, Emine Elçin

2016-06-01

Novel enantiopure 1,2,4-trizole-3-thiones containing a benzensulfonamide moiety were synthesized via multistep reaction sequence starting with D-phenylalanine methyl ester and L-phenylalanine ethyl ester as a source of chirality. The chemical structures of all compounds were characterized by elemental analysis, UV, IR, (1) H NMR, (13) C NMR, 2D NMR (HETCOR), and mass spectral data. All compounds were tested in vitro antiviral activity against a broad variety of DNA and RNA viruses and in vitro cytostatic activity against murine leukemia (L1210), human T-lymphocyte (CEM) and human cervix carcinoma (HeLa) cell lines. Although enantiopure 1,2,4-triazole-3-thione analogs in (R) configuration emerged as promising anti-influenza A H1N1 subtype in Madin Darby canine kidney cell cultures (MDCK), their enantiomers exhibited no activity. Especially compounds , , , , and (EC50 : 6.5, 6.1, 2.4, 1.6, 1.7 μM, respectively) had excellent activity against influenza A H1N1 subtype compared to the reference drug ribavirin (EC50 : 8.0 μM). Several compounds have been found to inhibit proliferation of L1210, CEM and HeLa cell cultures with IC50 in the 12-53 μM range. Compound and in (R) configuration were the most active compounds (IC50 : 12-22 μM for and IC50 : 19-23 μM for ). Chirality 28:495-513, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Unfertilized frog eggs die by apoptosis following meiotic exit

PubMed Central

2011-01-01

Background A characteristic feature of frog reproduction is external fertilization accomplished outside the female's body. Mature fertilization-competent frog eggs are arrested at the meiotic metaphase II with high activity of the key meiotic regulators, maturation promoting factor (MPF) and cytostatic factor (CSF), awaiting fertilization. If the eggs are not fertilized within several hours of ovulation, they deteriorate and ultimately die by as yet unknown mechanism. Results Here, we report that the vast majority of naturally laid unfertilized eggs of the African clawed frog Xenopus laevis spontaneously exit metaphase arrest under various environmental conditions and degrade by a well-defined apoptotic process within 48 hours after ovulation. The main features of this process include cytochrome c release, caspase activation, ATP depletion, increase of ADP/ATP ratio, apoptotic nuclear morphology, progressive intracellular acidification, and egg swelling. Meiotic exit seems to be a prerequisite for execution of the apoptotic program, since (i) it precedes apoptosis, (ii) apoptotic events cannot be observed in the eggs maintaining high activity of MPF and CSF, and (iii) apoptosis in unfertilized frog eggs is accelerated upon early meiotic exit. The apoptotic features cannot be observed in the immature prophase-arrested oocytes, however, the maturation-inducing hormone progesterone renders oocytes susceptible to apoptosis. Conclusions The study reveals that naturally laid intact frog eggs die by apoptosis if they are not fertilized. A maternal apoptotic program is evoked in frog oocytes upon maturation and executed after meiotic exit in unfertilized eggs. The meiotic exit is required for execution of the apoptotic program in eggs. The emerging anti-apoptotic role of meiotic metaphase arrest needs further investigation. PMID:22195698

Suppression of AKT phosphorylation restores rapamycin-based synthetic lethality in SMAD4-defective pancreatic cancer cells.

PubMed

Le Gendre, Onica; Sookdeo, Ayisha; Duliepre, Stephie-Anne; Utter, Matthew; Frias, Maria; Foster, David A

2013-05-01

mTOR has been implicated in survival signals for many human cancers. Rapamycin and TGF-β synergistically induce G1 cell-cycle arrest in several cell lines with intact TGF-β signaling pathway, which protects cells from the apoptotic effects of rapamycin during S-phase of the cell cycle. Thus, rapamycin is cytostatic in the presence of serum/TGF-β and cytotoxic in the absence of serum. However, if TGF-β signaling is defective, rapamycin induced apoptosis in both the presence and absence of serum/TGF-β in colon and breast cancer cell lines. Because genetic dysregulation of TGF-β signaling is commonly observed in pancreatic cancers-with defects in the Smad4 gene being most prevalent, we hypothesized that pancreatic cancers would display a synthetic lethality to rapamycin in the presence of serum/TGF-β. We report here that Smad4-deficient pancreatic cancer cells are killed by rapamycin in the absence of serum; however, in the presence of serum, we did not observe the predicted synthetic lethality with rapamycin. Rapamycin also induced elevated phosphorylation of the survival kinase Akt at Ser473. Suppression of rapamycin-induced Akt phosphorylation restored rapamycin sensitivity in Smad4-null, but not Smad4 wild-type pancreatic cancer cells. This study shows that the synthetic lethality to rapamycin in pancreatic cancers with defective TGF-β signaling is masked by rapamycin-induced increases in Akt phosphorylation. The implication is that a combination of approaches that suppress both Akt phosphorylation and mTOR could be effective in targeting pancreatic cancers with defective TGF-β signaling. ©2013 AACR.

Antibacterial Activity of Hawaiian Corals: Possible Protection from Disease?

NASA Astrophysics Data System (ADS)

Gochfeld, D. J.; Aeby, G. S.; Miller, J. D.

2006-12-01

Reports of coral diseases in the Caribbean have appeared with increasing frequency over the past two decades; however, records of coral diseases in the Pacific have lagged far behind. Recent surveys of coral disease in the Hawaiian Islands indicate relatively low, but consistent, levels of disease throughout the inhabited Main and uninhabited Northwestern Hawaiian Islands, and demonstrate variation in levels of disease among the major genera of Hawaiian corals. Although little is known about immune defense to disease in corals, one potential mechanism of defense is the production of antimicrobial compounds that protect corals from pathogens. A preliminary survey of antibacterial chemical defenses among three dominant species of Hawaiian corals was undertaken. Crude aqueous extracts of Porites lobata, Pocillopora meandrina and Montipora capitata were tested against nine strains of bacteria in a growth inhibition assay. Inhibitory extracts were further tested to determine whether their effects were cytostatic or cytotoxic. The bacteria selected included known coral pathogens, potential marine pathogens found in human waste and strains previously identified from the surfaces of Hawaiian corals. Extracts from all three species of coral exhibited a high degree of antibacterial activity, but also a high degree of selectivity against different bacterial strains. In addition, some extracts were stimulatory to some bacteria. In addition to interspecific variability, extracts also exhibited intraspecific variability, both within and between sites. Hawaiian corals have significant antibacterial activity, which may explain the relatively low prevalence of disease in these corals; however, further characterization of pathogens specifically responsible for disease in Hawaiian corals is necessary before we can conclude that antibacterial activity protects Hawaiian corals from disease.

Small-molecule inhibitors of multidrug resistance-associated protein 1 and related processes: A historic approach and recent advances.

PubMed

Stefan, Sven Marcel; Wiese, Michael

2018-05-29

Multidrug resistance-associated protein 1 (MRP1, ABCC1) is an ATP-binding cassette (ABC) transport protein. This efflux pump uses the energy of ATP hydrolysis to export structurally diverse antineoplastic agents in human cancers. The upregulation of MRP1 (either inherent or acquired) is one major reason for the occurrence of the phenomenon called multidrug resistance (MDR). MDR is characterized by a reduced outcome of chemotherapy due to the active intracellular clearance of cytostatic drugs below the necessary effect concentration. Much effort has been made to overcome MDR, which implied high-throughput screenings of already known pharmacological and natural compounds, modification of intrinsic substrates, as well as design and synthesis of new inhibitors. This review is meant not only to summarize the most recent results over the past 10 years, but also to highlight major achievements regarding reversal of MRP1-mediated MDR, from the time of its discovery until today. The focus lies on small-molecule compounds that feature either direct MRP1 inhibition/transport blockage, toxicity against MRP1-overexpressing cells, inhibition/modification of intracellular processes necessary for MRP1 function, or modification of MRP1-related metabolic and genomic mechanisms. Considering all aspects, this review might be useful to (re)consider possible strategies to overcome MRP1-mediated MDR. Furthermore, it may be the basis for developing new, even better, highly potent, less toxic, and selective (as well as broad-spectrum) MRP1 inhibitors that will enter clinical evaluations in different malignancies and finally conduce to overcome MDR in general. © 2018 Wiley Periodicals, Inc.

Characterization of Neutropenia in Advanced Cancer Patients Following Palbociclib Treatment Using a Population Pharmacokinetic-Pharmacodynamic Modeling and Simulation Approach.

PubMed

Sun, Wan; O'Dwyer, Peter J; Finn, Richard S; Ruiz-Garcia, Ana; Shapiro, Geoffrey I; Schwartz, Gary K; DeMichele, Angela; Wang, Diane

2017-09-01

Neutropenia is the most commonly reported hematologic toxicity following treatment with palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for metastatic breast cancer. Using data from 185 advanced cancer patients receiving palbociclib in 3 clinical trials, a pharmacokinetic-pharmacodynamic model was developed to describe the time course of absolute neutrophil count (ANC) and quantify the exposure-response relationship for neutropenia. These analyses help in understanding neutropenia associated with palbociclib and its comparison with chemotherapy-induced neutropenia. In the model, palbociclib plasma concentration was related to its antiproliferative effect on precursor cells through drug-related parameters (ie, maximum estimated drug effect and concentration corresponding to 50% of the maximum effect), and neutrophil physiology was mimicked through system-related parameters (ie, mean transit time, baseline ANC, and feedback parameter). Sex and baseline albumin level were significant covariates for baseline ANC. It was demonstrated by different model evaluation approaches (eg, prediction-corrected visual predictive check and standardized visual predictive check) that the final model adequately described longitudinal ANC with good predictive capability. The established model suggested that higher palbociclib exposure was associated with lower longitudinal neutrophil counts. The ANC nadir was reached approximately 21 days after palbociclib treatment initiation. Consistent with their mechanisms of action, neutropenia associated with palbociclib (cytostatic) was rapidly reversible and noncumulative, with a notably weaker antiproliferative effect on precursor cells relative to chemotherapies (cytotoxic). This pharmacokinetic-pharmacodynamic model aids in predicting neutropenia and optimizing dosing for future palbociclib trials with different dosing regimen combinations. © 2017, The American College of Clinical Pharmacology.

Increased levels of nitrite in the sera of children infected with human immunodeficiency virus type 1.

PubMed

Torre, D; Ferrario, G; Speranza, F; Martegani, R; Zeroli, C

1996-04-01

Nitric oxide (NO) is a newly discovered gas that plays an important role in cell communication and host resistance to infection. The production of NO was examined in the sera of seven children infected with human immunodeficiency virus type 1 (HIV-1) and in the sera of 14 children who became seronegative for HIV-1 during the first year of life. In addition, we determined serum levels of various cytokines, such as interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, and gamma interferon (IFN-gamma), inasmuch as these cytokines are potent inducers of NO production. Production of NO, detected as circulating serum levels of nitrite, was measured with use of the Griess reagent. Serum levels of cytokines were determined by enzyme immunoassay. Increased serum levels of nitrite were observed in children with HIV-1 infection (0.4 +/- 0.2 mumol/L; P = .013), and in those who became seronegative for HIV-1 during the first year of life (0.5 +/- 0.3 mumol/L; P = .04). Furthermore, serum levels of IL-1 beta and TNF-alpha were significantly elevated in children with HIV-1 infection (37.5 +/- 23.6 pg/mL and 91.2 +/- 45.1 pg/mL, respectively). Prophylactic administration of intravenous immune globulin provoked a significant decrease of circulating levels of nitrite in children with HIV-1 infection. In conclusion, NO may play a role as a cytostatic or cytotoxic factor for invading microorganisms, and thus it is probably involved in limiting and/or eradicating infection.

[6]-Gingerol Induces Cell Cycle Arrest and Cell Death of Mutant p53-expressing Pancreatic Cancer Cells

PubMed Central

Park, Yon Jung; Wen, Jing; Bang, Seungmin; Park, Seung Woo

2006-01-01

[6]-Gingerol, a major phenolic compound derived from ginger, has anti-bacterial, anti-inflammatory and anti-tumor activities. While several molecular mechanisms have been described to underlie its effects on cells in vitro and in vivo, the underlying mechanisms by which [6]-gingerol exerts anti-tumorigenic effects are largely unknown. The purpose of this study was to investigate the action of [6]-gingerol on two human pancreatic cancer cell lines, HPAC expressing wild-type (wt) p53 and BxPC-3 expressing mutated p53. We found that [6]-gingerol inhibited the cell growth through cell cycle arrest at G1 phase in both cell lines. Western blot analyses indicated that [6]-gingerol decreased both Cyclin A and Cyclin-dependent kinase (Cdk) expression. These events led to reduction in Rb phosphorylation followed by blocking of S phase entry. p53 expression was decreased by [6]-gingerol treatment in both cell lines suggesting that the induction of Cyclin-dependent kinase inhibitor, p21cip1, was p53-independent. [6]-Gingerol induced mostly apoptotic death in the mutant p53-expressing cells, while no signs of early apoptosis were detected in wild type p53-expressing cells and this was related to the increased phosphorylation of AKT. These results suggest that [6]-gingerol can circumvent the resistance of mutant p53-expressing cells towards chemotherapy by inducing apoptotic cell death while it exerts cytostatic effect on wild type p53-expressing cells by inducing temporal growth arrest. PMID:17066513

Assessment of DNA damage in underground coal miners using the cytokinesis-block micronucleus assay in peripheral blood lymphocytes.

