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Sample records for activities including anti-cancer

  1. Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities

    PubMed Central

    Zhang, Yong; Jiang, Peixin; Ye, Min; Kim, Sung-Hoon; Jiang, Cheng; Lü, Junxuan

    2012-01-01

    Tanshinones are a class of abietane diterpene compound isolated from Salvia miltiorrhiza (Danshen or Tanshen in Chinese), a well-known herb in Traditional Chinese Medicine (TCM). Since they were first identified in the 1930s, more than 40 lipophilic tanshinones and structurally related compounds have been isolated from Danshen. In recent decades, numerous studies have been conducted to investigate the isolation, identification, synthesis and pharmacology of tanshinones. In addition to the well-studied cardiovascular activities, tanshinones have been investigated more recently for their anti-cancer activities in vitro and in vivo. In this review, we update the herbal and alternative sources of tanshinones, and the pharmacokinetics of selected tanshinones. We discuss anti-cancer properties and identify critical issues for future research. Whereas previous studies have suggested anti-cancer potential of tanshinones affecting multiple cellular processes and molecular targets in cell culture models, data from in vivo potency assessment experiments in preclinical models vary greatly due to lack of uniformity of solvent vehicles and routes of administration. Chemical modifications and novel formulations had been made to address the poor oral bioavailability of tanshinones. So far, human clinical trials have been far from ideal in their design and execution for the purpose of supporting an anti-cancer indication of tanshinones. PMID:23202971

  2. Potential Anti-Cancer Activities and Mechanisms of Costunolide and Dehydrocostuslactone

    PubMed Central

    Lin, Xuejing; Peng, Zhangxiao; Su, Changqing

    2015-01-01

    Costunolide (CE) and dehydrocostuslactone (DE) are derived from many species of medicinal plants, such as Saussurea lappa Decne and Laurus nobilis L. They have been reported for their wide spectrum of biological effects, including anti-inflammatory, anticancer, antiviral, antimicrobial, antifungal, antioxidant, antidiabetic, antiulcer, and anthelmintic activities. In recent years, they have caused extensive interest in researchers due to their potential anti-cancer activities for various types of cancer, and their anti-cancer mechanisms, including causing cell cycle arrest, inducing apoptosis and differentiation, promoting the aggregation of microtubule protein, inhibiting the activity of telomerase, inhibiting metastasis and invasion, reversing multidrug resistance, restraining angiogenesis has been studied. This review will summarize anti-cancer activities and associated molecular mechanisms of these two compounds for the purpose of promoting their research and application. PMID:25984608

  3. Plant derived substances with anti-cancer activity: from folklore to practice.

    PubMed

    Fridlender, Marcelo; Kapulnik, Yoram; Koltai, Hinanit

    2015-01-01

    Plants have had an essential role in the folklore of ancient cultures. In addition to the use as food and spices, plants have also been utilized as medicines for over 5000 years. It is estimated that 70-95% of the population in developing countries continues to use traditional medicines even today. A new trend, that involved the isolation of plant active compounds begun during the early nineteenth century. This trend led to the discovery of different active compounds that are derived from plants. In the last decades, more and more new materials derived from plants have been authorized and subscribed as medicines, including those with anti-cancer activity. Cancer is among the leading causes of morbidity and mortality worldwide. The number of new cases is expected to rise by about 70% over the next two decades. Thus, there is a real need for new efficient anti-cancer drugs with reduced side effects, and plants are a promising source for such entities. Here we focus on some plant-derived substances exhibiting anti-cancer and chemoprevention activity, their mode of action and bioavailability. These include paclitaxel, curcumin, and cannabinoids. In addition, development and use of their synthetic analogs, and those of strigolactones, are discussed. Also discussed are commercial considerations and future prospects for development of plant derived substances with anti-cancer activity. PMID:26483815

  4. Plant derived substances with anti-cancer activity: from folklore to practice

    PubMed Central

    Fridlender, Marcelo; Kapulnik, Yoram; Koltai, Hinanit

    2015-01-01

    Plants have had an essential role in the folklore of ancient cultures. In addition to the use as food and spices, plants have also been utilized as medicines for over 5000 years. It is estimated that 70–95% of the population in developing countries continues to use traditional medicines even today. A new trend, that involved the isolation of plant active compounds begun during the early nineteenth century. This trend led to the discovery of different active compounds that are derived from plants. In the last decades, more and more new materials derived from plants have been authorized and subscribed as medicines, including those with anti-cancer activity. Cancer is among the leading causes of morbidity and mortality worldwide. The number of new cases is expected to rise by about 70% over the next two decades. Thus, there is a real need for new efficient anti-cancer drugs with reduced side effects, and plants are a promising source for such entities. Here we focus on some plant-derived substances exhibiting anti-cancer and chemoprevention activity, their mode of action and bioavailability. These include paclitaxel, curcumin, and cannabinoids. In addition, development and use of their synthetic analogs, and those of strigolactones, are discussed. Also discussed are commercial considerations and future prospects for development of plant derived substances with anti-cancer activity. PMID:26483815

  5. Anti-cancer activity of bromelain nanoparticles by oral administration.

    PubMed

    Bhatnagar, Priyanka; Patnaik, Soma; Srivastava, Amit K; Mudiam, Mohan K R; Shukla, Yogeshwer; Panda, Amulya K; Pant, Aditya B; Kumar, Pradeep; Gupta, Kailash C

    2014-12-01

    Oral administration of anti-cancer drugs is an effective alternative to improve their efficacy and reduce undesired toxicity. Bromelain (BL) is known as an effective anti-cancer phyto-therapeutic agent, however, its activity is reduced upon oral administration. In addressing the issue, BL was encapsulated in Poly(lactic-co-glycolic acid) (PLGA) to formulate nanoparticles (NPs). Further, the NPs were coated with Eudragit L30D polymer to introduce stability against the gastric acidic conditions. The resultant coated NPs were characterized for BL entrapment, proteolytic activity and mean particle size. The stability and release pattern of NPs were evaluated under simulated gastrointestinal tract (GIT) pH conditions. Cytotoxicity studies carried out in human cell lines of diverse origin have shown significant dose advantage (-7-10 folds) with NPs in reducing the IC50 values compared with free BL. The cellular uptake of NPs in MCF-7, HeLa and Caco-2 cells monolayer was significantly enhanced several folds as compared to free BL. Altered expression of marker proteins associated with apoptosis and cell death (P53, P21, Bcl2, Bax) also confirmed the enhanced anti-carcinogenic potential of formulated NPs. Oral administration of NPs reduced the tumor burden of Ehrlich ascites carcinoma (EAC) in Swiss albino mice and also increased their life-span (160.0 ± 5.8%) when compared with free BL (24 ± 3.2%). The generation of reactive oxygen species, induction of apoptosis and impaired mitochondrial membrane potential in EAC cells treated with NPs confirmed the suitability of Eudragit coated BL-NPs as a promising candidate for oral chemotherapy. PMID:26000370

  6. Anti-cancer activity of carbamate derivatives of melampomagnolide B

    PubMed Central

    Janganati, Venumadhav; Penthala, Narsimha Reddy; Madadi, Nikhil Reddy; Chen, Zheng; Crooks, Peter A.

    2015-01-01

    Melampomagnolide B (MMB) is a natural sesquiterpene structurally related to parthenolide (PTL). We have shown that MMB exhibits anti-leukemic properties similar to PTL. Unlike PTL, the presence of a primary hydroxyl group in the MMB molecule allows the opportunity for examining the biological activity of a variety of conjugated analogs of MMB. We have now synthesized a series of carbamate analogs of MMB and evaluated these derivatives for anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 6a and 6e exhibited promising anti-leukemic activity against human leukemia cell line CCRF-CEM with GI50 values of 680 and 620 nM, respectively. 6a also showed GI50 values of 1.98 and 1.38 µM respectively, against RPMI-8226 and SR leukemia cell lines and GI50 values of 460 and 570 nM against MDA-MB-435 melanoma and MDA-MB-468 breast cancer cell lines, respectively. 6e had GI50 values of 650 nM and 900 nM against HOP-92 non-small cell lung and RXF 393 renal cancer cell lines. PMID:24928404

  7. Salinomycin: A Novel Anti-Cancer Agent with Known Anti-Coccidial Activities

    PubMed Central

    Zhou, Shuang; Wang, Fengfei; Wong, Eric T.; Fonkem, Ekokobe; Hsieh, Tze-Chen; Wu, Joseph M.; Wu, Erxi

    2014-01-01

    Salinomycin, traditionally used as an anti-coccidial drug, has recently been shown to possess anti-cancer and anti-cancer stem cell (CSC) effects, as well as activities to overcome multi-drug resistance based on studies using human cancer cell lines, xenograft mice, and in case reports involving cancer patients in pilot clinical trials. Therefore, salinomycin may be considered as a promising novel anti-cancer agent despite its largely unknown mechanism of action. This review summarizes the pharmacologic effects of salinomycin and presents possible mechanisms by which salinomycin exerts its anti-tumorigenic activities. Recent advances and potential complications that might limit the utilization of salinomycin as an anti-cancer and anti-CSC agent are also presented and discussed. PMID:23931281

  8. Anti-Cancer Activity of Nitrones and Observations on Mechanism of Action

    PubMed Central

    Floyd, Robert A.; Chandru, Hema K.; He, Ting; Towner, Rheal

    2011-01-01

    The nitrone compound PBN, α-phenyl-tert-butylnitrone, and closely related nitrones have anti-cancer activity in several experimental cancer models. The three experimental models most extensively studied include A) the rat choline deficiency liver cancer model, B) the rat C6 glioma model and C) the mouse APCMin/+ colon cancer model. The two PBN-nitrones mostly studied are PBN and a PBN derivative 2,4-disulfophenyl-tert-butylnitrone, referred as OKN-007. OKN-007 is a proprietary compound that has had extensive commercial development (designated as NXY-059) for another indication, acute ischemic stroke, and after extensive clinical studies was shown to lack efficacy for this indication but was shown to be very safe for human use. This compound administered orally in the rat glioma model has potent activity in treating fully formed gliomas. In this report observations made on the PBN-nitrones in experimental cancer models will be summarized. In addition the experimental results will be discussed in the general framework of the properties of the compounds with a view to try to understand the mechanistic basis of how the PBN-nitrones act as anti-cancer agents. Possible mechanisms related to the suppression of NO production, S-nitrosylation of critical proteins and inhibition of NF-κB activation are discussed. PMID:21651461

  9. Anti-inflammatory and anti-cancer activity of mulberry (Morus alba L.) root bark

    PubMed Central

    2014-01-01

    Background Root bark of mulberry (Morus alba L.) has been used in herbal medicine as anti-phlogistic, liver protective, kidney protective, hypotensive, diuretic, anti-cough and analgesic agent. However, the anti-cancer activity and the potential anti-cancer mechanisms of mulberry root bark have not been elucidated. We performed in vitro study to investigate whether mulberry root bark extract (MRBE) shows anti-inflammatory and anti-cancer activity. Methods In anti-inflammatory activity, NO was measured using the griess method. iNOS and proteins regulating NF-κB and ERK1/2 signaling were analyzed by Western blot. In anti-cancer activity, cell growth was measured by MTT assay. Cleaved PARP, ATF3 and cyclin D1 were analyzed by Western blot. Results In anti-inflammatory effect, MRBE blocked NO production via suppressing iNOS over-expression in LPS-stimulated RAW264.7 cells. In addition, MRBE inhibited NF-κB activation through p65 nuclear translocation via blocking IκB-α degradation and ERK1/2 activation via its hyper-phosphorylation. In anti-cancer activity, MRBE deos-dependently induced cell growth arrest and apoptosis in human colorectal cancer cells, SW480. MRBE treatment to SW480 cells activated ATF3 expression and down-regulated cyclin D1 level. We also observed that MRBE-induced ATF3 expression was dependent on ROS and GSK3β. Moreover, MRBE-induced cyclin D1 down-regulation was mediated from cyclin D1 proteasomal degradation, which was dependent on ROS. Conclusions These findings suggest that mulberry root bark exerts anti-inflammatory and anti-cancer activity. PMID:24962785

  10. Horner-Wadsworth-Emmons approach to piperlongumine analogues with potent anti-cancer activity.

    PubMed

    Han, Li-Chen; Stanley, Paul A; Wood, Paul J; Sharma, Pallavi; Kuruppu, Anchala I; Bradshaw, Tracey D; Moses, John E

    2016-08-21

    Natural products with anti-cancer activity play a vital role in lead and target discovery. We report here the synthesis and biological evaluation of the plant-derived alkaloid, piperlongumine and analogues. Using a Horner-Wadsworth-Emmons coupling approach, a selection of piperlongumine-like compounds were prepared in good overall yield from a novel phosphonoacetamide reagent. A number of the compounds displayed potent anti-cancer activity against colorectal (HCT 116) and ovarian (IGROV-1) carcinoma cell lines, via a mechanism of action which may involve ROS generation. Contrary to previous reports, no selective action in cancer cell (MRC-5) was observed for piperlongumine analogues. PMID:27443386

  11. Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships

    PubMed Central

    Rasko, Nathalie; Potůčková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Małecki, Jan G.; Sajewicz, Mieczysław; Ratuszna, Alicja; Muchowicz, Angelika; Gołąb, Jakub; Šimůnek, Tomáš; Richardson, Des R.; Polanski, Jaroslaw

    2014-01-01

    Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized “soft” donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination. PMID:25329549

  12. Exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships.

    PubMed

    Serda, Maciej; Kalinowski, Danuta S; Rasko, Nathalie; Potůčková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Małecki, Jan G; Sajewicz, Mieczysław; Ratuszna, Alicja; Muchowicz, Angelika; Gołąb, Jakub; Simůnek, Tomáš; Richardson, Des R; Polanski, Jaroslaw

    2014-01-01

    Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination. PMID:25329549

  13. Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity.

    PubMed

    Newcomb, Elizabeth W

    2004-06-01

    Flavopiridol has potent anti-proliferative properties due to its direct action of binding to the ATP-binding pocket of cyclin-dependent kinases (cdks), and due to its indirect action reducing levels of other cyclins and cdk inhibitors, contributing to its pleiotropic effects. Flavopiridol is a potent apoptotic agent due to its ability to cause cell death in cycling as well as non-cycling tumor cells; to down-regulate important cell survival proteins, such as survivin, through inhibition of the phosphorylation of Thr34; to increase sensitivity for S phase cells to drug treatment by modulating E2F-1 transcription factor activity in tumor cells; to induce both caspase-dependent and -independent mitochondrial cell death pathways; and to inhibit the activation of p-Akt which in turn inhibits activation of NF-kappaB. Flavopiridol possesses several important anti-angiogenic activities including induction of apoptosis of endothelial cells; inhibition of the hypoxic induction of vascular endothelial growth factor and/or its production under hypoxic conditions through inhibition of HIF-1alpha transcription; and decreased secretion of matrix metalloproteinases that is linked with significant inhibition of invasive potential in Matrigel assays. Taken together, the anti-proliferative and anti-angiogenic properties of flavopiridol may contribute to its anti-tumor activities observed in several preclinical animal models of human cancers including prostate, lymphoid, head and neck, colon, and glioma. These promising preclinical observations opened the way for phase I and II clinical trials. Given the low toxicity profile of flavopiridol used as a single agent in patients, combination therapy now offers numerous opportunities in the near future to improve the efficacy of flavopiridol in the treatment of refractory cancers. PMID:15166614

  14. Diterpenes from rosemary (Rosmarinus officinalis): Defining their potential for anti-cancer activity.

    PubMed

    Petiwala, Sakina M; Johnson, Jeremy J

    2015-10-28

    Recently, rosemary extracts standardized to diterpenes (e.g. carnosic acid and carnosol) have been approved by the European Union (EU) and given a GRAS (Generally Recognized as Safe) status in the United States by the Food and Drug Administration (FDA). Incorporation of rosemary into our food system and through dietary selection (e.g. Mediterranean Diet) has increased the likelihood of exposure to diterpenes in rosemary. In consideration of this, a more thorough understanding of rosemary diterpenes is needed to understand its potential for a positive impact on human health. Three agents in particular have received the most attention that includes carnosic acid, carnosol, and rosmanol with promising results of anti-cancer activity. These studies have provided evidence of diterpenes to modulate deregulated signaling pathways in different solid and blood cancers. Rosemary extracts and the phytochemicals therein appear to be well tolerated in different animal models as evidenced by the extensive studies performed for approval by the EU and the FDA as an antioxidant food preservative. This mini-review reports on the pre-clinical studies performed with carnosic acid, carnosol, and rosmanol describing their mechanism of action in different cancers. PMID:26170168

  15. Synthesis, characterization and anti-cancer activity of a peptide nucleolipid bioconjugate.

    PubMed

    Rana, Niki; Huang, Suiying; Patel, Pradeepkumar; Samuni, Uri; Sabatino, David

    2016-08-01

    The synthesis, characterization and anti-cancer activity of a novel peptide nucleolipid bioconjugate is reported in this study. The prerequisite 5'-carboxy derived nucleolipid was synthesized following a five-step solution-phase approach and then coupled to the cytotoxic D-(KLAKLAK)2 sequence by solid-phase bioconjugation. The biophysical and structural properties of the peptide-nucleolipid bioconjugate were evaluated and compared to the peptide controls. These characterization studies revealed that the amphiphilic peptides favored helical-type secondary structures and well-defined nanoparticle formulations that were found to be contributive towards their biological activity. The peptide-nucleolipid bioconjugate displayed greater lethality in comparison to the native D-(KLAKLAK)2AK sequence when treated within the human A549 non-small cell lung carcinoma cell line. Thus, the amphiphilic peptide-nucleolipid forms a new class of anti-cancer peptides that may be developed into promising leads in the fight against cancer. PMID:27329798

  16. Design, synthesis and anti-cancer activity evaluation of podophyllotoxin-norcantharidin hybrid drugs.

    PubMed

    Han, Hong-Wei; Qiu, Han-Yue; Hu, Cui; Sun, Wen-Xue; Yang, Rong-Wu; Qi, Jin-Liang; Wang, Xiao-Ming; Lu, Gui-Hua; Yang, Yong-Hua

    2016-07-15

    In this study, we designed and synthesized eighteen podophyllotoxin-norcantharidin hybrid drugs which could exhibit more potent anti-cancer activity than the parent drugs. Through the anti-proliferation assay, the most potent anti-cancer agent was screened out, namely Q9 (IC50=0.88±0.18μM against MCF-7 cell line), and it showed lower cytotoxicity against non-cancer cells, human embryonic kidney cells (293T) (IC50=54.38±3.78μM). Additionally, based on the flow cytometry analysis result, it can cause a remarkable cell cycle arrest at G2/M phase and induce apoptosis in MCF-7 cells more significantly than podophyllotoxin or norcantharidin per se. Moreover, the expression of cell cycle relative protein CDK1 was up regulated while a protein required for mitotic initiation, Cyclin B1 was down regulated. Furthermore, according to the confocal microscopy observation results, it was shown that Q9 was a potent tubulin polymerization inhibitor and the effect is comparable to that of colchicine. For further investigation on the aforementioned mechanisms, we performed western blot experiments, thus finding the increase of the cleavage of PARP. Consistent with these new findings, molecular docking observations suggested that compound Q9 could be developed as a potential anticancer agent. PMID:27262599

  17. Synthesis and anti-cancer activity of covalent conjugates of artemisinin and a transferrin-receptor targeting peptide.

    PubMed

    Oh, Steve; Kim, Byung Ju; Singh, Narendra P; Lai, Henry; Sasaki, Tomikazu

    2009-02-01

    Artemisinin, a natural product isolated from Artemisia annua L., shows a unique anti-cancer activity by an iron dependent mechanism. Artemisinin was covalently conjugated to a transferrin-receptor targeting peptide, HAIYPRH that binds to a cavity on the surface of transferrin receptor. This enables artemisinin to be co-internalized with receptor-bound transferrin. The iron released from transferrin can activate artemisinin to generate toxic radical species to kill cells. The artemisinin-peptide conjugates showed potent anti-cancer activity against Molt-4 leukemia cells with a significantly improved cancer/normal cells selectivity. PMID:18838215

  18. Anti-cancer activity of the cholesterol exporter ABCA1 gene

    PubMed Central

    Smith, Bradley; Land, Hartmut

    2012-01-01

    Summary The ABCA1 protein mediates the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I. Loss-of-function mutations in the ABCA1 gene induce Tangier disease and familial hypoalphalipoproteinemia, both cardio-vascular conditions characterized by abnormally low levels of serum cholesterol, increased cholesterol in macrophages and subsequent formation of vascular plaque. Increased intra-cellular cholesterol levels are also frequently found in cancer cells. Here we demonstrate anti-cancer activity of ABCA1 efflux function, which is compromised following inhibition of ABCA1 gene expression by oncogenic mutations or cancer-specific ABCA1 loss-of-function mutations. In concert with elevated cholesterol synthesis found in cancer cells, ABCA1 deficiency allows for increased mitochondrial cholesterol, inhibits release of mitochondrial cell death-promoting molecules and thus facilitates cancer cell survival, overall suggesting that elevated mitochondrial cholesterol is essential to the cancer phenotype. PMID:22981231

  19. Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells

    DOE PAGESBeta

    Martins, Murillo L.; Ignazzi, Rosanna; Eckert, Juergen; Watts, Benjamin; Kaneno, Ramon; Zambuzzi, Willian F.; Daemen, Luke; Saeki, Margarida J.; Bordallo, Heloisa N.

    2016-03-02

    Here, the most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigatemore » the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. In conclusion, from these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells.« less

  20. Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells

    PubMed Central

    Martins, Murillo L.; Ignazzi, Rosanna; Eckert, Juergen; Watts, Benjamin; Kaneno, Ramon; Zambuzzi, Willian F.; Daemen, Luke; Saeki, Margarida J.; Bordallo, Heloisa N.

    2016-01-01

    The most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigate the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. From these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells. PMID:26932808

  1. Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells

    NASA Astrophysics Data System (ADS)

    Martins, Murillo L.; Ignazzi, Rosanna; Eckert, Juergen; Watts, Benjamin; Kaneno, Ramon; Zambuzzi, Willian F.; Daemen, Luke; Saeki, Margarida J.; Bordallo, Heloisa N.

    2016-03-01

    The most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigate the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. From these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells.

  2. Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells.

    PubMed

    Martins, Murillo L; Ignazzi, Rosanna; Eckert, Juergen; Watts, Benjamin; Kaneno, Ramon; Zambuzzi, Willian F; Daemen, Luke; Saeki, Margarida J; Bordallo, Heloisa N

    2016-01-01

    The most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigate the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. From these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells. PMID:26932808

  3. Tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity: Potential role of tannins in cancer chemotherapy

    SciTech Connect

    Tikoo, Kulbhushan Sane, Mukta Subhash; Gupta, Chanchal

    2011-03-15

    Doxorubicin, an anthracycline antibiotic, is widely used in the treatment of various solid tumors including breast cancer. However, its use is limited due to a variety of toxicities including cardiotoxicity. The present study aimed to evaluate the effect of tannic acid, a PARG/PARP inhibitor and an antioxidant, on doxorubicin-induced cardiotoxicity in H9c2 embryonic rat heart myoblasts and its anti-cancer activity in MDA-MB-231 human breast cancer cells as well as in DMBA-induced mammary tumor animals. Doxorubicin-induced cardiotoxicity was assessed by measurement of heart weight, plasma LDH level and histopathology. Bcl-2, Bax, PARP-1 and p53 expression were examined by western blotting. Our results show that tannic acid prevents activation of PARP-1, reduces Bax and increases Bcl-2 expression in H9c2 cells, thus, preventing doxorubicin-induced cell death. Further, it reduces the cell viability of MDA-MB-231 breast cancer cells, increases p53 expression in mammary tumors and shows maximum tumor volume reduction, suggesting that tannic acid potentiates the anti-cancer activity of doxorubicin. To the best of our knowledge, this is the first report which shows that tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity both in vitro (H9c2 and MDA-MB-231 cells) as well as in in vivo model of DMBA-induced mammary tumor animals.

  4. p21 induction plays a dual role in anti-cancer activity of ursolic acid.

    PubMed

    Zhang, Xudong; Song, Xinhua; Yin, Shutao; Zhao, Chong; Fan, Lihong; Hu, Hongbo

    2016-03-01

    Previous studies have shown that induction of G1 arrest and apoptosis by ursolic acid is associated with up-regulation of cyclin-dependent kinase inhibitor (CDKI) protein p21 in multiple types of cancer cells. However, the functional role of p21 induction in G1 cell cycle arrest and apoptosis, and the mechanisms of p21 induction by ursolic acid have not been critically addressed. In the current study, we demonstrated that p21 played a mediator role in G1 cell cycle arrest by ursolic acid, whereas p21-mediated up-regulation of Mcl-1 compromised apoptotic effect of ursolic acid. These results suggest that p21 induction plays a dual role in the anti-cancer activity of ursolic acid in terms of cell cycle and apoptosis regulation. p21 induction by ursolic acid was attributed to p53 transcriptional activation. Moreover, we found that ursolic acid was able to inhibit murine double minute-2 protein (MDM2) and T-LAK cell-originated protein kinase (TOPK), the two negative regulator of p53, which in turn contributed to ursolic acid-induced p53 activation. Our findings provided novel insights into understanding of the mechanisms involved in cell cycle arrest and apoptosis induction in response to ursolic acid exposure. PMID:26582056

  5. Synthesis, Characterization and Anti-Cancer Activity of Hydrazide Derivatives Incorporating a Quinoline Moiety.

    PubMed

    Bingul, Murat; Tan, Owen; Gardner, Christopher R; Sutton, Selina K; Arndt, Greg M; Marshall, Glenn M; Cheung, Belamy B; Kumar, Naresh; Black, David StC

    2016-01-01

    Identification of the novel (E)-N'-((2-chloro-7-methoxyquinolin-3-yl)methylene)-3-(phenylthio)propanehydrazide scaffold 18 has led to the development of a new series of biologically active hydrazide compounds. The parent compound 18 and new quinoline derivatives 19-26 were prepared from the corresponding quinoline hydrazones and substituted carboxylic acids using EDC-mediated peptide coupling reactions. Further modification of the parent compound 18 was achieved by replacement of the quinoline moiety with other aromatic systems. All the newly synthesized compounds were evaluated for their anti-cancer activity against the SH-SY5Y and Kelly neuroblastoma cell lines, as well as the MDA-MB-231 and MCF-7 breast adenocarcinoma cell lines. Analogues 19 and 22 significantly reduced the cell viability of neuroblastoma cancer cells with micromolar potency and significant selectivity over normal cells. The quinoline hydrazide 22 also induced G₁ cell cycle arrest, as well as upregulation of the p27(kip1) cell cycle regulating protein. PMID:27428941

  6. Anti-cancer activity of withaferin A in B-cell lymphoma

    PubMed Central

    McKenna, MK; Gachuki, BW; Alhakeem, SS; Oben, KN; Rangnekar, VM; Gupta, RC; Bondada, S

    2015-01-01

    Withaferin A (WA), a withanolide from the plant, Ashwagandha (Withania somnifera) used in Ayurvedic medicine, has been found to be valuable in the treatment of several medical ailments. WA has been found to have anticancer activity against various solid tumors, but its effects on hematological malignancies have not been studied in detail. WA strongly inhibited the survival of several human and murine B cell lymphoma cell lines. Additionally, in vivo studies with syngeneic-graft lymphoma cells suggest that WA inhibits the growth of tumor but does not affect other proliferative tissues. We demonstrate that WA inhibits the efficiency of NF-κB nuclear translocation in diffuse large B cell lymphomas and found that WA treatment resulted in a significant decrease in protein levels involved in B cell receptor signaling and cell cycle regulation. WA inhibited the activity of heat shock protein (Hsp) 90 as reflected by a sharp increase in Hsp70 expression levels. Hence, we propose that the anti-cancer effects of WA in lymphomas are likely due to its ability to inhibit Hsp90 function and subsequent reduction of critical kinases and cell cycle regulators that are clients of Hsp90. PMID:26020511

  7. Anti-cancer, anti-diabetic and other pharmacologic and biological activities of penta-galloyl-glucose

    PubMed Central

    Zhang, Jinhui; Li, Li; Kim, Sung-Hoon; Hagerman, Ann E.; Lü, Junxuan

    2010-01-01

    1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucose (PGG) is a polyphenolic compound highly enriched in a number of medicinal herbals. Several in vitro and a handful of in vivo studies have shown that PGG exhibits multiple biological activities which implicate a great potential for PGG in the therapy and prevention of several major diseases including cancer and diabetes. Chemically and functionally, PGG appears to be distinct from its constituent gallic acid or tea polyphenols. For anti-cancer activity, three published in vivo preclinical cancer model studies with PGG support promising efficacy to selectively inhibit malignancy without host toxicity. Potential mechanisms include anti-angiogenesis, anti-proliferative actions through inhibition of DNA replicative synthesis and S-phase arrest and also G1 arrest, induction of apoptosis, anti-inflammation and anti-oxidation. Putative molecular targets include p53, Stat3, Cox-2, VEGFR1, AP-1, SP-1, Nrf-2 and MMP-9. For anti-diabetic activity, PGG and analogues appear to improve glucose uptake. However, very little is known about the absorption, pharmacokinetics and metabolism of PGG, nor its toxicity profile. The lack of large quantity of highly pure PGG has been a bottleneck limiting in vivo validation of cancer preventive and therapeutic efficacies in clinically relevant models. PMID:19575286

  8. Synthesis and anti-cancer activity of 1,4-disubstituted imidazo[4,5-c]quinolines.

    PubMed

    Thigulla, Yadagiri; Akula, Mahesh; Trivedi, Prakruti; Ghosh, Balaram; Jha, Mukund; Bhattacharya, Anupam

    2016-01-21

    The synthesis and anti-cancer activity evaluation of fused imidazoquinoline compounds is reported in this paper. Yb(OTf)3 has been utilized as a catalyst for the synthesis of 1,4-diaryl substituted imidazo[4,5-c]quinolines via a modified Pictet-Spengler approach. The desired imidazole ring was synthesized from imines using TosMIC (toluenesulfonylmethyl isocyanide) and subsequently functionalized at the C-4 position yielding an imidazoquinoline skeleton. Importantly, the final step was carried out without the aid of any prefunctionalization to obtain the resultant compounds in good yields. The synthesized compounds, when screened for anti-cancer activity, revealed the highest activity with 4-(2-bromophenyl)-1-phenyl-1H-imidazo[4,5-c]quinoline (IC50: 103.3 μM). PMID:26592542

  9. Anti-cancer activity of novel dibenzo[b,f]azepine tethered isoxazoline derivatives

    PubMed Central

    2012-01-01

    Background Dibenzoazepine (DB) derivatives are important and valuable compounds in medicinal chemistry. The synthesis and chemotherapeutic properties of naturally occurring DBs and different heterocyclic moiety tethered DBs are reported. Herein, we report the DB-fused hybrid structure that containing isoxazolines (DBIs) and their anti-cancer activity, which could throw light on the structural and functional features of new molecules. Results and Conclusion The synthesis and characterization of novel ring DB tethered isoxazoline derivatives (DBIs) were carried out. After the detailed structural characterization using 2D-NMR experiments, the compounds were identified as 5-substituted isoxazolines. The effect of newly synthesized DBIs against the invasion of murine osteosarcoma (LM8G7) cells was studied. Among the tested molecules, compound 4g (5-[−3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f]azepine), was found to inhibit the invasion of LM8G7 cells strongly, when compared to other structurally related compounds. Cumulatively, the compound 4g inhibited the invasion MDA-MB-231 cells completely at 10 μM. In addition to anti-invasion property the compound 4g also inhibited the migration of LM8G7 and human ovarian cancer cells (OVSAHO) dose-dependently. Compound 4g inhibited the proliferation of LM8G7, OVSAHO, human breast cancer cells (MCF-7) and human melphalan-resistant multiple myeloma (RPMI8226-LR5) cells that are comparable to cisplatin and suramin. PMID:23033888

  10. [Preparation and anti-cancer activity in vitro of curcumin loaded mesoporous silica nanoparticle].

    PubMed

    He, Li-li; Gu, Jian

    2015-11-01

    This paper is to prepare curcumin (Cur) loaded mesoporous silica nanoparticle (Cur-MSN), evaluate its release behavior and anti-cancer activity in vitro. Mesoporous silica nanoparticle (MSN) was prepared by polymerization method and Cur-MSN was obtained using solvent evaporation method and impregnation centrifugation method. The preparation method was optimized using entrapment efficiency (EE) and loading efficiency (LE) as indexes. Cur-MSN was characterized with scanning electron microscope and its particle size and zeta potential were determined. Finally, in vitro release behavior in 0.2% SDS solution and its cell-killing effect on HeLa cells were also evaluated. The Cur-MSN prepared with process optimization method was round and uniform and exhibited typical mesoporous characterization. The mean particle size and Zeta potential of Cur-MSN were 75.8 nm and -30.1 mV, respectively. EE and LE of three batches of Cur-MSN were (72.55 ± 2.01)% and (16.21 ± 1.12)%, respectively. In vitro release behavior of Cur-MSN showed a sustained release profile with 83.5% cumulative release within 96 h. The killing effect of Cur-MSN on HeLa cells was dose-dependent with IC50 of 19.40 mg x L(-1), which was similar to that of Cur. PMID:27071254

  11. Biocompatible and biodegradable nanoparticles for enhancement of anti-cancer activities of phytochemicals.

    PubMed

    Li, Chuan; Zhang, Jia; Zu, Yu-Jiao; Nie, Shu-Fang; Cao, Jun; Wang, Qian; Nie, Shao-Ping; Deng, Ze-Yuan; Xie, Ming-Yong; Wang, Shu

    2015-09-01

    Many phytochemicals show promise in cancer prevention and treatment, but their low aqueous solubility, poor stability, unfavorable bioavailability, and low target specificity make administering them at therapeutic doses unrealistic. This is particularly true for (-)-epigallocatechin gallate, curcumin, quercetin, resveratrol, and genistein. There is an increasing interest in developing novel delivery strategies for these natural products. Liposomes, micelles, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers and poly (lactide-co-glycolide) nanoparticles are biocompatible and biodegradable nanoparticles. Those nanoparticles can increase the stability and solubility of phytochemicals, exhibit a sustained release property, enhance their absorption and bioavailability, protect them from premature enzymatic degradation or metabolism, prolong their circulation time, improve their target specificity to cancer cells or tumors via passive or targeted delivery, lower toxicity or side-effects to normal cells or tissues through preventing them from prematurely interacting with the biological environment, and enhance anti-cancer activities. Nanotechnology opens a door for developing phytochemical-loaded nanoparticles for prevention and treatment of cancer. PMID:26412423

  12. Enhancing Cell Nucleus Accumulation and DNA Cleavage Activity of Anti-Cancer Drug via Graphene Quantum Dots

    NASA Astrophysics Data System (ADS)

    Wang, Chong; Wu, Congyu; Zhou, Xuejiao; Han, Ting; Xin, Xiaozhen; Wu, Jiaying; Zhang, Jingyan; Guo, Shouwu

    2013-10-01

    Graphene quantum dots (GQDs) maintain the intrinsic layered structural motif of graphene but with smaller lateral size and abundant periphery carboxylic groups, and are more compatible with biological system, thus are promising nanomaterials for therapeutic applications. Here we show that GQDs have a superb ability in drug delivery and anti-cancer activity boost without any pre-modification due to their unique structural properties. They could efficiently deliver doxorubicin (DOX) to the nucleus through DOX/GQD conjugates, because the conjugates assume different cellular and nuclear internalization pathways comparing to free DOX. Also, the conjugates could enhance DNA cleavage activity of DOX markedly. This enhancement combining with efficient nuclear delivery improved cytotoxicity of DOX dramatically. Furthermore, the DOX/GQD conjugates could also increase the nuclear uptake and cytotoxicity of DOX to drug-resistant cancer cells indicating that the conjugates may be capable to increase chemotherapy efficacy of anti-cancer drugs that are suboptimal due to the drug resistance.

  13. The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate.

    PubMed

    O'Connor, Stephen; Szwej, Emilia; Nikodinovic-Runic, Jasmina; O'Connor, Aisling; Byrne, Annette T; Devocelle, Marc; O'Donovan, Norma; Gallagher, William M; Babu, Ramesh; Kenny, Shane T; Zinn, Manfred; Zulian, Qun Ren; O'Connor, Kevin E

    2013-04-01

    The biodegradable polymer medium chain length polyhydroxyalkanoate (mclPHA), produced by Pseudomonas putida CA-3, was depolymerised and the predominant monomer (R)-3-hydroxydecanoic acid (R10) purified. R10 was conjugated to a d-peptide DP18 and its derivatives. All peptides conjugated with R10 exhibited greater anti-cancer activity compared to the unconjugated peptides. Unconjugated and conjugated peptides were cytocidal for cancer cells. Conjugation of R10 to peptides was essential for enhanced anti-proliferation activity, as unconjugated mixes did not result in enhancement of anti-cancer activity. The conjugation of R10 resulted in more rapid uptake of peptides into HeLa and MiaPaCa cells compared to unconjugated peptide. Both unconjugated and R10 conjugated peptides localized to the mitochondria of HeLa and MiaPaCa cells and induced apoptosis. Peptide conjugated with a terminally hydroxylated decanoic acid (ω-hydroxydecanoic acid) exhibited 3.3 and 6.3 fold higher IC(50) values compared to R10 conjugated peptide indicating a role for the position of the hydroxyl moiety in enhancement of anti-cancer activity. Conjugation of decanoic acid (C10) to peptides resulted in similar or higher IC(50) values compared to R10 conjugates but C10 conjugates did not exhibit any cancer selectivity. Combination studies showed that R10DP18L exhibited synergy with cisplatin, gemcitabine, and taxotere with IC(50) values in the nanomolar range. PMID:23343631

  14. The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides.

    PubMed

    Szwej, Emilia; Devocelle, Marc; Kenny, Shane; Guzik, Maciej; O'Connor, Stephen; Nikodinovic-Runic, Jasmina; Radivojevic, Jelena; Maslak, Veselin; Byrne, Annete T; Gallagher, William M; Zulian, Qun Ren; Zinn, Manfred; O'Connor, Kevin E

    2015-06-20

    Conjugation of DP18L peptide with (R)-3-hydroxydecanoic acid, derived from the biopolymer polyhydroxyalkanoate, enhances its anti-cancer activity (O'Connor et al., 2013. Biomaterials 34, 2710-2718). However, it is unknown if other (R)-3-hydroxyalkanoic acids (R3HAs) can enhance peptide activity, if chain length affects enhancement, and what effect R3HAs have on peptide structure. Here we show that the degree of enhancement of peptide (DP18L) anti-cancer activity by R3HAs is carbon chain length dependent. In all but one example the R3HA conjugated peptides were more active against cancer cells than the unconjugated peptides. However, R3HAs with 9 and 10 carbons were most effective at improving DP18L activity. DP18L peptide variant DP17L, missing a hydrophobic amino acid (leucine residue 4) exhibited lower efficacy against MiaPaCa cells. Circular dichroism analysis showed DP17L had a lower alpha helix content and the conjugation of any R3HA ((R)-3-hydroxyhexanoic acid to (R)-3-hydroxydodecanoic acid) to DP17L returned the helix content back to levels of DP18L. However (R)-3-hydroxyhexanoic did not enhance the anti-cancer activity of DP17L and at least 7 carbons were needed in the R3HA to enhance activity of D17L. DP17L needs a longer chain R3HA to achieve the same activity as DP18L conjugated to an R3HA. As a first step to assess the synthetic potential of polyhydroxyalkanoate derived R3HAs, (R)-3-hydroxydecanoic acid was synthetically converted to (±)3-chlorodecanoic acid, which when conjugated to DP18L improved its antiproliferative activity against MiaPaCa cells. PMID:25820126

  15. Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma

    PubMed Central

    Friesen, Claudia; Hormann, Inis; Roscher, Mareike; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf; Debatin, Klaus-Michael; Miltner, Erich

    2014-01-01

    Glioblastoma are the most frequent and malignant human brain tumors, having a very poor prognosis. The enhanced radio- and chemoresistance of glioblastoma and the glioblastoma stem cells might be the main reason why conventional therapies fail. The second messenger cyclic AMP (cAMP) controls cell proliferation, differentiation, and apoptosis. Downregulation of cAMP sensitizes tumor cells for anti-cancer treatment. Opioid receptor agonists triggering opioid receptors can activate inhibitory Gi proteins, which, in turn, block adenylyl cyclase activity reducing cAMP. In this study, we show that downregulation of cAMP by opioid receptor activation improves the effectiveness of anti-cancer drugs in treatment of glioblastoma. The µ-opioid receptor agonist D,L-methadone sensitizes glioblastoma as well as the untreatable glioblastoma stem cells for doxorubicin-induced apoptosis and activation of apoptosis pathways by reversing deficient caspase activation and deficient downregulation of XIAP and Bcl-xL, playing critical roles in glioblastomas’ resistance. Blocking opioid receptors using the opioid receptor antagonist naloxone or increasing intracellular cAMP by 3-isobutyl-1-methylxanthine (IBMX) strongly reduced opioid receptor agonist-induced sensitization for doxorubicin. In addition, the opioid receptor agonist D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux, whereas doxorubicin increased opioid receptor expression in glioblastomas. Furthermore, opioid receptor activation using D,L-methadone inhibited tumor growth significantly in vivo. Our findings suggest that opioid receptor activation triggering downregulation of cAMP is a promising strategy to inhibit tumor growth and to improve the effectiveness of anti-cancer drugs in treatment of glioblastoma and in killing glioblastoma stem cells. PMID:24626197

  16. In vitro anti-cancer activity of two ethno-pharmacological healing plants from Guatemala Pluchea odorata and Phlebodium decumanum.

    PubMed

    Gridling, Manuela; Stark, Nicole; Madlener, Sibylle; Lackner, Andreas; Popescu, Ruxandra; Benedek, Birgit; Diaz, Rene; Tut, Foster M; Nha Vo, Thanh Phuong; Huber, Daniela; Gollinger, Michaela; Saiko, Philipp; Ozmen, Ali; Mosgoeller, Wilhelm; De Martin, Rainer; Eytner, Ruth; Wagner, Karl-Heinz; Grusch, Michael; Fritzer-Szekeres, Monika; Szekeres, Thomas; Kopp, Brigitte; Frisch, Richard; Krupitza, Georg

    2009-04-01

    Many traditional healing plants successfully passed several hundred years of empirical testing against specific diseases and thereby demonstrating that they are well tolerated in humans. Although quite a few ethno-pharmacological plants are applied against a variety of conditions there are still numerous plants that have not been cross-tested in diseases apart from the traditional applications. Herein we demonstrate the anti-neoplastic potential of two healing plants used by the Maya of the Guatemala/Belize area against severe inflammatory conditions such as neuritis, rheumatism, arthritis, coughs, bruises and tumours. Phlebodium decumanum and Pluchea odorata were collected, dried and freeze dried, and extracted with five solvents of increasing polarity. We tested HL-60 and MCF-7 cells, the inhibition of proliferation and the induction of cell death were investigated as hallmark endpoints to measure the efficiency of anti-cancer drugs. Western blot and FACS analyses elucidated the underlying mechanisms. While extracts of P. decumanum showed only moderate anti-cancer activity and were therefore not further analysed, particularly the dichloromethane extract of P. odorata inhibited the cell cycle in G2-M which correlated with the activation of checkpoint kinase 2, and down-regulation of Cdc25A and cyclin D1 as well as inactivation of Erk1/2. In HL-60 and MCF-7 cells this extract was a very strong inducer of cell death activating caspase-3 followed by PARP signature type cleavage. The initiating death trigger was likely the stabilization of microtubules monitored by the rapid acetylation of alpha-tubulin, which was even more pronounced than that triggered by taxol. The dichloromethane extract of P. odorata contains apolar constituents which inhibit inflammatory responses and exhibit anti-cancer activity. The strong proapoptotic potential warrants further bioassay-guided fractionation to discover and test the active principle(s). PMID:19287970

  17. Re-engineering Cytochrome P450 2B11dH for Enhanced Metabolism of Several Substrates Including the Anti-cancer Prodrugs Cyclophosphamide and Ifosfamide

    PubMed Central

    Sun, Ling; Chen, Chong S.; Waxman, David J.; Liu, Hong; Halpert, James R.; Kumar, Santosh

    2007-01-01

    Based on recent directed evolution of P450 2B1, six P450 2B11 mutants at three positions were created in an N-terminal modified construct termed P450 2B11dH and characterized for enzyme catalysis using five substrates. Mutant I209A demonstrated a 3.2-fold enhanced kcat/Km for 7-ethoxy-4-trifluoromethylcourmarin O-deethylation, largely due to a dramatic decrease in Km (0.72 vs. 18 μM). I209A also demonstrated enhanced selectivity for testosterone 16β-hydroxylation over 16α-hydroxylation. In contrast, V183L showed a 4-fold increased kcat for 7-benzyloxyresorufin debenzylation and a 4.7-fold increased kcat/Km for testosterone 16α-hydroxylation. V183L also displayed a 1.7-fold higher kcat/Km than P450 2B11dH with the anti-cancer prodrugs cyclophosphamide and ifosfamide, resulting from a ~4-fold decrease in Km. Introduction of the V183L mutation into full-length P450 2B11 did not enhance the kcat/Km. Overall, the re-engineered P450 2B11dH enzymes exhibited enhanced catalytic efficiency with several substrates including the anti-cancer prodrugs. PMID:17254539

  18. Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites.

    PubMed

    Engel, Jessica A; Jones, Amy J; Avery, Vicky M; Sumanadasa, Subathdrage D M; Ng, Susanna S; Fairlie, David P; Adams, Tina S; Andrews, Katherine T

    2015-12-01

    Histone deacetylase (HDAC) enzymes work together with histone acetyltransferases (HATs) to reversibly acetylate both histone and non-histone proteins. As a result, these enzymes are involved in regulating chromatin structure and gene expression as well as other important cellular processes. HDACs are validated drug targets for some types of cancer, with four HDAC inhibitors clinically approved. However, they are also showing promise as novel drug targets for other indications, including malaria and other parasitic diseases. In this study the in vitro activity of four anti-cancer HDAC inhibitors was examined against parasites that cause malaria and trypanosomiasis. Three of these inhibitors, suberoylanilide hydroxamic acid (SAHA; vorinostat(®)), romidepsin (Istodax(®)) and belinostat (Beleodaq(®)), are clinically approved for the treatment of T-cell lymphoma, while the fourth, panobinostat, has recently been approved for combination therapy use in certain patients with multiple myeloma. All HDAC inhibitors were found to inhibit the growth of asexual-stage Plasmodium falciparum malaria parasites in the nanomolar range (IC50 10-200 nM), while only romidepsin was active at sub-μM concentrations against bloodstream form Trypanosoma brucei brucei parasites (IC50 35 nM). The compounds were found to have some selectivity for malaria parasites compared with mammalian cells, but were not selective for trypanosome parasites versus mammalian cells. All compounds caused hyperacetylation of histone and non-histone proteins in P. falciparum asexual stage parasites and inhibited deacetylase activity in P. falciparum nuclear extracts in addition to recombinant PfHDAC1 activity. P. falciparum histone hyperacetylation data indicate that HDAC inhibitors may differentially affect the acetylation profiles of histone H3 and H4. PMID:26199860

  19. Separation of glycine-rich proteins from sea hare eggs and their anti-cancer activity against U937 leukemia cell line.

    PubMed

    Lee, Won Woo; Kim, Won-Suck; Ahn, Ginnae; Kim, Kil-Nam; Heo, Soo-Jin; Cho, Moonjae; Fernando, I P Shanura; Kang, Nalae; Jeon, You-Jin

    2016-01-01

    The present study was designed to investigate the anti-cancer effects of Sea hare eggs (SE) in U937 cells and its major active components. The aqueous extract of SE (ASE), which contained the highest protein content, dose-dependently inhibited the cancer cell's growth (IC50 value, 10.42 ± 0.5 µg/mL). Additionally, ASE markedly caused DNA damage by inducing apoptotic body formation, DNA fragmentation, and accumulation of sub-G1 DNA contents. ASE induced apoptosis by activating caspase-3 and 9 and poly (ADP-ribose) polymerase (PARP) by regulating the expression of Bcl-2/Bax. Moreover, among its molecular weight fractions, the > 30 kDa fraction showed the highest cell-growth-inhibitory effects, which was inhibited by heat treatment. Furthermore, the > 30 kDa fraction had markedly higher glycine content than the ASE. The presence of two protein bands at around 16 and 32 kDa was identified. In addition, two fractions, F1 and F2, were obtained using anion-exchange chromatography, with the F1 having an improved cell-growth-inhibitory effect than the > 30 kDa fraction. Taken together, these results suggest that the ASE contains glycine-rich proteins, including the active 16 and 32 kDa proteins, which account for its anti-cancer effects by inducing apoptosis via regulation of the mitochondrial pathway. PMID:27366143

  20. Separation of glycine-rich proteins from sea hare eggs and their anti-cancer activity against U937 leukemia cell line

    PubMed Central

    Lee, Won Woo; Kim, Won-Suck; Ahn, Ginnae; Kim, Kil-Nam; Heo, Soo-Jin; Cho, Moonjae; Fernando, I. P. Shanura; Kang, Nalae; Jeon, You-Jin

    2016-01-01

    The present study was designed to investigate the anti-cancer effects of Sea hare eggs (SE) in U937 cells and its major active components. The aqueous extract of SE (ASE), which contained the highest protein content, dose-dependently inhibited the cancer cell's growth (IC50 value, 10.42 ± 0.5 µg/mL). Additionally, ASE markedly caused DNA damage by inducing apoptotic body formation, DNA fragmentation, and accumulation of sub-G1 DNA contents. ASE induced apoptosis by activating caspase-3 and 9 and poly (ADP-ribose) polymerase (PARP) by regulating the expression of Bcl-2/Bax. Moreover, among its molecular weight fractions, the > 30 kDa fraction showed the highest cell-growth-inhibitory effects, which was inhibited by heat treatment. Furthermore, the > 30 kDa fraction had markedly higher glycine content than the ASE. The presence of two protein bands at around 16 and 32 kDa was identified. In addition, two fractions, F1 and F2, were obtained using anion-exchange chromatography, with the F1 having an improved cell-growth-inhibitory effect than the > 30 kDa fraction. Taken together, these results suggest that the ASE contains glycine-rich proteins, including the active 16 and 32 kDa proteins, which account for its anti-cancer effects by inducing apoptosis via regulation of the mitochondrial pathway. PMID:27366143

  1. The Anti-cancer Activity of Vernonia divaricata Sw against Leukaemia, Breast and Prostate Cancers In Vitro

    PubMed Central

    Lowe, HIC; Daley-Beckford, D; Toyang, NJ; Watson, C; Hartley, S; Bryant, J

    2014-01-01

    Background: Vernonia divaricata is one of five endemic Vernonia species of Jamaica. The ethnomedicinal uses of other species have been established, however, scientific validation of this species has not yet been done and as such this paper is aimed at identifying the anti-cancer activity of V divaricata against leukaemia, breast and prostate cancer cell lines. Methods: Leaves and stems of V divaricata were dried and milled into powder. The crude hexane and methanol extracts of the leaves and stems were obtained and bio-assayed using WST-1 cell proliferation assay against leukaemia, breast and prostate cancer cell lines. Results: The crude hexane and methanol extracts of V divaricata were able to significantly retard the growth of the MCF-7 (breast), HL-60 (leukaemia) and the PC-3 (prostate) cancer cell lines. The crude methanol extract of the stem was the strongest, exhibiting anti-proliferation activity with IC50 values of 10.14, 12.63 and 9.894 μg/ml for the HL-60, MCF-7 and PC-3 cancer cell lines, respectively, with the most potent toward prostate cancer. Conclusion: The medicinal use of V divaricata as an anti-cancer agent was corroborated as the crude hexane and methanol extracts demonstrated potent anti-proliferation activity and as such hold potential for further research and development into a drug to prevent or treat various cancers. PMID:25429469

  2. Structures of Phytosterols and Triterpenoids with Potential Anti-Cancer Activity in Bran of Black Non-Glutinous Rice

    PubMed Central

    Suttiarporn, Panawan; Chumpolsri, Watcharapong; Mahatheeranont, Sugunya; Luangkamin, Suwaporn; Teepsawang, Somsuda; Leardkamolkarn, Vijittra

    2015-01-01

    Structures of some bioactive phytochemicals in bran extract of the black rice cv. Riceberry that had demonstrated anti-cancer activity in leukemic cell line were investigated. After saponification with potassium hydroxide, separation of the unsaponified fraction by reversed-phase high performance liquid chromatography (HPLC) resulted in four sub-fractions that had a certain degree of anti-proliferation against a mouse leukemic cell line (WEHI-3 cell), this being IC50 at 24 h ranging between 2.80–467.11 μg/mL. Further purification of the bioactive substances contained in these four sub-fractions was performed by normal-phase HPLC. Structural characterization by gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance spectroscopy (NMR) resulted in, overall, the structures of seven phytosterols and four triterpenoids. Four phytosterols, 24-methylene-ergosta-5-en-3β-ol, 24-methylene-ergosta-7-en-3β-ol, fucosterol, and gramisterol, along with three triterpenoids, cycloeucalenol, lupenone, and lupeol, were found in the two sub-fractions that showed strong anti-leukemic cell proliferation (IC50 = 2.80 and 32.89 μg/mL). The other sterols and triterpenoids were campesterol, stigmasterol, β-sitosterol and 24-methylenecycloartanol. Together with the data from in vitro biological analysis, we suggest that gramisterol is a significant anti-cancer lead compound in Riceberry bran extract. PMID:25756784

  3. Three-dimensional quantitative structure-activity relationship study on anti-cancer activity of 3,4-dihydroquinazoline derivatives against human lung cancer A549 cells

    NASA Astrophysics Data System (ADS)

    Cho, Sehyeon; Choi, Min Ji; Kim, Minju; Lee, Sunhoe; Lee, Jinsung; Lee, Seok Joon; Cho, Haelim; Lee, Kyung-Tae; Lee, Jae Yeol

    2015-03-01

    A series of 3,4-dihydroquinazoline derivatives with anti-cancer activities against human lung cancer A549 cells were subjected to three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using the comparative molecular similarity indices analysis (CoMSIA) approaches. The most potent compound, 1 was used to align the molecules. As a result, the best prediction was obtained with CoMSIA combined the steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor fields (q2 = 0.720, r2 = 0.897). This model was validated by an external test set of 6 compounds giving satisfactory predictive r2 value of 0.923 as well as the scrambling stability test. This model would guide the design of potent 3,4-dihydroquinazoline derivatives as anti-cancer agent for the treatment of human lung cancer.

  4. The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity

    PubMed Central

    Wagner, Jessica; Kline, Christina Leah; Pottorf, Richard S.; Nallaganchu, Bhaskara Rao; Olson, Gary L.; Dicker, David T.; Allen, Joshua E.; El-Deiry, Wafik S.

    2014-01-01

    We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anti-cancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers. PMID:25587031

  5. Discovery of Compound A – a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activity

    PubMed Central

    Lesovaya, Ekaterina; Yemelyanov, Alexander; Swart, Amanda C.; Swart, Pieter; Haegeman, Guy; Budunova, Irina

    2015-01-01

    Glucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids, but with fewer adverse effects. GR regulates gene expression by transactivation (TA), by binding as homodimer to gene promoters, or transrepression (TR), via diverse mechanisms including negative interaction between monomeric GR and other transcription factors. It is well accepted that metabolic and atrophogenic effects of glucocorticoids are mediated by GR TA. Here we summarized the results of extensive international collaboration that led to discovery and characterization of Compound A (CpdA), a unique SEGRA with a proven “dissociating” GR ligand profile, preventing GR dimerization and shifting GR activity towards TR both in vitro and in vivo. We outlined here the unusual story of compound's discovery, and presented a comprehensive overview of CpdA ligand properties, its anti-inflammatory effects in numerous animal models of inflammation and autoimmune diseases, as well as its anti-cancer effects. Finally, we presented mechanistic analysis of CpdA and glucocorticoid effects in skin, muscle, bone, and regulation of glucose and fat metabolism to explain decreased CpdA side effects compared to glucocorticoids. Overall, the results obtained by our and other laboratories underline translational potential of CpdA and its derivatives for treatment of inflammation, autoimmune diseases and cancer. PMID:26436695

  6. Jaeumganghwa-Tang Induces Apoptosis via the Mitochondrial Pathway and Lactobacillus Fermentation Enhances Its Anti-Cancer Activity in HT1080 Human Fibrosarcoma Cells

    PubMed Central

    Kim, Aeyung; Im, Minju; Hwang, Youn-Hwan; Yang, Hye Jin; Ma, Jin Yeul

    2015-01-01

    Jaeumganghwa-tang (JGT, Zi-yin-jiang-huo-tang in Chinese and Jiin-koka-to in Japanese) is an oriental herbal formula that has long been used as a traditional medicine to treat respiratory and kidney diseases. Recent studies revealed that JGT exhibited potent inhibitory effects on allergies, inflammation, pain, convulsions, and prostate hyperplasia. Several constituent herbs in JGT induce apoptotic cancer cell death. However, the anti-cancer activity of JGT has not been examined. In this study, we investigated the anti-cancer effects of JGT using highly tumorigenic HT1080 human fibrosarcoma cells and elucidated the underlying mechanisms. In addition, we examined whether the Lactobacillus fermentation of JGT enhanced its anti-cancer activity using an in vivo xenograft model because fermentation of herbal extracts is thought to strengthen their therapeutic effects. Data revealed that JGT suppressed the growth of cancer cells efficiently by stimulating G1 cell cycle arrest and then inducing apoptotic cell death by causing mitochondrial damage and activating caspases. The phosphorylation of p38 and ERK also played a role in JGT-induced cell death. In vitro experiments demonstrated that JGT fermented with Lactobacillus acidophilus, designated fJGT162, elicited similar patterns of cell death as did non-fermented JGT. Meanwhile, the daily oral administration of 120 mg/kg fJGT162 to HT1080-bearing BALB/c nude mice suppressed tumor growth dramatically (up to 90%) compared with saline treatment, whereas the administration of non-fermented JGT suppressed tumor growth by ~70%. Collectively, these results suggest that JGT and fJGT162 are safe and useful complementary and alternative anti-cancer herbal therapies, and that Lactobacillus fermentation improves the in vivo anti-cancer efficacy of JGT significantly. PMID:26020238

  7. Jaeumganghwa-Tang Induces Apoptosis via the Mitochondrial Pathway and Lactobacillus Fermentation Enhances Its Anti-Cancer Activity in HT1080 Human Fibrosarcoma Cells.

    PubMed

    Kim, Aeyung; Im, Minju; Hwang, Youn-Hwan; Yang, Hye Jin; Ma, Jin Yeul

    2015-01-01

    Jaeumganghwa-tang (JGT, Zi-yin-jiang-huo-tang in Chinese and Jiin-koka-to in Japanese) is an oriental herbal formula that has long been used as a traditional medicine to treat respiratory and kidney diseases. Recent studies revealed that JGT exhibited potent inhibitory effects on allergies, inflammation, pain, convulsions, and prostate hyperplasia. Several constituent herbs in JGT induce apoptotic cancer cell death. However, the anti-cancer activity of JGT has not been examined. In this study, we investigated the anti-cancer effects of JGT using highly tumorigenic HT1080 human fibrosarcoma cells and elucidated the underlying mechanisms. In addition, we examined whether the Lactobacillus fermentation of JGT enhanced its anti-cancer activity using an in vivo xenograft model because fermentation of herbal extracts is thought to strengthen their therapeutic effects. Data revealed that JGT suppressed the growth of cancer cells efficiently by stimulating G1 cell cycle arrest and then inducing apoptotic cell death by causing mitochondrial damage and activating caspases. The phosphorylation of p38 and ERK also played a role in JGT-induced cell death. In vitro experiments demonstrated that JGT fermented with Lactobacillus acidophilus, designated fJGT162, elicited similar patterns of cell death as did non-fermented JGT. Meanwhile, the daily oral administration of 120 mg/kg fJGT162 to HT1080-bearing BALB/c nude mice suppressed tumor growth dramatically (up to 90%) compared with saline treatment, whereas the administration of non-fermented JGT suppressed tumor growth by ~70%. Collectively, these results suggest that JGT and fJGT162 are safe and useful complementary and alternative anti-cancer herbal therapies, and that Lactobacillus fermentation improves the in vivo anti-cancer efficacy of JGT significantly. PMID:26020238

  8. Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells

    PubMed Central

    Kim, Seong-Hoon; Ryu, Hye Guk; Lee, Juhyun; Shin, Joon; Harikishore, Amaravadhi; Jung, Hoe-Youn; Kim, Ye Seul; Lyu, Ha-Na; Oh, Eunji; Baek, Nam-In; Choi, Kwan-Yong; Yoon, Ho Sup; Kim, Kyong-Tai

    2015-01-01

    Many mitotic kinases have been targeted for the development of anti-cancer drugs, and inhibitors of these kinases have been expected to perform well for cancer therapy. Efforts focused on selecting good targets and finding specific drugs to target are especially needed, largely due to the increased frequency of anti-cancer drugs used in the treatment of lung cancer. Vaccinia-related kinase 1 (VRK1) is a master regulator in lung adenocarcinoma and is considered a key molecule in the adaptive pathway, which mainly controls cell survival. We found that ursolic acid (UA) inhibits the catalytic activity of VRK1 via direct binding to the catalytic domain of VRK1. UA weakens surveillance mechanisms by blocking 53BP1 foci formation induced by VRK1 in lung cancer cells, and possesses synergistic anti-cancer effects with DNA damaging drugs. Taken together, UA can be a good anti-cancer agent for targeted therapy or combination therapy with DNA damaging drugs for lung cancer patients. PMID:26412148

  9. Protocatechualdehyde possesses anti-cancer activity through downregulating cyclin D1 and HDAC2 in human colorectal cancer cells

    SciTech Connect

    Jeong, Jin Boo; Lee, Seong-Ho

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer Protocatechualdehyde (PCA) suppressed cell proliferation and induced apoptosis in human colorectal cancer cells. Black-Right-Pointing-Pointer PCA enhanced transcriptional downregulation of cyclin D1 gene. Black-Right-Pointing-Pointer PCA suppressed HDAC2 expression and activity. Black-Right-Pointing-Pointer These findings suggest that anti-cancer activity of PCA may be mediated by reducing HDAC2-derived cyclin D1 expression. -- Abstract: Protocatechualdehyde (PCA) is a naturally occurring polyphenol found in barley, green cavendish bananas, and grapevine leaves. Although a few studies reported growth-inhibitory activity of PCA in breast and leukemia cancer cells, the underlying mechanisms are still poorly understood. Thus, we performed in vitro study to investigate if treatment of PCA affects cell proliferation and apoptosis in human colorectal cancer cells and define potential mechanisms by which PCA mediates growth arrest and apoptosis of cancer cells. Exposure of PCA to human colorectal cancer cells (HCT116 and SW480 cells) suppressed cell growth and induced apoptosis in dose-dependent manner. PCA decreased cyclin D1 expression in protein and mRNA level and suppressed luciferase activity of cyclin D1 promoter, indicating transcriptional downregulation of cyclin D1 gene by PCA. We also observed that PCA treatment attenuated enzyme activity of histone deacetylase (HDAC) and reduced expression of HDAC2, but not HDAC1. These findings suggest that cell growth inhibition and apoptosis by PCA may be a result of HDAC2-mediated cyclin D1 suppression.