PubMed

Sinitsky, Maxim Yu; Minina, Varvara I; Gafarov, Nikolay I; Asanov, Maxim A; Larionov, Aleksey V; Ponasenko, Anastasia V; Volobaev, Valentin P; Druzhinin, Vladimir G

2016-11-01

Coal miners are exposed to coal dust, containing mineral particles, inorganic compounds and polycyclic aromatic hydrocarbons, and to ionizing radiation. These factors can induce oxidative stress and promote inflammation that leads to DNA damage. The aim of this investigation is to analyse the degree of DNA damage in miners working in underground coal mines in Kemerovo Region (Russian Federation) using the cytokinesis-block micronucleus assay (CBMN) in peripheral blood lymphocytes. The exposed group included 143 coal miners (mean age = 50.11±7.36 years; mean length of service in coal mining conditions = 23.26±9.66 years). As a control group, we have used venous blood extracted from 127 healthy non-exposed men. The mean age in this group was 47.67±8.45 years. We have discovered that coal miners are characterized by a significant increase in the frequency of binucleated lymphocytes with micronuclei (MN), nucleoplasmic bridges (NPBs) and protrusions (NBUDs) compared to non-exposed donors. In addition, we report, for the first time, a reduction of cell proliferation in a cohort of coal miners. These data are evidence of the genotoxic and cytostatic effects of occupational harmful factors of the coal mining industry. No correlation between the level of chromosome damage and age, smoking status or length of service in coal mining conditions were discovered. We suggest that the CBMN assay would be useful in biomonitoring studies to monitor hygiene and prevention strategies in occupational settings in coal mining countries. © The Author 2016. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Radiotherapy and "new" drugs-new side effects?

PubMed Central

2011-01-01

Background and purpose Targeted drugs have augmented the cancer treatment armamentarium. Based on the molecular specificity, it was initially believed that these drugs had significantly less side effects. However, currently it is accepted that all of these agents have their specific side effects. Based on the given multimodal approach, special emphasis has to be placed on putative interactions of conventional cytostatic drugs, targeted agents and other modalities. The interaction of targeted drugs with radiation harbours special risks, since the awareness for interactions and even synergistic toxicities is lacking. At present, only limited is data available regarding combinations of targeted drugs and radiotherapy. This review gives an overview on the current knowledge on such combined treatments. Materials and methods Using the following MESH headings and combinations of these terms pubmed database was searched: Radiotherapy AND cetuximab/trastuzumab/panitumumab/nimotuzumab, bevacizumab, sunitinib/sorafenib/lapatinib/gefitinib/erlotinib/sirolimus, thalidomide/lenalidomide as well as erythropoietin. For citation crosscheck the ISI web of science database was used employing the same search terms. Results Several classes of targeted substances may be distinguished: Small molecules including kinase inhibitors and specific inhibitors, antibodies, and anti-angiogenic agents. Combination of these agents with radiotherapy may lead to specific toxicities or negatively influence the efficacy of RT. Though there is only little information on the interaction of molecular targeted radiation and radiotherapy in clinical settings, several critical incidents are reported. Conclusions The addition of molecular targeted drugs to conventional radiotherapy outside of approved regimens or clinical trials warrants a careful consideration especially when used in conjunction in hypo-fractionated regimens. Clinical trials are urgently needed in order to address the open question in regard to efficacy, early and late toxicity. PMID:22188921

Five-year follow-up of the endothelial progenitor cell capturing stent versus the paxlitaxel-eluting stent in de novo coronary lesions with a high risk of coronary restenosis.

PubMed

Woudstra, Pier; Kalkman, Deborah N; Beijk, Marcel A; Klomp, Margo; Damman, Peter; Koch, Karel T; Henriques, Jose P S; Baan, Jan; Vis, Marije M; Piek, Jan J; Tijssen, Jan G P; de Winter, Robbert J

2018-06-01

To assess the long-term safety and clinical efficacy of the Genous endothelial progenitor cell capturing stent (ECS) compared with the TAXUS Liberté paclitaxel-eluting stent (PES) in lesions with a high risk of restenosis. Instead of the use of cytotoxic or cytostatic drugs in drug-eluting stents, a "pro-healing" approach in ECS may overcome impeded healing response due to delayed functional endothelialization of the stent struts. In the prospective, randomized TRIAS pilot study 193 patients with coronary artery lesions carrying a high risk of restenosis were included (ECS: n = 98, PES: n = 95). The primary focus of this analysis was target vessel failure (TVF) at 5 years. Dual antiplatelet therapy was prescribed for ≥1 month after ECS and for ≥6 months after PES. At 5 years follow-up, no significant differences were found in TVF (ECS 24% vs. PES 29%, risk difference 95% confidence interval (RDCI) -17.3% to 7.4%). Between 2 and 5 years after the index procedure, low numbers of TVF were observed in ECS compared with PES (ECS 4% vs. PES 16%, RDCI -20.8% to -2.3%). There was no definite stent thrombosis in ECS compared with four patients in the PES group. This is the first randomized study providing very long-term clinical efficacy and safety of the ECS in lesions carrying a high risk of restenosis. At 5 years follow-up, TVF rates in ECS group are numerically lower compared with PES due to an increase of events between 2 and 5 years after the index procedure. © 2017 Wiley Periodicals, Inc.

Intact LKB1 activity is required for survival of dormant ovarian cancer spheroids

PubMed Central

Peart, Teresa; Valdes, Yudith Ramos; Correa, Rohann J. M.; Fazio, Elena; Bertrand, Monique; McGee, Jacob; Préfontaine, Michel; Sugimoto, Akira; DiMattia, Gabriel E.; Shepherd, Trevor G.

2015-01-01

Metastatic epithelial ovarian cancer (EOC) cells can form multicellular spheroids while in suspension and disperse directly throughout the peritoneum to seed secondary lesions. There is growing evidence that EOC spheroids are key mediators of metastasis, and they use specific intracellular signalling pathways to control cancer cell growth and metabolism for increased survival. Our laboratory discovered that AKT signalling is reduced during spheroid formation leading to cellular quiescence and autophagy, and these may be defining features of tumour cell dormancy. To further define the phenotype of EOC spheroids, we have initiated studies of the Liver kinase B1 (LKB1)-5′-AMP-activated protein kinase (AMPK) pathway as a master controller of the metabolic stress response. We demonstrate that activity of AMPK and its upstream kinase LKB1 are increased in quiescent EOC spheroids as compared with proliferating adherent EOC cells. We also show elevated AMPK activity in spheroids isolated directly from patient ascites. Functional studies reveal that treatment with the AMP mimetic AICAR or allosteric AMPK activator A-769662 led to a cytostatic response in proliferative adherent ovarian cancer cells, but they fail to elicit an effect in spheroids. Targeted knockdown of STK11 by RNAi to reduce LKB1 expression led to reduced viability and increased sensitivity to carboplatin treatment in spheroids only, a phenomenon which was AMPK-independent. Thus, our results demonstrate a direct impact of altered LKB1-AMPK signalling function in EOC. In addition, this is the first evidence in cancer cells demonstrating a pro-survival function for LKB1, a kinase traditionally thought to act as a tumour suppressor. PMID:26068970

Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): Potential role of cyclin D1

PubMed Central

Pervin, Shehla; Singh, Rajan; Chaudhuri, Gautam

2001-01-01

DETA-NONOate, a nitric oxide (NO) donor, induced cytostasis in the human breast cancer cells MDA-MB-231, and the cells were arrested in the G1 phase of the cell cycle. This cytostatic effect of the NO donor was associated with the down-regulation of cyclin D1 and hypophosphorylation of the retinoblastoma protein. No changes in the levels of cyclin E or the catalytic partners of these cyclins, CDK2, CDK4, or CDK6, were observed. This NO-induced cytostasis and decrease in cyclin D1 was reversible for up to 48 h of DETA-NONOate (1 mM) treatment. DETA-NONOate (1 mM) produced a steady-state concentration of 0.5 μM of NO over a 24-h period. Synchronized population of the cells exposed to DETA-NONOate remained arrested at the G1 phase of the cell cycle whereas untreated control cells progressed through the cell cycle after serum stimulation. The cells arrested at the G1 phase after exposure to the NO donor had low cyclin D1 levels compared with the control cells. The levels of cyclin E and CDK4, however, were similar to the control cells. The decline in cyclin D1 protein preceded the decrease of its mRNA. This decline of cyclin D1 was due to a decrease in its synthesis induced by the NO donor and not due to an increase in its degradation. We conclude that down-regulation of cyclin D1 protein by DETA-NONOate played an important role in the cytostasis and arrest of these tumor cells in the G1 phase of the cell cycle. PMID:11248121

Butyrate activates the monocarboxylate transporter MCT4 expression in breast cancer cells and enhances the antitumor activity of 3-bromopyruvate.

PubMed

Queirós, Odília; Preto, Ana; Pacheco, António; Pinheiro, Céline; Azevedo-Silva, João; Moreira, Roxana; Pedro, Madalena; Ko, Young H; Pedersen, Peter L; Baltazar, Fátima; Casal, Margarida

2012-02-01

Most malignant tumors exhibit the Warburg effect, which consists in increased glycolysis rates with production of lactate, even in the presence of oxygen. Monocarboxylate transporters (MCTs), maintain these glycolytic rates, by mediating the influx and/or efflux of lactate and are overexpressed in several cancer cell types. The lactate and pyruvate analogue 3-bromopyruvate (3-BP) is an inhibitor of the energy metabolism, which has been proposed as a specific antitumor agent. In the present study, we aimed at determining the effect of 3-BP in breast cancer cells and evaluated the putative role of MCTs on this effect. Our results showed that the three breast cancer cell lines used presented different sensitivities to 3-BP: ZR-75-1 ER (+)>MCF-7 ER (+)>SK-BR-3 ER (-). We also demonstrated that 3-BP reduced lactate production, induced cell morphological alterations and increased apoptosis. The effect of 3-BP appears to be cytotoxic rather than cytostatic, as a continued decrease in cell viability was observed after removal of 3-BP. We showed that pre-incubation with butyrate enhanced significantly 3-BP cytotoxicity, especially in the most resistant breast cancer cell line, SK-BR-3. We observed that butyrate treatment induced localization of MCT1 in the plasma membrane as well as overexpression of MCT4 and its chaperone CD147. Our results thus indicate that butyrate pre-treatment potentiates the effect of 3-BP, most probably by increasing the rates of 3-BP transport through MCT1/4. This study supports the potential use of butyrate as adjuvant of 3-BP in the treatment of breast cancer resistant cells, namely ER (-).

GDC-0941 enhances the lysosomal compartment via TFEB and primes glioblastoma cells to lysosomal membrane permeabilization and cell death.

PubMed

Enzenmüller, Stefanie; Gonzalez, Patrick; Karpel-Massler, Georg; Debatin, Klaus-Michael; Fulda, Simone

2013-02-01

Since phosphatidylinositol-3-kinase (PI3K) inhibitors are primarily cytostatic against glioblastoma, we searched for new drug combinations. Here, we discover that the PI3K inhibitor GDC-0941 acts in concert with the natural compound B10, a glycosylated derivative of betulinic acid, to induce cell death in glioblastoma cells. Importantly, parallel experiments in primary glioblastoma cultures similarly show that GDC-0941 and B10 cooperate to trigger cell death, underscoring the clinical relevance of this finding. Molecular studies revealed that treatment with GDC-0941 stimulates the expression and nuclear translocation of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, the lysosomal membrane marker LAMP-1 and the mature form of cathepsin B. Also, GDC-0941 triggers a time-dependent increase of the lysosomal compartment in a TFEB-dependent manner, since knockdown of TFEB significantly reduces this GDC-0941-stimulated lysosomal enhancement. Importantly, GDC-0941 cooperates with B10 to trigger lysosomal membrane permeabilization, leading to increased activation of Bax, loss of mitochondrial membrane potential (MMP), caspase-3 activation and cell death. Addition of the cathepsin B inhibitor CA-074me reduces Bax activation, loss of MMP, caspase-3 activation and cell death upon treatment with GDC-0941/B10. By comparison, knockdown of caspase-3 or the broad-range caspase inhibitor zVAD.fmk inhibits GDC-0941/B10-induced DNA fragmentation, but does not prevent cell death, thus pointing to both caspase-dependent and -independent pathways. By identifying the combination of GDC-0941 and B10 as a new, potent strategy to trigger cell death in glioblastoma cells, our findings have important implications for the development of novel treatment approaches for glioblastoma. Copyright © 2012. Published by Elsevier Ireland Ltd.

Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer.

PubMed

Alagesan, Brinda; Contino, Gianmarco; Guimaraes, Alex R; Corcoran, Ryan B; Deshpande, Vikram; Wojtkiewicz, Gregory R; Hezel, Aram F; Wong, Kwok-Kin; Loda, Massimo; Weissleder, Ralph; Benes, Cyril H; Engelman, Jeffrey; Bardeesy, Nabeel

2015-01-15

Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being used in clinical trials for patients with PDAC, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMM). We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD6244, for efficacy alone or in combination with the PI3K inhibitors, BKM120 or GDC-0941, in a Kras(G12D)-driven GEMM that recapitulates the histopathogenesis of human PDAC. In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD6244, was an outlier, showing the highest selective efficacy in PDAC. Although MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM120 or GDC-0941). When tested in a PDAC GEMM and compared with the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed. Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some patients with PDAC. Clin Cancer Res; 21(2); 396-404. ©2014 AACR. ©2014 American Association for Cancer Research.

Comparison of saliva interleukin-2 concentration to the condition of gums in children with acute lymphoblastic leukaemia during anti-tumour treatment.