  10. PreQ0 base, an unusual metabolite with anti-cancer activity from Streptomyces qinglanensis 172205.

    PubMed

    Xu, Dongbo; Ma, Min; Liu, Yongfeng; Zhou, Ting; Wang, Kexin; Deng, Zixin; Hong, Kui

    2015-01-01

    PreQ0 base (7-cyano-7-deazaguanine, compound 1) is the biosynthetic precursor of queuosine-tRNA and important synthetic intermediate for bioactive compounds. It was obtained for the first time as a new natural product from a mangrove actinomycete Streptomyces qinglanensis 172205, during the course of searching for anti-cancer compounds from marine microbes. PreQ0 base showed anti-HeLa (IC50 = 62.0 μg/ml) and anti-HepG2 (IC50 = 80.6 μg/ml) activities, higher cytotoxicity than the positive control, fluorouracil. Furthermore, it exhibited weak α -glucosidase inhibitory activity, but no obvious antimicrobial and Aβ1-42 fibrillation inhibitory activities. In silico analysis of the genome of the strain 172205 revealed a putative biosynthetic gene cluster directing the biosynthesis of PreQ0 base. The gene cluster only contained three Open Reading Frames (ORFs), queC, queD and queE. The absence of the key gene queF encoding 7-cyano-7-deazaguanine reductase catalyzing PreQ0 base to PreQ1 base suggested that the strain only has the capacity of accumulation of PreQ0 base as a metabolite, consistent with our observation in chemical identification. PMID:25353335

  11. Purification of a dimeric arginine deiminase from Enterococcus faecium GR7 and study of its anti-cancerous activity.

    PubMed

    Kaur, Baljinder; Kaur, Rajinder

    2016-09-01

    The arginine deiminase (ADI, E.C 3.5.3.6) - a key enzyme of ADI pathway of Enterococcus faecium GR7 was purified to homogeneity. A sequential purification strategy involving ammonium sulfate fractionation, molecular sieve followed by Sephadex G-100 gel filtration was applied to the crude culture filtrate to obtain a pure enzyme preparation. The enzyme was purified with a fold of 16.92 and showed a final specific activity of 76.65IU/mg with a 49.17% yield. The dimeric ADI has a molecular mass of about 94,364.929Da, and comprises of hetrodimers of 49.1kDa and 46.5kDa as determined by MALDI-TOF and PAGE analysis. To assess anti-cancerous activity of ADI by MTT assay was carried out against cancer cell lines (MCF-7, Sp2/0-Ag14 and Hep-G2). Purified ADI exhibited the most profound antiproliferative activity against Hep-G2 cells; with half-maximal inhibitory concentration (IC50) of 1.95μg/ml. Purified ADI from E. faecium GR7 was observed to induce apoptosis in the Hep-G2 cells by DNA fragmentation assay. Our findings suggest the possibility of a future use of ADI from E. faecium GR7 as a potential anticancer drug. PMID:26363115

  12. A novel green one-step synthesis of gold nanoparticles using crocin and their anti-cancer activities.

    PubMed

    Hoshyar, Reyhane; Khayati, Gholam Reza; Poorgholami, Maliheh; Kaykhaii, Massoud

    2016-06-01

    Functionalized nanoparticles are specifically designed to deliver drugs at tumor cells and can potentially enhance anticancer activity of drugs such as crocin. In the present study, we have applied antioxidant crocin as a reducing agent for one pot green synthesis of controlled size gold nanoparticles (AuNPs). Spherical, stable and uniform AuNPs were synthesized using crocin. These AuNPs are characterized by UV-Vis, TEM and XRD techniques. The prepared AuNPs showed surface plasm on resonance centered at 520nm with the average particle size of about 4-10nm. The anti-cancer effect of AuNPs was determined using MTT and LDH tests. The cellular data showed that these AuNPs significantly decreased cancerous cells' growth after 24 and 48hours in a time- and dose-dependent manner (P<0.05). The results suggest that such AuNPs can be synthesized simply and quickly with invaluable clinical as well as pharmaceutical activities which can help to treat human breast cancer. PMID:27085640

  13. Modulating chromatin structure and DNA accessibility by deacetylase inhibition enhances the anti-cancer activity of silver nanoparticles.

    PubMed

    Igaz, Nóra; Kovács, Dávid; Rázga, Zsolt; Kónya, Zoltán; Boros, Imre M; Kiricsi, Mónika

    2016-10-01

    Histone deacetylase (HDAC) inhibitors are considered as novel therapeutic agents inducing cell cycle arrest and apoptotic cell death in various cancer cells. Inhibition of deacetylase activity results in a relaxed chromatin structure thereby rendering the genetic material more vulnerable to DNA targeting agents that could be exploited by combinational cancer therapy. The unique potential of silver nanoparticles (AgNPs) in tumor therapy relies on the generation of reactive radicals which trigger oxidative stress, DNA damage and apoptosis in cancer cells. The revolutionary application of AgNPs as chemotherapeutical drugs seems very promising, nevertheless the exact molecular mechanisms of AgNP action in combination with other anti-cancer agents have yet to be elucidated in details before clinical administrations. As a step towards this we investigated the combinational effect of HDAC inhibition and AgNP administration in HeLa cervical cancer cells. We identified synergistic inhibition of cancer cell growth and migration upon combinational treatments. Here we report that the HDAC inhibitor Trichostatin A enhances the DNA targeting capacity and apoptosis inducing efficacy of AgNPs most probably due to its effect on chromatin condensation. These results point to the potential benefits of combinational application of HDAC inhibitors and AgNPs in novel cancer medication protocols. PMID:27434153

  14. Anti cancer activity on Graviola, an exciting medicinal plant extract vs various cancer cell lines and a detailed computational study on its potent anti-cancerous leads.

    PubMed

    Paul, Jeno; Gnanam, R; Jayadeepa, R M; Arul, L

    2013-01-01

    Nature is the world's best chemist: Many naturally occurring compounds have very complicated structures that present great challenges to chemists wishing to determine their structures or replicate them. The plant derived herbal compounds have a long history of clinical use, better patient tolerance and acceptance. Their high ligand binding affinity to the target introduce the prospect of their use in chemo preventive applications; in addition they are freely available natural compounds that can be safely used to prevent various ailments. Plants became the basis of traditional medicine system throughout the world for thousands of years and continue to provide mankind with new remedies. Here, we present a research study on a medicinal plant, Graviola, a native of North America but rarely grown in India. It has a wide potent anticancerous agents coined as Acetogenins which play a key role towards many varieties of cancer, Acetogenins are potent inhibitors of NADH oxidase of the plasma membranes of cancer cells. Potent leads were taken for the study through literature survey, major types of cancer targets were identified, the natureceuticals and the cancer protein were subjected to docking analysis, further with the help of the dock score and other descriptor properties top ranked molecules were collected, commercial drug was also selected and identified as a Test compound for the study. Later, the phytochemicals were subjected to toxicity analysis. Those screened compounds were then considered for active site analysis and to find the best binding site for the study. R Programming library was used to find the best leads. Phytochemicals such as Anonaine, Friedelin, Isolaureline, Annonamine, Anomurine, Kaempferol, Asimilobine, Quercetin, Xylopine were clustered and the highly clustered compounds such as Annonamine , Kaempferol termed to be a potential lead for the study. Further study on experimental analysis may prove the potentiality of these compounds. In the

  15. Dioxol and dihydrodioxin analogs of 2- and 3-phenylacetonitriles as potent anti-cancer agents with nanomolar activity against a variety of human cancer cells.

    PubMed

    Madadi, Nikhil R; Ketkar, Amit; Penthala, Narsimha R; Bostian, April C L; Eoff, Robert L; Crooks, Peter A

    2016-05-01

    A small library of (Z)-2-(benzo[d][1,3]dioxol-5-yl) and (Z)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl analogs of 2- and 3-phenylacetonitriles has been synthesized and evaluated for their anti-cancer activities against a panel of 60 human cancer cell lines. The dihydrodioxin analog 3j and dioxol analogs 5e and 7e exhibited the most potent anti-cancer activity of all the analogs synthesized in this study, with GI50 values of <100nM against almost all of the cell lines in the human cancer cell panel. Of these three, only compound 3j inhibited tubulin polymerization to any degree in vitro. The binding modes of 3j and the structurally related tubulin-inhibitor DMU-212 were determined by virtual docking studies with tubulin dimer. Compound 3j docked at the colchicine-binding site at the dimer interface of tubulin. The Full-Fitness (FF) score of 3j was observed to be substantially higher than DMU-212, which agrees well with the observed anti-cancer potency (GI50 values). The mechanism by which dioxol analogs 5e and 7e exert their cytotoxic effects remains unknown at this stage, but it is unlikely that they affect tubulin dynamics. Nevertheless, these findings suggest that both dioxol and dihydrodioxin analogs of phenylacrylonitrile may have potential for development as clinical candidates to treat a variety of human cancers. PMID:27017113

  16. Synthesis of isatin thiosemicarbazones derivatives: In vitro anti-cancer, DNA binding and cleavage activities

    NASA Astrophysics Data System (ADS)

    Ali, Amna Qasem; Teoh, Siang Guan; Salhin, Abdussalam; Eltayeb, Naser Eltaher; Khadeer Ahamed, Mohamed B.; Majid, A. M. S. Abdul

    New derivatives of thiosemicarbazone Schiff base with isatin moiety were synthesized L1-L6. The structures of these compounds were characterized based on the spectroscopic techniques. Compound L6 was further characterized by XRD single crystal. The interaction of these compounds with calf thymus (CT-DNA) exhibited high intrinsic binding constant (kb = 5.03-33.00 × 105 M-1) for L1-L3 and L5 and (6.14-9.47 × 104 M-1) for L4 and L6 which reflect intercalative activity of these compounds toward CT-DNA. This result was also confirmed by the viscosity data. The electrophoresis studies reveal the higher cleavage activity of L1-L3 than L4-L6. The in vitro anti-proliferative activity of these compounds against human colon cancer cell line (HCT 116) revealed that the synthesized compounds (L3, L6 and L2) exhibited good anticancer potency.

  17. DNA-Binding, Photocleavage, and Photodynamic Anti-cancer Activities of Pyridyl Corroles.

    PubMed

    Liang, Zhen-Hua; Liu, Hai-Yang; Zhou, Rong; Zhang, Zao; Ali, Atif; Han, Bing-Jie; Liu, Yun-Jun; Xiao, Xin-Yan

    2016-08-01

    The DNA-binding, photocleavage, and antitumor activity of three free base pyridyl corroles 1, 2, and 3 have been investigated. The binding affinity toward CT-DNA decreases with increasing number of pentafluorophenyl, whereas the photocleavage activity toward pBR322 DNA becomes more efficient. Singlet oxygen was demonstrated as active species responsible for DNA cleavage. These corroles exhibited high cytotoxicity against three tested cancer cells (Hela, HapG2, and A549) and the cytotoxicity could be further enhanced under irradiation. Intracellular reactive oxygen species level was also monitored using HeLa Cells upon the combined treatment of corroles and light. These corroles could be absorbed by HeLa cells at low concentration. They can induce the decrease of mitochondrial membrane potential and apoptosis of tumor cells under irradiation. PMID:26895317

  18. Combined Delivery and Anti-Cancer Activity of Paclitaxel and Curcumin Using Polymeric Micelles.

    PubMed

    Gao, Xiang; Wang, Bilan; Wu, Qinjie; Wei, Xiawei; Zheng, Fengjin; Men, Ke; Shi, Huashan; Huang, Ning; Wei, Yuquan; Gong, Changyang

    2015-04-01

    Paclitaxel (PTX) is efficacious in treating various solid tumors. However, the severe adverse effects of its present formulation (Cremophor EL and ethanol) and the development of drug resistance by the activation of nuclear factor-κB (NF-κB) reduce the anti-tumor activities of PTX. Curcumin (Cur) demonstrates anti-tumor activity by means of antiangiogenesis and induction of apoptosis as well as suppression of the activity of NF-κB. Therefore, to improve its antitumor activity and eliminate the toxicity of the commercial formulation of PTX, we prepared biodegradable monomethoxy poly(ethyleneglycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to co-deliver PTX and Cur using a solid dispersion method. The mixed PTX and Cur polymeric micelles (PTX-Cur-M) produced were monomorphous micelles of 38 nm in diameter that released PTX and Cur for an extended period of time and induced cell apoptosis in vitro. In addition, the PTX-Cur-M exhibited anti-angiogenic activity in vitro and in vivo. Furthermore, the therapeutic efficacy of PTX-Cur-M in a mouse model of colon cancer was evaluated. PTX-Cur-M micelles produced significantly more inhibition of tumor growth than Cur micelles (Cur-M) and PTX micelles (PTX-M) alone at the same dose (P < 0.05 and P < 0.05, respectively). Immunohistochemical and immunofluorescent analyses demonstrated that PTX-Cur-M enhanced tumor cell apoptosis and inhibited angiogenesis to a greater extent than control treatment. Our data suggested that PTX-Cur-M may have potential clinical applications in cancer therapy. PMID:26310065

  19. Ascophyllan functions as an adjuvant to promote anti-cancer effect by dendritic cell activation

    PubMed Central

    Zhang, Wei; Okimura, Takasi; Xu, Li; Zhang, Lijun; Oda, Tatsuya; Kwak, Minseok; Yu, Qing; Jin, Jun-O

    2016-01-01

    Our previous study demonstrated that ascophyllan, a sulfated polysaccharide purified from brown alga, has immune-activating effects. In this study, we evaluated ascophyllan as an adjuvant for its therapeutic and preventive effect on tumor in a mouse melanoma model. Ascophyllan induced migration of DCs to spleen and tumor-draining lymph node (drLN) in a mouse B16 melanoma model. Moreover, ascophyllan induced activation of dendritic cells (DCs), and promoted IFN-γ- and TNF-α-producing Th1 immune responses in tumor-bearing mice. In addition, treatment with a combination of ascophyllan and ovalbumin (OVA) in the tumor-bearing mice promoted proliferation of OVA-specific CD4 and CD8 T cells and migration of those cells into the tumor, consequently inhibiting the tumor growth. Immunization with the combination of ascophyllan and OVA caused enhanced OVA-specific antibody production and memory T cell responses compared to OVA immunization alone, and almost completely prevented B16-OVA tumor growth upon subsequent tumor challenge. Finally, the combination of ascophyllan and OVA prevented B16-OVA tumor invasion and metastasis into the liver. Thus, these results demonstrate that ascophyllan can function as an adjuvant to induce DC activation, antigen specific CTL activation, Th1 immune response and antibody production, and hence may be useful as a therapeutic and preventive tumor vaccine. PMID:27008707

  20. Identification and Analysis of the Active Phytochemicals from the Anti-Cancer Botanical Extract Bezielle

    PubMed Central

    Chen, Vivian; Staub, Richard E.; Baggett, Scott; Chimmani, Ramesh; Tagliaferri, Mary; Cohen, Isaac; Shtivelman, Emma

    2012-01-01

    Bezielle is a botanical extract that has selective anti-tumor activity, and has shown a promising efficacy in the early phases of clinical testing. Bezielle inhibits mitochondrial respiration and induces reactive oxygen species (ROS) in mitochondria of tumor cells but not in non-transformed cells. The generation of high ROS in tumor cells leads to heavy DNA damage and hyper-activation of PARP, followed by the inhibition of glycolysis. Bezielle therefore belongs to a group of drugs that target tumor cell mitochondria, but its cytotoxicity involves inhibition of both cellular energy producing pathways. We found that the cytotoxic activity of the Bezielle extract in vitro co-purified with a defined fraction containing multiple flavonoids. We have isolated several of these Bezielle flavonoids, and examined their possible roles in the selective anti-tumor cytotoxicity of Bezielle. Our results support the hypothesis that a major Scutellaria flavonoid, scutellarein, possesses many if not all of the biologically relevant properties of the total extract. Like Bezielle, scutellarein induced increasing levels of ROS of mitochondrial origin, progressive DNA damage, protein oxidation, depletion of reduced glutathione and ATP, and suppression of both OXPHOS and glycolysis. Like Bezielle, scutellarein was selectively cytotoxic towards cancer cells. Carthamidin, a flavonone found in Bezielle, also induced DNA damage and oxidative cell death. Two well known plant flavonoids, apigenin and luteolin, had limited and not selective cytotoxicity that did not depend on their pro-oxidant activities. We also provide evidence that the cytotoxicity of scutellarein was increased when other Bezielle flavonoids, not necessarily highly cytotoxic or selective on their own, were present. This indicates that the activity of total Bezielle extract might depend on a combination of several different compounds present within it. PMID:22272282

  1. Anti-cancer activity of doxorubicin-loaded liposomes co-modified with transferrin and folic acid.

    PubMed

    Sriraman, Shravan Kumar; Salzano, Giusseppina; Sarisozen, Can; Torchilin, Vladimir

    2016-08-01

    Cancer-specific drug delivery represents an attractive approach to prevent undesirable side-effects and increase the accumulation of the drug in the tumor. Surface modification of nanoparticles such as liposomes with targeting moieties specific to the up-regulated receptors on the surface of tumor cells thus represents an effective strategy. Furthermore, since this receptor expression can be heterogeneous, using a dual-combination of targeting moieties may prove advantageous. With this in mind, the anti-cancer activity of PEGylated doxorubicin-loaded liposomes targeted with folic acid (F), transferrin (Tf) or both (F+Tf) was evaluated. The dual-targeted liposomes showed a 7-fold increase in cell association compared to either of the single-ligand targeted ones in human cervical carcinoma (HeLa) cell monolayers. The increased penetration and cell association of the dual-targeted liposomes were also demonstrated using HeLa cell spheroids. The in vitro cytotoxicity of the doxorubicin liposomes (LD) was then evaluated using HeLa and A2780-ADR ovarian carcinoma cell monolayers. In both these cell lines, the (F+Tf) LD showed significantly higher cytotoxic effects than the untargeted, or single-ligand targeted liposomes. In a HeLa xenograft model in nude mice, compared to the untreated group, though the untargeted LD showed 42% tumor growth inhibition, both the (F) LD and (F+Tf) LD showed 75% and 79% tumor growth inhibition respectively. These results thus highlight that though the dual-targeted liposomes represent an effective cytotoxic formulation in the in vitro setting, they were equally effective as the folic acid-targeted liposomes in reducing tumor burden in the more complex in vivo setting in this particular model. PMID:27264717

  2. Anti-cancer activities of pH- or heat-modified pectin

    PubMed Central

    Leclere, Lionel; Cutsem, Pierre Van; Michiels, Carine

    2013-01-01

    Despite enormous efforts that have been made in the search for novel drugs and treatments, cancer continues to be a major public health problem. Moreover, the emergence of resistance to cancer chemotherapy often prevents complete remission. Researchers have thus turned to natural products mainly from plant origin to circumvent resistance. Pectin and pH- or heat-modified pectin have demonstrated chemopreventive and antitumoral activities against some aggressive and recurrent cancers. The focus of this review is to describe how pectin and modified pectin display these activities and what are the possible underlying mechanisms. The failure of conventional chemotherapy to reduce mortality as well as serious side effects make natural products, such as pectin-derived products, ideal candidates for exerting synergism in combination with conventional anticancer drugs. PMID:24115933

  3. Dihydroartemisinin is a Hypoxia-Active Anti-Cancer Drug in Colorectal Carcinoma Cells

    PubMed Central

    Ontikatze, Teona; Rudner, Justine; Handrick, René; Belka, Claus; Jendrossek, Verena

    2014-01-01

    Tumor hypoxia is one main biological factor that drives resistance to chemotherapy and radiotherapy. To develop a novel strategy for overcoming hypoxia-induced therapy resistance, we examined the anti-neoplastic activity of the reactive oxygen donor dihydroartemisinin (DHA) in human colon cancer cell lines in normoxia and severe hypoxia. In addition, we analyzed the involvement of the intrinsic apoptosis pathway for DHA-mediated cytotoxicity in HCT116 cells in short-term and long-term in vitro assays. When applied at lower concentrations (≤25 μM), DHA induced apoptosis in Colo205, HCT15, and HCT116 cells, whereas necrotic cell death was increased when cells were treated with higher DHA concentrations (50 μM). However, no preference for DHA-induced apoptosis or necrosis could be detected between the treatment under normoxic or hypoxic conditions. Moreover, DHA potently reduced clonogenic survival of HCT116 cells in normoxia and hypoxia. Treatment of HCT116 cells with 25 μM DHA resulted in activation of Bax under normoxic and hypoxic conditions. Interestingly, cytochrome c release from the mitochondria and caspase-activation were observed only under normoxic conditions, whereas, under hypoxic conditions DHA induced a caspase-independent apoptosis-like cell death. However, under both conditions, generation of reactive oxygen species was an important mediator of DHA-induced toxicity. Further molecular analysis suggests that DHA-mediated cell death involves different sets of pro-apoptotic Bcl-2 family members. The pronounced cytotoxic activity of DHA in severe hypoxia as well as normoxia offers new perspectives for targeting the hypoxic tumor cell fraction to improve treatment outcome for cancer patients. PMID:24904829

  4. A Review on the Synthesis and Anti-cancer Activity of 2-substituted Quinolines.

    PubMed

    Gopaul, Kaalin; Shintre, Suhas A; Koorbanally, Neil A

    2015-01-01

    Quinolines substituted at C-2 on the quinoline scaffold have shown interesting anticancer activity in a number of anticancer assays such as breast (MCF-7, MDA-MB 231), human cervical epithelioid (HeLa), oral squamous cell carcinoma (SAS), human stomach adenocarcinoma (AGS, MKN45), hepatocellular (SKHep, HepG-2, Hep-3B), prostate (PC-3, DU145), lung (A549, H-460), gastric (HGC, MNK-74), leukemia (K562, U937, REH, NALM6, CEM/ADR 5000), colon (Colo-205, HCT 116, SW620, Caco-2, HT29), neuroblastoma (IMR32), CNS (SF-268), oesophageal (EAC) and melanoma (A-375). They have been synthesised by a number of strategies starting with isatin, anilines, nitrobenzenes and benzamides and some even with cyclohexanone and cyclohexa-1,3-diones with ammonium acetate. Many of the synthetic strategies employ the derivatisation of quinoline precursors itself. We review here the synthesis of 145 bioactive anticancer quinolines substituted at the 2-position and their anticancer activity. PMID:25511516

  5. Water soluble polysaccharides from Spirulina platensis: extraction and in vitro anti-cancer activity.

    PubMed

    Kurd, Forouzan; Samavati, Vahid

    2015-03-01

    Polysaccharides from Spirulina platensis algae (SP) were extracted by ultrasound-assisted extraction procedure. The optimal conditions for ultrasonic extraction of SP were determined by response surface methodology. The four parameters were, extraction time (X1), extraction temperature (X2), ultrasonic power (X3) and the ratio of water to raw material (X4), respectively. The experimental data obtained were fitted to a second-order polynomial equation. The optimum conditions were extraction time of 25 min, extraction temperature 85°C, ultrasonic power 90 W and ratio of water to raw material 20 mL/g. Under these optimal conditions, the experimental yield was 13.583±0.51%, well matched with the predicted models with the coefficients of determination (R2) of 0.9971. Then, we demonstrated that SP polysaccharides had strong scavenging activities in vitro on DPPH and hydroxyl radicals. Overall, SP may have potential applications in the medical and food industries. PMID:25583023

  6. Identification of an iridium(III) complex with anti-bacterial and anti-cancer activity

    PubMed Central

    Lu, Lihua; Liu, Li-Juan; Chao, Wei-chieh; Zhong, Hai-Jing; Wang, Modi; Chen, Xiu-Ping; Lu, Jin-Jian; Li, Ruei-nian; Ma, Dik-Lung; Leung, Chung-Hang

    2015-01-01

    Group 9 transition metal complexes have been widely explored as therapeutic agents due to their unique geometry, their propensity to undergo ligand exchanges with biomolecules and their diverse steric and electronic properties. These metal complexes can offer distinct modes of action in living organisms compared to carbon-based molecules. In this study, we investigated the antimicrobial and anti-proliferative abilities of a series of cyclometallated iridium(III) complexes. The iridium(III) complex 1 inhibited the growth of S. aureus with MIC and MBC values of 3.60 and 7.19 μM, respectively, indicating its potent bactericidal activity. Moreover, complex 1 also exhibited cytotoxicity against a number of cancer cell lines, with particular potency against ovarian, cervical and melanoma cells. This cyclometallated iridium(III) complex is the first example of a substitutionally-inert, Group 9 organometallic compound utilized as a direct and selective inhibitor of S. aureus. PMID:26416333

  7. Could B7-H4 serve as a target to activate anti-cancer immunity?

    PubMed

    Wang, Lijuan; Heng, Xueyuan; Lu, Yong; Cai, Zhen; Yi, Qing; Che, Fengyuan

    2016-09-01

    It has been over 13years since the identification of B7-H4, the co-stimulatory molecule of B7 family members. While B7-H4 mRNA is widely distributed protein expression seems to be limited on tissues. Various cytokines and inflammatory mediators induce the expression of B7-H4. However, the specific regulatory mechanisms of B7-H4 remain to be defined. Recently, it has been shown that B7-H4 executes an inhibitory function in the T-cell response via reduced expansion, cell cycle arrest, decreased cytokine secretion and induced apoptosis of activated T-cells. Furthermore, B7-H4 suppresses the function of antigen presenting cells (APCs) and promotes the proliferation and development of regulatory T-cells (Treg). Moreover, a growing body of literature demonstrates that various cancers express B7-H4 and that the expression levels of B7-H4 correlate with cancer size, histological type, pathologic stage, grade, infiltration, lymph node metastasis, cancer progression, recurrence and death. The over-expression of B7-H4 in cancer may be related to an increased resistance to immune responses. The aim of this review is to supply an overview of the advances in the regulation and function of B7-H4. Additionally, many studies have suggested that B7-H4 is a molecular target for therapeutic intervention in cancer and that targeting B7-H4 may have promising potential for improving the efficacy of immunotherapy for cancer patients. PMID:27258187

  8. Anti-cancer effects of cerium oxide nanoparticles and its intracellular redox activity.

    PubMed

    Pešić, Milica; Podolski-Renić, Ana; Stojković, Sonja; Matović, Branko; Zmejkoski, Danica; Kojić, Vesna; Bogdanović, Gordana; Pavićević, Aleksandra; Mojović, Miloš; Savić, Aleksandar; Milenković, Ivana; Kalauzi, Aleksandar; Radotić, Ksenija

    2015-05-01

    Data on medical applications of cerium oxide nanoparticles CeO2 (CONP) are promising, yet information regarding their action in cells is incomplete and there are conflicting reports about in vitro toxicity. Herein, we have studied cytotoxic effect of CONP in several cancer and normal cell lines and their potential to change intracellular redox status. The IC50 was achieved only in two of eight tested cell lines, melanoma 518A2 and colorectal adenocarcinoma HT-29. Self-propagating room temperature method was applied to produce CONP with an average crystalline size of 4 nm. The results confirmed presence of Ce(3+) and O(2-) vacancies. The induction of cell death by CONP and the production of reactive oxygen species (ROS) were analyzed by flow-cytometry. Free radicals related antioxidant capacity of the cells was studied by the reduction of stable free radical TEMPONE using electron spin resonance spectroscopy. CONP showed low or moderate cytotoxicity in cancer cell lines: adenocarcinoma DLD1 and multi-drug resistant DLD1-TxR, non-small cell lung carcinoma NCI-H460 and multi-drug resistant NCI-H460/R, while normal cell lines (keratinocytes HaCaT, lung fetal fibroblasts MRC-5) were insensitive. The most sensitive were 518A2 melanoma and HT-29 colorectal adenocarcinoma cell lines, with the IC50 values being between 100 and 200 μM. Decreased rate of TEMPONE reduction and increased production of certain ROS species (peroxynitrite and hydrogen peroxide anion) indicates that free radical metabolism, thus redox status was changed, and antioxidant capacity damaged in the CONP treated 518A2 and HT-29 cells. In conclusion, changes in intracellular redox status induced by CONP are partly attributed to the prooxidant activity of the nanoparticles. Further, ROS induced cell damages might eventually lead to the cell death. However, low inhibitory potential of CONP in the other human cell lines tested indicates that CONP may be safe for human usage in industry and medicine. PMID

  9. Synthesis, Nitric Oxide Release, and Anti-Leukemic Activity of Glutathione-Activated Nitric Oxide Prodrugs: Structural Analogues of PABA/NO, an Anti-Cancer Lead Compound

    PubMed Central

    Chakrapani, Harinath; Wilde, Thomas C.; Citro, Michael L.; Goodblatt, Michael M.; Keefer, Larry K.; Saavedra, Joseph E.

    2008-01-01

    Diazeniumdiolate anions and their prodrug forms are reliable sources of nitric oxide (NO) that have generated interest as promising therapeutic agents. A number of structural analogues of O2-(2,4-dinitro-5-(4-(N-methylamino)benzoyloxy)phenyl) 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO), an anti-cancer lead compound that is designed to release NO upon activation by glutathione, were prepared. The nitric oxide release patterns of these O2-(2,4-dinitrophenyl) diazeniumdiolates in the presence of glutathione were tested and it was found that in the absence of competing pathways, these compounds release nearly quantitative amounts of NO. The ability of PABA/NO and its structural analogues to inhibit human leukemia cell proliferation was determined and it was found that compounds releasing elevated amounts of NO displayed superior cytotoxic effects. PMID:18060792

  10. Impedimetric DNA-biosensor for the study of anti-cancer action of mitomycin C: comparison between acid and electroreductive activation.

    PubMed

    Ensafi, Ali A; Amini, Maryam; Rezaei, Behzad

    2014-09-15

    An electrochemical protocol is described for direct monitoring of anti-cancer properties of MMC. Using electrochemical impedance spectroscopy, a pretreated pencil graphite electrode (PGE) modified with multiwall carbon nanotubes (MWCNTs) and poly(diallyldimethylmmonium chloride), PDDA, decorated with ds-DNA was employed in this study to identify DNA damages induced by MMC. The change in charge transfer resistance after incubation of the DNA-biosensor in MMC solution for a known time was used as indication of DNA damage. It was found that MMC did not interact with DNA. As MMC does not inherently possess any anti-cancer activity, it is, therefore, necessary to activate it by either of two ways: activation in acidic media or electrochemical activation. Incubation of DNA-modified electrode in activated MMC led to alterations in DNA and changes in its electrochemical properties (which forms the theme of the present study). Acid and electroreductive MMC activations were compared and different adducts were subsequently generated, suggesting that the drug can bind to DNA in more than one way. Impedance spectroscopy was used for the first time as a novel technique for detecting DNA-drug adducts. PMID:24747202

  11. Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells.

    PubMed

    Charepalli, Venkata; Reddivari, Lavanya; Vadde, Ramakrishna; Walia, Suresh; Radhakrishnan, Sridhar; Vanamala, Jairam K P

    2016-01-01

    The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources. Eugenia jambolana (Java plum) is a tropical medicinal fruit rich in anthocyanins, however, its anti-colon cancer properties are not well characterized. Furthermore, recent evidence suggests that colon cancer stem cells (colon CSCs) promote resistance to chemotherapy, relapse of tumors and contribute to poor prognosis. The objectives of this study were to 1) characterize the anthocyanin profile of Java plum using HPLC-MS; and 2) determine the anti-proliferative (cell counting and MTT) and pro-apoptotic (TUNEL and caspase 3/7 glo assay) properties of Java plum fruit extract (JPE) using HCT-116 colon cancer cell line and colon CSCs (positive for CD 44, CD 133 and ALDH1b1 markers). HPLC-MS analysis showed that JPE contains a variety of anthocyanins including glucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin. JPE anthocyanins suppressed (p < 0.05) proliferation in HCT-116 cells and elevated (p < 0.05) apoptosis in both HCT-116 cells and colon CSCs. JPE also suppressed the stemness in colon CSCs as evaluated using colony formation assay. These results warrant further assessment of the anti-cancer activity of JPE, and its molecular mechanisms using pre-clinical models of colon cancer. PMID:26927179

  12. Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells

    PubMed Central

    Charepalli, Venkata; Reddivari, Lavanya; Vadde, Ramakrishna; Walia, Suresh; Radhakrishnan, Sridhar; Vanamala, Jairam K. P

    2016-01-01

    The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources. Eugenia jambolana (Java plum) is a tropical medicinal fruit rich in anthocyanins, however, its anti-colon cancer properties are not well characterized. Furthermore, recent evidence suggests that colon cancer stem cells (colon CSCs) promote resistance to chemotherapy, relapse of tumors and contribute to poor prognosis. The objectives of this study were to 1) characterize the anthocyanin profile of Java plum using HPLC-MS; and 2) determine the anti-proliferative (cell counting and MTT) and pro-apoptotic (TUNEL and caspase 3/7 glo assay) properties of Java plum fruit extract (JPE) using HCT-116 colon cancer cell line and colon CSCs (positive for CD 44, CD 133 and ALDH1b1 markers). HPLC-MS analysis showed that JPE contains a variety of anthocyanins including glucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin. JPE anthocyanins suppressed (p < 0.05) proliferation in HCT-116 cells and elevated (p < 0.05) apoptosis in both HCT-116 cells and colon CSCs. JPE also suppressed the stemness in colon CSCs as evaluated using colony formation assay. These results warrant further assessment of the anti-cancer activity of JPE, and its molecular mechanisms using pre-clinical models of colon cancer. PMID:26927179

  13. Cdc7 is a potent anti-cancer target in pancreatic cancer due to abrogation of the DNA origin activation checkpoint

    PubMed Central

    Huggett, Matthew T.; Tudzarova, Slavica; Proctor, Ian; Loddo, Marco; Keane, Margaret G.; Stoeber, Kai; Williams, Gareth H.; Pereira, Stephen P.

    2016-01-01

    Purpose Cdc7 is a serine/threonine kinase which is responsible for the ‘firing’ of replication origins leading to initiation of DNA replication. Inhibition or depletion of Cdc7 in normal cells triggers a DNA origin activation checkpoint causing a reversible G1 arrest. Here we investigate Cdc7 as a novel therapeutic target in pancreatic cancer. Experimental design Cdc7 target validation was performed by immunoexpression profiling in a cohort of 73 patients with pancreatic adenocarcinoma including 24 controls. Secondly Cdc7 kinase was targeted in Capan-1 and PANC-1 pancreatic cancer cell line models using either an siRNA against Cdc7 or alternatively a small molecule inhibitor (SMI) of Cdc7 (PHA-767491). Results Cdc7 was significantly overexpressed in pancreatic adenocarcinoma compared to benign pancreatic tissue (median LI 34.3% vs. 1.3%; P<0.0001). Cdc7 knockdown using siRNA in Capan-1 and PANC-1 cells resulted in marked apoptotic cell death when compared with control cells. A prominent sub-G1 peak was seen on flow cytometry (sub-G1 51% vs. 3% and 45% vs. 0.7% in Capan-1 and PANC-1 cells, respectively). Annexin V labelling confirmed apoptosis in 64% vs. 11% and 75% vs. 8%, respectively. Western blotting showed cleavage of PARP-1 and caspase-3 and presence of γH2A.X. TUNEL assay showed strong staining in treated cells. These results were mirrored following Cdc7 kinase inhibition with PHA-767491. Conclusions Our findings show that Cdc7 is a potent anti-cancer target in pancreatic adenocarcinoma and that Cdc7 immunoexpression levels might be used as a companion diagnostic to predict response to therapeutic siRNAs or SMIs directed against this kinase. PMID:26921250

  14. Outcome of active anti-cancer treatment in elderly patients with advanced non-small cell lung cancer: A single center experience

    PubMed Central

    Kim, Ji Hye; Ryu, Min Sun; Ryu, Yon Ju; Lee, Jin Hwa; Shim, Sung Shine; Kim, Yookyung; Chang, Jung Hyun

    2014-01-01

    Background This study aimed to evaluate the characteristics of active anti-cancer treatment (AAT) compared with best supportive care (BSC) in elderly patients with advanced non-small cell lung cancer (NSCLC). Methods A retrospective analysis of 144 patients, aged 70 or older, with stage IIIb/IV NSCLC from 672 patients with confirmed lung cancer, was conducted. Results Median age at diagnosis was 77 years and median survival time was five months. On multivariate analysis, AAT independently contributed to a decreased hazard ratio of death (P = 0.04), whereas male gender (P = 0.004), a body mass index of less than 18.5 (P = 0.004), and a poor performance score were associated with an increased risk of death (P < 0.001). The 52 subjects receiving AAT experienced longer survival than the 92 subjects receiving BSC (median seven months [AAT] versus three months [BSC]; P < 0.001). When sub-classified into five-year age intervals, AAT was a significant advantage in overall survival (OS) to patients aged 70–74, but not to those ≥75 years old. Conclusions AAT for patients ≥70 years old with advanced NSCLC extended OS. However, care should be taken in decisions on active anti-cancer treatments for patients over 75 years old. A prospective multicenter trial is required in the near future. PMID:26766990

  15. An appraisal of cinnamyl sulfonamide hydroxamate derivatives (HDAC inhibitors) for anti-cancer, anti-angiogenic and anti-metastatic activities in human cancer cells.

    PubMed

    Reddy, Neetinkumar D; Shoja, M H; Biswas, Subhankar; Nayak, Pawan G; Kumar, Nitesh; Rao, C Mallikarjuna

    2016-06-25

    Multiple genetic mutations along with unusual epigenetic modifications play a major role in cancer development. Histone deacetylase (HDAC) enzyme overexpression observed in the majority of cancers is responsible for tumor suppressor gene silencing and activation of proto-oncogenes to oncogenes. Cinnamic acid derivatives exhibit anti-cancer potential through HDAC enzyme inhibition. We have synthesized a few cinnamyl sulfonamide hydroxamate derivatives (NMJ-1, -2 and -3) by already published in-house procedures and their purity, and chemical characterization were performed by NMR, mass spectrometry and elemental analysis. The anti-cancer activities were also evaluated against colon cancer. The rationale for synthesis was based on bioisosterism concept. To take the work forward, these compounds were considered for in vitro anti-angiogenic and anti-metastatic activities in cancer cells. The effectiveness of these compounds was determined by SRB assay. The compounds showed cancer cell cytotoxicity (IC50 range of 5.7 ± 0.43 to 20.5 ± 1.9 μM). The mechanism of compound-induced cell death involves an intrinsic apoptosis pathway which was supported by the following: increase in apoptotic index, arrest in cell cycle at G2/M phase, increase in annexin V binding and induction of p21(Waf1/Cip1) expression in the treated cells. Further, their target modulating effect, measured as the expression of acetyl-H3 histone and acetyl α-tubulin was determined by Western blots. Hyper acetylation of H3 histone and α-tubulin were observed. Furthermore, increased expression of cleaved caspase-3, cleaved PARP, total Bad was estimated by ELISA. The anti-angiogenic effect was examined through cobalt (II) chloride (CoCl2)-induced HIF-1α expression, where the compounds reduced the expression of induced HIF-1α. In addition, their anti-metastatic ability was determined through phorbol-12-myristate-13-acetate (PMA)-induced expression of MMP-2 and -9 by Western blotting and gelatin

  16. Coadministration of the FNIII14 Peptide Synergistically Augments the Anti-Cancer Activity of Chemotherapeutic Drugs by Activating Pro-Apoptotic Bim.

    PubMed

    Iyoda, Takuya; Nagamine, Yumi; Nakane, Yoshitomi; Tokita, Yuya; Akari, Shougo; Otsuka, Kazuki; Fujita, Motomichi; Itagaki, Keisuke; Takizawa, You-Ichi; Orita, Hiroaki; Owaki, Toshiyuki; Taira, Jyunichi; Hayashi, Ryo; Kodama, Hiroaki; Fukai, Fumio

    2016-01-01

    The acquisition of drug resistance mediated by the interaction of tumor cells with the extracellular matrix (ECM), commonly referred to as cell adhesion-mediated drug resistance (CAM-DR), has been observed not only in hematopoietic tumor cells but also in solid tumor cells. We have previously demonstrated that a 22-mer peptide derived from fibronectin, FNIII14, can inhibit cell adhesion through the inactivation of β1 integrin; when coadministered with cytarabine, FNIII14 completely eradicates acute myelogenous leukemia by suppressing CAM-DR. In this study, we show that our FNIII14 peptide also enhances chemotherapy efficacy in solid tumors. Coadministration of FNIII14 synergistically enhances the cytotoxicity of doxorubicin and aclarubicin in mammary tumor and melanoma cells, respectively. The solid tumor cell chemosensitization induced by FNIII14 is dependent upon the upregulation and activation of the pro-apoptotic protein, Bim. Furthermore, the metastasis of tumor cells derived from ventrally transplanted mammary tumor grafts is suppressed by the coadministration of FNIII14 and doxorubicin. These results suggest that the coadministration of our FNIII14 peptide with chemotherapy could achieve efficient solid tumor eradication by increasing chemosensitivity and decreasing metastasis. The major causes of tumor recurrence are the existence of chemotherapy-resistant primary tumor cells and the establishment of secondary metastatic lesions. As such, coadministering FNIII14 with anti-cancer drugs could provide a promising new approach to improve the prognosis of patients with solid tumors. PMID:27622612

  17. In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database

    PubMed Central

    Dai, Shao-Xing; Li, Wen-Xing; Han, Fei-Fei; Guo, Yi-Cheng; Zheng, Jun-Juan; Liu, Jia-Qian; Wang, Qian; Gao, Yue-Dong; Li, Gong-Hua; Huang, Jing-Fei

    2016-01-01

    There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents. PMID:27145869

  18. In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database.

    PubMed

    Dai, Shao-Xing; Li, Wen-Xing; Han, Fei-Fei; Guo, Yi-Cheng; Zheng, Jun-Juan; Liu, Jia-Qian; Wang, Qian; Gao, Yue-Dong; Li, Gong-Hua; Huang, Jing-Fei

    2016-01-01

    There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents. PMID:27145869

  19. In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database

    NASA Astrophysics Data System (ADS)

    Dai, Shao-Xing; Li, Wen-Xing; Han, Fei-Fei; Guo, Yi-Cheng; Zheng, Jun-Juan; Liu, Jia-Qian; Wang, Qian; Gao, Yue-Dong; Li, Gong-Hua; Huang, Jing-Fei

    2016-05-01

    There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents.

  20. Anti-cancer scopes and associated mechanisms of Scutellaria extract and flavonoid wogonin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Extracts of Scutellaria species have been used in Eastern traditional medicine as well in the Americas for the treatment of several human ailments, including cancer. Crude extracts or flavonoids derived from Scutellaria have been scientifically studied for potential anti-cancer activity using in vit...

  1. Anti-Cancer Properties of the Naturally Occurring Aphrodisiacs: Icariin and Its Derivatives

    PubMed Central

    Tan, Hui-Li; Chan, Kok-Gan; Pusparajah, Priyia; Saokaew, Surasak; Duangjai, Acharaporn; Lee, Learn-Han; Goh, Bey-Hing

    2016-01-01

    Epimedium (family Berberidaceae), commonly known as Horny Goat Weed or Yin Yang Huo, is commonly used as a tonic, aphrodisiac, anti-rheumatic and anti-cancer agent in traditional herbal formulations in Asian countries such as China, Japan, and Korea. The major bioactive compounds present within this plant include icariin, icaritin and icariside II. Although it is best known for its aphrodisiac properties, scientific and pharmacological studies suggest it possesses broad therapeutic capabilities, especially for enhancing reproductive function and osteoprotective, neuroprotective, cardioprotective, anti-inflammatory and immunoprotective effects. In recent years, there has been great interest in scientific investigation of the purported anti-cancer properties of icariin and its derivatives. Data from in vitro and in vivo studies suggests these compounds demonstrate anti-cancer activity against a wide range of cancer cells which occurs through various mechanisms such as apoptosis, cell cycle modulation, anti-angiogenesis, anti-metastasis and immunomodulation. Of note, they are efficient at targeting cancer stem cells and drug-resistant cancer cells. These are highly desirable properties to be emulated in the development of novel anti-cancer drugs in combatting the emergence of drug resistance and overcoming the limited efficacy of current standard treatment. This review aims to summarize the anti-cancer mechanisms of icariin and its derivatives with reference to the published literature. The currently utilized applications of icariin and its derivatives in cancer treatment are explored with reference to existing patents. Based on the data compiled, icariin and its derivatives are shown to be compounds with tremendous potential for the development of new anti-cancer drugs. PMID:27445824

  2. Anti-Cancer Properties of the Naturally Occurring Aphrodisiacs: Icariin and Its Derivatives.

    PubMed

    Tan, Hui-Li; Chan, Kok-Gan; Pusparajah, Priyia; Saokaew, Surasak; Duangjai, Acharaporn; Lee, Learn-Han; Goh, Bey-Hing

    2016-01-01

    Epimedium (family Berberidaceae), commonly known as Horny Goat Weed or Yin Yang Huo, is commonly used as a tonic, aphrodisiac, anti-rheumatic and anti-cancer agent in traditional herbal formulations in Asian countries such as China, Japan, and Korea. The major bioactive compounds present within this plant include icariin, icaritin and icariside II. Although it is best known for its aphrodisiac properties, scientific and pharmacological studies suggest it possesses broad therapeutic capabilities, especially for enhancing reproductive function and osteoprotective, neuroprotective, cardioprotective, anti-inflammatory and immunoprotective effects. In recent years, there has been great interest in scientific investigation of the purported anti-cancer properties of icariin and its derivatives. Data from in vitro and in vivo studies suggests these compounds demonstrate anti-cancer activity against a wide range of cancer cells which occurs through various mechanisms such as apoptosis, cell cycle modulation, anti-angiogenesis, anti-metastasis and immunomodulation. Of note, they are efficient at targeting cancer stem cells and drug-resistant cancer cells. These are highly desirable properties to be emulated in the development of novel anti-cancer drugs in combatting the emergence of drug resistance and overcoming the limited efficacy of current standard treatment. This review aims to summarize the anti-cancer mechanisms of icariin and its derivatives with reference to the published literature. The currently utilized applications of icariin and its derivatives in cancer treatment are explored with reference to existing patents. Based on the data compiled, icariin and its derivatives are shown to be compounds with tremendous potential for the development of new anti-cancer drugs. PMID:27445824

  3. Validating Aurora B as an anti-cancer drug target.

    PubMed

    Girdler, Fiona; Gascoigne, Karen E; Eyers, Patrick A; Hartmuth, Sonya; Crafter, Claire; Foote, Kevin M; Keen, Nicholas J; Taylor, Stephen S

    2006-09-01

    The Aurora kinases, a family of mitotic regulators, have received much attention as potential targets for novel anti-cancer therapeutics. Several Aurora kinase inhibitors have been described including ZM447439, which prevents chromosome alignment, spindle checkpoint function and cytokinesis. Subsequently, ZM447439-treated cells exit mitosis without dividing and lose viability. Because ZM447439 inhibits both Aurora A and B, we set out to determine which phenotypes are due to inhibition of which kinase. Using molecular genetic approaches, we show that inhibition of Aurora B kinase activity phenocopies ZM447439. Furthermore, a novel ZM compound, which is 100 times more selective for Aurora B over Aurora A in vitro, induces identical phenotypes. Importantly, inhibition of Aurora B kinase activity induces a penetrant anti-proliferative phenotype, indicating that Aurora B is an attractive anti-cancer drug target. Using molecular genetic and chemical-genetic approaches, we also probe the role of Aurora A kinase activity. We show that simultaneous repression of Aurora A plus induction of a catalytic mutant induces a monopolar phenotype. Consistently, another novel ZM-related inhibitor, which is 20 times as potent against Aurora A compared with ZM447439, induces a monopolar phenotype. Expression of a drug-resistant Aurora A mutant reverts this phenotype, demonstrating that Aurora A kinase activity is required for spindle bipolarity in human cells. Because small molecule-mediated inhibition of Aurora A and Aurora B yields distinct phenotypes, our observations indicate that the Auroras may present two avenues for anti-cancer drug discovery. PMID:16912073

  4. Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke.

    PubMed

    Van Kanegan, Michael J; Dunn, Denise E; Kaltenbach, Linda S; Shah, Bijal; He, Dong Ning; McCoy, Daniel D; Yang, Peiying; Peng, Jiangnan; Shen, Li; Du, Lin; Cichewicz, Robert H; Newman, Robert A; Lo, Donald C

    2016-01-01

    We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0-4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0-4 provides broad neuroprotection in organotypic brain slice models for neurodegeneration driven by amyloid precursor protein (APP) and tau implicated in Alzheimer's disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD. PMID:27172999

  5. Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke

    PubMed Central

    Van Kanegan, Michael J.; Dunn, Denise E.; Kaltenbach, Linda S.; Shah, Bijal; He, Dong Ning; McCoy, Daniel D.; Yang, Peiying; Peng, Jiangnan; Shen, Li; Du, Lin; Cichewicz, Robert H.; Newman, Robert A.; Lo, Donald C.

    2016-01-01

    We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0–4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0–4 provides broad neuroprotection in organotypic brain slice models for neurodegeneration driven by amyloid precursor protein (APP) and tau implicated in Alzheimer’s disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD. PMID:27172999

  6. Anti-Cancer Potential of a Novel SERM Ormeloxifene

    PubMed Central

    Gara, Rishi Kumar; Sundram, Vasudha; Chauhan, Subhash C.; Jaggi, Meena

    2014-01-01

    Ormeloxifene is a non-steroidal Selective Estrogen Receptor Modulator (SERM) that is used as an oral contraceptive. Recent studies have shown its potent anti-cancer activities in breast, head and neck, and chronic myeloid leukemia cells. Several in vivo and clinical studies have reported that ormeloxifene possesses an excellent therapeutic index and has been well-tolerated, without any haematological, biochemical or histopathological toxicity, even with chronic administration. A reasonably long period of time and an enormous financial commitment are required to develop a lead compound into a clinically approved anti-cancer drug. For these reasons and to circumvent these obstacles, ormeloxifene is a promising candidate on a fast track for the development or repurposing established drugs as anti-cancer agents for cancer treatment. The current review summarizes recent findings on ormeloxifene as an anti-cancer agent and future prospects of this clinically safe pharmacophore. PMID:23895678

  7. Downregulation of microRNA miR-520h by E1A Contributes to Anti-cancer Activity

    PubMed Central

    Su, Jen-Liang; Chen, Poshen B.; Chen, Ya-Huey; Chen, Shang-Chih; Chang, Yi-Wen; Jan, Yi-Hua; Cheng, Xiaoyun; Hsiao, Michael; Hung, Mien-Chie

    2010-01-01

    The leading cause of death in cancer patients is cancer metastasis, for which there is no effective treatment. MicroRNAs have been shown to play a significant role in cancer metastasis through regulation of gene expression. The Adenoviral type 5 E1A is associated with multiple tumor suppressing activities including the inhibition of metastasis, and E1A gene therapies have been tested in several clinical trials. However, the mechanisms involved in E1A-mediated tumor suppressing activities are not yet completely defined. Here we demonstrated that E1A down-regulated the expression of miRNA, miR-520h, which was critical for E1A-mediated cancer cell mobility and in vitro invasion activity. In addition, we identified a signal cascade, namely, E1A —| miRNA-520h —| PP2A/C —| IKK → NF-κB → Twist, in which E1A inhibited the expression of Twist through downregulation of miR-520h and the signal cascade. Our results indicated a functional link between miR-520h and tumorigenicity/invasive ability, and provided a new insight into the role of E1A-mediated miRNA regulation in tumor suppression. Therefore, the results identified a new cascade of E1A-mediated tumor suppression activity via downregulation of miRNA-520h expression. PMID:20501832

  8. A Survey of Marine Natural Compounds and Their Derivatives with Anti-cancer Activity Reported in 2012.

    PubMed

    Sawadogo, Wamtinga Richard; Boly, Rainatou; Cerella, Claudia; Teiten, Marie Hélène; Dicato, Mario; Diederich, Marc

    2015-01-01

    Although considerable effort and progress has been made in the search for new anticancer drugs and treatments in the last several decades, cancer remains a major public health problem and one of the major causes of death worldwide. Many sources, including plants, animals, and minerals, are of interest in cancer research because of the possibility of identifying novel molecular therapeutics. Moreover, structure-activity-relationship (SAR) investigations have become a common way to develop naturally derived or semi-synthetic molecular analogues with improved efficacy and decreased toxicity. In 2012, approximately 138 molecules from marine sources, including isolated compounds and their associated analogues, were shown to be promising anticancer drugs. Among these, 62% are novel compounds. In this report, we review the marine compounds identified in 2012 that may serve as novel anticancer drugs. PMID:25903364

  9. Anti-cancer Activity of Osmanthus matsumuranus Extract by Inducing G2/M Arrest and Apoptosis in Human Hepatocellular Carcinoma Hep G2 Cells

    PubMed Central

    Jin, Soojung; Park, Hyun-Jin; Oh, You Na; Kwon, Hyun Ju; Kim, Jeong-Hwan; Choi, Yung Hyun; Kim, Byung Woo

    2015-01-01

    Background: Osmanthus matsumuranus, a species of Oleaceae, is found in East Asia and Southeast Asia. The bioactivities of O. matsumuranus have not yet been fully understood. Here, we studied on the molecular mechanisms underlying anti-cancer effect of ethanol extract of O. matsumuranus (EEOM). Methods: Inhibitory effect of EEOM on cell growth and proliferation was determined by WST assay in various cancer cells. To investigate the mechanisms of EEOM-mediated cytotoxicity, HepG2 cells were treated with various concentration of EEOM and analyzed the cell cycle arrest and apoptosis induction by flow cytometry, Western blot analysis, 4,6-diamidino-2-phenylindole (DAPI) staining and DNA fragmentation. Results: EEOM showed the cytotoxic activities in a dose-dependent manner in various cancer cell lines but not in normal cells, and HepG2 cells were most susceptible to EEOM-induced cytotoxicity. EEOM induced G2/M arrest in HepG2 cells associated with decreased expression of cyclin-dependent kinase 1 (CDK1), cyclin A and cylcin B, and increased expression of phospho-checkpoint kinase 2, p53 and CDK inhibitor p21. Immunofluorescence staining showed that EEOM-treated HepG2 increased doublet nuclei and condensed actin, resulting in cell rounding. Furthermore, EEOM-mediated apoptosis was determined by Annexin V staining, chromatin condensation and DNA fragmentation. EEOM caused upregulation of FAS and Bax, activation of caspase-3, -8, -9, and fragmentation of poly ADP ribose polymerase. Conclusions: These results suggest that EEOM efficiently inhibits proliferation of HepG2 cells by inducing both G2/M arrest and apoptosis via intrinsic and extrinsic pathways, and EEOM may be used as a cancer chemopreventive agent in the food or nutraceutical industry. PMID:26734586

  10. Synthesis, docking and ADMET studies of novel chalcone triazoles for anti-cancer and anti-diabetic activity.

    PubMed

    Chinthala, Yakaiah; Thakur, Sneha; Tirunagari, Shalini; Chinde, Srinivas; Domatti, Anand Kumar; Arigari, Niranjana Kumar; K V N S, Srinivas; Alam, Sarfaraz; Jonnala, Kotesh Kumar; Khan, Feroz; Tiwari, Ashok; Grover, Paramjit

    2015-03-26

    A series of novel chalcone-triazole derivatives were synthesized and screened for in vitro anticancer activity on the human cancer cell lines IMR32 (neuroblastoma), HepG2 (hepatoma) and MCF-7 (breast adenocarcinoma), DU-145 (prostate carcinoma), and A549 (lung adenocarcinoma). Among the tested compounds, 4r showed the most promising anticancer activity in all the cell lines whereas, compounds 4c (IC50 65.86 μM), 4e (IC50 66.28 μM), 4o (IC50 35.81 μM), 4q (IC50 50.82 μM) and 4s (IC50 48.63 μM) showed better activity than the standard doxorubicin (IC50 69.33 μM) in A549 cell line alone. Rat intestinal α-glucosidase inhibitory activity of the synthesized derivatives showed 4m (IC50 67.77 μM), 4p (IC50 74.94 in μM) and 4s (IC50 102.10 μM) as most active compared to others. The in silico docking of synthesized derivatives 4a-4t with DNA topoisomerase IIα revealed the LibDock score in the range of 71.2623-118.29 whereas, compounds 4h, 4m, 4p and 4s with docking target α-glucosidase were in the range of 100.372-107.784. PMID:25743216

  11. Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Natural products are rich source of gene modulators for prevention and treatment of cancer. In recent days, nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) has been focused as a new target of diverse cancers like colorectal, pancreatic, prostate, and breast. A variety of natural...

  12. Synthesis and structure-activity relationships of novel furazan-3,4-diamide analogs as potent anti-cancer agents.

    PubMed

    Li, Wen-Shan; More, Shivaji V; Wang, Chie-Hong; Jen, Ya Ching; Yao, Ching-Fa; Wang, Tein-Fu; Hung, Chin-Chun; Jao, Shu-Chuan

    2010-02-01

    This study describes the synthesis and structure-activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect. PMID:20022505

  13. Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity.

    PubMed Central

    Batrakova, E. V.; Dorodnych, T. Y.; Klinskii, E. Y.; Kliushnenkova, E. N.; Shemchukova, O. B.; Goncharova, O. N.; Arjakov, S. A.; Alakhov, V. Y.; Kabanov, A. V.

    1996-01-01

    The chemosensitising effects of poly(ethylene oxide)-poly(propylene oxide)-poly-(ethylene oxide) (PEO-PPO-PEO) block copolymers (Pluronic) in multidrug-resistant cancer cells has been described recently (Alakhov VY, Moskaleva EY, Batrakova EV, Kabanov AV 1996, Biocon. Chem., 7, 209). This paper presents initial studies on in vivo evaluation of Pluronic copolymers in the treatment of cancer. The anti-tumour activity of epirubicin (EPI) and doxorubicin (DOX), solubilised in micelles of Pluronic L61, P85 and F108, was investigated using murine leukaemia P388 and daunorubicin-sensitive Sp2/0 and -resistant Sp2/0(DNR) myeloma cells grown subcutaneously (s.c.). The study revealed that the lifespan of the animals and inhibition of tumour growth were considerably increased in mice treated with drug/copolymer compositions compared with animals treated with the free drugs. The anti-tumour activity of the drug/copolymer compositions depends on the concentration of the copolymer and its hydrophobicity, as determined by the ratio of the lengths of hydrophilic PEO and hydrophobic PPO segments. The data suggest that higher activity is associated with more hydrophobic copolymers. In particular, a significant increase in lifespan (T/C> 150%) and tumour growth inhibition (> 90%) was observed in animals with Sp2/0 tumours with EPI/P85 and DOX/L61 compositions. The effective doses of these compositions caused inhibition of Sp2/0 tumour growth and complete disappearance of tumour in 33-50% of animals. Future studies will focus on the evaluation of the activity of Pluronic-based compositions against human drug-resistant tumours. PMID:8932333

  14. Synthesis and anti-cancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs.

    PubMed

    Wang, Hao-Meng; Zhang, Li; Liu, Jiang; Yang, Zhao-Liang; Zhao, Hong-Ye; Yang, Yao; Shen, Di; Lu, Kui; Fan, Zhen-Chuan; Yao, Qing-Wei; Zhang, Yong-Min; Teng, Yu-Ou; Peng, Yu

    2015-03-01

    Four natural chalcones bearing prenyl or geranyl groups, i.e., bavachalcone (1a), xanthoangelol (1b), isobavachalcone (1c), and isoxanthoangelol (1d) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. The first total synthesis of isoxanthoangelol (1d) was achieved in 36% overall yield. A series of diprenylated and digeranylated chalcone analogs were also synthesized by alkylation, regio-selective iodination, aldol condensation, Suzuki coupling and [1,3]-sigmatropic rearrangement. The structures of the 11 new derivatives were confirmed by (1)H NMR, (13)C NMR and HRMS. The anticancer activity of these new chalcone derivatives against human tumor cell line K562 were evaluated by MTT assay in vitro. SAR studies suggested that the 5'-prenylation/geranylation of the chalcones significantly enhance their cytotoxic activity. Among them, Bavachalcone (1a) displayed the most potent cytotoxic activity against K562 with IC50 value of 2.7 μM. The morphology changes and annexin-V/PI staining studies suggested that those chalcone derivatives inhibited the proliferation of K562 cells by inducing apoptosis. PMID:25590864

  15. Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-gingerol in cervical cancer cells.