PubMed

Pels, Elżbieta

2015-07-01

Subjects undergoing chemotherapy often develop disorders in salivation and changes in salivary composition. Therefore, a tendency to inflammatory states developing within oral mucosa is often observed. The objective of the study was to assess the effect of disturbed immunity on the gum condition in children with acute lymphoblastic leukaemia (ALL) during anti-tumour treatment and to compare saliva interleukin-2 (IL-2) concentration in relation to the condition of gums oral mucositis-must be removed in children with ALL. The study included 78 children with ALL in followed three examinations and a control group included 78 healthy children. Dental examination of the children with ALL and the control group included the evaluation of gingival condition by gingival index (GI). Children's unstimulated saliva samples were taken, and IL-2 concentration was determined by Human IL-2 EIA. Mean GI higher than 1 was observed in 3.17 % children with ALL. The results found higher frequency of gingival inflammations in children with ALL on chemotherapy compared with the healthy controls. A comparison of results for a given patient during anti-tumour therapy with regard to salivary IL-2 showed significant differences between examination 2 and examination 3. The results indicated that IL-2 level in saliva was twice higher in a patient during chemotherapy. An increase in salivary level of the proinflammatory IL-2 cytokine in ALL children during chemotherapy may cause pathological changes in the condition of the gums. An increase in salivary IL-2 level most probably results from a micro-injury of oral mucosa following administration of cytostatics, which in turn may cause oral mucositis in children with ALL.

Nanomedicinal products: a survey on specific toxicity and side effects

PubMed Central

Giannakou, Christina; De Jong, Wim H; Kooi, Myrna W; Park, Margriet VDZ; Vandebriel, Rob J; Bosselaers, Irene EM; Scholl, Joep HG; Geertsma, Robert E

2017-01-01

Due to their specific properties and pharmacokinetics, nanomedicinal products (NMPs) may present different toxicity and side effects compared to non-nanoformulated, conventional medicines. To facilitate the safety assessment of NMPs, we aimed to gain insight into toxic effects specific for NMPs by systematically analyzing the available toxicity data on approved NMPs in the European Union. In addition, by comparing five sets of products with the same active pharmaceutical ingredient (API) in a conventional formulation versus a nanoformulation, we aimed to identify any side effects specific for the nano aspect of NMPs. The objective was to investigate whether specific toxicity could be related to certain structural types of NMPs and whether a nanoformulation of an API altered the nature of side effects of the product in humans compared to a conventional formulation. The survey of toxicity data did not reveal nanospecific toxicity that could be related to certain types of structures of NMPs, other than those reported previously in relation to accumulation of iron nanoparticles (NPs). However, given the limited data for some of the product groups or toxicological end points in the analysis, conclusions with regard to (a lack of) potential nanomedicine-specific effects need to be considered carefully. Results from the comparison of side effects of five sets of drugs (mainly liposomes and/or cytostatics) confirmed the induction of pseudo-allergic responses associated with specific NMPs in the literature, in addition to the side effects common to both nanoformulations and regular formulations, eg, with liposomal doxorubicin, and possibly liposomal daunorubicin. Based on the available data, immunotoxicological effects of certain NMPs cannot be excluded, and we conclude that this end point requires further attention. PMID:28883724

Evaluation of the Distribution of Paclitaxel After Application of a Paclitaxel-Coated Balloon in the Rabbit Urethra.

PubMed

Barbalias, Dimitrios; Lappas, Georgios; Ravazoula, Panagiotia; Liourdi, Despoina; Kyriazis, Iason; Liatsikos, Evangelos; Kallidonis, Panagiotis

2018-05-01

Urethral strictures are a common urologic problem that could require complex reconstructive procedures. Urethral dilatation represents a frequent practiced intervention associated with high recurrence rates. Drug-coated percutaneous angioplasty balloons (DCBs) with cytostatic drugs have been effectively used for the prevention of vascular restenosis after balloon dilatation. To reduce restenosis rates of urethral dilatation, these balloons could be used in the urethra. Nevertheless, the urothelium is different than the endothelium and these drugs may not be distributed to the outer layers of the urethra. Thus, an experiment was performed to evaluate the distribution of paclitaxel (PTX) in the rabbit urethra after the inflation of a PTX-coated balloon (PCB). Eleven rabbits underwent dilatation of the posterior urethra with common endoscopic balloons after urethrography. Nine of these rabbits were additionally treated with PCB. The urethras of the two control animals were removed along with three more dilated with PCB urethras immediately after the dilatation. The remaining of the urethras were removed after 24 (n = 3) and 48 hours (n = 3). The posterior segments of the urethras were evaluated with hematoxylin and eosin staining as well as with immunohistochemistry with polyclonal anti-PTX antibody. The two control specimens showed denudation of the urothelium after balloon dilatations and no PTX was observed. All specimens from dilated PCB urethras showed distribution of PTX to all layers of the urethra. The specimens that were immediately removed exhibited denudation of the urothelium without any inflammation. The specimens removed at 24 and 48 hours showed mild acute inflammation. PTX was distributed to the urothelial, submucosal, and smooth muscle layers of the normal rabbit urethra immediately after dilatation with a DCB. PTX and mild inflammation were present at the site 24 and 48 hours after the dilatation.

Microsomal Glutathione Transferase 1 Protects Against Toxicity Induced by Silica Nanoparticles but Not by Zinc Oxide Nanoparticles

PubMed Central

2012-01-01

Microsomal glutathione transferase 1 (MGST1) is an antioxidant enzyme located predominantly in the mitochondrial outer membrane and endoplasmic reticulum and has been shown to protect cells from lipid peroxidation induced by a variety of cytostatic drugs and pro-oxidant stimuli. We hypothesized that MGST1 may also protect against nanomaterial-induced cytotoxicity through a specific effect on lipid peroxidation. We evaluated the induction of cytotoxicity and oxidative stress by TiO2, CeO2, SiO2, and ZnO in the human MCF-7 cell line with or without overexpression of MGST1. SiO2 and ZnO nanoparticles caused dose- and time-dependent toxicity, whereas no obvious cytotoxic effects were induced by nanoparticles of TiO2 and CeO2. We also noted pronounced cytotoxicity for three out of four additional SiO2 nanoparticles tested. Overexpression of MGST1 reversed the cytotoxicity of the main SiO2 nanoparticles tested and for one of the supplementary SiO2 nanoparticles but did not protect cells against ZnO-induced cytotoxic effects. The data point toward a role of lipid peroxidation in SiO2 nanoparticle-induced cell death. For ZnO nanoparticles, rapid dissolution was observed, and the subsequent interaction of Zn2+ with cellular targets is likely to contribute to the cytotoxic effects. A direct inhibition of MGST1 by Zn2+ could provide a possible explanation for the lack of protection against ZnO nanoparticles in this model. Our data also showed that SiO2 nanoparticle-induced cytotoxicity is mitigated in the presence of serum, potentially through masking of reactive surface groups by serum proteins, whereas ZnO nanoparticles were cytotoxic both in the presence and in the absence of serum. PMID:22303956

[Sonographically detectable splenic disorders in dogs with malignant lymphoma].

PubMed

Eberhardt, F; Köhler, C; Krastel, D; Winter, K; Alef, M; Kiefer, I

2015-01-01

To evaluate the frequency of different sonographic splenic disorders in dogs with different anatomic forms of malignant lymphoma. Additionally, the occurrence of the moth-eaten pattern in the parenchyma of the spleen in patients with diseases other than lymphoma should be investigated. Retrospective analysis of patient data collected from dogs histologically or cytologically diagnosed with malignant lymphoma and for which ultrasonographic images were available before the initiation of therapy. Patient data from dogs with a moth-eaten pattern within the splenic parenchyma were evaluated separately. Exclusion criterion was the administration of cytostatic agents prior to diagnosis. In 84% of 164 dogs with malignant lymphoma, an altered pattern of the spleen was diagnosed ultrasonographically. Ninety-four of these 137 patients had a moth-eaten pattern of the splenic parenchyma and 43 dogs displayed abnormalities in the form of splenomegaly, coarse echotexture or other changes of the parenchyma. When a moth-eaten pattern was diagnosed, the affected dogs suffered significantly more often from a multicentric lymphoma (95%) than from any other anatomical lymphoma form. Only one dog displayed a moth-eaten pattern of the splenic parenchyma without diagnosis of a malignant lymphoma. The positive predictive value of the moth-eaten pattern for malignant lymphoma was 99% and, in particular, for the multicentric lymphoma this was 95%. In total, 84% of the 164 dogs displayed a multicentric lymphoma, 5% a mediastinal or a cutaneous lymphoma, respectively, 4% a gastrointestinal lymphoma, and one animal had an ocular or renal lymphoma, respectively. Sonographic changes of the spleen are often diagnosed in dogs with malignant lymphoma, independent of the anatomical lymphoma form. When the moth-eaten pattern is observed, it is very likely that the affected dog suffers from a malignant lymphoma, most probably a multicentric lymphoma.

Platinum(II)-dendrimer conjugates: synthesis and investigations on cytotoxicity, cellular distribution, platinum release, DNA, and protein binding.

PubMed

Kapp, Timo; Dullin, Anja; Gust, Ronald

2010-02-17

A set of polyamidoamine dendrimers were modified in such a way that they are able to act as carrier and drug delivery systems for cytostatics. The terminal binding of the non-proteinogenic D,L-2,3-diaminopropionic acid allowed the attachment of the cytotoxic PtX(2) moiety (X = Cl, I: A(PtI(2))(2), A(PtCl(2))(2), B(PtI(2))(2), B(PtCl(2))(2)), while the 2-carboxypentanedioic acid acted as leaving group for [meso-1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) ((m-4F-Pt)(3)C, (m-4F-Pt)(3)D). Poly(ethylene glycol) chains at C(PtI(2))(3) and C(PtCl(2))(3) as well as (m-4F-Pt)(3)C and (m-4F-Pt)(3)D mediated sufficient water solubility. Additional dansyl residues (B(PtI(2))(2) and (m-4F-Pt)(3)D) made a simultaneous determination of platinum (graphite furnace atomic absorption spectroscopy (GF-AAS)) and dendrimer (fluorimetry) possible. The ethylenediamine-terminated dendrimers were typically accumulated into MCF-7 cells in clathrin-dependent pathways and targeted the platinum moieties to the nuclear compartment. The highest intracellular platinum concentration and DNA binding caused the dendrimers A(PtX(2))(2) and B(PtX(2))(2). A coordinative DNA binding, however, is very unlikely because of low cytotoxic effects. (m-4F-Pt)(3)C and (m-4F-Pt)(3)D are labile conjugates and liberated the m-4F-Pt moiety in biological systems. The effects of these dendrimers were similar to that of the reference compounds m-4F-PtCl(2) and m-4F-Pt(H(2)O)(2).

[In vitro effect of lupeol and casearin G on peripheral blood mononuclear and tumor cells].

PubMed

Dupuy L, Omar A; Bonilla V, José A; Murillo, Renato; Taylor, Peter; Abad, María Jesús; González, Lorena; Juliao A, Johanna

2013-09-01

The rainforest is an important source of natural compounds with therapeutic properties. Although there are many anti-inflammatory and antineoplastic drugs available to the clinician, there is an ongoing need for new therapeutic drugs with fewer serious adverse effects. To evaluate the in vitro cytotoxic effects of lupeol and casearin G on tumor cells, on phagocytic activity and nitric oxide (NO) production by blood mononuclear cells. The cytotoxic effect of these compounds on cell lines MCF-7 (human breast adenocarcinoma) and PC-3 (human prostate cancer) was measured by a colorimetric assay (MTS/PMS) and the sulphorhodamine B assay. Peripheral blood mononuclear cells were obtained from eight healthy volunteers. The effect of these compounds on nitric oxide (NO) production was measured using the Griess reaction. Their effect on phagocytic activity of PBMC was also evaluated. Lupeol (≥ 2 mM) resulted in a reduction of both the phagocytic index and the percentage of phagocytic monocytes and macrophages. Treatment of monocytes/macrophages with lupeol (72 µM) and casearin G (4 µM) reduced the production of NO. Neither lupeol (< 969 µM) nor casearin G (< 55 µM) had cytotoxic effects on PBMC. Casearin G showed both cytotoxic (IC50, LC50) and cytostatic (GI50) effects against tumor cells, PC-3 (IC50 = 12.5 µM; GI50 = 13.3 µM; LC50 = 51.9 µM) and MCF-7 (IC50 = 112.8 µM; GI50 = 11.8 µM; LC50 = 49.4 µM), as well as a hemolytic effect (≥ 182 µM). These observations indicate that lupeol and casearin G might be useful compounds in the preparation of anti-inflammatory drugs, whereas casearin G might be useful in the elaboration of antitumor drugs.

A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies.

PubMed

Gilbert, J; Baker, S D; Bowling, M K; Grochow, L; Figg, W D; Zabelina, Y; Donehower, R C; Carducci, M A

2001-08-01

Phenylbutyrate (PB) is an aromatic fatty acid with multiple mechanisms of action including histone deacetylase inhibition. Preclinically, PB demonstrates both cytotoxic and differentiating effects at a concentration of 0.5 mM. We conducted a Phase I trial of p.o. PB patients with refractory solid tumor malignancies to evaluate toxicity, pharmacokinetic parameters, and feasibility of p.o. administration. Twenty-eight patients with refractory solid tumor malignancies were enrolled on this dose-escalation to maximally tolerated dose trial. Five dose levels of PB were studied: 9 g/day (n = 4), 18 g/day (n = 4), 27 g/day (n = 4), 36 g/day (n = 12), and 45 g/day (n = 4). Pharmacokinetic studies were performed and included an p.o. bioavailability determination. Compliance data were also collected. The recommended Phase II dose is 27 g/day. Overall the drug was well tolerated with the most common toxicities being grade 1-2 dyspepsia and fatigue. Nonoverlapping dose-limiting toxicities of nausea/vomiting and hypocalcemia were seen at 36 g/day. The p.o. bioavailability of PB was 78% for all dose levels, and the biologically active concentration of 0.5 mM was achieved at all dose levels. Compliance was excellent with 93.5% of all possible doses taken. No partial remission or complete remission was seen, but 7 patients had stable disease for more than 6 months while on the drug. PB (p.o.) is well tolerated and achieves the concentration in vivo that has been shown to have biological activity in vitro. PB may have a role as a cytostatic agent and should be additionally explored in combination with cytotoxics and other novel drugs.