    PubMed

    Rastogi, Namrata; Duggal, Shivali; Singh, Shailendra Kumar; Porwal, Konica; Srivastava, Vikas Kumar; Maurya, Rakesh; Bhatt, M L B; Mishra, Durga Prasad

    2015-12-22

    Human papilloma virus (HPV) expressing E6 and E7 oncoproteins, is known to inactivate the tumor suppressor p53 through proteasomal degradation in cervical cancers. Therefore, use of small molecules for inhibition of proteasome function and induction of p53 reactivation is a promising strategy for induction of apoptosis in cervical cancer cells. The polyphenolic alkanone, 6-Gingerol (6G), present in the pungent extracts of ginger (Zingiber officinale Roscoe) has shown potent anti-tumorigenic and pro-apoptotic activities against a variety of cancers. In this study we explored the molecular mechanism of action of 6G in human cervical cancer cells in vitro and in vivo. 6G potently inhibited proliferation of the HPV positive cervical cancer cells. 6G was found to: (i) inhibit the chymotrypsin activity of proteasomes, (ii) induce reactivation of p53, (iii) increase levels of p21, (iv) induce DNA damage and G2/M cell cycle arrest, (v) alter expression levels of p53-associated apoptotic markers like, cleaved caspase-3 and PARP, and (vi) potentiate the cytotoxicity of cisplatin. 6G treatment induced significant reduction of tumor volume, tumor weight, proteasome inhibition and p53 accumulation in HeLa xenograft tumor cells in vivo. The 6G treatment was devoid of toxic effects as it did not affect body weights, hematological and osteogenic parameters. Taken together, our data underscores the therapeutic and chemosensitizing effects of 6G in the management and treatment of cervical cancer. PMID:26621832

  16. ATF3 Mediates Anti-Cancer Activity of Trans-10, cis-12-Conjugated Linoleic Acid in Human Colon Cancer Cells

    PubMed Central

    Kim, Kui-Jin; Lee, Jihye; Park, Yeonhwa; Lee, Seong-Ho

    2015-01-01

    Conjugated linoleic acids (CLA) are a family of isomers of linoleic acid. CLA increases growth arrest and apoptosis of human colorectal cancer cells through an isomer-specific manner. ATF3 belongs to the ATF/CREB family of transcription factors and is associated with apoptosis in colorectal cancer. The present study was performed to investigate the molecular mechanism by which t10, c12-CLA stimulates ATF3 expression and apoptosis in human colorectal cancer cells. t10, c12-CLA increased an apoptosis in human colorectal cancer cells in dose dependent manner. t10, c12-CLA induced ATF3 mRNA and luciferase activity of ATF3 promoter in a dose-dependent manner. The responsible region for ATF3 transcriptional activation by t10, c12-CLA is located between −147 and −1850 of ATF3 promoter. mRNA stability of ATF3 was not affected by t10, c12-CLA treatment. t10, c12-CLA increases GSK3β expression and suppresses IGF-1-stimulated phosphorylation of Akt. The knockdown of ATF3 suppressed expression of GSK3β and NAG-1 and PARP cleavage. The results suggest that t10, c12-CLA induces apoptosis through ATF3-mediated pathway in human colorectal cancer cells. PMID:25767681

  17. Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-Gingerol in cervical cancer cells

    PubMed Central

    Rastogi, Namrata; Duggal, Shivali; Singh, Shailendra Kumar; Porwal, Konica; Srivastava, Vikas Kumar; Maurya, Rakesh; Bhatt, Madan L.B.; Mishra, Durga Prasad

    2015-01-01

    Human papilloma virus (HPV) expressing E6 and E7 oncoproteins, is known to inactivate the tumor suppressor p53 through proteasomal degradation in cervical cancers. Therefore, use of small molecules for inhibition of proteasome function and induction of p53 reactivation is a promising strategy for induction of apoptosis in cervical cancer cells. The polyphenolic alkanone, 6-Gingerol (6G), present in the pungent extracts of ginger (Zingiber officinale Roscoe) has shown potent anti-tumorigenic and pro-apoptotic activities against a variety of cancers. In this study we explored the molecular mechanism of action of 6G in human cervical cancer cells in vitro and in vivo. 6G potently inhibited proliferation of the HPV positive cervical cancer cells. 6G was found to: (i) inhibit the chymotrypsin activity of proteasomes, (ii) induce reactivation of p53, (iii) increase levels of p21, (iv) induce DNA damage and G2/M cell cycle arrest, (v) alter expression levels of p53-associated apoptotic markers like, cleaved caspase-3 and PARP, and (vi) potentiate the cytotoxicity of cisplatin. 6G treatment induced significant reduction of tumor volume, tumor weight, proteasome inhibition and p53 accumulation in HeLa xenograft tumor cells in vivo. The 6G treatment was devoid of toxic effects as it did not affect body weights, hematological and osteogenic parameters. Taken together, our data underscores the therapeutic and chemosensitizing effects of 6G in the management and treatment of cervical cancer. PMID:26621832

  18. Synthesis, crystal structure, spectroscopic properties and potential anti-cancerous activities of four unsaturated bis-norcantharimides

    NASA Astrophysics Data System (ADS)

    Cheng, Shuang-Shuang; Shi, Yan; Ma, Xiao-Na; Xing, Dian-Xiang; Liu, Lian-Dong; Liu, Yun; Zhao, Yun-Xue; Sui, Qi-Cheng; Tan, Xue-Jie

    2016-07-01

    Four unsaturated norcantharimide (UNCI) dimers were synthesized and characterized by elemental analysis, ESI-QTOF-MS, FT/IR, UV-Vis, 1H and 13C NMR as well as single crystal X-ray diffraction. In addition, theoretical studies have been investigated to compare with the experimental findings. Introduction of various lengths of single bond link chains provides high conformational flexibility and thus unusual molecular and crystal structures for dimers. Two of the four dimers twist into helicate, but crystallize into centrosymmetric lattice; one adopts approximately centrosymmetric conformer, but packs into non-centrosymmetric polar space group (P21). Moreover, in vitro cytotoxic activities of four UNCI dimers and their corresponding saturated NCI dimers were evaluated. All four UNCI dimers are inactive and one NCI dimer shows modest cytotoxicity. These findings were compared with the relevant results in literature. It is found that the antitumor properties of UNCI/NCI dimers depend mainly on the length of link chains (the longer chain, the higher therapeutic efficacy) and have relationship with the double bond, which requires more experimental support.

  19. Functional nanoemulsion-hybrid lipid nanocarriers enhance the bioavailability and anti-cancer activity of lipophilic diferuloylmethane

    NASA Astrophysics Data System (ADS)

    Sun, Lili; Wan, Kun; Hu, Xueyuan; Zhang, Yonghong; Yan, Zijun; Feng, Jiao; Zhang, Jingqing

    2016-02-01

    The purpose of this study was to assess the enhanced physicochemical characteristics, in vitro release behavior, anti-lung cancer activity, gastrointestinal absorption, in vivo bioavailability and bioequivalence of functional nanoemulsion-hybrid lipid nanocarriers containing diferuloylmethane (DNHLNs). The DNHLNs were first fabricated by loading water-in-oil nanoemulsions into hybrid lipid nanosystems using nanoemulsion-thin film-sonication dispersion technologies. The in situ absorption and in vitro and in vivo kinetic features of DNHLNs were measured using an in situ unidirectional perfusion method, a dynamic dialysis method and a plasma concentration-time profile-based method, respectively. The cytotoxic effects of DNHLNs in lung adenocarcinoma A549 cells were examined using MTT colorimetric analysis. The absorptive constants and permeabilities of DNHLNs in four gastrointestinal sections increased by 1.43-3.23 times and by 3.10-7.76 times that of diferuloylmethane (DIF), respectively. The relative bioavailability of DNHLNs to free DIF was 855.02%. DNHLNs inhibited cancer cell growth in a time- and dose-dependent manner. DNHLNs markedly improved the absorption and bioavailability of DIF after oral administration. DNHLNs had stronger inhibitory effects on the viability of A549 cells than that of free DIF. DNHLNs might be potentially promising nanocarriers for DIF delivery via the oral route to address unmet clinical needs.

  20. Discovery of new low-molecular-weight p53-Mdmx disruptors and their anti-cancer activities.

    PubMed

    Uesato, Shinichi; Matsuura, Yoshihiro; Matsue, Saki; Sumiyoshi, Takaaki; Hirata, Yoshiyuki; Takemoto, Suzuho; Kawaratani, Yasuyuki; Yamai, Yusuke; Ishida, Kyoji; Sasaki, Tsutomu; Enari, Masato

    2016-04-15

    Although several p53-Mdm2-binding disruptors have been identified to date, few studies have been published on p53-Mdmx-interaction inhibitors. In the present study, we demonstrated that o-aminothiophenol derivatives with molecular weights of 200-300 selectively inhibited the p53-Mdmx interaction. S-2-Isobutyramidophenyl 2-methylpropanethioate (K-178) (1c) activated p53, up-regulated the expression of its downstream genes such as p21 and Mdm2, and preferentially inhibited the growth of cancer cells with wild-type p53 over those with mutant p53. Furthermore, we found that the S-isobutyryl-deprotected forms 1b and 3b of 1c and S-2-benzamidophenyl 2-methylpropanethioate (K-181) (3c) preferentially inhibited the p53-Mdmx interaction over the p53-Mdm2 interaction, respectively, by using a Flag-p53 and glutathione S-transferase (GST)-fused protein complex (Mdm2, Mdmx, DAPK1, or PPID). In addition, the interaction of p53 with Mdmx was lost by replacing a sulfur atom with an oxygen atom in 1b and 1c. These results suggest that sulfides such as 1b, 3b, 4b, and 5b interfere with the binding of p53-Mdmx, resulting in the dissociation of the two proteins. Furthermore, the results of oral administration experiments using xenografts in nude mice indicated that 1c reduced the volume of tumor masses to 49.0% and 36.6% that of the control at 100mg/kg and 150mg/kg, respectively, in 40days. PMID:27010502

  1. A journey under the sea: the quest for marine anti-cancer alkaloids.

    PubMed

    Tohme, Rita; Darwiche, Nadine; Gali-Muhtasib, Hala

    2011-01-01

    The alarming increase in the global cancer death toll has fueled the quest for new effective anti-tumor drugs thorough biological screening of both terrestrial and marine organisms. Several plant-derived alkaloids are leading drugs in the treatment of different types of cancer and many are now being tested in various phases of clinical trials. Recently, marine-derived alkaloids, isolated from aquatic fungi, cyanobacteria, sponges, algae, and tunicates, have been found to also exhibit various anti-cancer activities including anti-angiogenic, anti-proliferative, inhibition of topoisomerase activities and tubulin polymerization, and induction of apoptosis and cytotoxicity. Two tunicate-derived alkaloids, aplidin and trabectedin, offer promising drug profiles, and are currently in phase II clinical trials against several solid and hematologic tumors. This review sheds light on the rich array of anti-cancer alkaloids in the marine ecosystem and introduces the most investigated compounds and their mechanisms of action. PMID:22113577

  2. [Review about mechanisms of anti-cancer of Solanum nigrum].

    PubMed

    An, Lei; Tang, Jin-tian; Liu, Xin-min; Gao, Nan-nan

    2006-08-01

    This paper gave a brief introduction of the effect of Solanum nigrum on anti-cancer. The experimental results showed that the total alkaloid isolated from S. nigrum interfered structure and function of tumor cell membrane, disturbed the synthesis of DNA and RNA, changed the cell cycle distribution, so that total alkaloids could play in inhibabition to tumor cells, while the glycoprotein (150 x 10(3)) isolated from S. nigrum might have shown anti-cancer abilities by blocking the anti-apoptotic pathway of NF-kappaB, activating caspase cascades reaction and increasing the production of nitric oxide. PMID:17048560

  3. Steroidal cardiac Na+/K+ ATPase inhibitors exhibit strong anti-cancer potential in vitro and in prostate and lung cancer xenografts in vivo.

    PubMed

    Dimas, Konstantinos; Papadopoulou, Natalia; Baskakis, Constantinos; Prousis, Kyriakos C; Tsakos, Michail; Alkahtani, Saad; Honisch, Sabina; Lang, Florian; Calogeropoulou, Theodora; Alevizopoulos, Konstantinos; Stournaras, Christos

    2014-06-01

    Sodium potassium pump (Na(+)/K(+)ATPase) is a validated pharmacological target for the treatment of congestive heart failure. Recent data with inotropic drugs such as digoxin & digitoxin (digitalis) suggest a potent anti-cancer action of these drugs and promote Na(+)/K(+)ATPase as a novel therapeutic target in cancer. However, digitalis have narrow therapeutic indices, are pro-arrhythmic and are considered non-developable drugs by the pharmaceutical industry. On the contrary, a series of recently-developed steroidal inhibitors showed better pharmacological properties and clinical activities in cardiac patients. Their anti-cancer activity however, remained unknown. In this study, we synthesized seventeen steroidal cardiac inhibitors and explored for the first time their anti-cancer activity in vitro and in vivo. Our results indicate potent anti-cancer actions of steroidal cardiac inhibitors in multiple cell lines from different tumor panels including multi-drug resistant cells. Furthermore, the most potent compound identified in our studies, the 3-[(R)-3- pyrrolidinyl]oxime derivative 3, showed outstanding potencies (as measured by GI50, TGI and LC50 values) in most cells in vitro, was selectively cytotoxic in cancer versus normal cells showing a therapeutic index of 31.7 and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. Collectively, our results suggest that previously described cardiac Na(+)/K(+)ATPase inhibitors have potent anti-cancer actions and may thus constitute strong re-purposing candidates for further cancer drug development. PMID:24066843

  4. The Anti-Cancer Activities of Vernonia amygdalina Extract in Human Breast Cancer Cell Lines Are Mediated through Caspase-Dependent and p53-Independent Pathways

    PubMed Central

    Wong, Fang Cheng; Woo, Chern Chiuh; Hsu, Annie; Tan, Benny Kwong Huat

    2013-01-01

    Breast cancer is currently the leading cause of cancer-related deaths among women globally. Notably, medicinal plant extracts may be a potential source for treatments of breast cancer. Vernonia amygdalina (VA) is a woody shrub reported to have not only diverse therapeutic effects but also anti-cancer properties. However, current research about the mechanisms of the anti-cancer potential of VA has been limited. This study aimed to investigate the mechanisms of action of VA that underlie its anti-cancer effects in human breast cancer cell lines (MCF-7 and MDA-MB-231 cells). Results from MTT assay revealed that VA inhibits the proliferation of MCF-7 and MDA-MB-231, in a time- and dose-dependent manner. The underlying mechanism of this growth inhibition involved the stimulation of cell-type specific G1/S phase cell cycle arrest in only MCF-7 cells, and not in MDA-MB-231 cells. While the growth arrest was associated with increased levels of p53 and p21, and a concomitant decrease in the levels of cyclin D1 and cyclin E, it was shown that VA causes cell cycle arrest through a p53-independent pathway as tested by the wild type p53 inhibitor, pifithrin-α. Furthermore, this study revealed that VA induces apoptosis in the two cell lines, as indicated by the increase in Annexin V-positive cells and sub-G1 population, and that this VA-induced apoptosis occurred through both extrinsic and intrinsic apoptotic pathways. The apoptosis in MCF-7 cells was also likely to be caspase-dependent and not p53 transcriptional-dependent. Given that approximately 70% of diagnosed breast cancers express ER-α, a crucial finding was that VA inhibits the expression of ER-α and its downstream player, Akt, highlighting the potential clinical significance of VA. Moreover, VA exhibits synergism when combined with doxorubicin, suggesting that it can complement current chemotherapy. Overall, this study demonstrates the potential applications of VA as an anti-cancer drug for breast cancer treatment

  5. Preparation and evaluation of tributyrin emulsion as a potent anti-cancer agent against melanoma.

    PubMed

    Kang, Sung Nam; Lee, Eunmyong; Lee, Mi-Kyung; Lim, Soo-Jeong

    2011-02-01

    Histone deacetylase inhibitors such as butyrate are known to exhibit anti-cancer activities in a wide range of cancer including melanoma. In spite of these potencies, butyrate is not practically used for cancer treatment due to its rapid metabolism and very short plasma half-life. Tributyrin, a triglyceride analog of butyrate, can act as a pro-drug of butyrate after being cleaved by intracellular enzymes. The present study sought to investigate a possibility to develop tributyrin emulsion as a potent anti-cancer agent against melanoma. Mixture of Tween80 and 1, 2-dimyristoyl-sn-glycero-3-phosphocholine as a surfactant to disperse tributyrin produced homogeneous emulsions with nanometer sizes, even without a harsh homogenization procedure. Tributyrin emulsion was more potent than butyrate in inhibiting the growth of B16-F10 melanoma cells. Accumulation of cells at sub G(0)/G(1) phase and the DNA fragmentation induced by tributyrin emulsion treatment revealed that tributyrin emulsion inhibited the growth of B16-F10 cells by inducing apoptosis. Treatment with tributyrin emulsion suppressed the colony formation of melanoma cells in a dose-dependent manner. Furthermore, after intraperitoneal administration into mice, tributyrin emulsion inhibited the formation of tumor colonies in the lung following intravenous injection of melanoma cells. Taken together, our data suggests that tributyrin emulsion may be developed as a potent anti-cancer agent against melanoma. PMID:20946006

  6. Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition.

    PubMed

    Sweeney, Martin; Coyle, Robert; Kavanagh, Paul; Berezin, Andrey A; Lo Re, Daniele; Zissimou, Georgia A; Koutentis, Panayiotis A; Carty, Michael P; Aldabbagh, Fawaz

    2016-08-15

    The thioredoxin (Trx)-thioredoxin reductase (TrxR) system plays a key role in maintaining the cellular redox balance with Trx being over-expressed in a number of cancers. Inhibition of TrxR is an important strategy for anti-cancer drug discovery. The natural product pleurotin is a well-known irreversible inhibitor of TrxR. The cytotoxicity data for benzo[1,2,4]triazin-7-ones showed very strong correlation (Pearson correlation coefficients ∼0.8) to pleurotin using National Cancer Institute COMPARE analysis. A new 3-CF3 substituted benzo[1,2,4]triazin-7-one gave submicromolar inhibition of TrxR, although the parent compound 1,3-diphenylbenzo[1,2,4]triazin-7-one was more cytotoxic against cancer cell lines. Benzo[1,2,4]triazin-7-ones exhibited different types of reversible inhibition of TrxR, and cyclic voltammetry showed characteristic quasi-reversible redox processes. Cell viability studies indicated strong dependence of cytotoxicity on substitution at the 6-position of the 1,3-diphenylbenzo[1,2,4]triazin-7-one ring. PMID:27290691

  7. Synthesis, characterization and biological evaluation of anti-cancer indolizine derivatives via inhibiting β-catenin activity and activating p53.

    PubMed

    Moon, Seong-Hee; Jung, Youngeun; Kim, Seong Hwan; Kim, Ikyon

    2016-01-01

    Diversity-oriented construction of new indolizine scaffolds was accomplished by utilizing domino Knoevenagel condensation/intramolecular aldol cyclization. Biological evaluation revealed anticancer activity of these compounds through inhibition of β-catenin and activation of p53. PMID:26608553

  8. Recent advances in the field of anti-cancer immunotherapy

    PubMed Central

    Neves, Henrique; Kwok, Hang Fai

    2015-01-01

    Background The main goal of anti-cancer therapy is to specifically inhibit the malignant activity of cancer cells, while leaving healthy cells unaffected. As such, for every proposed therapy, it is important to keep in mind the therapeutic index — the ratio of the toxic dose over the therapeutic dose. The use of immunotherapy has allowed a means to both specifically block protein–protein interaction and deliver cytotoxic events to a tumor-specific antigen. Review scope It is the objective of this review to give an overview on current immunotherapy treatment for cancers using monoclonal antibodies. We demonstrate three exciting targets for immunotherapy, TNF-α Converting Enzyme (TACE), Cathepsin S and Urokinase Plasmogen Activator and go over the advances made with one of the most used monoclonal antibodies in cancer therapy, Rituximab; as well as Herceptin, which is used for breast cancer therapy. Furthermore, we touch on other venues of immunotherapy, such as adaptive cell transfer, the use of nucleic acids and the use of dendritic cells. Finally, we summarize some ongoing studies that spell tentative advancements for anti-cancer immunotherapy. General significance Immunotherapy is at the forefront of anti-cancer therapies, allying both a high degree of specificity to general high effectiveness and fewer side-effects. PMID:26673349

  9. Theobroma cacao: Review of the Extraction, Isolation, and Bioassay of Its Potential Anti-cancer Compounds.

    PubMed

    Baharum, Zainal; Akim, Abdah Md; Hin, Taufiq Yap Yun; Hamid, Roslida Abdul; Kasran, Rosmin

    2016-02-01

    Plants have been a good source of therapeutic agents for thousands of years; an impressive number of modern drugs used for treating human diseases are derived from natural sources. The Theobroma cacao tree, or cocoa, has recently garnered increasing attention and become the subject of research due to its antioxidant properties, which are related to potential anti-cancer effects. In the past few years, identifying and developing active compounds or extracts from the cocoa bean that might exert anti-cancer effects have become an important area of health- and biomedicine-related research. This review provides an updated overview of T. cacao in terms of its potential anti-cancer compounds and their extraction, in vitro bioassay, purification, and identification. This article also discusses the advantages and disadvantages of the techniques described and reviews the processes for future perspectives of analytical methods from the viewpoint of anti-cancer compound discovery. PMID:27019680

  10. Theobroma cacao: Review of the Extraction, Isolation, and Bioassay of Its Potential Anti-cancer Compounds

    PubMed Central

    Baharum, Zainal; Akim, Abdah Md; Hin, Taufiq Yap Yun; Hamid, Roslida Abdul; Kasran, Rosmin

    2016-01-01

    Plants have been a good source of therapeutic agents for thousands of years; an impressive number of modern drugs used for treating human diseases are derived from natural sources. The Theobroma cacao tree, or cocoa, has recently garnered increasing attention and become the subject of research due to its antioxidant properties, which are related to potential anti-cancer effects. In the past few years, identifying and developing active compounds or extracts from the cocoa bean that might exert anti-cancer effects have become an important area of health- and biomedicine-related research. This review provides an updated overview of T. cacao in terms of its potential anti-cancer compounds and their extraction, in vitro bioassay, purification, and identification. This article also discusses the advantages and disadvantages of the techniques described and reviews the processes for future perspectives of analytical methods from the viewpoint of anti-cancer compound discovery. PMID:27019680

  11. Potential anti-cancer drugs commonly used for other indications.

    PubMed

    Hanusova, Veronika; Skalova, Lenka; Kralova, Vera; Matouskova, Petra

    2015-01-01

    An increasing resistance of mammalian tumor cells to chemotherapy along with the severe side effects of commonly used cytostatics has raised the urgency in the search for new anti-cancer agents. Several drugs originally approved for indications other than cancer treatment have recently been found to have a cytostatic effect on cancer cells. These drugs could be expediently repurposed as anti-cancer agents, since they have already been tested for toxicity in humans and animals. The groups of newly recognized potential cytostatics discussed in this review include benzimidazole anthelmintics (albendazole, mebendazole, flubendazole), anti-hypertensive drugs (doxazosin, propranolol), psychopharmaceuticals (chlorpromazine, clomipramine) and antidiabetic drugs (metformin, pioglitazone). All these drugs have a definite potential to be used especially in combinations with other cytostatics; the chemotherapy targeting of multiple sites now represents a promising approach in cancer treatment. The present review summarizes recent information about the anti-cancer effects of selected drugs commonly used for other medical indications. Our aim is not to collect all the reported results, but to present an overview of various possibilities. Advantages, disadvantages and further perspectives regarding individual drugs are discussed and evaluated. PMID:25544649

  12. The Chromone Alkaloid, Rohitukine, Affords Anti-Cancer Activity via Modulating Apoptosis Pathways in A549 Cell Line and Yeast Mitogen Activated Protein Kinase (MAPK) Pathway

    PubMed Central

    Safia; Kamil, Mohd; Jadiya, Pooja; Sheikh, Saba; Haque, Ejazul; Nazir, Aamir; Lakshmi, Vijai; Mir, Snober S.

    2015-01-01

    The field of cancer research and treatment has made significant progress, yet we are far from having completely safe, efficient and specific therapies that target cancer cells and spare the healthy tissues. Natural compounds may reduce the problems related to cancer treatment. Currently, many plant products are being used to treat cancer. In this study, Rohitukine, a natural occurring chromone alkaloid extracted from Dysoxylum binectariferum, was investigated for cytotoxic properties against budding yeast as well as against lung cancer (A549) cells. We endeavored to specifically study Rohitukine in S. cerevisiae in the context of MAPK pathways as yeast probably represents the experimental model where the organization and regulation of MAPK pathways are best understood. MAPK are evolutionarily conserved protein kinases that transfer extracellular signals to the machinery controlling essential cellular processes like growth, migration, differentiation, cell division and apoptosis. We aimed at carrying out hypothesis driven studies towards targeting the important network of cellular communication, a critical process that gets awry in cancer. Employing mutant strains of genetic model system Saccharomyces cerevisiae. S. cerevisiae encodes five MAPKs involved in control of distinct cellular responses such as growth, differentiation, migration and apoptosis. Our study involves gene knockouts of Slt2 and Hog1 which are functional homologs of human ERK5 and mammalian p38 MAPK, respectively. We performed cytotoxicity assay to evaluate the effect of Rohitukine on cell viability and also determined the effects of drug on generation of reactive oxygen species, induction of apoptosis and expression of Slt2 and Hog1 gene at mRNA level in the presence of drug. The results of this study show a differential effect in the activity of drug between the WT, Slt2 and Hog1 gene deletion strain indicating involvement of MAPK pathway. Further, we investigated Rohitukine induced cytotoxic

  13. Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy.

    PubMed

    Piktel, Ewelina; Niemirowicz, Katarzyna; Wątek, Marzena; Wollny, Tomasz; Deptuła, Piotr; Bucki, Robert

    2016-01-01

    The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti-cancer agents. However, the physicochemical and biological diversity of nanomaterials and a broad spectrum of unique features influencing their biological action requires continuous research to assess their activity. Among numerous nanosystems designed to eradicate cancer cells, only a limited number of them entered the clinical trials. It is anticipated that progress in development of nanotechnology-based anti-cancer materials will provide modern, individualized anti-cancer therapies assuring decrease in morbidity and mortality from cancer diseases. In this review we discussed the implication of nanomaterials in design of new drugs for effective antineoplastic therapy and describe a variety of mechanisms and challenges for selective tumor targeting. We emphasized the recent advantages in the field of nanotechnology-based strategies to fight cancer and discussed their part in effective anti-cancer therapy and successful drug delivery. PMID:27229857

  14. Nanopharmaceutical Approach for Enhanced Anti-cancer Activity of Betulinic Acid in Lung-cancer Treatment via Activation of PARP: Interaction with DNA as a Target

    PubMed Central

    Das, Jayeeta; Samadder, Asmita; Das, Sreemanti; Paul, Avijit; Khuda-Bukhsh, Anisur Rahman

    2016-01-01

    Objectives: This study examined the relative efficacies of a derivative of betulinic acid (dBA) and its poly (lactide- co-glycolide) (PLGA) nano-encapsulated form in A549 lung cancer cells in vivo and in co-mutagen [sodium arsenite (SA) + benzo]undefined[a]pyrene (BaP)]-induced lung cancer in mice in vivo. Methods: dBA was loaded with PLGA nanoparticles by using the standard solvent displacement method. The sizes and morphologies of nano-dBA (NdBA) were determined by using transmission electron microscopy (TEM), and their intracellular localization was verified by using confocal microscopy. The binding and interaction of NdBA with calf thymus deoxyribonucleic acid (CT-DNA) as a target were analyzed by using conventional circular dichroism (CD) and melting temperature (Tm) profile data. Apoptotic signalling cascades in vitro and in vivo were studied by using an enzyme-linked immunosorbent assay (ELISA); the ability of NdBA to cross the blood-brain barrier (BBB) was also examined. The stage of cell cycle arrest was confirmed by using a fluorescence-activated cell-sorting (FACS) data analysis. Results: The average size of the nanoparticles was ~ 110 nm. Confocal microscopy images confirmed the presence of NdBA in the cellular cytoplasm. The bio-physical properties of dBA and NdBA ascertained from the CD and the Tm profiles revealed that NdBA had greater interaction with the target DNA than dBA did. Both dBA and NdBA arrested cell proliferation at G0/G1, NdBA showing the greater effect. NdBA also induced a greater degree of cytotoxicity in A549 cells, but it had an insignificant cytotoxic effect in normal L6 cells. The results of flow cytometric, cytogenetial and histopathological studies in mice revealed that NdBA caused less nuclear condensation and DNA damage than dBA did. TEM images showed the presence of NdBA in brain samples of NdBA fed mice, indicating its ability to cross the BBB. Conclusion: Thus, compared to dBA, NdBA appears to have greater chemoprotective

  15. Influence of Ecological Factors on the Production of Active Substances in the Anti-Cancer Plant Sinopodophyllum hexandrum (Royle) T.S. Ying

    PubMed Central

    Liu, Wei; Liu, Jianjun; Yin, Dongxue; Zhao, Xiaowen

    2015-01-01

    The quality of traditional Chinese herbal medicine, which plays a very important role in the health system of China, is determined by the active substances produced by the plants. The type, content, and proportion of these substances may vary depending on ecological factors in areas where the plants are grown. Sinopodophyllum hexandrum (Royle) T.S. Ying, an endangered plant species with great medical value, was investigated in eight production locations representative of its natural geographical distribution range in China. The correlation between the contents of the active ingredients extracted from the roots and rhizomes of S. hexandrum and the ecological factors were evaluated step-by-step using a series of computational biology methodologies. The results showed that ecological factors had significant effects on the contents but not on the types of the active ingredients in eight production locations. The primary ecological factors influencing the active substances included the annual average precipitation, July mean temperature, frost-free period, sunshine duration, soil pH, soil organic matter, and rapidly available potassium in the soil. The annual average precipitation was the most important determinant factor and was significantly and negatively correlated with the active ingredient contents (P < 0.001). In contrast, organic matter was the most important limiting factor and was significantly and positively correlated with the active substances. These ecological factors caused 98.13% of the total geographical variation of the active ingredient contents. The climate factors contributed more to the active ingredient contents than did the soil factors. It was concluded that from the view of the contents of the secondary metabolites and ecological factors of each growing location, in Jingyuan, Ningxia Province, and Yongdeng, Gansu Province, conditions were favorable to the production of podophyllotoxin and lignans, whereas in Shangri-La, Yunnan Province, and

  16. Influence of ecological factors on the production of active substances in the anti-cancer plant Sinopodophyllum hexandrum (Royle) T.S. Ying.