Preclinical Testing of an Oncolytic Parvovirus: Standard Protoparvovirus H-1PV Efficiently Induces Osteosarcoma Cell Lysis In Vitro

PubMed Central

Leuchs, Barbara; Frank-Stöhr, Monika; Schlehofer, Jörg R.; Rommelaere, Jean; Lacroix, Jeannine

2017-01-01

Osteosarcoma is the most frequent malignant disease of the bone. On the basis of early clinical experience in the 1960s with H-1 protoparvovirus (H-1PV) in osteosarcoma patients, this effective oncolytic virus was selected for systematic preclinical testing on various osteosarcoma cell cultures. A panel of five human osteosarcoma cell lines (CAL 72, H-OS, MG-63, SaOS-2, U-2OS) was tested. Virus oncoselectivity was confirmed by infecting non-malignant human neonatal fibroblasts and osteoblasts used as culture models of non-transformed mesenchymal cells. H-1PV was found to enter osteosarcoma cells and to induce viral DNA replication, transcription of viral genes, and translation to viral proteins. After H-1PV infection, release of infectious viral particles from osteosarcoma cells into the supernatant indicated successful viral assembly and egress. Crystal violet staining revealed progressive cytomorphological changes in all osteosarcoma cell lines. Infection of osteosarcoma cell lines with the standard H-1PV caused an arrest of the cell cycle in the G2 phase, and these lines had a limited capacity for standard H-1PV virus replication. The cytotoxicity of wild-type H-1PV virus towards osteosarcoma cells was compared in vitro with that of two variants, Del H-1PV and DM H-1PV, previously described as fitness variants displaying higher infectivity and spreading in human transformed cell lines of different origins. Surprisingly, wild-type H-1PV displayed the strongest cytostatic and cytotoxic effects in this analysis and thus seems the most promising for the next preclinical validation steps in vivo. PMID:29039746

Implementation of an Integrative Oncological Concept in the Daily Care of a German Certified Breast Cancer Center.

PubMed

Schad, Friedemann; Thronicke, Anja; Merkle, Antje; Steele, Megan L; Kröz, Matthias; Herbstreit, Cornelia; Matthes, Harald

2018-01-01

In recent decades the concept of integrative medicine has attracted growing interest in patients and professionals. At the Gemeinschaftskrankenhaus Havelhöhe (GKH), a hospital specialized in anthroposophical medicine, a breast cancer center (BCC) has been successfully certified for more than 5 years. The objective of the present study was to analyze how integrative strategies were implemented in the daily care of primary breast cancer patients. Clinical, demographic, and follow-up data as well as information on non-pharmacological interventions were analyzed. In addition, BCC quality measures were compared with data of the National Breast Cancer Benchmarking Report 2016. Between 2011 and 2016, 741 primary breast cancer patients (median age 57.4 years) were treated at the GKH BCC. 91.5% of the patients showed Union for International Cancer Control (UICC) stage 0, I, II, or III and 8.2% were in UICC stage IV. 97% of the patients underwent surgery, 53% radiation, 38% had hormone therapy, and 25% received cytostatic drugs. 96% of the patients received non-pharmacological interventions and 32% received Viscum album L. Follow-up was performed in up to 93% of the patients 2 years after first diagnosis. Compared to nationwide benchmarking BCCs, the GKH BCC met the requirements in central items. The results of the present study show that integrative therapies offered by the concept of anthroposophical medicine can be implemented in the daily care and treatment of a certified BCC. However, as national guidelines on integrative concepts in oncology are missing, further studies are needed for a systematic evaluation of integrative treatment and care concepts in this field. © 2018 The Author(s). Published by S. Karger GmbH, Freiburg.

The hematopoietic tumor suppressor interferon regulatory factor 8 (IRF8) is upregulated by the antimetabolite cytarabine in leukemic cells involving the zinc finger protein ZNF224, acting as a cofactor of the Wilms' tumor gene 1 (WT1) protein.

PubMed

Montano, Giorgia; Ullmark, Tove; Jernmark-Nilsson, Helena; Sodaro, Gaetano; Drott, Kristina; Costanzo, Paola; Vidovic, Karina; Gullberg, Urban

2016-01-01

The transcription factor interferon regulatory factor-8 (IRF8) is highly expressed in myeloid progenitors, while most myeloid leukemias show low or absent expression. Loss of IRF8 in mice leads to a myeloproliferative disorder, indicating a tumor-suppressive role of IRF8. The Wilms tumor gene 1 (WT1) protein represses the IRF8-promoter. The zinc finger protein ZNF224 can act as a transcriptional co-factor of WT1 and potentiate the cytotoxic response to the cytostatic drug cytarabine. We hypothesized that cytarabine upregulates IRF8 and that transcriptional control of IRF8 involves WT1 and ZNF224. Treatment of leukemic K562 cells with cytarabine upregulated IRF8 protein and mRNA, which was correlated to increased expression of ZNF224. Knock down of ZNF224 with shRNA suppressed both basal and cytarabine-induced IRF8 expression. While ZNF224 alone did not affect IRF8 promoter activity, ZNF224 partially reversed the suppressive effect of WT1 on the IRF8 promoter, as judged by luciferase reporter experiments. Coprecipitation revealed nuclear binding of WT1 and ZNF224, and by chromatin immunoprecipitation (ChIP) experiments it was demonstrated that WT1 recruits ZNF224 to the IRF8 promoter. We conclude that cytarabine-induced upregulation of the IRF8 in leukemic cells involves increased levels of ZNF224, which can counteract the repressive activity of WT1 on the IRF8-promoter. Copyright © 2015 Elsevier Ltd. All rights reserved.

Reverse chemomodulatory effects of the SIRT1 activators resveratrol and SRT1720 in Ewing's sarcoma cells: resveratrol suppresses and SRT1720 enhances etoposide- and vincristine-induced anticancer activity.

PubMed

Sonnemann, Jürgen; Kahl, Melanie; Siranjeevi, Priyanka M; Blumrich, Annelie; Blümel, Lisa; Becker, Sabine; Wittig, Susan; Winkler, René; Krämer, Oliver H; Beck, James F

2016-01-01

SIRT1-activating compounds (STACs) may have potential in the management of cancer. However, the best-studied STAC, the naturally occurring compound resveratrol, is reported to have contradictory effects in combination chemotherapy regimens: It has been shown both to increase and to decrease the action of anticancer agents. To shed more light on this issue, we comparatively investigated the impact of resveratrol and the synthetic STAC SRT1720 on the responsiveness of Ewing's sarcoma (ES) cells to the chemotherapeutic drugs etoposide and vincristine. Because the effects of STACs can depend on the functionality of the tumor suppressor protein p53, we used three ES cell lines differing in their p53 status, i.e., wild-type p53 WE-68 cells, mutant p53 SK-ES-1 cells and p53 null SK-N-MC cells. Single agent and combination therapy effects were assessed by flow cytometric analyses of propidium iodide uptake and mitochondrial depolarization, by measuring caspase 3/7 activity and by gene expression profiling. When applied as single agents, both STACs were effective in ES cells irrespective of their p53 status. Strikingly, however, when applied in conjunction with cytostatic agents, the STACs displayed reverse effects: SRT1720 largely enhanced etoposide- and vincristine-induced cell death, while resveratrol inhibited it. Combination index analyses validated the antipodal impact of the STACs on the effectiveness of the chemotherapeutics. These findings suggest that the synthetic STAC SRT1720 may be useful to enhance the efficacy of anticancer therapy in ES. But they also suggest that the dietary intake of the natural STAC resveratrol may be detrimental during chemotherapy of ES.

High-throughput drug screen identifies chelerythrine as a selective inducer of death in a TSC2-null setting.

PubMed

Medvetz, Doug; Sun, Yang; Li, Chenggang; Khabibullin, Damir; Balan, Murugabaskar; Parkhitko, Andrey; Priolo, Carmen; Asara, John M; Pal, Soumitro; Yu, Jane; Henske, Elizabeth P

2015-01-01

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome associated with tumors of the brain, heart, kidney, and lung. The TSC protein complex inhibits the mammalian or mechanistic target of rapamycin complex 1 (mTORC1). Inhibitors of mTORC1, including rapamycin, induce a cytostatic response in TSC tumors, resulting in temporary disease stabilization and prompt regrowth when treatment is stopped. The lack of TSC-specific cytotoxic therapies represents an important unmet clinical need. Using a high-throughput chemical screen in TSC2-deficient, patient-derived cells, we identified a series of molecules antagonized by rapamycin and therefore selective for cells with mTORC1 hyperactivity. In particular, the cell-permeable alkaloid chelerythrine induced reactive oxygen species (ROS) and depleted glutathione (GSH) selectively in TSC2-null cells based on metabolic profiling. N-acetylcysteine or GSH cotreatment protected TSC2-null cells from chelerythrine's effects, indicating that chelerythrine-induced cell death is ROS dependent. Induction of heme-oxygenase-1 (HMOX1/HO-1) with hemin also blocked chelerythrine-induced cell death. In vivo, chelerythrine inhibited the growth of TSC2-null xenograft tumors with no evidence of systemic toxicity with daily treatment over an extended period of time. This study reports the results of a bioactive compound screen and the identification of a potential lead candidate that acts via a novel oxidative stress-dependent mechanism to selectively induce necroptosis in TSC2-deficient tumors. This study demonstrates that TSC2-deficient tumor cells are hypersensitive to oxidative stress-dependent cell death, and provide critical proof of concept that TSC2-deficient cells can be therapeutically targeted without the use of a rapalog to induce a cell death response. ©2014 American Association for Cancer Research.

Cytostatic action of two nitrosoureas derived from cysteamine.

PubMed Central

Bourut, C.; Chenu, E.; Godenèche, D.; Madelmont, J. C.; Maral, R.; Mathé, G.; Meyniel, G.

1986-01-01

2-Chloroethyl nitrosocarbamoylcystamine or ICIG-1325 (CNCC) is a lipid-soluble isomeric mixture of nitrosoureas. Its dose-effect relationship on L1210 leukaemia is characterized by a large maximally efficient dose-range (MEDR), greater than that of other nitrosoureas. CNCC also demonstrated significant therapeutic activity on intracerebrally (i.c.) transplanted L1210 leukaemia and on six transplanted solid tumours, TM2 mammary carcinoma, M555 ovarian carcinoma, B16 melanoma, glioma 26, 3LL, Lewis lung carcinoma and colon 26 carcinoma. It was inactive on fibrosarcoma ICIG-Ci4. Its antitumour activity spectrum is wider than that of the related compounds 2-[3-(2-chloroethyl) 3-nitrosoureido]D-glucopyranose (CZT), (chloro-2-ethyl)-1(ribofuranosyl-isopropylidene-2'-3' paranitrobenzoate-5')-3 nitrosourea (RFCNU), and (chloro-2-ethyl)-1 (ribopyranosyl triacetate-2'-3'-4')-3 nitrosourea (RPCNU). A study of its metabolic disposition in animals has shown that CNCC undergoes extensive first-pass metabolism leading to the formation of four main plasma metabolites. These metabolites are water-soluble nitrosoureas that arose from the bioreduction of the disulphide bridge followed by the methylation and the oxidation of the thiol groups. Experimental screening was performed with these chemically synthesized metabolites. Both N'-(2-chloroethyl)-N-[2-(methylsulphinyl)ethyl]-N'-nitrosourea (CMSOEN2) and N'-(2-chloroethyl)-N-[2-(methylsulphonyl)ethyl]-N'-nitrosourea (CMSO2EN2) are very active on L1210 leukaemia grafted intraperitoneally (i.p.) and i.c., L40 leukaemia, B16 melanoma, glioma 26 and Lewis lung carcinoma. Their effectiveness is better than that of the parent compound CNCC. In addition,the percentage of mice cured after CMSOEN2 or CMSO2EN2 treatment is increased especially on B16 melanoma and glioma 26.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3801787

Receptor tyrosine kinase inhibitors and cytotoxic drugs affect pleural mesothelioma cell proliferation: insight into EGFR and ERK1/2 as antitumor targets.

PubMed

Barbieri, Federica; Würth, Roberto; Favoni, Roberto E; Pattarozzi, Alessandra; Gatti, Monica; Ratto, Alessandra; Ferrari, Angelo; Bajetto, Adriana; Florio, Tullio

2011-11-15

Malignant pleural mesothelioma (MPM) is an aggressive chemotherapy-resistant cancer. Up-regulation of epidermal growth factor receptor (EGFR) plays an important role in MPM development and EGFR-tyrosine kinase inhibitors (TKIs) may represent novel therapeutic options. We tested the effects of the EGFR TKIs gefitinib and erlotinib and TKIs targeted to other growth factors (VEGFR and PDGFR), in comparison to standard antineoplastic agents, in two human MPM cell lines, IST-Mes2 and ZL55. All drugs showed IC(50) values in the micromolar range: TKIs induced cytostatic effects at concentrations up to the IC(50,) while conventional drug growth-inhibitory activity was mainly cytotoxic. Moreover, the treatment of IST-Mes2 with TKIs (gefitinib and imatinib mesylate) in combination with cisplatin and gemcitabine did not show additivity. Focusing on the molecular mechanisms underlying the antiproliferative and pro-apoptotic effects of EGFR-TKIs, we observed that gefitinib induced the formation and stabilization of inactive EGFR homodimers, even in absence of EGF, as demonstrated by EGFR B(max) and number of sites/cell. The analysis of downstream effectors of EGFR signaling demonstrated that EGF-induced proliferation, reverted by gefitinib, involved ERK1/2 activation, independently from Akt pathway. Gefitinib inhibits MPM cell growth and survival, preventing EGF-dependent activation of ERK1/2 pathway by blocking EGFR-TK phosphorylation and stabilizing inactive EGFR dimers. Along with the molecular definition of TKIs pharmacological efficacy in vitro, these results may contribute to delve deep into the promising but still controversial role for targeted and conventional drugs in the therapy of MPM. Copyright © 2011 Elsevier Inc. All rights reserved.

The role of plant processing for the cancer preventive potential of Ethiopian kale (Brassica carinata)

PubMed Central

Odongo, Grace Akinyi; Schlotz, Nina; Herz, Corinna; Hanschen, Franziska S.; Baldermann, Susanne; Neugart, Susanne; Trierweiler, Bernhard; Frommherz, Lara; Franz, Charles M. A. P.; Ngwene, Benard; Luvonga, Abraham Wahid; Schreiner, Monika; Rohn, Sascha; Lamy, Evelyn

2017-01-01

ABSTRACT Background: Ethiopian kale (Brassica carinata) is a horticulturally important crop used as leafy vegetable in large parts of East and Southern Africa. The leaves are reported to contain high concentrations of health-promoting secondary plant metabolites. However, scientific knowledge on their health benefits is scarce. Objective: This study aimed to determine the cancer preventive potential of B. carinata using a human liver in vitro model focusing on processing effects on the pattern of secondary plant metabolites and bioactivity. Design: B. carinata was cultivated under controlled conditions and differentially processed (raw, fermented, or cooked) after harvesting. Human liver cancer cells (HepG2) were treated with ethanolic extracts of raw or processed B. carinata leaves and analyzed for their anti-genotoxic, anti-oxidant, and cytostatic potential. Chemical analyses were carried out on glucosinolates including breakdown products, phenolic compounds, carotenoids, and chlorophyll content. Results: Pre-treatment with B. carinata extracts concentration dependently reduced aflatoxin-induced DNA damage in the Comet assay, reduced the production of reactive oxygen species as determined by electron paramagnetic resonance spectroscopy, and induced Nrf2-mediated gene expression. Increasing extract concentrations also promoted cytostasis. Processing had a significant effect on the content of secondary plant metabolites. However, different processing methodologies did not dramatically decrease bioactivity, but enhanced the protective effect in some of the endpoints studied. Conclusion: Our findings highlight the cancer preventive potential of B. carinata as indicated by the protection of human liver cells against aflatoxin in vitro. In general, consumption of B. carinata should be encouraged as part of chemopreventive measures to combat prevalence of aflatoxin-induced diseases. PMID:28326001

Low oxygen tension reverses antineoplastic effect of iron chelator deferasirox in human glioblastoma cells.

PubMed

Legendre, Claire; Avril, Sylvie; Guillet, Catherine; Garcion, Emmanuel

2016-02-01

Overcoming resistance to treatment is an essential issue in many cancers including glioblastoma (GBM), the deadliest primary tumor of the central nervous system. As dependence on iron is a key feature of tumor cells, using chelators to reduce iron represents an opportunity to improve conventional GBM therapies. The aim of the present study was, therefore, to investigate the cytostatic and cytotoxic impact of the new iron chelator deferasirox (DFX) on human GBM cells in well-defined clinical situations represented by radiation therapy and mild-hypoxia. Under experimental normoxic condition (21% O2), deferasirox (DFX) used at 10 μM for 3 days reduced proliferation, led cell cycle arrest in S and G2-M phases and induced cytotoxicity and apoptosis in U251 and U87 GBM cells. The abolition of the antineoplastic DFX effects when cells were co-treated with ferric ammonium sulfate supports the hypothesis that its effects result from its ability to chelate iron. As radiotherapy is the main treatment for GBM, the combination of DFX and X-ray beam irradiation was also investigated. Irradiation at a dose of 16 Gy repressed proliferation, cytotoxicity and apoptosis, but only in U251 cells, while no synergy with DFX was observed in either cell line. Importantly, when the same experiment was conducted in mild-hypoxic conditions (3% O2), the antiproliferative and cytotoxic effects of DFX were abolished, and its ability to deplete iron was also impaired. Taken together, these in vitro results could raise the question of the benefit of using iron chelators in their native forms under the hypoxic conditions often encountered in solid tumors such as GBM. Developing new chemistry or a new drug delivery system that would keep DFX active in hypoxic cells may be the next step toward their application.

Cloning and characterization of full-length mouse thymidine kinase 2: the N-terminal sequence directs import of the precursor protein into mitochondria.

PubMed Central

Wang, L; Eriksson, S

2000-01-01

The subcellular localization of mitochondrial thymidine kinase (TK2) has been questioned, since no mitochondrial targeting sequences have been found in cloned human TK2 cDNAs. Here we report the cloning of mouse TK2 cDNA from a mouse full-length enriched cDNA library. The mouse TK2 cDNA codes for a protein of 270 amino acids, with a 40-amino-acid presumed N-terminal mitochondrial targeting signal. In vitro translation and translocation experiments with purified rat mitochondria confirmed that the N-terminal sequence directed import of the precursor TK2 into the mitochondrial matrix. A single 2.4 kb mRNA transcript was detected in most tissues examined, except in liver, where an additional shorter (1.0 kb) transcript was also observed. There was no correlation between the tissue distribution of TK2 activity and the expression of TK2 mRNA. Full-length mouse TK2 protein and two N-terminally truncated forms, one of which corresponds to the mitochondrial form of TK2 and a shorter form corresponding to the previously characterized recombinant human TK2, were expressed in Escherichia coli and affinity purified. All three forms of TK2 phosphorylated thymidine, deoxycytidine and 2'-deoxyuridine, but with different kinetic efficiencies. A number of cytostatic pyrimidine nucleoside analogues were also tested and shown to be good substrates for the various forms of TK2. The active form of full-length mouse TK2 was a dimer, as judged by Superdex 200 chromatography. These results enhance our understanding of the structure and function of TK2, and may help to explain the mitochondrial disorder, mitochondrial neurogastrointestinal encephalomyopathy. PMID:11023833

Fluoroquinolones inhibit human polyomavirus BK (BKV) replication in primary human kidney cells.

PubMed

Sharma, Biswa Nath; Li, Ruomei; Bernhoff, Eva; Gutteberg, Tore Jarl; Rinaldo, Christine Hanssen

2011-10-01

Reactivation of human polyomavirus BK (BKV) may cause polyomavirus-associated nephropathy or polyomavirus-associated hemorrhagic cystitis in renal- or bone marrow-transplant patients, respectively. Lack of treatment options has led to exploration of fluoroquinolones that inhibit topoisomerase II and IV in prokaryotes and possibly large T-antigen (LT-ag) helicase activity in polyomavirus. We characterized the effects of ofloxacin and levofloxacin on BKV replication in the natural host cells - primary human renal proximal tubular epithelial cells (RPTECs). Ofloxacin and levofloxacin inhibited BKV load in a dose-dependent manner yielding a ∼90% inhibition at 150 μg/ml. Ofloxacin at 150 μg/ml inhibited LT-ag mRNA and protein expression from 24h post infection (hpi). BKV genome replication was 77% reduced at 48 hpi and a similar reduction was found in VP1 and agnoprotein expression. At 72 hpi, the reduction in genome replication and protein expression was less pronounced. A dose-dependent cytostatic effect was noted. In infected cells, 150 μg/ml ofloxacin led to a 26% and 6% inhibition of cellular DNA replication and total metabolic activity, respectively while 150 μg/ml levofloxacin affected this slightly more, particularly in uninfected cells. Cell counting and xCELLigence results revealed that cell numbers were not reduced. In conclusion, ofloxacin and levofloxacin inhibit but do not eradicate BKV replication in RPTECs. At a concentration of ofloxacin giving ∼90% inhibition in BKV load, no significant cytotoxicity was observed. This concentration can be achieved in urine and possibly in the kidneys. Our results support a mechanism involving inhibition of LT-ag expression or functions but also suggest inhibition of cellular enzymes. Copyright © 2011 Elsevier B.V. All rights reserved.

Tangeretin, a citrus pentamethoxyflavone, exerts cytostatic effect via p53/p21 up-regulation and suppresses metastasis in 7,12-dimethylbenz(α)anthracene-induced rat mammary carcinoma.

PubMed

Arivazhagan, Lakshmi; Sorimuthu Pillai, Subramanian

2014-11-01

Breast cancer is the most commonly diagnosed cancer among women worldwide, which is characterized by unregulated cell growth and metastasis. Many bioactive compounds of plant origin such as tangeretin have been shown to possess potent antioxidant and anticancerous properties. In the present study we have investigated the chemotherapeutic effect of tangeretin against 7,12-dimethylbenz(α)anthracene (DMBA)-induced rat mammary carcinogenesis and studied its underlying mechanism of action. Breast cancer was induced by "air pouch technique" with a single dose of 25mg/kg of DMBA. Tangeretin (50 mg/kg) was administered orally for four weeks. Remarkably, tangeretin treatment controlled the growth of cancer cells which was clearly evidenced by morphological and histological analysis. Also, serum levels of estradiol, progesterone and prolactin; lipid bound sialic acid and total sialic acid and the tissue levels of nitric oxide and protein carbonyls of cancer induced animals were decreased upon tangeretin treatment. Staining of breast tissues for nucleolar organizer regions, mast cells, glycoproteins, lipids and collagen showed that tangeretin treatment to breast cancer induced rats significantly reduced tumorigenesis. Oral tangeretin treatment also effectively reduced the tumor cell proliferation markers such as PCNA, COX-2 and Ki-67. Further, tangeretin treatment arrested the cancer cell division at the G1/S phase via p53/p21 up-regulation and inhibited metastasis by suppressing matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor. Taken together, the data provides new evidence on the mechanism of action of tangeretin in breast cancer and hence extends the hypothesis supporting its potential use in chemotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Benzylserine inhibits breast cancer cell growth by disrupting intracellular amino acid homeostasis and triggering amino acid response pathways.

PubMed

van Geldermalsen, Michelle; Quek, Lake-Ee; Turner, Nigel; Freidman, Natasha; Pang, Angel; Guan, Yi Fang; Krycer, James R; Ryan, Renae; Wang, Qian; Holst, Jeff

2018-06-26

Cancer cells require increased levels of nutrients such as amino acids to sustain their rapid growth. In particular, leucine and glutamine have been shown to be important for growth and proliferation of some breast cancers, and therefore targeting the primary cell-surface transporters that mediate their uptake, L-type amino acid transporter 1 (LAT1) and alanine, serine, cysteine-preferring transporter 2 (ASCT2), is a potential therapeutic strategy. The ASCT2 inhibitor, benzylserine (BenSer), is also able to block LAT1 activity, thus inhibiting both leucine and glutamine uptake. We therefore aimed to investigate the effects of BenSer in breast cancer cell lines to determine whether combined LAT1 and ASCT2 inhibition could inhibit cell growth and proliferation. BenSer treatment significantly inhibited both leucine and glutamine uptake in MCF-7, HCC1806 and MDA-MB-231 breast cancer cells, causing decreased cell viability and cell cycle progression. These effects were not primarily leucine-mediated, as BenSer was more cytostatic than the LAT family inhibitor, BCH. Oocyte uptake assays with ectopically expressed amino acid transporters identified four additional targets of BenSer, and gas chromatography-mass spectrometry (GCMS) analysis of intracellular amino acid concentrations revealed that this BenSer-mediated inhibition of amino acid uptake was sufficient to disrupt multiple pathways of amino acid metabolism, causing reduced lactate production and activation of an amino acid response (AAR) through activating transcription factor 4 (ATF4). Together these data showed that BenSer blockade inhibited breast cancer cell growth and viability through disruption of intracellular amino acid homeostasis and inhibition of downstream metabolic and growth pathways.

Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme.

PubMed

Jun, H J; Acquaviva, J; Chi, D; Lessard, J; Zhu, H; Woolfenden, S; Bronson, R T; Pfannl, R; White, F; Housman, D E; Iyer, L; Whittaker, C A; Boskovitz, A; Raval, A; Charest, A

2012-06-21

Glioblastoma multiforme (GBM) is an aggressive brain tumor for which there is no cure. Overexpression of wild-type epidermal growth factor receptor (EGFR) and loss of the tumor suppressor genes Ink4a/Arf and PTEN are salient features of this deadly cancer. Surprisingly, targeted inhibition of EGFR has been clinically disappointing, demonstrating an innate ability for GBM to develop resistance. Efforts at modeling GBM in mice using wild-type EGFR have proven unsuccessful to date, hampering endeavors at understanding molecular mechanisms of therapeutic resistance. Here, we describe a unique genetically engineered mouse model of EGFR-driven gliomagenesis that uses a somatic conditional overexpression and chronic activation of wild-type EGFR in cooperation with deletions in the Ink4a/Arf and PTEN genes in adult brains. Using this model, we establish that chronic activation of wild-type EGFR with a ligand is necessary for generating tumors with histopathological and molecular characteristics of GBMs. We show that these GBMs are resistant to EGFR kinase inhibition and we define this resistance molecularly. Inhibition of EGFR kinase activity using tyrosine kinase inhibitors in GBM tumor cells generates a cytostatic response characterized by a cell cycle arrest, which is accompanied by a substantial change in global gene expression levels. We demonstrate that an important component of this pattern is the transcriptional activation of the MET receptor tyrosine kinase and that pharmacological inhibition of MET overcomes the resistance to EGFR inhibition in these cells. These findings provide important new insights into mechanisms of resistance to EGFR inhibition and suggest that inhibition of multiple targets will be necessary to provide therapeutic benefit for GBM patients.