    PubMed

    Liu, Wei; Liu, Jianjun; Yin, Dongxue; Zhao, Xiaowen

    2015-01-01

    The quality of traditional Chinese herbal medicine, which plays a very important role in the health system of China, is determined by the active substances produced by the plants. The type, content, and proportion of these substances may vary depending on ecological factors in areas where the plants are grown. Sinopodophyllum hexandrum (Royle) T.S. Ying, an endangered plant species with great medical value, was investigated in eight production locations representative of its natural geographical distribution range in China. The correlation between the contents of the active ingredients extracted from the roots and rhizomes of S. hexandrum and the ecological factors were evaluated step-by-step using a series of computational biology methodologies. The results showed that ecological factors had significant effects on the contents but not on the types of the active ingredients in eight production locations. The primary ecological factors influencing the active substances included the annual average precipitation, July mean temperature, frost-free period, sunshine duration, soil pH, soil organic matter, and rapidly available potassium in the soil. The annual average precipitation was the most important determinant factor and was significantly and negatively correlated with the active ingredient contents (P < 0.001). In contrast, organic matter was the most important limiting factor and was significantly and positively correlated with the active substances. These ecological factors caused 98.13% of the total geographical variation of the active ingredient contents. The climate factors contributed more to the active ingredient contents than did the soil factors. It was concluded that from the view of the contents of the secondary metabolites and ecological factors of each growing location, in Jingyuan, Ningxia Province, and Yongdeng, Gansu Province, conditions were favorable to the production of podophyllotoxin and lignans, whereas in Shangri-La, Yunnan Province, and

  17. Synthesis, structure elucidation, DNA-PK and PI3K and anti-cancer activity of 8- and 6-aryl-substituted-1-3-benzoxazines.

    PubMed

    Morrison, Rick; Al-Rawi, Jasim M A; Jennings, Ian G; Thompson, Philip E; Angove, Michael J

    2016-03-01

    The synthesis of 6-aryl, 8- aryl, and 8-aryl-6-chloro-2-morpholino-1,3-benzoxazines with potent activity against PI3K and DNA-PK is described. Synthesis of thirty one analogues was facilitated by an improved synthesis of 3-bromo-2-hydroxybenzoic acid 13 by de-sulphonation of 3-bromo-2-hydroxy-5-sulfobenzoic acid 12 en route to 2-methylthio-substituted-benzoxazine intermediates 17-19. From this series, compound 20k (LTURM34) (dibenzo[b,d]thiophen-4-yl) (IC50 = 0.034 μM) was identified as a specific DNA-PK inhibitor, 170 fold more selective for DNA-PK activity compared to PI3K activity. Other compounds of the series show markedly altered selectivity for various PI3K isoforms including compound 20i (8-(naphthalen-1-yl) a potent and quite selective PI3Kδ inhibitor (IC50 = 0.64 μM). Finally, nine compounds were evaluated and showed antiproliferative activity against an NCI panel of cancer cell lines. Compound 20i (8-(naphthalen-1-yl) showed strong anti-proliferative activity against A498 renal cancer cells that warrants further investigation. PMID:26854431

  18. Anti-Cancer Effects of Green Tea by Either Anti- or Pro- Oxidative Mechanisms.

    PubMed

    Hayakawa, Sumio; Saito, Kieko; Miyoshi, Noriyuki; Ohishi, Tomokazu; Oishi, Yumiko; Miyoshi, Mamoru; Nakamura, Yoriyuki

    2016-01-01

    Tea derived from the leaves and buds of Camellia sinensis (Theaceae) is consumed worldwide. Green tea contains various components with specific health-promoting effects, and is believed to exert protective effects against diseases including cancer, diabetes and hepatitis, as well as obesity. Of the various tea components, the polyphenol catechins have been the subject of extensive investigation and among the catechins, (-)-epigallocatechin gallate has the strongest bioactivity in most cases. Our research group has postulated that hepatocyte nuclear factor-4α, sterol regulatory element-binding proteins, and tumor necrosis factor-α are targets of green tea constituents including (-)-epigallocatechin gallate for their anti-diabetes, anti-obesity, and anti-hepatitis effects, respectively. Published papers were reviewed to determine whether the observed changes in these factors can be correlated with anti-cancer effects of green tea. Two major action mechanisms of (-)-epigallocatechin gallate have been proposed; one associated with its anti-oxidative properties and the other with its pro-oxidative activity. When reactive oxygen species are assumed to be involved, our findings that (-)-epigallocatechin gallate down- regulated hepatocyte nuclear factor-4α, sterol regulatory element-binding proteins, and tumor necrosis factor-α may explain the anti-cancer effect of green tea as well. However, further studies are required to elucidate which determinant directs (-)-epigallocatechin gallate action as an anti-oxidant or a pro-oxidant for favorable activity. PMID:27221834

  19. N,N-Bis(glycityl)amines as anti-cancer drugs.

    PubMed

    Waghorne, Charlotte L; Corkran, Hilary M; Hunt-Painter, Alex A; Niktab, Eliatan; Baty, James W; Berridge, Michael V; Munkacsi, Andrew B; McConnell, Melanie J; Timmer, Mattie S M; Stocker, Bridget L

    2016-09-01

    A series of N,N-bis(glycityl)amines with promising anti-cancer activity were prepared via the reductive amination of pentoses and hexoses, and subsequently screened for their ability to selectively inhibit the growth of cancerous versus non-cancerous cells. For the first time, we show that this class of compounds possesses anti-proliferative activity, and, while the selective killing of brain cancer (LN18) cells versus matched (SVG-P12) cells was modest, several of the amines, including d-arabinitylamine 1a and d-fucitylamine 1g, exhibited low micromolar IC50 values for HL60 cells. Moreover, these two amines showed good selectivity towards HL60 cells when compared to non-cancerous HEK-293 cells. The compounds also showed low micromolar inhibition of the leukaemic cell line, THP-1. The modes of action of amines 1a and 1g were then determined using yeast chemical genetics, whereby it was established that both compounds affect similar but distinct sets of biochemical pathways. Notably purine nucleoside monophosphate biosynthesis was identified as an enriched mechanism. The rapid synthesis of the amines and their unique mode of action thus make them attractive targets for further development as anti-cancer drugs. PMID:27108400

  20. Cell Targeting in Anti-Cancer Gene Therapy

    PubMed Central

    Lila, Mohd Azmi Mohd; Siew, John Shia Kwong; Zakaria, Hayati; Saad, Suria Mohd; Ni, Lim Shen; Abdullah, Jafri Malin

    2004-01-01

    Gene therapy is a promising approach towards cancer treatment. The main aim of the therapy is to destroy cancer cells, usually by apoptotic mechanisms, and preserving others. However, its application has been hindered by many factors including poor cellular uptake, non-specific cell targeting and undesirable interferences with other genes or gene products. A variety of strategies exist to improve cellular uptake efficiency of gene-based therapies. This paper highlights advancements in gene therapy research and its application in relation to anti-cancer treatment. PMID:22977356

  1. The In Vitro and In Vivo Anti-Cancer Activities of a Standardized Quassinoids Composition from Eurycoma longifolia on LNCaP Human Prostate Cancer Cells

    PubMed Central

    Tong, Kind Leng; Chan, Kit Lam; AbuBakar, Sazaly; Low, Bin Seng; Ma, Hai Qiu; Wong, Pooi Fong

    2015-01-01

    Quassinoids are a group of diterpenoids found in plants from the Simaroubaceae family. They are also the major bioactive compounds found in Eurycoma longifolia which is commonly used as traditional medicine in South East Asia to treat various ailments including sexual dysfunction and infertility. These uses are attributed to its ability to improve testosterone level in men. Chronic consumption of E. longifolia extracts has been reported to increase testosterone level in men and animal model but its effect on prostate growth remains unknown. Therefore, the present study investigates the effects of a standardized total quassinoids composition (SQ40) containing 40% of the total quassinoids found in E. longifolia on LNCaP human prostate cancer cell line. SQ40 inhibited LNCaP cell growth at IC50 value of 5.97 μg/mL while the IC50 on RWPE-1 human prostate normal cells was 59.26 μg/mL. SQ40 also inhibited 5α-dihydrotestosterone-stimulated growth in LNCaP cells dose-dependently. The inhibitory effect of SQ40 in anchorage-independent growth of LNCaP cells was also demonstrated using soft agar assay. SQ40 suppressed LNCaP cell growth via G0/G1 phase arrest which was accompanied by the down-regulation of CDK4, CDK2, Cyclin D1 and Cyclin D3 and up-regulation of p21Waf1/Cip1 protein levels. SQ40 at higher concentrations or longer treatment duration can cause G2M growth arrest leading to apoptotic cell death as demonstrated by the detection of poly(ADP-ribose) polymerase cleavage in LNCaP cells. Moreover, SQ40 also inhibited androgen receptor translocation to nucleus which is important for the transactivation of its target gene, prostate-specific antigen (PSA) and resulted in a significant reduction of PSA secretion after the treatment. In addition, intraperitoneal injection of 5 and 10 mg/kg of SQ40 also significantly suppressed the LNCaP tumor growth on mouse xenograft model. Results from the present study suggest that the standardized total quassinoids composition from E

  2. Synthesis of new isoxazoline derivatives from harmine and evaluation of their anti-Alzheimer, anti-cancer and anti-inflammatory activities.

    PubMed

    Filali, Insaf; Bouajila, Jalloul; Znati, Mansour; Bousejra-El Garah, Fatima; Ben Jannet, Hichem

    2015-06-01

    In our study, a series of new harmine derivatives has been prepared by cycloaddition reaction using various arylnitrile oxides and evaluated in vitro against acetylcholinesterase and 5-lipoxygenase enzymes, MCF7 and HCT116 cancer cell lines. Some of these molecules have been shown to be potent inhibitors of acetylcholinesterase and MCF7 cell line. The greatest activity against acetylcholinesterase (IC50 = 10.4 µM) was obtained for harmine 1 and cytotoxic activities (IC50 = 0.2 µM) for compound 3a. Two derivatives 3e and 3f with the thiophene and furan systems, respectively, showed good activity against 5- lipoxygenase enzyme (IC50 = 29.2 and 55.5 µM, respectively). PMID:25068731

  3. Tailored-CuO-nanowire decorated with folic acid mediated coupling of the mitochondrial-ROS generation and miR425-PTEN axis in furnishing potent anti-cancer activity in human triple negative breast carcinoma cells.

    PubMed

    Ahir, Manisha; Bhattacharya, Saurav; Karmakar, Soumendu; Mukhopadhyay, Ayan; Mukherjee, Sudeshna; Ghosh, Swatilekha; Chattopadhyay, Sreya; Patra, Prasun; Adhikary, Arghya

    2016-01-01

    Metal oxide nanoparticles are the forthcoming anti-tumor therapeutics and provide a versatile platform in the development of therapeutic approaches for drug-resistant cancers such as triple negative breast cancer (TNBC). Copper oxide nanoparticles have been characterized as anti-cancer agents but its toxicity has been a matter of concern. Herein, we have developed a targeted CuO Nanowire fabricated with Folic acid (CuO-Nw-FA) that enables enhanced cellular uptake in TNBC cells without imparting significant toxicity in normal cellular system. In the present study, we enumerated that CuO-Nw-FA caused mitochondrial-dependent apoptosis in MDAMB-231 cells. Furthermore, CuO-Nw-FA mediated cytosolic retardation of NF-κB favoured inactivation of miR-425 and henceforth activated PTEN to induce apoptosis in TNBC cells. Simultaneously, CuO-Nw-FA also restricted the in-vitro cell migration through the miR-425/PTEN axis via pFAK. Studies extended to ex-ovo and in-vivo mice models further validated the efficacy of CuO-Nw-FA. Additionally, the accumulations of nanoparticles in tumor as well as different organs in mice were examined by in-vivo biodistribution and ex-vivo optical imaging studies. Thus our results cumulatively propose that CuO-Nw-FA cross-talks two distinct signalling pathways to induce apoptosis and retard migration in TNBC cells and raises the possibility for the use of CuO-Nw-FA as a potent anti-tumor agent. PMID:26520043

  4. Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity.

    PubMed

    Trabbic, Christopher J; George, Sage M; Alexander, Evan M; Du, Shengnan; Offenbacher, Jennifer M; Crissman, Emily J; Overmeyer, Jean H; Maltese, William A; Erhardt, Paul W

    2016-10-21

    Certain indolyl-pyridinyl-propenone analogues kill glioblastoma cells that have become resistant to conventional therapeutic drugs. Some of these analogues induce a novel form of non-apoptotic cell death called methuosis, while others primarily cause microtubule disruption. Ready access to 5-indole substitution has allowed characterization of this position to be important for both types of mechanisms when a simple methoxy group is present. We now report the syntheses and biological effects of isomeric methoxy substitutions on the indole ring. Additionally, analogues containing a trimethoxyphenyl group in place of the pyridinyl moiety were evaluated for anticancer activity. The results demonstrate that the location of the methoxy group can alter both the potency and the mechanism of cell death. Remarkably, changing the methoxy from the 5-position to the 6-position switched the biological activity from induction of methuosis to disruption of microtubules. The latter may represent a prototype for a new class of mitotic inhibitors with potential therapeutic utility. PMID:27343855

  5. Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty?

    PubMed

    Matthews, Hayden; Ranson, Marie; Kelso, Michael J

    2011-11-01

    Amiloride.HCl is clinically used as an oral potassium-sparing diuretic, but multiple studies in biochemical, cellular and animal models have shown that the drug also possesses anti-tumour and anti-metastasis activities. The additional effects appear to arise through inhibition of two discrete targets: (i) the sodium-hydrogen exchanger 1 (NHE1), a membrane protein responsible for the characteristically low extracellular pH of tumours and (ii) the urokinase-type plasminogen activator (uPA), a serine protease mediator of cell migration, invasion and metastasis and well-known marker of poor prognosis in cancer. This mini-review summarises for the first time the reported anti-tumour/metastasis effects of amiloride in experimental models, discusses the putative molecular mechanisms responsible for these effects and concludes by commenting on the pros and cons of trialling amiloride or one of its structural analogues as potential new anti-tumour/metastasis drugs. PMID:21544803

  6. Recent advances in the discovery of heparanase inhibitors as anti-cancer agents.

    PubMed

    Jia, Li; Ma, Shutao

    2016-10-01

    Heparanase, an only endo-β-d-glucuronidase capable of cleaving heparan sulfate (HS) side chains at specific sites, contributes to remodeling of the extracellular matrix (ECM) and releasing of HS-linked growth factors, cytokines and signaling proteins. In addition, heparanase also plays an indispensable role in tumor angiogenesis, invasion and metastasis, indicating that it is a promising target for the development of antitumor drugs. Recent progress leads to three classes of heparanase inhibitors, including active analogs of endogenous substance, synthetic small molecule compounds and natural products. In this review, following an outline on the heparanase structure and function, an overview of the advancement of heparanase inhibitors as novel and potent anti-cancer agents will be given, especially introducing various existing heparanase inhibitors, as well as their inhibitory activities and mechanisms of action. PMID:27240275

  7. Anti-cancer effect of bee venom on colon cancer cell growth by activation of death receptors and inhibition of nuclear factor kappa B

    PubMed Central

    Zheng, Jie; Lee, Hye Lim; Ham, Young Wan; Song, Ho Sueb; Song, Min Jong; Hong, Jin Tae

    2015-01-01

    Bee venom (BV) has been used as a traditional medicine to treat arthritis, rheumatism, back pain, cancerous tumors, and skin diseases. However, the effects of BV on the colon cancer and their action mechanisms have not been reported yet. We used cell viability assay and soft agar colony formation assay for testing cell viability, electro mobility shift assay for detecting DNA binding activity of nuclear factor kappa B (NF-κB) and Western blotting assay for detection of apoptosis regulatory proteins. We found that BV inhibited growth of colon cancer cells through induction of apoptosis. We also found that the expression of death receptor (DR) 4, DR5, p53, p21, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 was increased by BV treatment in a dose dependent manner (0–5 μg/ml). Consistent with cancer cell growth inhibition, the DNA binding activity of nuclear factor kappa B (NF-κB) was also inhibited by BV treatment. Besides, we found that BV blocked NF-κB activation by directly binding to NF-κB p50 subunit. Moreover, combination treatment with BV and p50 siRNA or NF-κB inhibitor augmented BV-induced cell growth inhibition. However, p50 mutant plasmid (C62S) transfection partially abolished BV-induced cell growth inhibiton. In addition, BV significantly suppressed tumor growth in vivo. Therefore, these results suggested that BV could inhibit colon cancer cell growth, and these anti-proliferative effects may be related to the induction of apoptosis by activation of DR4 and DR5 and inhibition of NF-κB. PMID:26561202

  8. Identification of novel estrogen receptor (ER) agonists that have additional and complementary anti-cancer activities via ER-independent mechanism.

    PubMed

    Kim, Taelim; Kim, Hye-In; An, Ji-Young; Lee, Jun; Lee, Na-Rae; Heo, Jinyuk; Kim, Ji-Eun; Yu, Jihyun; Lee, Yong Sup; Inn, Kyung-Soo; Kim, Nam-Jung

    2016-04-01

    In this study, a series of bis(4-hydroxy)benzophenone oxime ether derivatives such as 12c, 12e and 12h were identified as novel estrogen receptor (ER) agonists that have additional and complementary anti-proliferative activities via ER-independent mechanism in cancer cells. These compounds are expected to overcome the therapeutic limitation of existing ER agonists such as estradiol and tamoxifen, which have been known to induce the proliferation of cancer cells. PMID:26905830

  9. FT-IR and Raman spectroscopic and DFT studies of anti-cancer active molecule N-{(meta-ferrocenyl) Benzoyl} - L-Alanine - Glycine ethyl ester

    NASA Astrophysics Data System (ADS)

    Xavier, T. S.; Kenny, Peter T. M.; Manimaran, D.; Joe, I. Hubert

    2015-06-01

    FT-Raman and FT-IR spectra of N-{(meta-ferrocenyl) Benzoyl} - L-alanine - glycine ethyl ester were recorded in solid phase. The optimized molecular geometry, the vibrational wavenumbers, the infrared intensities and the Raman scattering intensities were calculated by using density functional method(B3LYP) with 6-31G(d, p) basis set. Vibrational assignment of the molecule was done by using potential energy distribution analysis. Natural bond orbital analysis, Mulliken charge analysis and HOMO-LUMO energy were used to elucidate the reasons for intra molecular charge transfer. Docking studies were conducted to predict its anticancer activity.

  10. Review of procedures used for the extraction of anti-cancer compounds from tropical plants.

    PubMed

    Pandey, Saurabh; Shaw, Paul N; Hewavitharana, Amitha K

    2015-01-01

    Tropical plants are important sources of anti-cancer lead molecules. According to the US National Cancer Institute, out of the 3000 plants identified as active against cancer using in vitro studies, 70% are of tropical origin. The extraction of bioactive compounds from the plant materials is a fundamental step whose efficiency is critical for the success of drug discovery efforts. There has been no review published of the extraction procedures of anti-cancer compounds from tropical plants and hence the following is a critical evaluation of such procedures undertaken prior to the use of these compounds in cancer cell line studies, during the last five years. It presents a comprehensive analysis of all approaches taken to extract anti-cancer compounds from various tropical plants. (Databases searched were PubMed, SciFinder, Web of Knowledge, Scopus, Embase and Google Scholar). PMID:25403166

  11. Anti-cancer activity of an osthole derivative, NBM-T-BMX-OS01: targeting vascular endothelial growth factor receptor signaling and angiogenesis.

    PubMed

    Yang, Hung-Yu; Hsu, Ya-Fen; Chiu, Pei-Ting; Ho, Shiau-Jing; Wang, Chi-Han; Chi, Chih-Chin; Huang, Yu-Han; Lee, Cheng-Feng; Li, Ying-Shiuan; Ou, George; Hsu, Ming-Jen

    2013-01-01

    Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer. PMID:24312323

  12. Anti-cancer drug 3,3′-diindolylmethane activates Wnt4 signaling to enhance gastric cancer cell stemness and tumorigenesis

    PubMed Central

    Gong, Aihua; Fu, Hailong; Zhang, Xu; Shi, Hui; Sun, Yaoxiang; Wu, Lijun; Pan, Zhaoji; Mao, Fei; Zhu, Wei; Qian, Hui; Xu, Wenrong

    2016-01-01

    As a natural health supplement, 3,3′-diindolylmethane (DIM) is proposed as a preventive and chemotherapeutic agent for cancer by inhibiting cell proliferation and inducing cell apoptosis. However, we found that in contrary to high level of DIM (30 μM), low level of DIM (1 μM and 10 μM) obviously promoted gastric cancer cell growth and migration. In addition, we found that low level of DIM increased the expression of stemness factors and enhanced the pluripotency of gastric cancer cells. Low level of DIM promoted gastric cancer progression by inducing the PORCN-dependent secretion of Wnt4 and the activation of β-catenin signaling. Wnt4 knockdown reversed the effects of low level of DIM on gastric cancer cells. The results of in vivo studies showed that gastric cancer cells treated with low level of DIM (1 μM) grew faster and expressed higher level of Wnt4 than control cells. Taken together, our findings indicate that low level of DIM activates autocrine Wnt4 signaling to enhance the progression of gastric cancer, which may suggest an adverse aspect of DIM in cancer therapy. Our findings will provide a new aspect for the safety of DIM in its clinical application. PMID:26918831

  13. Antioxidant Activities and Anti-Cancer Cell Proliferation Properties of Natsuhaze (Vaccinium oldhamii Miq.), Shashanbo (V. bracteatum Thunb.) and Blueberry Cultivars

    PubMed Central

    Tsuda, Hirotoshi; Kunitake, Hisato; Kawasaki-Takaki, Ryoko; Nishiyama, Kazuo; Yamasaki, Masao; Komatsu, Haruki; Yukizaki, Chizuko

    2013-01-01

    Antioxidants are abundant in blueberries, and while there are many studies concerning the bioactive compound of fruit, it is only recently that the wild Vaccinium species has attracted attention for their diverse and abundant chemical components. The aim of this study was to investigate the bioactive compounds of blueberry cultivars and wild species found in Japan. Among the five extracts of the Vaccinium species, Natsuhaze (Vaccinium oldhamii Miq.) was found to be the most effective at inhibiting the growth of HL-60 human leukemia cells in vitro. Although all ethanol extracts showed a growth inhibitory effect on HL-60 cells, the degree of the effects differed among the species. The extract of Natsuhaze induced apoptotic bodies and nucleosomal DNA fragmentation in the HL-60 cells. Of the extracts tested, that of Natsuhaze contained the largest amount of total polyphenols and showed the greatest antioxidant activity, but the anthocyanin content of Natsuhaze was similar to that of rabbiteye blueberry (V. virgatum Ait.). The results showed that total polyphenols contributed to the high antioxidant activity and growth inhibitory effect on HL-60 human leukemia cells of Natsuhaze extract. PMID:27137366

  14. In-vitro immunomodulatory and anti-cancerous activities of biotransformed products of Dianabol through Azadirachta indica and its molecular docking studies

    PubMed Central

    2013-01-01

    Background Plant Biotransformation is one of the tools for structural modifications of the organic substrate of low, moderate or high biological value utilizing plant cultured cells, these modifications of organic structures may lead to biologically augmented products and which may be ultimately substantial in cure or improvement of various morbidities and diseases. Results Azadirachta indica A. Juss. suspension culture was employed for the biotransformation of dianabol (1) for the first time, and two metabolites, 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one (2), and 17β-hydroxy-17α-methyl-5α-androstan-3-one (3) were obtained. Conclusions Most important aspect of this work was the evaluation of metabolite 2, which strongly and differentially suppressed [not affecting whole blood and human polymorphonuclear cells (PMN)] the phytohemagglutinin (PHA)-activated T-cell proliferation (IC50: <10.33 μM), and also found to inhibit IL-2 production (IC50: 16.89 ± 1.32) unlike metabolite 3 and compound 1. Compound 2 also exhibited anticancer activity against lung cancer cell line; NCI-H460, it moderately inhibited the growth of cancer cells (22.5 ± 4.15 μM). Furthermore, a good correlation between the predicted binding energies of the compounds acquired by the FlexX program and the experimental affinities were speculated upon interacting with IL-2 protein during molecular docking studies. PMID:24764465

  15. Combination immunotherapy and active-specific tumor cell vaccination augments anti-cancer immunity in a mouse model of gastric cancer

    PubMed Central

    2011-01-01

    Background Active-specific immunotherapy used as an adjuvant therapeutic strategy is rather unexplored for cancers with poorly characterized tumor antigens like gastric cancer. The aim of this study was to augment a therapeutic immune response to a low immunogenic tumor cell line derived from a spontaneous gastric tumor of a CEA424-SV40 large T antigen (CEA424-SV40 TAg) transgenic mouse. Methods Mice were treated with a lymphodepleting dose of cyclophosphamide prior to reconstitution with syngeneic spleen cells and vaccination with a whole tumor cell vaccine combined with GM-CSF (a treatment strategy abbreviated as LRAST). Anti-tumor activity to subcutaneous tumor challenge was examined in a prophylactic as well as a therapeutic setting and compared to corresponding controls. Results LRAST enhances tumor-specific T cell responses and efficiently inhibits growth of subsequent transplanted tumor cells. In addition, LRAST tended to slow down growth of established tumors. The improved anti-tumor immune response was accompanied by a transient decrease in the frequency and absolute number of CD4+CD25+FoxP3+ T cells (Tregs). Conclusions Our data support the concept that whole tumor cell vaccination in a lymphodepleted and reconstituted host in combination with GM-CSF induces therapeutic tumor-specific T cells. However, the long-term efficacy of the treatment may be dampened by the recurrence of Tregs. Strategies to counteract suppressive immune mechanisms are required to further evaluate this therapeutic vaccination protocol. PMID:21859450

  16. Anti-cancer drugs targeting fatty acid synthase (FAS).

    PubMed

    Pandey, Puspa R; Liu, Wen; Xing, Fei; Fukuda, Koji; Watabe, Kounosuke

    2012-05-01

    Fatty acid synthase (FAS) is a key enzyme of the fatty acid biosynthetic pathway which catalyzes de novo lipid synthesis. FAS expression in normal adult tissues is generally very low or undetectable as majority of fatty acids obtained are from dietary sources, whereas it is significantly upregulated in cancer cells despite adequate nutritional lipid supply. Activation of FAS provides rapidly proliferating tumor cells sufficient amount of lipids for membrane biogenesis and confers growth and survival advantage possibly acting as a metabolic oncogene. Importantly, inhibition of FAS in cancer cells using the pharmacological FAS inhibitors results in tumor cell death by apoptosis whereas normal cells are resistant. Due to this differential expression of FAS, the inhibitors of this enzyme are selectively toxic to tumor cells and therefore FAS is considered an attractive therapeutic target for cancer. Several FAS inhibitors are already patented and commercially available; however, the potential toxicity of these FAS inhibitors remains to be tested in clinical trials. In this review, we discuss some of the potent FAS inhibitors along with their patent information, the mechanism of anti-cancer effects and the development of more specific and potent FAS inhibitors with lower side effects that are expected to emerge as anti-cancer treatment in the near future. PMID:22338595

  17. Cu(II) complexes with co-planar [Cu(II)(N-N)(HIMC⁻)], their anti-cancer activities, ΔG, ΔE and solid luminescence.

    PubMed

    Cheng, Yi-Feng; Lu, Xiao-Ming; Wang, Guo

    2014-04-14

    [Cu(II)(phen)(HIMC(-))(H2O)]·[Cu(II)(phen)(HIMC(-))(NO3(-))]·NO3(-)·H2O (1) and [Cu(II)(2,2'-bipy)(HIMC(-))]·NO3(-)·xH2O (2) (phen = 1,10-phenanthroline, 2,2'-bipy = 2,2'-bipyridine, HIMC(-) = 1H-imidazole-4-carboxylate acid anion) have been synthesized at 180 °C, of which the HIMC(-) is produced by an in situ decarboxylation from H3IDC (1H-imidazole-4,5-dicarboxylic acid) in a one-pot hydrothermal reaction. The anticancer activity experiments in vitro show that 1 exhibited excellent activities against A549, Bel-7402 and HCT-8 cancer cells and is even better than the clinical anticancer drug 5-Fu (5-fluorouracil), while 2 shows little response toward the cancer cells. The single crystal X-ray diffraction indicated that complex 1 possess a co-planar [Cu(II)(N-N)(HIMC(-))] coordination geometry. The IR, elemental analysis and solid-state luminescent spectra of complexes 1 and 2 indicated that the composition of these two complexes are similar, whereas the 2,2'-bipy in complex 2 replaced phen in complex 1. The calculation by the Gaussian 03 program illustrated that the decrease in the energy gaps between π*-π from the free to the coordinated ligand for 2,2'-bipy and phen (ΔE) are 5.3 eV to 4.0 eV and 4.8 eV to 4.5 eV separately, and the relative changes of the Gibbs free energies (ΔG) for complex 1 and 2 decomposing into free Cu(2+) and ligands are about 0 kcal mol(-1) and 7 kcal mol(-1) respectively, which revealed that it is more stable when 2,2'-bipy is coordinated with Cu(II) than phen, and 1 is easier to disassociate into free Cu(2+) than 2. By relating the ΔE, ΔG, luminescent qualities and anticancer toxicities of the complexes with their composition, it can be concluded that both Cu(II) and their coordinated ligands are responsible for the inhibition against cancer cells. PMID:24519174

  18. Phytochemical analyses and activity of herbal medicinal plants of North- East India for anti-diabetic, anti-cancer and anti-tuberculosis and their docking studies.

    PubMed

    Suhitha, Sivasubramanian; Devi, Seenivasan Karthiga; Gunasekaran, Krishnasamy; Pakyntein, H Carehome; Bhattacharjee, Atanu; Velmurugan, Devadasan

    2015-01-01

    The traditional knowledge of medicinal plants that are in use by the indigenous Jaintia tribes residing in few isolated pockets of North-East India is documented here. The present study was carried out through the personal discussion with the president of the Jaintia Indigenous Herbal Medicine Association, Dr.H.Carehome Pakyntein from Jowai, Meghalaya. The plants being used generation after generation by his family of herbalists to cure ailments like tuberculosis, cancer and diabetes were selected for the present study. In order to scientifically validate the use of these selected plants for the cure of selected diseases, phytochemical analyses, characterization and molecular docking studies of some of the selected compounds from these plants have been carried out. The compounds 2-hydroxy-4-methoxy- Benzaldehyde from methanolic extract of Strophanthus Wallichii and DL tetrahydropalmatine from Stephania Hernandifolia have been confirmed after determining their molecular structures, justifying the activity of these two plants against TB and cancer, respectively. The present study covers the potentials of some of the medicinal plants of North east India in curing common diseases due to which millions of people suffer and die. The presence of certain compounds in these plants related to the cure of the diseases deserves further studies. PMID:25579573

  19. Anti-Cancer Activity of Solanum nigrum (AESN) through Suppression of Mitochondrial Function and Epithelial-Mesenchymal Transition (EMT) in Breast Cancer Cells.

    PubMed

    Lai, Ying-Jang; Tai, Chen-Jei; Wang, Chia-Woei; Choong, Chen-Yen; Lee, Bao-Hong; Shi, Yeu-Ching; Tai, Cheng-Jeng

    2016-01-01

    Chemotherapy is the main approach for treating advanced and recurrent carcinoma, but the clinical performance of chemotherapy is limited by relatively low response rates, drug resistance, and adverse effects that severely affect the quality of life of patients. An association between epithelial-mesenchymal transition (EMT) and chemotherapy resistance has been investigated in recent studies. Our recent studies have found that the aqueous extract of Solanum nigrum (AESN) is a crucial ingredient in some traditional Chinese medicine formulas for treating various types of cancer patients and exhibits antitumor effects. We evaluated the suppression of EMT in MCF-7 breast cancer cells treated with AESN. The mitochondrial morphology was investigated using Mitotracker Deep-Red FM stain. Our results indicated that AESN markedly inhibited cell viability of MCF-7 breast cancer cells through apoptosis induction and cell cycle arrest mediated by activation of caspase-3 and production of reactive oxygen species. Furthermore, mitochondrial fission was observed in MCF-7 breast cancer cells treated with AESN. In addition to elevation of E-cadherin, downregulations of ZEB1, N-cadherin, and vimentin were found in AESN-treated MCF-7 breast cancer cells. These results suggested that AESN could inhibit EMT of MCF-7 breast cancer cells mediated by attenuation of mitochondrial function. AESN could be potentially beneficial in treating breast cancer cells, and may be of interest for future studies in developing integrative cancer therapy against proliferation, metastasis, and migration of breast cancer cells. PMID:27136519

  20. Heteroleptic arene Ru(ii) dipyrrinato complexes: DNA, protein binding and anti-cancer activity against the ACHN cancer cell line.

    PubMed

    Gupta, Rakesh Kumar; Kumar, Amit; Paitandi, Rajendra Prasad; Singh, Roop Shikha; Mukhopadhyay, Sujay; Verma, Shiv Prakash; Das, Parimal; Pandey, Daya Shankar

    2016-04-19

    Four organometallic complexes [(η(6)-C6H6)RuCl(pmpzdpm)], ; [(η(6)-C6H6)RuCl(pypzdpm)], ; [(η(6)-C10H14)RuCl(pmpzdpm)], and [(η(6)-C10H14)RuCl(pypzdpm)], containing 5-(2-pyrimidyl-piperazine)phenyldipyrromethene (pmpzdpm) and 5-(2-pyridylpiperazine)phenyldipyrromethene (pypzdpm) have been designed and synthesized. The complexes have been fully characterized by elemental analyses and spectroscopic studies (ESI-MS, IR, (1)H, (13)C NMR, UV-vis). Their electrostatic/intercalative interaction with CT DNA has been investigated by UV-vis and competitive ethidium bromide displacement studies while their protein binding affinity toward bovine serum albumin (BSA) was realized by UV-vis, fluorescence, synchronous and three dimensional (3D) fluorescence studies. The interaction with DNA and protein has further been validated by in silico studies. Cellular uptake, in vitro cytotoxicity and flow cytometric analyses have been performed to determine the mode of cell death against the kidney cancer cell line ACHN. Cell cycle analysis suggested that the complexes cause cell cycle arrest in the subG1 phase and overall results indicated that the in vitro antitumor activity of lies in the order of > > > (IC50, 7.0 ; 8.0 ; 2.0 ; 4.0 μM, ). PMID:27009608

  1. A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity.

    PubMed

    He, Zhijian; Wan, Xiaomeng; Schulz, Anita; Bludau, Herdis; Dobrovolskaia, Marina A; Stern, Stephan T; Montgomery, Stephanie A; Yuan, Hong; Li, Zibo; Alakhova, Daria; Sokolsky, Marina; Darr, David B; Perou, Charles M; Jordan, Rainer; Luxenhofer, Robert; Kabanov, Alexander V

    2016-09-01

    The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50% wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive "T11" mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials. PMID:27315213

  2. Paraptosis in the anti-cancer arsenal of natural products.

    PubMed

    Lee, Dongjoo; Kim, In Young; Saha, Sharmistha; Choi, Kyeong Sook

    2016-06-01

    Given the problems with malignant cancer cells showing innate and acquired resistance to apoptosis, we need alternative means to induce cell death in cancer. Paraptosis is a type of programmed cell death that is characterized by dilation of the endoplasmic reticulum (ER) and/or mitochondria. Although relatively little is known regarding the molecular basis of paraptosis, the underlying mechanism clearly differs from that of apoptosis. Recent studies have shown that various natural products, including curcumin, celastrol, 15d-PGJ2, ophiobolin A, and paclitaxel, demonstrate anti-cancer effects by inducing the paraptosis-associated cell death, which was commonly characterized by vacuolation derived from the ER. Perturbation of cellular proteostasis due to proteasomal inhibition and disruption of sulfhydryl homeostasis, generation of reactive oxygen species, and/or imbalanced homeostasis of ions (e.g., Ca(2+) and K(+)) appear to contribute to the accumulation of misfolded protein and proteotoxicity in this process. Given the pathophysiological importance of paraptosis and the debate regarding the importance of apoptosis in solid tumor, we need to collect the available knowledge regarding paraptosis and suggest future directions in the field. Here, we review the morphological and biochemical features of paraptosis, the natural products that induce paraptosis-associated cell death, their proposed mechanisms, and the significance of paraptosis as a potential anti-cancer strategy. Such work and future clarifications should enable the development of new strategies for preventing cancer and/or combating malignant cancer. PMID:26802901

  3. Nanovectors for anti-cancer drug delivery in the treatment of advanced pancreatic adenocarcinoma

    PubMed Central

    Hsueh, Chung-Tzu; Selim, Julie H; Tsai, James Y; Hsueh, Chung-Tsen

    2016-01-01

    Liposome, albumin and polymer polyethylene glycol are nanovector formulations successfully developed for anti-cancer drug delivery. There are significant differences in pharmacokinetics, efficacy and toxicity between pre- and post-nanovector modification. The alteration in clinical pharmacology is instrumental for the future development of nanovector-based anticancer therapeutics. We have reviewed the results of clinical studies and translational research in nanovector-based anti-cancer therapeutics in advanced pancreatic adenocarcinoma, including nanoparticle albumin-bound paclitaxel and nanoliposomal irinotecan. Furthermore, we have appraised the ongoing studies incorporating novel agents with nanomedicines in the treatment of pancreatic adenocarcinoma. PMID:27610018

  4. Nanovectors for anti-cancer drug delivery in the treatment of advanced pancreatic adenocarcinoma.

    PubMed

    Hsueh, Chung-Tzu; Selim, Julie H; Tsai, James Y; Hsueh, Chung-Tsen

    2016-08-21

    Liposome, albumin and polymer polyethylene glycol are nanovector formulations successfully developed for anti-cancer drug delivery. There are significant differences in pharmacokinetics, efficacy and toxicity between pre- and post-nanovector modification. The alteration in clinical pharmacology is instrumental for the future development of nanovector-based anticancer therapeutics. We have reviewed the results of clinical studies and translational research in nanovector-based anti-cancer therapeutics in advanced pancreatic adenocarcinoma, including nanoparticle albumin-bound paclitaxel and nanoliposomal irinotecan. Furthermore, we have appraised the ongoing studies incorporating novel agents with nanomedicines in the treatment of pancreatic adenocarcinoma. PMID:27610018

  5. Structure Identification and Anti-Cancer Pharmacological Prediction of Triterpenes from Ganoderma lucidum.

    PubMed

    Shao, Yanyan; Qiao, Liansheng; Wu, Lingfang; Sun, Xuefei; Zhu, Dan; Yang, Guanghui; Zhang, Xiaoxue; Mao, Xin; Chen, Wenjing; Liang, Wenyi; Zhang, Yanling; Zhang, Lanzhen

    2016-01-01

    Ganoderma triterpenes (GTs) are the major secondary metabolites of Ganoderma lucidum, which is a popularly used traditional Chinese medicine for complementary cancer therapy. In the present study, systematic isolation, and in silico pharmacological prediction are implemented to discover potential anti-cancer active GTs from G. lucidum. Nineteen GTs, three steroids, one cerebroside, and one thymidine were isolated from G. lucidum. Six GTs were first isolated from the fruiting bodies of G. lucidum, including 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid methyl ester (1), 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid (2), 3β,7β,15α,28-tetrahydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid (3), ganotropic acid (4), 26-nor-11,23-dioxo-5α-lanost-8-en-3β,7β,15α,25-tetrol (5) and (3β,7α)-dihydroxy-lanosta-8,24-dien- 11-one (6). (4E,8E)-N-d-2'-hydroxypalmitoyl-l-O-β-d-glucopyranosyl-9-methyl-4,8-spingodienine (7), and stigmasta-7,22-dien-3β,5α,6α-triol (8) were first reported from the genus Ganodema. By using reverse pharmacophoric profiling of the six GTs, thirty potential anti-cancer therapeutic targets were identified and utilized to construct their ingredient-target interaction network. Then nineteen high frequency targets of GTs were selected from thirty potential targets to construct a protein interaction network (PIN). In order to cluster the pharmacological activity of GTs, twelve function modules were identified by molecular complex detection (MCODE) and gene ontology (GO) enrichment analysis. The results indicated that anti-cancer effect of GTs might be related to histone acetylation and interphase of mitotic cell cycle by regulating general control non-derepressible 5 (GCN5) and cyclin-dependent kinase-2 (CDK2), respectively. This research mode of extraction, isolation, pharmacological prediction, and PIN analysis might be beneficial to rapidly predict and discover pharmacological activities of novel compounds

  6. Hydrofocusing Bioreactor Produces Anti-Cancer Alkaloids

    NASA Technical Reports Server (NTRS)

    Gonda, Steve R.; Valluri, Jagan V.

    2011-01-01

    microgravitation of an HFB do not need to maintain the same surface forces as in normal Earth gravitation, they can divert more energy sources to growth and differentiation and, perhaps, to biosynthesis of greater quantities of desired medicinal compounds. Because one can adjust the HFB to vary effective gravitation, one can also test the effects of intermediate levels of gravitation on biosynthesis of various products. The potential utility of this methodology for producing drugs was demonstrated in experiments in which sandalwood and Madagascar periwinkle cells were grown in an HFB. The conditions in the HFB were chosen to induce the cells to form into aggregate cultures that produced anti-cancer indole alkaloids in amounts greater than do comparable numbers of cells of the same species cultured according to previously known methodologies. The observations made in these experiments were interpreted as suggesting that the aggregation of the cells might be responsible for the enhancement of production of alkaloids.

  7. ER-Golgi network– a future target for anti-cancer therapy

    PubMed Central

    Wlodkowic, Donald; Skommer, Joanna; McGuinness, Dagmara; Hillier, Chris; Darzynkiewicz, Zbigniew

    2009-01-01

    Tumor cell demise is an important event in the elimination of abnormal malignant cells and provides an important mechanism of natural tumor suppression. Abnormalities incapacitating these finely tuned processes provide a strong advantage for cancer clones to succeed in evading both the physiological control systems and therapeutic intervention. Expanding our knowledge of the molecular “cross-talks” that regulate tumor cell demise is crucial in guiding the successful design of future anti-cancer therapeutics. Although currently available data indicate that elimination of malignant cells often depends on classical apoptotic pathways (mitochondrial and/or death receptor pathways), the evidence is mounting that alternative apoptotic and non-apoptotic pathways may effectively contribute to tumor cell death. The assumption that every organelle is capable of sensing, amplificating and executing cell death is also a relatively novel and unexplored concept. As recently shown, the secretory pathway can be actively involved in sensing stress stimuli and possibly even initiating and propagating cell death signaling. Experimental evidence indicates that ER and Golgi apparatus can activate both pro-survival (recovery) mechanisms as well as cell suicide programs if the stress-signaling threshold is exceeded. It is thus conceivable that the fragile balance of protein trafficking between various subcellular compartments provides an exceptional therapeutic opportunity. Interestingly, a growing number of reports recognize novel therapeutic targets, including proteins in control of endoplasmic reticulum (ER) and Golgi homeostasis. Further studies are, however, needed to elucidate precise signaling pathways emanating from ER-Golgi compartment. Development of more potent and selective small-molecule drugs that activate ER-Golgi mediated cell demise is also needed. As the interest in the role of ER-Golgi network during cancer cell death has been gaining momentum, we attempt here to

  8. Anti-cancer effects of traditional Korean wild vegetables in complementary and alternative medicine.

    PubMed

    Ju, Hyun-Mok; Yu, Kwang-Won; Cho, Sung-Dae; Cheong, Sun Hee; Kwon, Ki Han

    2016-02-01

    This research study explored the anti-cancer effects of natural materials in South Korea. Although South Korea has a long history of traditional medicine, many natural materials of South Korea have not yet been introduced to the rest of the world because of language barriers and inconsistent study conditions. In the past 3 years, 56 papers introducing 56 natural materials, which have anti-cancer effects, have been published by scientists in South Korea. Further, these studies have introduced five kinds of natural materials presented in research papers that were written in Korean and are therefore virtually unknown overseas. The anti-cancer effects were confirmed by 2-3 cancer markers in the majority of the studies, with the most common targets being breast cancer cells and gastric cancer cells. These cancers have the greatest incidence in South Korea. The natural materials studied not only exhibit anti-cancer activity but also display anti-inflammatory, anti-oxidative stress, and anti-diabetic activities. They have not yet been used for the direct treatment of disease but have potential as medicinal materials for alternative and complementary medicine for the treatment of many modern diseases. Many natural materials of South Korea are already known all over the world, and with this study, we hope to further future research to learn more about these natural medicines. PMID:26860801

  9. Access to expensive anti-cancer drugs.

    PubMed

    Mileshkin, Linda; Sullivan, Danny

    2011-12-01

    Expensive anti-cancer drugs expose controversy underlying the process for resource allocation decisions, and intermittently result in marked publicity, emotive discussions about access to novel and expensive treatments, and political involvement which may override existing processes. This column outlines the methods of determining whether or not a treatment is considered appropriate to fund, and focuses upon the evidence of patient and doctor wishes. The existing research illustrates the complexity of patient and oncologist decision-making when these drugs are to be considered. Past litigation to obtain access to expensive treatments is discussed, along with the interactions between patients, pharmaceutical companies, health services and oncologists. This evolving field is being transformed by developments in molecular biology enabling targeted drugs, and amply demonstrates the complexity of funding decisions and how expensive treatments are considered by a range of stakeholders. PMID:22319998

  10. Screening for Anti-Cancer Compounds in Marine Organisms in Oman

    PubMed Central

    Dobretsov, Sergey; Tamimi, Yahya; Al-Kindi, Mohamed A.; Burney, Ikram

    2016-01-01

    Objectives: Marine organisms are a rich source of bioactive molecules with potential applications in medicine, biotechnology and industry; however, few bioactive compounds have been isolated from organisms inhabiting the Arabian Gulf and the Gulf of Oman. This study aimed to isolate and screen the anti-cancer activity of compounds and extracts from 40 natural products of marine organisms collected from the Gulf of Oman. Methods: This study was carried out between January 2012 and December 2014 at the Sultan Qaboos University, Muscat, Oman. Fungi, bacteria, sponges, algae, soft corals, tunicates, bryozoans, mangrove tree samples and sea cucumbers were collected from seawater at Marina Bandar Al-Rowdha and Bandar Al-Khayran in Oman. Bacteria and fungi were isolated using a marine broth and organisms were extracted with methanol and ethyl acetate. Compounds were identified from spectroscopic data. The anti-cancer activity of the compounds and extracts was tested in a Michigan Cancer Foundation (MCF)-7 cell line breast adenocarcinoma model. Results: Eight pure compounds and 32 extracts were investigated. Of these, 22.5% showed strong or medium anti-cancer activity, with malformin A, kuanoniamine D, hymenialdisine and gallic acid showing the greatest activity, as well as the soft coral Sarcophyton sp. extract. Treatment of MCF-7 cells at different concentrations of Sarcophyton sp. extracts indicated the induction of concentration-dependent cell death. Ultrastructural analysis highlighted the presence of nuclear fragmentation, membrane protrusion, blebbing and chromatic segregation at the nuclear membrane, which are typical characteristics of cell death by apoptosis induction. Conclusion: Some Omani marine organisms showed high anti-cancer potential. The efficacy, specificity and molecular mechanisms of anti-cancer compounds from Omani marine organisms on various cancer models should be investigated in future in vitro and in vivo studies. PMID:27226907

  11. miR-217 and CAGE form feedback loop and regulates the response to anti-cancer drugs through EGFR and HER2

    PubMed Central

    Han, Minho; Lee, Hansoo; Lee, Yun Sil; Choe, Jongseon; Kim, Young Myeong; Jeoung, Dooil

    2016-01-01

    MicroRNA array analysis revealed that miR-217 expression was decreased in anti-cancer drug-resistant Malme3MR cancer cells. CAGE, a cancer/testis antigen, was predicted as a target of miR-217. Luciferase activity and ChIP assays revealed a negative feedback relationship between CAGE and miR-217. miR-217 and CAGE oppositely regulated the response to anti-cancer drugs such as taxol, gefitinib and trastuzumab, an inhibitor of HER2. miR-217 negatively regulated the tumorigenic, metastatic, angiogenic, migration and invasion potential of cancer cells. The xenograft of Malme3MR cells showed an increased expression of pEGFRY845. CAGE and miR-217 inhibitor regulated the expression of pEGFRY845. CAGE showed interactions with EGFR and HER2 and regulated the in vivo sensitivity to trastuzumab. The down-regulation of EGFR or HER2 enhanced the sensitivity to anti-cancer drugs. CAGE showed direct regulation of HER2 and was necessary for the interaction between EGFR and HER2 in Malme3MR cells. miR-217 inhibitor induced interactions of CAGE with EGFR and HER2 in Malme3M cells. The inhibition of EGFR by CAGE-binding GTGKT peptide enhanced the sensitivity to gefitinib and trastuzumab and prevented interactions of EGFR with CAGE and HER2. Our results show that miR-217-CAGE feedback loop serves as a target for overcoming resistance to various anti-cancer drugs, including EGFR and HER2 inhibitors. PMID:26863629

  12. Ganoderma lucidum: a potential for biotechnological production of anti-cancer and immunomodulatory drugs.

    PubMed

    Boh, Bojana

    2013-09-01

    Based on the analysis of more than 270 patents and scientific articles, this state-of-the-art review presents Ganoderma lucidum, a medicinal basidiomycete mushroom with immunomodulatory and anti-cancer effects. Cultivation methods for the commercial production of G. lucidum fruit bodies and mycelia are summarized, with main active compounds of triterpenoids, polysaccharides, and proteins, often found in forms of proteoglycans or glycopeptides. Pharmacological effects with emphasis on anti-cancer and immunomodulatory functions are presented, separately for spores and dry mycelia, and for the groups of triterpenoids, polysaccharides, proteins and glycoproteins. Patents disclosing preparation methods of extracts and purified pharmaceutical isolates are reviewed, and examples of anti-cancer formulations, used as pharmaceuticals or nutraceuticals, are given. The review suggests that according to the present understanding, the anti-cancer activity of G. lucidum may be attributed to at least five groups of mechanisms: (1) activation/modulation of the immune response of the host, (2) direct cytotoxicity to cancer cells, (3) inhibition of tumor-induced angiogenesis, (4) inhibition of cancer cells proliferation and invasive metastasis behaviour, and (5) carcinogens deactivation with protection of cells. Although, the data from recent in vitro and in vivo studies demonstrate promising anti-cancer effects, a need is identified for further (1) isolation and purification of compounds, with deeper understanding of their individual and synergistic pharmacological effects, (2) molecular level studies of the antitumor and immuno-supportive mechanisms, (3) well designed in vivo tests and controlled clinical studies, and (4) standardisation and quality control for G. lucidum strains, cultivation processes, extracts and commercial formulations. PMID:23227951

  13. A magnetic anti-cancer compound for magnet-guided delivery and magnetic resonance imaging

    PubMed Central

    Eguchi, Haruki; Umemura, Masanari; Kurotani, Reiko; Fukumura, Hidenobu; Sato, Itaru; Kim, Jeong-Hwan; Hoshino, Yujiro; Lee, Jin; Amemiya, Naoyuki; Sato, Motohiko; Hirata, Kunio; Singh, David J.; Masuda, Takatsugu; Yamamoto, Masahiro; Urano, Tsutomu; Yoshida, Keiichiro; Tanigaki, Katsumi; Yamamoto, Masaki; Sato, Mamoru; Inoue, Seiichi; Aoki, Ichio; Ishikawa, Yoshihiro

    2015-01-01

    Research on controlled drug delivery for cancer chemotherapy has focused mainly on ways to deliver existing anti-cancer drug compounds to specified targets, e.g., by conjugating them with magnetic particles or encapsulating them in micelles. Here, we show that an iron-salen, i.e., μ-oxo N,N'- bis(salicylidene)ethylenediamine iron (Fe(Salen)), but not other metal salen derivatives, intrinsically exhibits both magnetic character and anti-cancer activity. X-Ray crystallographic analysis and first principles calculations based on the measured structure support this. It promoted apoptosis of various cancer cell lines, likely, via production of reactive oxygen species. In mouse leg tumor and tail melanoma models, Fe(Salen) delivery with magnet caused a robust decrease in tumor size, and the accumulation of Fe(Salen) was visualized by magnetic resonance imaging. Fe(Salen) is an anti-cancer compound with magnetic property, which is suitable for drug delivery and imaging. We believe such magnetic anti-cancer drugs have the potential to greatly advance cancer chemotherapy for new theranostics and drug-delivery strategies. PMID:25779357

  14. A magnetic anti-cancer compound for magnet-guided delivery and magnetic resonance imaging.

    PubMed

    Eguchi, Haruki; Umemura, Masanari; Kurotani, Reiko; Fukumura, Hidenobu; Sato, Itaru; Kim, Jeong-Hwan; Hoshino, Yujiro; Lee, Jin; Amemiya, Naoyuki; Sato, Motohiko; Hirata, Kunio; Singh, David J; Masuda, Takatsugu; Yamamoto, Masahiro; Urano, Tsutomu; Yoshida, Keiichiro; Tanigaki, Katsumi; Yamamoto, Masaki; Sato, Mamoru; Inoue, Seiichi; Aoki, Ichio; Ishikawa, Yoshihiro

    2015-01-01

    Research on controlled drug delivery for cancer chemotherapy has focused mainly on ways to deliver existing anti-cancer drug compounds to specified targets, e.g., by conjugating them with magnetic particles or encapsulating them in micelles. Here, we show that an iron-salen, i.e., μ-oxo N,N'- bis(salicylidene)ethylenediamine iron (Fe(Salen)), but not other metal salen derivatives, intrinsically exhibits both magnetic character and anti-cancer activity. X-Ray crystallographic analysis and first principles calculations based on the measured structure support this. It promoted apoptosis of various cancer cell lines, likely, via production of reactive oxygen species. In mouse leg tumor and tail melanoma models, Fe(Salen) delivery with magnet caused a robust decrease in tumor size, and the accumulation of Fe(Salen) was visualized by magnetic resonance imaging. Fe(Salen) is an anti-cancer compound with magnetic property, which is suitable for drug delivery and imaging. We believe such magnetic anti-cancer drugs have the potential to greatly advance cancer chemotherapy for new theranostics and drug-delivery strategies. PMID:25779357

  15. Modulation of APC Function and Anti-Tumor Immunity by Anti-Cancer Drugs

    PubMed Central

    Martin, Kea; Schreiner, Jens; Zippelius, Alfred

    2015-01-01

    Professional antigen-presenting cells (APCs), such as dendritic cells (DCs), are central to the initiation and regulation of anti-cancer immunity. However, in the immunosuppressive environment within a tumor APCs may antagonize anti-tumor immunity by inducing regulatory T cells (Tregs) or anergy of effector T cells due to lack of efficient costimulation. Hence, in an optimal setting, anti-cancer drugs have the power to reduce tumor size and thereby may induce the release of tumor antigens and, at the same time, modulate APC function toward efficient priming of antigen-specific effector T cells. Selected cytotoxic agents may revert APC dysfunction either by directly maturing DCs or through induction of immunogenic tumor cell death. Furthermore, specific cytotoxic agents may support adaptive immunity by selectively depleting regulatory subsets, such as Tregs or myeloid-derived suppressor cells. Perspectively, this will allow developing effective combination strategies with novel immunotherapies to exert complementary pressure on tumors via direct toxicity as well as immune activation. We, here, review our current knowledge on the capacity of anti-cancer drugs to modulate APC functions to promote durable anti-cancer immune responses. PMID:26483791

  16. A magnetic anti-cancer compound for magnet-guided delivery and magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Eguchi, Haruki; Umemura, Masanari; Kurotani, Reiko; Fukumura, Hidenobu; Sato, Itaru; Kim, Jeong-Hwan; Hoshino, Yujiro; Lee, Jin; Amemiya, Naoyuki; Sato, Motohiko; Hirata, Kunio; Singh, David J.; Masuda, Takatsugu; Yamamoto, Masahiro; Urano, Tsutomu; Yoshida, Keiichiro; Tanigaki, Katsumi; Yamamoto, Masaki; Sato, Mamoru; Inoue, Seiichi; Aoki, Ichio; Ishikawa, Yoshihiro

    2015-03-01

    Research on controlled drug delivery for cancer chemotherapy has focused mainly on ways to deliver existing anti-cancer drug compounds to specified targets, e.g., by conjugating them with magnetic particles or encapsulating them in micelles. Here, we show that an iron-salen, i.e., μ-oxo N,N'- bis(salicylidene)ethylenediamine iron (Fe(Salen)), but not other metal salen derivatives, intrinsically exhibits both magnetic character and anti-cancer activity. X-Ray crystallographic analysis and first principles calculations based on the measured structure support this. It promoted apoptosis of various cancer cell lines, likely, via production of reactive oxygen species. In mouse leg tumor and tail melanoma models, Fe(Salen) delivery with magnet caused a robust decrease in tumor size, and the accumulation of Fe(Salen) was visualized by magnetic resonance imaging. Fe(Salen) is an anti-cancer compound with magnetic property, which is suitable for drug delivery and imaging. We believe such magnetic anti-cancer drugs have the potential to greatly advance cancer chemotherapy for new theranostics and drug-delivery strategies.

  17. Impedance spectroscopy with field-effect transistor arrays for the analysis of anti-cancer drug action on individual cells.

    PubMed

    Susloparova, A; Koppenhöfer, D; Vu, X T; Weil, M; Ingebrandt, S

    2013-02-15

    In this study, impedance spectroscopy measurements of silicon-based open-gate field-effect transistor (FET) devices were utilized to study the adhesion status of cancer cells at a single cell level. We developed a trans-impedance amplifier circuit for the FETs with a higher bandwidth compared to a previously described system. The new system was characterized with a fast lock-in amplifier, which enabled measuring of impedance spectra up to 50 MHz. We studied cellular activities, including cell adhesion and anti-cancer drug induced apoptosis of human embryonic kidney (HEK293) and human lung adenocarcinoma epithelial (H441) cells. A well-known chemotherapeutic drug, topotecan hydrochloride, was used to investigate the effect of this drug to tumor cells cultured on the FET devices. The presence of the drug resulted in a 20% change in the amplitude of the impedance spectra at 200 kHz as a result of the induced apoptosis process. Real-time impedance measurements were performed inside an incubator at a constant frequency. The experimental results can be interpreted with an equivalent electronic circuit to resolve the influence of the system parameters. The developed method could be applied for the analysis of the specificity and efficacy of novel anti-cancer drugs in cancer therapy research on a single cell level in parallelized measurements. PMID:22795530

  18. Anti-cancer agents counteracting tumor glycolysis

    PubMed Central

    Granchi, Carlotta

    2012-01-01

    Can we consider cancer as a “metabolic disease”? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have to deal with increased needs for both energy and biosynthetic intermediates, in order to support their growth and invasiveness. However, their high proliferation rate often generates regions that are not sufficiently oxygenated. Therefore, their carbohydrate metabolism has to rely mostly on a glycolytic process that is uncoupled from oxidative phosphorylation. This metabolic switch, also known as the “Warburg Effect”, constitutes a fundamental adaptation of the tumor cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumor glycolysis may constitute an attractive target for cancer therapy. This approach has often raised concerns that anti-glycolytic agents may cause serious side effects on normal cells. Actually, the key for a selective action against cancer cells can be found in their hyperbolic addiction to glycolysis, which may be exploited to generate new anti-cancer drugs showing minimal toxicity. In fact, there is growing evidence that supports many glycolytic enzymes and transporters as suitable candidate targets for cancer therapy. Herein we review some of the most relevant anti-glycolytic agents that have been investigated so far for the treatment of cancer. PMID:22684868

  19. Synthesis and evaluation of multi-wall carbon nanotube–paclitaxel complex as an anti-cancer agent

    PubMed Central

    Ghasemvand, Fariba; Biazar, Esmaeil; Tavakolifard, Sara; Khaledian, Mohammad; Rahmanzadeh, Saeid; Momenzadeh, Daruosh; Afroosheh, Roshanak; Zarkalami, Faezeh; Shabannezhad, Marjan; Hesami Tackallou, Saeed; Massoudi, Nilofar; Heidari Keshel, Saeed

    2016-01-01

    Aim: The aim of this study was to design multi-walled carbon nanotubes (MWCNTs) loaded with paclitaxel (PTX) anti-cancer drug and investigate its anti-cancerous efficacy of human gastric cancer. Background: Carbon nanotubes (CNTs) represent a novel nano-materials applied in various fields such as drug delivery due to their unique chemical properties and high drug loading. Patients and methods: In this study, multi-walled carbon nanotubes (MWCNTs) pre-functionalized covalently with a paclitaxel (PTX) as an anti-cancer drug and evaluated by different analyses including, scanning electron microscope (SEM), particle size analyzer and cellular analyses. Results: A well conjugated of anti-cancer drug on the carbon nanotube surfaces was shown. This study demonstrates that the MWCN-PTX complex is a potentially useful system for delivery of anti-cancer drugs. The flow cytometry, CFU and MTT assay results have disclosed that MWCNT/PTXs might promote apoptosis in MKN-45 gastric adenocarcinoma cell line. Conclusion: According to results, our simple method can be designed a candidate material for chemotherapy. It has presented a few bio-related applications including, their successful use as a nano-carriers for drug transport. PMID:27458512

  20. Derivatisation of buforin IIb, a cationic henicosapeptide, to afford its complexation to platinum(ii) resulting in a novel platinum(ii)-buforin IIb conjugate with anti-cancer activity.