The XTT Cell Proliferation Assay Applied to Cell Layers Embedded in Three-Dimensional Matrix

PubMed Central

Huyck, Lynn; Ampe, Christophe

2012-01-01

Abstract Cell proliferation, a main target in cancer therapy, is influenced by the surrounding three-dimensional (3D) extracellular matrix (ECM). In vitro drug screening is, thus, optimally performed under conditions in which cells are grown (embedded or trapped) in dense 3D matrices, as these most closely mimic the adhesive and mechanical properties of natural ECM. Measuring cell proliferation under these conditions is, however, technically more challenging compared with two-dimensional (2D) culture and other “3D culture conditions,” such as growth on top of a matrix (pseudo-3D) or in spongy scaffolds with large pore sizes. Consequently, such measurements are only slowly applied on a wider scale. To advance this, we report on the equal quality (dynamic range, background, linearity) of measuring the proliferation of cell layers embedded in dense 3D matrices (collagen, Matrigel) compared with cells in 2D culture using the easy (one-step) and in 2D well-validated, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT)-assay. The comparison stresses the differences in proliferation kinetics and drug sensitivity of matrix-embedded cells versus 2D culture. Using the specific cell-layer-embedded 3D matrix setup, quantitative measurements of cell proliferation and cell invasion are shown to be possible in similar assay conditions, and cytostatic, cytotoxic, and anti-invasive drug effects can thus be reliably determined and compared in physiologically relevant settings. This approach in the 3D matrix holds promise for improving early-stage, high-throughput drug screening, targeting either highly invasive or highly proliferative subpopulations of cancers or both. PMID:22574651

PIK3CA-mutated melanoma cells rely on cooperative signaling through mTORC1/2 for sustained proliferation.

PubMed

Silva, Jillian M; Deuker, Marian M; Baguley, Bruce C; McMahon, Martin

2017-05-01

Malignant conversion of BRAF- or NRAS-mutated melanocytes into melanoma cells can be promoted by PI3'-lipid signaling. However, the mechanism by which PI3'-lipid signaling cooperates with mutationally activated BRAF or NRAS has not been adequately explored. Using human NRAS- or BRAF-mutated melanoma cells that co-express mutationally activated PIK3CA, we explored the contribution of PI3'-lipid signaling to cell proliferation. Despite mutational activation of PIK3CA, melanoma cells were more sensitive to the biochemical and antiproliferative effects of broader spectrum PI3K inhibitors than to an α-selective PI3K inhibitor. Combined pharmacological inhibition of MEK1/2 and PI3K signaling elicited more potent antiproliferative effects and greater inhibition of the cell division cycle compared to single-agent inhibition of either pathway alone. Analysis of signaling downstream of MEK1/2 or PI3K revealed that these pathways cooperate to regulate cell proliferation through mTORC1-mediated effects on ribosomal protein S6 and 4E-BP1 phosphorylation in an AKT-dependent manner. Although PI3K inhibition resulted in cytostatic effects on xenografted NRAS Q61H /PIK3CA H1047R melanoma, combined inhibition of MEK1/2 plus PI3K elicited significant melanoma regression. This study provides insights as to how mutationally activated PIK3CA acts in concert with MEK1/2 signaling to cooperatively regulate mTORC1/2 to sustain PIK3CA-mutated melanoma proliferation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PTEN Loss Does Not Predict for Response to RAD001 (Everolimus) in a Glioblastoma Orthotopic Xenograft Test Panel

PubMed Central

Yang, Lin; Clarke, Michelle J.; Carlson, Brett L.; Mladek, Ann C.; Schroeder, Mark A.; Decker, Paul; Wu, Wenting; Kitange, Gaspar J.; Grogan, Patrick T.; Goble, Jennie M.; Uhm, Joon; Galanis, Evanthia; Giannini, Caterina; Lane, Heidi A.; James, C. David; Sarkaria, Jann N.

2014-01-01

Purpose Hyperactivation of the phosphatidylinositol 3-kinase/Akt signaling through disruption of PTEN function is common in glioblastoma multiforme, and these genetic changes are predicted to enhance sensitivity to mammalian target of rapamycin (mTOR) inhibitors such as RAD001 (everolimus). Experimental Design To test whether PTEN loss could be used as a predictive marker for mTOR inhibitor sensitivity, the response of 17 serially transplantable glioblastoma multiforme xenografts was evaluated in an orthotopic therapy evaluation model. Of these 17 xenograft lines, 7 have either genomic deletion or mutation of PTEN. Results Consistent with activation of Akt signaling, there was a good correlation between loss of PTEN function and elevated levels of Akt phosphorylation. However, of the 7 lines with disrupted PTEN function, only 1 tumor line (GBM10) was significantly sensitive to RAD001 therapy (25% prolongation in median survival), whereas1 of 10 xenograft lines with wild-type PTEN was significantly sensitive to RAD001 (GS22; 34% prolongation in survival). Relative to placebo, 5 days of RAD001 treatment was associated with a marked 66% reduction in the MIB1 proliferation index in the sensitive GBM10 line (deleted PTEN) compared with a 25% and 7% reduction in MIB1 labeling index in the insensitive GBM14 (mutant PTEN) and GBM15 (wild-type PTEN) lines, respectively. Consistent with a cytostatic antitumor effect, bioluminescent imaging of luciferase-transduced intracranial GBM10 xenografts showed slowed tumor growth without significant tumor regression during RAD001 therapy. Conclusion These data suggest that loss of PTEN function is insufficient to adequately predict responsiveness to mTOR inhibitors in glioblastoma multiforme. PMID:18559622

The Effect of Early Detection of Occult Brain Metastases in HER2-Positive Breast Cancer Patients on Survival and Cause of Death

DOE Office of Scientific and Technical Information (OSTI.GOV)

Niwinska, Anna, E-mail: alphaonetau@poczta.onet.p; Tacikowska, Malgorzata; Murawska, Magdalena

2010-07-15

Purpose: The aim of the study is to evaluate disease-free survival, survival from the detection of brain metastases, overall survival, and cause of death in patients with occult brain metastases (Group I) vs. patients with symptomatic brain metastases (Group II). Methods and Materials: In 80 HER2-positive breast cancer patients, treated with trastuzumab and cytostatic agents for metastatic disease, magnetic resonance imaging screening of the brain was performed, and in 29 patients (36%) occult brain metastasis was detected (Group I). Whole-brain radiotherapy was delivered to Group I. This first group was compared with 52 patients who had symptomatic brain metastases (Groupmore » II) and was treated the same way, at the same clinic, during the same time period. Results: Median disease-free survival was 17 months in Group I and 19.9 months in Group II (p = 0.58). The median time interval between the dissemination of the disease and the detection of occult or symptomatic brain metastases was 9 and 15 months, respectively (p = 0.11). When the brain metastases were detected, the median survival was 9 and 8.78 months, respectively (p = 0.80). The median overall survival was 53 and 51 months, respectively (p = 0.94). In the group with occult brain metastases (Group I) 16% of patients died because of progression within the brain. In the group with symptomatic brain metastases (Group II) the rate of cerebral death was 48% (p = 0.009). Conclusions: Whole-brain radiotherapy of occult brain metastases in HER2-positive breast cancer patients with visceral dissemination produces a three-fold decrease in cerebral deaths but does not prolong survival.« less

The insulin-like growth factor-1 receptor inhibitor PPP produces only very limited resistance in tumor cells exposed to long-term selection.

PubMed

Vasilcanu, D; Weng, W-H; Girnita, A; Lui, W-O; Vasilcanu, R; Axelson, M; Larsson, O; Larsson, C; Girnita, L

2006-05-25

The cyclolignan PPP was recently demonstrated to inhibit the activity of insulin-like growth factor-1 receptor (IGF-1R), without affecting the highly homologous insulin receptor. In addition, PPP caused complete regression of xenografts derived from various types of cancer. These data highlight the use of this compound in cancer treatment. However, a general concern with antitumor agents is development of resistance. In light of this problem, we aimed to investigate whether malignant cells may develop serious resistance to PPP. After trying to select 10 malignant cell lines, with documented IGF-1R expression and apoptotic responsiveness to PPP treatment (IC50s less than 0.1 microM), only two survived an 80-week selection but could only tolerate maximal PPP doses of 0.2 and 0.5 microM, respectively. Any further increase in the PPP dose resulted in massive cell death. These two cell lines were demonstrated not to acquire any essential alteration in responsiveness to PPP regarding IGF-1-induced IGF-1R phosphorylation. Neither did they exhibit any increase in expression of the multidrug resistance proteins MDR1 or MRP1. Consistently, they did not exhibit decreased sensitivity to conventional cytostatic drugs. Rather, the sensitivity was increased. During the first half of the selection period, both cell lines responded with a temporary and moderate increase in IGF-1R expression, which appeared to be because of an increased transcription of the IGF-1R gene. This increase in IGF-1R might be necessary to make cells competent for further selection but only up to a PPP concentration of 0.2 and 0.5 microM. In conclusion, malignant cells develop no or remarkably weak resistance to the IGF-1R inhibitor PPP.

Radioimmunoassay of tumor markers in serum of patients with renal carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cordoni-Voutsas, M.; Glaubitt, D.; Wagner, W.

1984-01-01

Having noted an increased serum level of TPA and CEA in patients with renal carcinoma the authors extended these studies by using a larger number of tumor markers. In 15 patients (11 men and 4 women after menopause) aged 33 to 74 years who had renal carcinoma, among them 3 with tumor metastases, the serum concentration of TPA, CA 12-5, CEA, AFP, ferritin, prolactin, ..beta..-HCG, and ..beta../sub 2/-microglobulin was measured by radioimmunoassay. Monoclonal antibodies were used in the determination of serum CA 12-5 and CEA. In all patients surgical treatment, irradiation, or cytostatic therapy had not been performed. In serummore » the normal range was exceeded by TPA in 7 patients, CA 12-5 in 3, CEA and AFP in one each, ferritin in 12, prolactin in 2, and ..beta../sub 2/-microglobulin in 10 patients. In one man serum prolactin was reduced. Serum ..beta..-HCG was normal in all patients. According to these results serum ferritin, TPA, and ..beta../sub 2/-microglobulin are of great value as tumor markers in patients with renal carcinoma. In several patients the increase of serum ..beta../sub 2/-microglobulin may be ascribed partly to deterioration of renal function. As no consistent patterns of tumor markers in serum were observed it is recommended to determine several tumor markers and not only one of them during the follow-up of patients. Radioimmunoassays for measuring the serum level of tumor markers, especially ferritin, TPA, and ..beta../sub 2/-microglobulin, may considerably assist in the management of patients with renal carcinoma by providing early information about tumor recurrence or metastases.« less

Development and application of a specially designed heating system for temperature-programmed high-performance liquid chromatography using subcritical water as the mobile phase.

PubMed

Teutenberg, T; Goetze, H-J; Tuerk, J; Ploeger, J; Kiffmeyer, T K; Schmidt, K G; Kohorst, W gr; Rohe, T; Jansen, H-D; Weber, H

2006-05-05

A specially designed heating system for temperature-programmed HPLC was developed based on experimental measurements of eluent temperature inside a stainless steel capillary using a very thin thermocouple. The heating system can be operated at temperatures up to 225 degrees C and consists of a preheating, a column heating and a cooling unit. Fast cycle times after a temperature gradient can be realized by an internal silicone oil bath which cools down the preheating and column heating unit. Long-term thermal stability of a polybutadiene-coated zirconium dioxide column has been evaluated using a tubular oven in which the column was placed. The packing material was stable after 50h of operation at 185 degrees C. A mixture containing four steroids was separated at ambient conditions using a mobile phase of 25% acetonitrile:75% deionized water and a mobile phase of pure deionized water at 185 degrees C using the specially designed heating system and the PBD column. Analysis time could be drastically reduced from 17 min at ambient conditions and a flow rate of 1 mL/min to only 1.2 min at 185 degrees C and a flow rate of 5 mL/min. At these extreme conditions, no thermal mismatch was observed and peaks were not distorted, thus underlining the performance of the developed heating system. Temperature programming was performed by separating cytostatic and antibiotic drugs with a temperature gradient using only water as the mobile phase. In contrast to an isocratic elution of this mixture at room temperature, overall analysis time could be reduced two-fold from 20 to 10 min.

Cr(VI) induces DNA damage, cell cycle arrest and polyploidization: a flow cytometric and comet assay study in Pisum sativum.

PubMed

Rodriguez, Eleazar; Azevedo, Raquel; Fernandes, Pedro; Santos, Conceição

2011-07-18

Chromium(VI) is recognized as the most toxic valency of Cr, but its genotoxicity and cytostaticity in plants is still poorly studied. In order to analyze Cr(VI) cyto- and gentotoxicity, Pisum sativum L. plants were grown in soil and watered with solutions with different concentrations of Cr up to 2000 mg/L. After 28 days of exposure, leaves showed no significant variations in either cell cycle dynamics or ploidy level. As for DNA damage, flow cytometric (FCM) histograms showed significant differences in full peak coefficient of variation (FPCV) values, suggesting clastogenicity. This is paralleled by the Comet assay results, showing an increase in DNA damage for 1000 and 2000 mg/L. In roots, exposure to 2000 mg/L resulted in cell cycle arrest at the G(2)/M checkpoint. It was also verified that under the same conditions 40% of the individuals analyzed suffered polyploidization having both 2C and 4C levels. DNA damage analysis by the Comet assay and FCM revealed dose-dependent increases in DNA damage and FPCV. Through this, we have unequivocally demonstrated for the first time in plants that Cr exposure can result in DNA damage, cell cycle arrest, and polyploidization. Moreover, we critically compare the validity of the Comet assay and FCM in evaluating cytogenetic toxicity tests in plants and demonstrate that the data provided by both techniques complement each other and present high correlation levels. In conclusion, the data presented provides new insight on Cr effects in plants in general and supports the use of the parameters tested in this study as reliable endpoints for this metal toxicity in plants. © 2011 American Chemical Society

Systems biology of cisplatin resistance: past, present and future.

PubMed

Galluzzi, L; Vitale, I; Michels, J; Brenner, C; Szabadkai, G; Harel-Bellan, A; Castedo, M; Kroemer, G

2014-05-29

The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant problem.

Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer

PubMed Central

Guimaraes, Alex R.; Corcoran, Ryan B.; Deshpande, Vikram; Wojtkiewicz, Gregory R.; Hezel, Aram F.; Wong, Kwok-Kin; Loda, Massimo; Weissleder, Ralph; Benes, Cyril H.; Engelman, Jeffrey; Bardeesy, Nabeel

2015-01-01

Purpose Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being employed in clinical trials for PDAC patients, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMMs). Experimental Design We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically-relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD-6244, for efficacy alone or in combination with the PI3K inhibitors, BKM-120 or GDC-0941, in a KRASG12D-driven GEMM that recapitulates the histopathogenesis of human PDAC. Results In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD-6244, was an outlier, showing the highest selective efficacy in PDAC. While MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM-120 or GDC-0941). When tested in a PDAC GEMM and compared to the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed. Conclusions Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some PDAC patients. PMID:25348516

Systemic treatment with n-6 polyunsaturated fatty acids attenuates EL4 thymoma growth and metastasis through enhancing specific and non-specific anti-tumor cytolytic activities and production of TH1 cytokines.

PubMed

Salem, Mohamed Labib

2005-06-01

Recently, there has been a great interest in the effects of different types of n-6 polyunsaturated acids (n-6 PUFAs) upon the immune system and cancer development. However, the effects of n-6 PUFAs are still controversial and as yet undefined. The present study aimed to investigate the anti-tumor effects of n-6 PUFAs against EL4 thymoma and the associated immune mechanisms. To this, sesame oil, a vegetable oil enriched with n-6 PUFAs, or free linoleic acid (LA) were administered intraperitoneally into C57BL/6 mice before and after challenge with EL4 lymphoma cells. Treatment with either sesame oil or LA attenuated the growth and metastasis of EL4 lymphoma. The anti-tumor effect of LA was superior to that of sesame oil, and associated with an increase in the survival rate of the tumor-bearing mice. In addition, both sesame oil and LA showed dose-dependent anti-lymphoma growth in vitro. Treatment with LA generated significant increases in the anti-lymphoma cytolytic and cytostatic activities of T cells and macrophages, respectively, and enhanced production of IL-2 and IFN-gamma while decreased production of IL-4, IL-6 and IL-10. In summation, the results suggest that n-6 PUFAs, represented by LA, can attenuate EL4 lymphoma growth and metastasis through enhancing the specific and non-specific anti-tumor cytolytic activities and production of TH1 cytokines. These findings might be of great importance for a proper design of systemic nourishment with PUFAs emulsions for cancer patients.

SYNTHESIS AND APPLICATIONS OF Fe3O4/SiO2 CORE-SHELL MATERIALS.

PubMed

Sonmez, Maria; Georgescu, Mihai; Alexandrescu, Laurentia; Gurau, Dana; Ficai, Anton; Ficai, Denisa; Andronescu, Ecaterina

2015-01-01

Multifunctional nanoparticles based on magnetite/silica core-shell, consisting of iron oxides coated with silica matrix doped with fluorescent components such as organic dyes (fluorescein isothiocyanate - FITC, Rhodamine 6G) or quantum dots, have drawn remarkable attention in the last years. Due to the bi-functionality of these types of nanoparticles (simultaneously having magnetic and fluorescent properties), they are successfully used in highly efficient human stem cell labeling, magnetic carrier for photodynamic therapy, drug delivery, hyperthermia and other biomedical applications. Another application of core-shell-based nanoparticles, in which the silica is functionalized with aminosilanes, is for immobilization and separation of various biological entities such as proteins, antibodies, enzymes etc. as well as in environmental applications, as adsorbents for heavy metal ions. In vitro tests on human cancerous cells, such as A549 (human lung carcinoma), breast, human cervical cancer, THP-1 (human acute monocytic leukaemia) etc. , were conducted to assess the potential cytotoxic effects that may occur upon contact of nanoparticles with cancerous tissue. Results show that core-shell nanoparticles doped with cytostatics (cisplatin, doxorubicin, etc.), are easily adsorbed by affected tissue and in some cases lead to an inhibition of cell proliferation and induce cell death by apoptosis. The goal of this review is to summarize the advances in the field of core-shell materials, particularly those based on magnetite/silica with applicability in medicine and environmental protection. This paper briefly describes synthesis methods of silica-coated magnetite nanoparticles (Stöber method and microemulsion), the method of encapsulating functional groups based on aminosilanes in silica shell, as well as applications in medicine of these types of simple or modified nanoparticles for cancer therapy, MRI, biomarker immobilization, drug delivery, biocatalysis etc., and in environmental applications (removal of heavy metal ions and catalysis).

Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors.

PubMed

Lindsay, Danika; Garvey, Colleen M; Mumenthaler, Shannon M; Foo, Jasmine

2016-08-01

Experimental studies have shown that one key factor in driving the emergence of drug resistance in solid tumors is tumor hypoxia, which leads to the formation of localized environmental niches where drug-resistant cell populations can evolve and survive. Hypoxia-activated prodrugs (HAPs) are compounds designed to penetrate to hypoxic regions of a tumor and release cytotoxic or cytostatic agents; several of these HAPs are currently in clinical trial. However, preliminary results have not shown a survival benefit in several of these trials. We hypothesize that the efficacy of treatments involving these prodrugs depends heavily on identifying the correct treatment schedule, and that mathematical modeling can be used to help design potential therapeutic strategies combining HAPs with standard therapies to achieve long-term tumor control or eradication. We develop this framework in the specific context of EGFR-driven non-small cell lung cancer, which is commonly treated with the tyrosine kinase inhibitor erlotinib. We develop a stochastic mathematical model, parametrized using clinical and experimental data, to explore a spectrum of treatment regimens combining a HAP, evofosfamide, with erlotinib. We design combination toxicity constraint models and optimize treatment strategies over the space of tolerated schedules to identify specific combination schedules that lead to optimal tumor control. We find that (i) combining these therapies delays resistance longer than any monotherapy schedule with either evofosfamide or erlotinib alone, (ii) sequentially alternating single doses of each drug leads to minimal tumor burden and maximal reduction in probability of developing resistance, and (iii) strategies minimizing the length of time after an evofosfamide dose and before erlotinib confer further benefits in reduction of tumor burden. These results provide insights into how hypoxia-activated prodrugs may be used to enhance therapeutic effectiveness in the clinic.

Inhibitors of Glioma Growth that Reveal the Tumour to the Immune System

PubMed Central

Nieto-Sampedro, Manuel; Valle-Argos, Beatriz; Gómez-Nicola, Diego; Fernández-Mayoralas, Alfonso; Nieto-Díaz, Manuel

2011-01-01

Treated glioblastoma patients survive from 6 to 14 months. In the first part of this review, we describe glioma origins, cancer stem cells and the genomic alterations that generate dysregulated cell division, with enhanced proliferation and diverse response to radiation and chemotherapy. We review the pathways that mediate tumour cell proliferation, neo-angiogenesis, tumor cell invasion, as well as necrotic and apoptotic cell death. Then, we examine the ability of gliomas to evade and suppress the host immune system, exhibited at the levels of antigen recognition and immune activation, limiting the effective signaling between glioma and host immune cells. The second part of the review presents current therapies and their drawbacks. This is followed by a summary of the work of our laboratory during the past 20 years, on oligosaccharide and glycosphingolipid inhibitors of astroblast and astrocytoma division. Neurostatins, the O-acetylated forms of gangliosides GD1b and GT1b naturally present in mammalian brain, are cytostatic for normal astroblasts, but cytotoxic for rat C6 glioma cells and human astrocytoma grades III and IV, with ID50 values ranging from 200 to 450 nM. The inhibitors do not affect neurons or fibroblasts up to concentrations of 4 μM or higher. At least four different neurostatin-activated, cell-mediated antitumoral processes, lead to tumor destruction: (i) inhibition of tumor neovascularization; (ii) activation of microglia; (iii) activation of natural killer (NK) cells; (iv) activation of cytotoxic lymphocytes (CTL). The enhanced antigenicity of neurostatin-treated glioma cells, could be related to their increased expression of connexin 43. Because neurostatins and their analogues show specific activity and no toxicity for normal cells, a clinical trial would be the logical next step. PMID:22084619

Melatonin: an inhibitor of breast cancer.

PubMed

Hill, Steven M; Belancio, Victoria P; Dauchy, Robert T; Xiang, Shulin; Brimer, Samantha; Mao, Lulu; Hauch, Adam; Lundberg, Peter W; Summers, Whitney; Yuan, Lin; Frasch, Tripp; Blask, David E

2015-06-01

The present review discusses recent work on melatonin-mediated circadian regulation, the metabolic and molecular signaling mechanisms that are involved in human breast cancer growth, and the associated consequences of circadian disruption by exposure to light at night (LEN). The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin suppresses ERα mRNA expression and ERα transcriptional activity via the MT1 receptor. Melatonin also regulates the transactivation of other members of the nuclear receptor superfamily, estrogen-metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (the Warburg effect) and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type-specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways, including inhibition of p38 MAPK and repression of epithelial-mesenchymal transition (EMT). Studies have demonstrated that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models has indicated that LEN-induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer and drives breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms that underpin the epidemiologic demonstration of elevated breast cancer risk in night-shift workers and other individuals who are increasingly exposed to LEN. © 2015 Society for Endocrinology.

Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

PubMed Central

Braidwood, Lynne; Graham, Sheila V; Graham, Alex; Conner, Joe

2013-01-01

Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVexGM-CSF]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with “standard-of-care” drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with “standard-of-care” drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions. PMID:27512658

Synthesis, photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones.

PubMed

DoganKoruznjak, Jasna; Slade, Neda; Zamola, Branimir; Pavelić, Kresimir; Karminski-Zamola, Grace

2002-05-01

The novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones 6a, 6b, 7, 10a and 10b were synthesized in multistep synthesis starting from thiophene-3-carboxaldehyde and malonic acid reacting in aldol condensation or from 3-bromothiophenes or methyl 4-bromothiophene-2-carboxylate reacting in Heck reaction. They resulted in corresponding substituted thienylacrylic acids 3a-c, which were cyclized into thieno[2,3-c]thiophene-2-carbonyl chlorides 4a-c and converted into thieno[2,3-c]thiophene-2-carboxamides 5a-d. Prepared carboxamides were photochemically dehydrohalogenated into corresponding substituted thieno[3',2':4,5]thieno[2,3-c]quinolones 6a-d. Compound 7 was prepared from 6d by alkylation with N-[3-(dimethylamino)propyl]chloride hydrochloride in the presence of NaH. Compounds 10a and 10b were prepared from 6c in the multistep synthesis over acid 8 and acid chloride 9. Compounds 6a, 6b, 7, 10a and 10b were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). The compound 6b, which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibited marked antitumor activity. On the contrary, compound 7, which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen but anilido substituent on position 9, exhibited less antitumor activity than the others.

Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations

PubMed Central

Matthews, Holly; Deakin, Jon; Rajab, May; Idris-Usman, Maryam

2017-01-01

The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with its anti-amoebic potency (ED50 26–32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil). The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product. PMID:28257497

Systems biology of cisplatin resistance: past, present and future

PubMed Central

Galluzzi, L; Vitale, I; Michels, J; Brenner, C; Szabadkai, G; Harel-Bellan, A; Castedo, M; Kroemer, G

2014-01-01

The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant problem. PMID:24874729

Nanoparticles for the delivery of zoledronic acid to prostate cancer cells: A comparative analysis through time lapse video-microscopy technique

PubMed Central

Schiraldi, Chiara; Zappavigna, Silvia; D' Agostino, Antonella; Porto, Stefania; Gaito, Ornella; Lusa, Sara; Lamberti, Monica; De Rosa, Mario; De Rosa, Giuseppe; Caraglia, Michele

2014-01-01

Time-lapse live cell imaging is a powerful tool for studying the responses of cells to drugs. Zoledronic acid (ZOL) is the most potent aminobiphosphonate able to induce cell growth inhibition at very low concentrations. The lack of clear evidence of ZOL-induced anti-cancer effects is likely due to its unfavorable pharmacokinetic profile. The use of nanotechnology-based formulations allows overcoming these limitations in ZOL pharmaco-distribution. Recently, stealth liposomes (LIPOs) and new self-assembly PEGylated nanoparticles (NPs) encapsulating ZOL were developed. Both the delivery systems showed promising anticancer activity in vitro and in vivo. In this work, we investigated the cytostatic effect of these novel formulations (LIPOs and NPs) compared with free ZOL on 2 different prostate cancer cell lines, PC 3 and DU 145 and on prostate epithelial primary cells EPN using time lapse video-microscopy (TLVM). In PC3 cells, free ZOL showed a significant anti-proliferative effect but this effect was lower than that induced by LIPOs and NPs encapsulating ZOL; moreover, LIPO-ZOL was more potent in inducing growth inhibition than NP-ZOL. On the other hand, LIPO-ZOL slightly enhanced the free ZOL activity on growth inhibition of DU 145, while the anti-proliferative effect of NP-ZOL was not statistically relevant. These novel formulations did not induce anti-proliferative effects on EPN cells. Finally, we evaluated cytotoxic effects on DU145 where, LIPO-ZOL induced the highest cytotoxicity compared with NP-ZOL and free ZOL. In conclusion, ZOL can be transformed in a powerful anticancer agent, if administered with nanotechnology-based formulations without damaging the healthy tissues. PMID:25482949

Validation of osteogenic properties of Cytochalasin D by high-resolution RNA-sequencing in mesenchymal stem cells derived from bone marrow and adipose tissues.

PubMed

Samsonraj, Rebekah; Paradise, Christopher R; Dudakovic, Amel; Sen, Buer; Nair, Asha A; Dietz, Allan B; Deyle, David R; Cool, Simon M; Rubin, Janet; van Wijnen, Andre

2018-06-08

Differentiation of mesenchymal stromal/stem cells (MSCs) involves a series of molecular signals and gene transcription events required for attaining cell lineage commitment. Modulation of the actin cytoskeleton using cytochalasin D (CytoD) drives osteogenesis at early time points in bone marrow-derived MSCs, and also initiates a robust osteogenic differentiation program in adipose-derived MSCs. To understand the molecular basis for these pronounced effects on osteogenic differentiation, we investigated global changes in gene expression in CytoD-treated murine and human MSCs by high-resolution RNA-sequencing (RNA-seq) analysis. A three-way bioinformatic comparison between human adipose-derived, human bone marrow-derived and mouse bone marrow-derived MSCs revealed significant upregulation of genes linked to extracellular matrix organization, cell adhesion and bone metabolism. As anticipated, the activation of these differentiation related genes is accompanied by a downregulation of nuclear and cell cycle-related genes presumably reflecting cytostatic effects of CytoD. We also identified eight novel CytoD activated genes - VGLL4, ARHGAP24, KLHL24, RCBTB2, BDH2, SCARF2, ACAD10, HEPH - which are commonly upregulated across the two species and tissue sources of our MSC samples. We selected the Hippo-pathway related VGLL4 gene, which encodes the transcriptional co-factor Vestigial-like 4, for further study because this pathway is linked to osteogenesis. VGLL4 siRNA depletion reduces mineralization of adipose-derived MSCs during CytoD-induced osteogenic differentiation. Together, our RNA-seq analyses suggest that while the stimulatory effects of CytoD on osteogenesis are pleiotropic and depend on the biological state of the cell type, a small group of genes including VGLL4 may contribute to MSC commitment towards the bone lineage.

A phase II trial of recombinant tumor necrosis factor in patients with metastatic colorectal adenocarcinoma: a Southwest Oncology Group study.

PubMed

Whitehead, R P; Fleming, T; Macdonald, J S; Goodman, P J; Neefe, J; Braun, T J; Swinnen, L J; Hersh, E M

1990-12-01

Tumor necrosis factor (TNF) induces hemorrhagic necrosis in the Meth A mouse tumor model and has shown cytostatic and cytotoxic antitumor effects against a wide range of human tumors both in vitro and as human tumor xenografts in nude mice. Because of in vitro activity against colorectal tumors and antitumor responses in colon cancer patients in phase I trials, this phase II study was undertaken. Patients were treated with TNF administered daily for 5 days/week every other week at a dose of 150 micrograms/m2/day as a 30-min i.v. infusion. One cycle consisted of 4 weeks of treatment over an 8-week period. Twenty-five patients have been entered into this study with three patients ineligible. The 22 eligible patients ranged in age from 38-73 years and had initial performance status of 0 in 10 patients, 1 in 10 patients, and 2 in 2 patients. No complete or partial responses were seen. Two patients had stable disease (no response) and 18 patients progressed. Two patients had no evaluation and were assumed to have had no response. The response rate is therefore 0%, with a 95% exact confidence interval of 0% to 15%. There was one grade 4 toxicity consisting of nausea and vomiting. Most common grade 3 toxicities were chills and fever in four patients, nausea and vomiting in three patients, and anemia and elevated liver enzymes in two patients. Headache, myalgia/arthralgia, and elevated serum triglycerides were frequently seen. Mildly elevated levels of fibrin split products were seen after TNF treatment in 5/13 evaluable patients and one ineligible patient.(ABSTRACT TRUNCATED AT 250 WORDS)

pH sensitive core-shell magnetic nanoparticles for targeted drug delivery in cancer therapy.

PubMed

Lungu, Iulia Ioana; Rădulescu, Marius; Mogoşanu, George Dan; Grumezescu, Alexandru Mihai

2016-01-01

In the last decade, nanobiotechnology has evolved rapidly with an extensive impact on biomedical area. In order to improve bioavailability and minimize adverse effects, drug delivery systems based on magnetic nanocomposites are under development mainly for cancer imaging and antitumor therapy. In this regard, pH sensitive core-shell magnetic nanoparticles (NPs) with accurate controlled size and shape are synthesized by various modern methods, such as homogeneous precipitation, coprecipitation, microemulsion or polyol approaches, high temperature and hydrothermal reactions, sol-gel reactions, aerosol÷vapor processes and sonolysis. Due to their unique combined physico-chemical and biological properties (such as higher dispensability, chemical and thermal stability, biocompatibility), pH responsive core-shell magnetic NPs are widely investigated for controlled release of cytostatic drugs into the tumor site by means of pH change: magnetite@silicon dioxide (Fe3O4@SiO2), Fe3O4@titanium dioxide (TiO2), β-thiopropionate-polyethylene glycol (PEG)-modified Fe3O4@mSiO2, Fe3O4 NPs core coated with SiO2 with an imidazole group modified PEG-polypeptide (mPEG-poly-L-Asparagine), polyacrylic acid (PAA) and folic acid (FA) coating of the iron oxide NP core, methoxy polyethylene glycol-block-polymethacrylic acid-block-polyglycerol monomethacrylate (MPEG-b-PMAA-b-PGMA) attached by a PGMA block to a Fe3O4 core, PEG-modified polyamidoamine (PAMAM) dendrimer shell with Fe3O4 core and mesoporous silica coated on Fe3O4, mostly coated with an anticancer drug. This review paper highlights the modern research directions currently employed to demonstrate the utility of the pH responsive core-shell magnetic NPs in diagnosis and treatment of oncological diseases.

nanoCAGE reveals 5′ UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs

PubMed Central

Gandin, Valentina; Masvidal, Laia; Hulea, Laura; Gravel, Simon-Pierre; Cargnello, Marie; McLaughlan, Shannon; Cai, Yutian; Balanathan, Preetika; Morita, Masahiro; Rajakumar, Arjuna; Furic, Luc; Pollak, Michael; Porco, John A.; St-Pierre, Julie; Pelletier, Jerry; Larsson, Ola; Topisirovic, Ivan

2016-01-01

The diversity of MTOR-regulated mRNA translation remains unresolved. Whereas ribosome-profiling suggested that MTOR almost exclusively stimulates translation of the TOP (terminal oligopyrimidine motif) and TOP-like mRNAs, polysome-profiling indicated that MTOR also modulates translation of mRNAs without the 5′ TOP motif (non-TOP mRNAs). We demonstrate that in ribosome-profiling studies, detection of MTOR-dependent changes in non-TOP mRNA translation was obscured by low sensitivity and methodology biases. Transcription start site profiling using nano-cap analysis of gene expression (nanoCAGE) revealed that not only do many MTOR-sensitive mRNAs lack the 5′ TOP motif but that 5′ UTR features distinguish two functionally and translationally distinct subsets of MTOR-sensitive mRNAs: (1) mRNAs with short 5′ UTRs enriched for mitochondrial functions, which require EIF4E but are less EIF4A1-sensitive; and (2) long 5′ UTR mRNAs encoding proliferation- and survival-promoting proteins, which are both EIF4E- and EIF4A1-sensitive. Selective inhibition of translation of mRNAs harboring long 5′ UTRs via EIF4A1 suppression leads to sustained expression of proteins involved in respiration but concomitant loss of those protecting mitochondrial structural integrity, resulting in apoptosis. Conversely, simultaneous suppression of translation of both long and short 5′ UTR mRNAs by MTOR inhibitors results in metabolic dormancy and a predominantly cytostatic effect. Thus, 5′ UTR features define different modes of MTOR-sensitive translation of functionally distinct subsets of mRNAs, which may explain the diverse impact of MTOR and EIF4A inhibitors on neoplastic cells. PMID:26984228

Enhancing the anti-lymphoma potential of 3,4-methylenedioxymethamphetamine ('ecstasy') through iterative chemical redesign: mechanisms and pathways to cell death.

PubMed

Wasik, Agata M; Gandy, Michael N; McIldowie, Matthew; Holder, Michelle J; Chamba, Anita; Challa, Anita; Lewis, Katie D; Young, Stephen P; Scheel-Toellner, Dagmar; Dyer, Martin J; Barnes, Nicholas M; Piggott, Matthew J; Gordon, John

2012-08-01

While 3,4-methylenedioxymethamphetamine (MDMA/'ecstasy') is cytostatic towards lymphoma cells in vitro, the concentrations required militate against its translation directly to a therapeutic in vivo. The possibility of 'redesigning the designer drug', separating desired anti-lymphoma activity from unwanted psychoactivity and neurotoxicity, was therefore mooted. From an initial analysis of MDMA analogues synthesized with a modified α-substituent, it was found that incorporating a phenyl group increased potency against sensitive, Bcl-2-deplete, Burkitt's lymphoma (BL) cells 10-fold relative to MDMA. From this lead, related analogs were synthesized with the 'best' compounds (containing 1- and 2-naphthyl and para-biphenyl substituents) some 100-fold more potent than MDMA versus the BL target. When assessed against derived lines from a diversity of B-cell tumors MDMA analogues were seen to impact the broad spectrum of malignancy. Expressing a BCL2 transgene in BL cells afforded only scant protection against the analogues and across the malignancies no significant correlation between constitutive Bcl-2 levels and sensitivity to compounds was observed. Bcl-2-deplete cells displayed hallmarks of apoptotic death in response to the analogues while BCL2 overexpressing equivalents died in a caspase-3-independent manner. Despite lymphoma cells expressing monoamine transporters, their pharmacological blockade failed to reverse the anti-lymphoma actions of the analogues studied. Neither did reactive oxygen species account for ensuing cell death. Enhanced cytotoxic performance did however track with predicted lipophilicity amongst the designed compounds. In conclusion, MDMA analogues have been discovered with enhanced cytotoxic efficacy against lymphoma subtypes amongst which high-level Bcl-2--often a barrier to drug performance for this indication--fails to protect.

3-Hydroxyflavone inhibits human osteosarcoma U2OS and 143B cells metastasis by affecting EMT and repressing u-PA/MMP-2 via FAK-Src to MEK/ERK and RhoA/MLC2 pathways and reduces 143B tumor growth in vivo.

PubMed

Lu, Ko-Hsiu; Chen, Pei-Ni; Hsieh, Yi-Hsien; Lin, Chin-Yin; Cheng, Fu-Yuan; Chiu, Peng-Chou; Chu, Shu-Chen; Hsieh, Yih-Shou

2016-11-01

Many natural flavonoids have cytostatic and apoptotic properties; however, we little know whether the effect of synthetic 3-hydroxyflavone on metastasis and tumor growth of human osteosarcoma. Here, we tested the hypothesis that 3-hydroxyflavone suppresses human osteosarcoma cells metastasis and tumor growth. 3-hydroxyflavone, up to 50 μM without cytotoxicity, inhibited U2OS and 143B cells motility, invasiveness and migration by reducing matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen activator (u-PA) and also impaired cell adhesion to gelatin. 3-hydroxyflavone significantly reduced p-focal adhesion kinase (FAK) Tyr397, p-FAK Tyr925, p-steroid receptor coactivator (Src), p-mitogen/extracellular signal-regulated kinase (MEK)1/2, p-myosin light chain (MLC)2 Ser19, epithelial cell adhesion molecule, Ras homolog gene family (Rho)A and fibronectin expressions. 3-hydroxyflavone also affected the epithelial-mesenchymal transition (EMT) by down-regulating expressions of Vimentin and α-catenin with activation of the transcription factor Slug. In nude mice xenograft model and tail vein injection model showed that 3-hydroxyflavone reduced 143B tumor growth and lung metastasis. 3-hydroxyflavone possesses the anti-metastatic activity of U2OS and 143B cells by affecting EMT and repressing u-PA/MMP-2 via FAK-Src to MEK/ERK and RhoA/MLC2 pathways and suppresses 143B tumor growth in vivo. This may lead to clinical trials of osteosarcoma chemotherapy to confirm the promising result in the future. Copyright © 2016 Elsevier Ltd. All rights reserved.

Differential effects of rapalogues, dual kinase inhibitors on human ovarian carcinoma cells in vitro

PubMed Central

ROGERS-BROADWAY, KARLY-RAI; CHUDASAMA, DIMPLE; PADOS, GEORGE; TSOLAKIDIS, DIMITRIS; GOUMENOU, ANASTASIA; HALL, MARCIA; KARTERIS, EMMANOUIL

2016-01-01

Ovarian cancer is the second most common gynaecological malignancy and was diagnosed in over 7,000 women in 2011 in the UK. There are currently no reliable biomarkers available for use in a regular screening assay for ovarian cancer and due to characteristic late presentation (78% in stages III and IV) ovarian cancer has a low survival rate (35% after 10 years). The mTOR pathway is a central regulator of growth, proliferation, apoptosis and angiogenesis; providing balance between available resources such as amino acids and growth factors, and stresses such as hypoxia, to control cellular behaviour accordingly. Emerging data links mTOR with the aetiopathogenesis of ovarian cancer. We hypothesised that mTOR inhibitors could play a therapeutic role in ovarian cancer treatment. In this study we began by validating the expression of four main mTOR pathway components, mTOR, DEPTOR, rictor and raptor, at gene and protein level in in vitro models of endometrioid (MDAH-2774) and clear cell (SKOV3) ovarian cancer using qPCR and ImageStream technology. Using a wound healing assay we show that inhibition of the mTOR pathway using rapamycin, rapalogues, resveratrol and NVP BEZ-235 induces a cytostatic and not cytotoxic response up to 18 h in these cell lines. We extended these findings up to 72 h with a proliferation assay and show that the effects of inhibition of the mTOR pathway are primarily mediated by the dephosphorylation of p70S6 kinase. We show that mTOR inhibition does not involve alteration of mTOR pathway components or induce caspase 9 cleavage. Preclinical studies including ovarian tissue of ovarian cancer patients, unaffected controls and patients with unrelated gynaecological conditions show that DEPTOR is reliably upregulated in ovarian cancer. PMID:27211906