    PubMed

    Parker, J P; Devocelle, M; Morgan, M P; Marmion, C J

    2016-08-16

    Herein we report the synthesis of buforin IIb, its novel malonate derivative malBuf and its Pt(ii) complex cis-[Pt(NH3)2(malBuf-2H)]. We decided to harness the cell targeting, cell-penetrating and anti-proliferative effects of buforin IIb to help target a cytotoxic dose of a Pt DNA binding species, {Pt(NH3)2} to cancer cells whilst also delivering a peptide with potent anti-cancer properties. Preliminary in vitro data shows cis-[Pt(NH3)2(malBuf-2H)] to be more cytotoxic against the cisplatin resistant ovarian cancer cell line (A2780cisR) relative to buforin IIb, cisplatin and cis-[Pt(NH3)2(malonate)]. PMID:27292799

  1. Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents.

    PubMed

    Dar, Bilal Ahmad; Lone, Ali Mohd; Shah, Wajaht Amin; Qurishi, Mushtaq Ahmad

    2016-03-23

    Ursolic acid present abundantly in plant kingdom is a well-known compound with various promising biological activities including, anti-cancer, anti-inflammatory, hepatoprotective, antiallergic and anti-HIV properties. Herein, a library of ursolic acid-benzylidine derivatives have been designed and synthesized using Claisen Schmidt condensation of ursolic acid with various aromatic aldehydes in an attempt to develop potent antitumor agents. The compounds were evaluated against a panel of four human carcinoma cell lines including, A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2). The results from MTT assay revealed that all the compounds displayed high level of antitumor activities compared with the triazole analogs (previously reported) and the parent ursolic acid. However, compound 3b, the most active derivative was subjected to mechanistic studies to understand the underlying mechanism. The results revealed that compound 3b induced apoptosis in HCT-116 cell lines, arrest cell cycle in the G1 phase, caused accumulation of cytochrome c in the cytosol and increased the expression levels of caspase-9 and caspase-3 proteins. Therefore, compound 3b induces apoptosis in HCT-116 cells through mitochondrial pathway. PMID:26854375

  2. Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development

    PubMed Central

    Senese, S; Lo, Y C; Huang, D; Zangle, T A; Gholkar, A A; Robert, L; Homet, B; Ribas, A; Summers, M K; Teitell, M A; Damoiseaux, R; Torres, J Z

    2014-01-01

    Cancer cell proliferation relies on the ability of cancer cells to grow, transition through the cell cycle, and divide. To identify novel chemical probes for dissecting the mechanisms governing cell cycle progression and cell division, and for developing new anti-cancer therapeutics, we developed and performed a novel cancer cell-based high-throughput chemical screen for cell cycle modulators. This approach identified novel G1, S, G2, and M-phase specific inhibitors with drug-like properties and diverse chemotypes likely targeting a broad array of processes. We further characterized the M-phase inhibitors and highlight the most potent M-phase inhibitor MI-181, which targets tubulin, inhibits tubulin polymerization, activates the spindle assembly checkpoint, arrests cells in mitosis, and triggers a fast apoptotic cell death. Importantly, MI-181 has broad anti-cancer activity, especially against BRAFV600E melanomas. PMID:25321469

  3. Moringa oleifera as an Anti-Cancer Agent against Breast and Colorectal Cancer Cell Lines.

    PubMed

    Al-Asmari, Abdulrahman Khazim; Albalawi, Sulaiman Mansour; Athar, Md Tanwir; Khan, Abdul Quaiyoom; Al-Shahrani, Hamoud; Islam, Mozaffarul

    2015-01-01

    In this study we investigated the anti-cancer effect of Moringa oleifera leaves, bark and seed extracts. When tested against MDA-MB-231 and HCT-8 cancer cell lines, the extracts of leaves and bark showed remarkable anti-cancer properties while surprisingly, seed extracts exhibited hardly any such properties. Cell survival was significantly low in both cells lines when treated with leaves and bark extracts. Furthermore, a striking reduction (about 70-90%) in colony formation as well as cell motility was observed upon treatment with leaves and bark. Additionally, apoptosis assay performed on these treated breast and colorectal cancer lines showed a remarkable increase in the number of apoptotic cells; with a 7 fold increase in MD-MB-231 to an increase of several fold in colorectal cancer cell lines. However, no significant apoptotic cells were detected upon seeds extract treatment. Moreover, the cell cycle distribution showed a G2/M enrichment (about 2-3 fold) indicating that these extracts effectively arrest the cell progression at the G2/M phase. The GC-MS analyses of these extracts revealed numerous known anti-cancer compounds, namely eugenol, isopropyl isothiocynate, D-allose, and hexadeconoic acid ethyl ester, all of which possess long chain hydrocarbons, sugar moiety and an aromatic ring. This suggests that the anti-cancer properties of Moringa oleifera could be attributed to the bioactive compounds present in the extracts from this plant. This is a novel study because no report has yet been cited on the effectiveness of Moringa extracts obtained in the locally grown environment as an anti-cancer agent against breast and colorectal cancers. Our study is the first of its kind to evaluate the anti-malignant properties of Moringa not only in leaves but also in bark. These findings suggest that both the leaf and bark extracts of Moringa collected from the Saudi Arabian region possess anti-cancer activity that can be used to develop new drugs for treatment of breast

  4. Moringa oleifera as an Anti-Cancer Agent against Breast and Colorectal Cancer Cell Lines

    PubMed Central

    Al-Asmari, Abdulrahman Khazim; Albalawi, Sulaiman Mansour; Athar, Md Tanwir; Khan, Abdul Quaiyoom; Al-Shahrani, Hamoud; Islam, Mozaffarul

    2015-01-01

    In this study we investigated the anti-cancer effect of Moringa oleifera leaves, bark and seed extracts. When tested against MDA-MB-231 and HCT-8 cancer cell lines, the extracts of leaves and bark showed remarkable anti-cancer properties while surprisingly, seed extracts exhibited hardly any such properties. Cell survival was significantly low in both cells lines when treated with leaves and bark extracts. Furthermore, a striking reduction (about 70–90%) in colony formation as well as cell motility was observed upon treatment with leaves and bark. Additionally, apoptosis assay performed on these treated breast and colorectal cancer lines showed a remarkable increase in the number of apoptotic cells; with a 7 fold increase in MD-MB-231 to an increase of several fold in colorectal cancer cell lines. However, no significant apoptotic cells were detected upon seeds extract treatment. Moreover, the cell cycle distribution showed a G2/M enrichment (about 2–3 fold) indicating that these extracts effectively arrest the cell progression at the G2/M phase. The GC-MS analyses of these extracts revealed numerous known anti-cancer compounds, namely eugenol, isopropyl isothiocynate, D-allose, and hexadeconoic acid ethyl ester, all of which possess long chain hydrocarbons, sugar moiety and an aromatic ring. This suggests that the anti-cancer properties of Moringa oleifera could be attributed to the bioactive compounds present in the extracts from this plant. This is a novel study because no report has yet been cited on the effectiveness of Moringa extracts obtained in the locally grown environment as an anti-cancer agent against breast and colorectal cancers. Our study is the first of its kind to evaluate the anti-malignant properties of Moringa not only in leaves but also in bark. These findings suggest that both the leaf and bark extracts of Moringa collected from the Saudi Arabian region possess anti-cancer activity that can be used to develop new drugs for treatment of

  5. Procaspase-3 Activation as an Anti-Cancer Strategy: Structure-Activity Relationship of Procaspase-Activating Compound 1 (PAC-1) and its Cellular Co-Localization with Caspase-3

    PubMed Central

    Peterson, Quinn P.; Hsu, Danny C.; Goode, David R.; Novotny, Chris J.; Totten, Ryan K.; Hergenrother, Paul J.

    2009-01-01

    A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivatives where key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently-labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc. PMID:19708658

  6. Male contraceptive Adjudin is a potential anti-cancer drug

    PubMed Central

    Xie, Qian Reuben; Liu, Yewei; Shao, Jiaxiang; Yang, Jian; Liu, Tengyuan; Zhang, Tingting; Wang, Boshi; Mruk, Dolores D.; Silvestrini, Bruno; Cheng, C. Yan; Xia, Weiliang

    2014-01-01

    Adjudin, also known as AF-2364 and an analog of lonidamine (LND), is a male contraceptive acting through the induction of premature sperm depletion from the seminiferous epithelium when orally administered to adult rats, rabbits or dogs. It is also known that LND can target mitochondria and block energy metabolism in tumor cells. However, whether Adjudin exhibits any anti-cancer activity remains to be elucidated. Herein we described the anti-proliferative activity of Adjudin on cancer cells in vitro and on lung and prostate tumors inoculated in nude mice. We found that Adjudin induced apoptosis in cancer cells through a Caspase-3-dependent pathway. Further experiments revealed that Adjudin could trigger mitochondrial dysfunction in cancer cells, apparently affecting the mitochondrial mass, inducing the loss of mitochondrial membrane potential and reducing cellular ATP levels. Intraperitoneal administration of Adjudin to tumor-bearing athymic nude mice also significantly suppressed the lung and prostate tumor growth. When used in combination with cisplatin, Adjudin enhances the sensitivity to cisplatin-induced cancer cell cytotoxicity. Taken together, these findings have demonstrated that Adjudin may be a potential drug for cancer therapy. PMID:23178657

  7. DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells

    SciTech Connect

    Obara, Akio; Fujita, Yoshihito; Abudukadier, Abulizi; Fukushima, Toru; Oguri, Yasuo; Ogura, Masahito; Harashima, Shin-ichi; Hosokawa, Masaya; Inagaki, Nobuya

    2015-05-15

    Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti-cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosome protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR-dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy. - Highlights: • We elucidated a novel pathway of metformin's anti-cancer action in HCC cells. • DEPTOR is involved in the suppressing effect of metformin on mTOR signaling. • Metformin increases DEPTOR protein levels via suppression of proteasome activity. • DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action.

  8. Mechanistic study of the anti-cancer effect of Gynostemma pentaphyllum saponins in the Apc(Min/+) mouse model.

    PubMed

    Tai, William Chi-Shing; Wong, Wing-Yan; Lee, Magnolia Muk-Lan; Chan, Brandon Dow; Lu, Cheng; Hsiao, Wen-Luan Wendy

    2016-05-01

    Gynostemma pentaphyllum saponins (GpS) have been shown to have anti-cancer activity. However, the underlying mechanisms remain unclear. In this study, we used the Apc(Min) (/+) colorectal cancer (CRC) mouse model to investigate the anti-cancer effect of GpS and we demonstrated that GpS treatment could significantly reduce the number and size of intestinal polyps in Apc(Min) (/+) mice. In order to identify the potential targets and mechanisms involved, a comparative proteomics analysis was performed and 40 differentially expressed proteins after GpS treatment were identified. Bioinformatics analyses suggested a majority of these proteins were involved in processes related to cellular redox homeostasis, and predicted Raf-1 as a potential target of GpS. The upregulation of two proteins known to be involved in redox homeostasis, peroxiredoxin-1 (Prdx1) and peroxiredoxin-2 (Prdx2), and the downregulation of Raf-1 were validated using Western blot analysis. After further investigation of the associated signaling networks, we postulated that the anti-cancer effect of GpS was mediated through the upregulation of Prdx1 and Prdx2, suppression of Ras, RAF/MEK/ERK/STAT, PI3K/AKT/mTOR signaling and modulation of JNK/p38 MAPK signaling. We also examined the potential combinatorial effect of GpS with the chemotherapeutic 5-fluorouracil (5-FU) and found that GpS could enhance the anti-cancer efficacy of 5-FU, further suppressing the number of polyps in Apc(Min/+) mice. Our findings highlight the potential of GpS as an anti-cancer agent, the potential mechanisms of its anti-cancer activities, and its effect as an adjuvant of 5-FU in the chemotherapy of CRC. PMID:26970558

  9. Repurposing drugs in oncology (ReDO)—cimetidine as an anti-cancer agent

    PubMed Central

    Pantziarka, Pan; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vidula; Sukhatme, Vikas P

    2014-01-01

    Cimetidine, the first H2 receptor antagonist in widespread clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical and clinical studies for a number of different cancer types. These data are summarised and discussed in relation to a number of distinct mechanisms of action. Based on the evidence presented, it is proposed that cimetidine would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of cimetidine as an anti-cancer therapeutic is warranted. Furthermore, there is compelling evidence that cimetidine administration during the peri-operative period may provide a survival benefit in some cancers. A number of possible combinations with other drugs are discussed in the supplementary material accompanying this paper. PMID:25525463

  10. Anti-Cancer Vaccines — A One-Hit Wonder?

    PubMed Central

    Liu, Justin K.H.

    2014-01-01

    Immunization against common bacterial and viral diseases has helped prevent millions of deaths worldwide. More recently, the concept of vaccination has been developed into a potentially novel strategy to treat and prevent cancer formation, progression, and spread. Over the past few years, a handful of anti-cancer vaccines have been licensed and approved for use in clinical practice, thus providing a breakthrough in the field. However, the path has not always been easy, with many hurdles that have had to be overcome in order to reach this point. Nevertheless, with more anti-cancer vaccines currently in development, there is still hope that they can eventually become routine tools used in the treatment and prevention of cancer in the future. This review will discuss in detail both types of anti-cancer vaccine presently used in clinical practice — therapeutic and preventive — before considering some of the more promising anti-cancer vaccines that are currently in development. Finally, the issue of side effects and the debate surrounding the overall cost-effectiveness of anti-cancer vaccines will be examined. PMID:25506282

  11. IL-1 Contributes to the Anti-Cancer Efficacy of Ingenol Mebutate

    PubMed Central

    Le, Thuy T.; Skak, Kresten; Schroder, Kate; Schroder, Wayne A.; Boyle, Glen M.; Pierce, Carly J.; Suhrbier, Andreas

    2016-01-01

    Ingenol mebutate is approved for the topical treatment of actinic keratoses and may ultimately also find utility in treating skin cancers. Here we show that relapse rates of subcutaneous B16 melanoma tumours treated topically with ingenol mebutate were not significantly different in C57BL/6 and Rag1-/- mice, suggesting B and T cells do not play a major role in the anti-cancer efficacy of ingenol mebutate. Relapse rates were, however, significantly increased in MyD88-/- mice and in C57BL/6 mice treated with the anti-IL-1 agent, anakinra. Ingenol mebutate treatment induces a pronounced infiltration of neutrophils, which have been shown to have anti-cancer activity in mice. Herein we provide evidence that IL-1 promotes neutrophil recruitment to the tumour, decreases apoptosis of infiltrating neutrophils and increases neutrophil tumour killing activity. These studies suggest IL-1, via its action on neutrophils, promotes the anti-cancer efficacy of ingenol mebutate, with ingenol mebutate treatment causing both IL-1β induction and IL-1α released from keratinocytes. PMID:27100888

  12. Delivering anti-cancer drugs with endosomal pH-sensitive anti-cancer liposomes.

    PubMed

    Moku, Gopikrishna; Gulla, Suresh Kumar; Nimmu, Narendra Varma; Khalid, Sara; Chaudhuri, Arabinda

    2016-04-01

    Numerous prior studies have been reported on the use of pH-sensitive drug carriers such as micelles, liposomes, peptides, polymers, nanoparticles, etc. that are sensitive to the acidic (pH = ∼6.5) microenvironments of tumor tissues. Such systems have been primarily used in the past as effective drug/gene/microRNA carriers for releasing their anti-cancer payloads selectively to tumor cells/tissues. Herein, we report on the development of new liposomal drug carriers prepared from glutamic acid backbone-based cationic amphiphiles containing both endosomal pH-sensitive histidine as well as cellular uptake & solubility enhancing guanidine moieties in their polar head-group regions. The most efficient one among the four presently described endosomal pH-sensitive liposomal drug carriers not only effectively delivers potent anti-cancer drugs (curcumin & paclitaxel) to mouse tumor, but also significantly contributes to inhibiting mouse tumor growth. The findings in the in vitro mechanistic studies are consistent with apoptosis of tumor cells being mediated through increased cell cycle arrest in the G2/M phase. Findings in the FRET assay and in vitro drug release studies conducted with the liposomes of the most efficient pH-sensitive lipid demonstrated its pH dependent fusogenic and controlled curcumin release properties. Importantly, the presently described liposomal formulation of curcumin & paclitaxel enhanced overall survivability of tumor bearing mice. To the best of our knowledge, the presently described system (curcumin, paclitaxel and liposomal carrier itself) is the first of its kind pH-sensitive liposomal formulation of potent chemotherapeutics in which the liposomal drug itself exhibits significant mouse tumor growth inhibition properties. PMID:26806172

  13. Immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: A mini review

    PubMed Central

    Ziaei, Samira; Halaby, Reginald

    2016-01-01

    Objective: Triptolide, the active component of Tripterygium wilfordii Hook F has been used to treat autoimmune and inflammatory conditions for over two hundred years in traditional Chinese medicine. However, the processes through which triptolide exerts immunosuppression and anti-inflammation are not understood well. In this review, we discuss the autoimmune disorders and inflammatory conditions that are currently treated with triptolide. Triptolide also possesses anti-tumorigenic effects. We discuss the toxicity of various triptolide derivatives and offer suggestions to improve its safety. This study also examines the clinical trials that have investigated the efficacy of triptolide. Our aim is to examine the mechanisms that are responsible for the immunosuppressive, anti-inflammatory, and anti-cancer effects of triptolide. Materials and Methods: The present review provides a comprehensive summary of the literature with respect to the immunosuppressive, anti-inflammatory, and anti-cancer properties of triptolide. Results: Triptolide possesses immunosuppressive, anti-inflammatory, and anti-cancer effects. Conclusion: Triptolide can be used alone or in combination with existing therapeutic modalities as novel treatments for autoimmune disorders, cancers, and for immunosuppression. PMID:27222828

  14. Virtual screening strategies: recent advances in the identification and design of anti-cancer agents.

    PubMed

    Kumar, Vikash; Krishna, Shagun; Siddiqi, Mohammad Imran

    2015-01-01

    Virtual screening (VS) is a well-established technique, which is now routinely employed in computer aided drug designing process. VS can be broadly classified into two categories, i.e., ligand-based and structure-based approach. In recent years, VS has emerged as a time saving and cost effective technique, capable of screening millions of compounds in a user friendly manner. In the area of cancer drug design, VS methods have been widely used and helped in identifying novel molecules as potential anti-cancer agents. Both ligand-based VS (LBVS) structure-based VS (SBVS) methods have been highly useful in the identification of a number of potential anti-cancer agents exhibiting activities in nanomolar range. In tune with the rapid progress in the enhancement of computational power, VS has witnessed significant change in terms of speed and hit rate and in future it is expected that VS will be a preferential alternative to high throughput screening (HTS). This review, discusses recent trends and contribution of VS in the area of anti-cancer drug discovery. PMID:25171960

  15. In Vivo Fluorescence Resonance Energy Transfer Imaging for Targeted Anti-Cancer Drug Delivery Kinetics

    NASA Astrophysics Data System (ADS)

    Webb, Kevin; Gaind, Vaibhav; Tsai, Hsiaorho; Bentz, Brian; Chelvam, Venkatesh; Low, Philip

    2012-02-01

    We describe an approach for the evaluation of targeted anti-cancer drug delivery in vivo. The method emulates the drug release and activation process through acceptor release from a targeted donor-acceptor pair that exhibits fluorescence resonance energy transfer (FRET). In this case, folate targeting of the cancer cells is used - 40 % of all human cancers, including ovarian, lung, breast, kidney, brain and colon cancer, over-express folate receptors. We demonstrate the reconstruction of the spatially-dependent FRET parameters in a mouse model and in tissue phantoms. The FRET parameterization is incorporated into a source for a diffusion equation model for photon transport in tissue, in a variant of optical diffusion tomography (ODT) called FRET-ODT. In addition to the spatially-dependent tissue parameters in the diffusion model (absorption and diffusion coefficients), the FRET parameters (donor-acceptor distance and yield) are imaged as a function of position. Modulated light measurements are made with various laser excitation positions and a gated camera. More generally, our method provides a new vehicle for studying disease at the molecular level by imaging FRET parameters in deep tissue, and allows the nanometer FRET ruler to be utilized in deep tissue.

  16. Phytochemical, Antioxidant and Anti-Cancer Properties of Euphorbia tirucalli Methanolic and Aqueous Extracts

    PubMed Central

    Munro, Benjamin; Vuong, Quan V.; Chalmers, Anita C.; Goldsmith, Chloe D.; Bowyer, Michael C.; Scarlett, Christopher J.

    2015-01-01

    Euphorbia tirucalli is a succulent shrub or small tree that is native to the African continent, however, it is widely cultivated across the globe due to its use in traditional medicines to treat ailments, ranging from scorpion stings to HIV. Recent studies have identified compounds present in the latex of the plant, including a range of bi- and triterpenoids that exhibit bioactivity, including anticancer activity. This study aimed to optimize water extraction conditions for high-yield total phenolic content recovery, to prepare methanol and aqueous extracts from the aerial sections of the plant, and to test the phytochemical, antioxidant, and anti-cancer properties of these extracts. Water extraction of total phenolic compounds (TPC) was optimized across a range of parameters including temperature, extraction time, and plant mass-to-solvent ratio. The water extract of the E. tirucalli powder was found to contain TPC of 34.01 mg GAE (gallic acid equivalents)/g, which was approximately half that of the methanol extract (77.33 mg GAE/g). The results of antioxidant assays showed a uniform trend, with the methanol extract’s antioxidant reducing activity exceeding that of water extracts, typically by a factor of 2:1. Regression analysis of the antioxidant assays showed the strongest correlation between extract TPC and antioxidant activity for the ABTS (2,2-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) and DPPH (2,2-diphenyl-1-picrylhydrazyl) methods. The methanol extract also showed greater growth inhibition capacity towards the MiaPaCa-2 pancreatic cancer cell line. These data suggest that further investigations are required to confirm the source of activity within the E. tirucalli leaf and stems for potential use in the nutraceutical and pharmaceutical industries. PMID:26783950

  17. Phytochemical, Antioxidant and Anti-Cancer Properties of Euphorbia tirucalli Methanolic and Aqueous Extracts.

    PubMed

    Munro, Benjamin; Vuong, Quan V; Chalmers, Anita C; Goldsmith, Chloe D; Bowyer, Michael C; Scarlett, Christopher J

    2015-01-01

    Euphorbia tirucalli is a succulent shrub or small tree that is native to the African continent, however, it is widely cultivated across the globe due to its use in traditional medicines to treat ailments, ranging from scorpion stings to HIV. Recent studies have identified compounds present in the latex of the plant, including a range of bi- and triterpenoids that exhibit bioactivity, including anticancer activity. This study aimed to optimize water extraction conditions for high-yield total phenolic content recovery, to prepare methanol and aqueous extracts from the aerial sections of the plant, and to test the phytochemical, antioxidant, and anti-cancer properties of these extracts. Water extraction of total phenolic compounds (TPC) was optimized across a range of parameters including temperature, extraction time, and plant mass-to-solvent ratio. The water extract of the E. tirucalli powder was found to contain TPC of 34.01 mg GAE (gallic acid equivalents)/g, which was approximately half that of the methanol extract (77.33 mg GAE/g). The results of antioxidant assays showed a uniform trend, with the methanol extract's antioxidant reducing activity exceeding that of water extracts, typically by a factor of 2:1. Regression analysis of the antioxidant assays showed the strongest correlation between extract TPC and antioxidant activity for the ABTS (2,2-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) and DPPH (2,2-diphenyl-1-picrylhydrazyl) methods. The methanol extract also showed greater growth inhibition capacity towards the MiaPaCa-2 pancreatic cancer cell line. These data suggest that further investigations are required to confirm the source of activity within the E. tirucalli leaf and stems for potential use in the nutraceutical and pharmaceutical industries. PMID:26783950

  18. Mitochondrial chaperones may be targets for anti-cancer drugs

    Cancer.gov

    Scientists at NCI have found that a mitochondrial chaperone protein, TRAP1, may act indirectly as a tumor suppressor as well as a novel target for developing anti-cancer drugs. Chaperone proteins, such as TRAP1, help other proteins adapt to stress, but sc

  19. Synthesis, anti-cancer evaluation of benzenesulfonamide derivatives as potent tubulin-targeting agents.

    PubMed

    Yang, Jun; Yang, Simin; Zhou, Shanshan; Lu, Dongbo; Ji, Liyan; Li, Zhongjun; Yu, Siwang; Meng, Xiangbao

    2016-10-21

    A series of benzenesulfonamide derivatives were synthesized and evaluated for their anti-proliferative activity and interaction with tubulin. These new derivatives showed significant activities against cellular proliferative and tubulin polymerization. Compound BA-3b proved to be the most potent compound with IC50 value ranging from 0.007 to 0.036 μM against seven cancer cell lines, and three drug-resistant cancer cell lines, which indicated a promising anti-cancer agent. The target tubulin was also verified by dynamic tubulin polymerization assay and tubulin intensity assay. PMID:27423028

  20. Synthesis of xanthone derivatives based on α-mangostin and their biological evaluation for anti-cancer agents.

    PubMed

    Fei, Xiang; Jo, Minmi; Lee, Bit; Han, Sang-Bae; Lee, Kiho; Jung, Jae-Kyung; Seo, Seung-Yong; Kwak, Young-Shin

    2014-05-01

    A xanthone-derived natural product, α-mangostin is isolated from various parts of the mangosteen, Garcinia mangostana L. (Clusiaceae), a well-known tropical fruit. Novel xanthone derivatives based on α-mangostin were synthesized and evaluated as anti-cancer agents by cytotoxicity activity screening using 5 human cancer cell lines. Some of these analogs had potent to moderate inhibitory activities. The structure-activity relationship studies revealed that phenol groups on C3 and C6 are critical to anti-proliferative activity and C4 modification is capable to improve both anti-cancer activity and drug-like properties. Our findings provide new possibilities for further explorations to improve potency. PMID:24717154

  1. DNA binding and anti-cancer activity of redox-active heteroleptic piano-stool Ru(II), Rh(III), and Ir(III) complexes containing 4-(2-methoxypyridyl)phenyldipyrromethene.

    PubMed

    Gupta, Rakesh Kumar; Pandey, Rampal; Sharma, Gunjan; Prasad, Ritika; Koch, Biplob; Srikrishna, Saripella; Li, Pei-Zhou; Xu, Qiang; Pandey, Daya Shankar

    2013-04-01

    The synthesis of four novel heteroleptic dipyrrinato complexes [(η(6)-arene)RuCl(2-pcdpm)] (η(6)-arene = C6H6, 1; C10H14, 2) and [(η(5)-C5Me5)MCl(2-pcdpm)] (M = Rh, 3; Ir, 4) containing a new chelating ligand 4-(2-methoxypyridyl)-phenyldipyrromethene (2-pcdpm) have been described. The complexes 1-4 have been fully characterized by various physicochemical techniques, namely, elemental analyses, spectral (ESI-MS, IR, (1)H, (13)C NMR, UV/vis) and electrochemical studies (cyclic voltammetry (CV) and differential pulse voltammetry (DPV)). Structures of 3 and 4 have been determined crystallographically. In vitro antiproliferative and cytotoxic activity of these complexes has been evaluated by trypan blue exclusion assay, cell morphology, apoptosis, acridine orange/ethidium bromide (AO/EtBr) fluorescence staining, and DNA fragmentation assay in Dalton lymphoma (DL) cell lines. Interaction of 1-4 with calf thymus DNA (CT DNA) has also been supported by absorption titration and electrochemical studies. Our results suggest that in vitro antitumor activity of 1-4 lies in the order 2 > 1 > 4 > 3. PMID:23477351

  2. Nutrition: An Anti-Cancer Diet?

    ERIC Educational Resources Information Center

    Grady, Denise; Siwolop, Sana

    1984-01-01

    Presents seven dietary guidelines on ways to reduce the risk of contracting cancer, discussing scientific evidence supporting the guidelines. Includes a list of foods indicating possible role in cancer, sources, recommendations related to amount/frequency of intake, and hazards of megadoses. Foods cited include fats, vitamins, alcohol, caffeine,…

  3. Recent Development in Carbohydrate Based Anti-cancer Vaccines

    PubMed Central

    Yin, Zhaojun; Huang, Xuefei

    2012-01-01

    The development of carbohydrate based anti-cancer vaccines is of high current interests. Herein, the latest development in this exciting field is reviewed. After a general introduction about tumor associated carbohydrate antigens and immune responses, the review is focused on the various strategies that have been developed to enhance the immunogenecity of these antigens. The results from animal studies and clinical trials are presented. PMID:22468019

  4. Phenethyl Isothiocyanate: A comprehensive review of anti-cancer mechanisms

    PubMed Central

    Gupta, Parul; Wright, Stephen E.; Kim, Sung-Hoon; Srivastava, Sanjay K.

    2014-01-01

    The epidemiological evidence suggests a strong inverse relationship between dietary intake of cruciferous vegetables and the incidence of cancer. Among other constituents of cruciferous vegetables, isothiocyanates (ITC) are the main bioactive chemicals present. Phenethyl isothiocyanate (PEITC) is present as gluconasturtiin in many cruciferous vegetables with remarkable anti-cancer effects. PEITC is known to not only prevent the initiation phase of carcinogenesis process but also to inhibit the progression of tumorigenesis. PEITC targets multiple proteins to suppress various cancer-promoting mechanisms such as cell proliferation, progression and metastasis. Pre-clinical evidence suggests that combination of PEITC with conventional anti-cancer agents is also highly effective in improving overall efficacy. Based on accumulating evidence, PEITC appears to be a promising agent for cancer therapy and is already under clinical trials for leukemia and lung cancer. This is the first review which provides a comprehensive analysis of known targets and mechanisms along with a critical evaluation of PEITC as a future anti-cancer agent. PMID:25152445

  5. Synthesis and in vitro anti-cancer evaluation of luteinizing hormone-releasing hormone-conjugated peptide.

    PubMed

    Deng, Xin; Qiu, Qianqian; Ma, Ke; Huang, Wenlong; Qian, Hai

    2015-11-01

    Luteinizing hormone-releasing hormone (LHRH) is a decapeptide hormone released from the hypothalamus and shows high affinity binding to the LHRH receptors. It is reported that several cancer cells also express LHRH receptors such as breast, ovarian, prostatic, bladder and others. In this study, we linked B1, an anti-cancer peptide, to LHRH and its analogs to improve the activity against cancer cells with LHRH receptor. Biological evaluation revealed that TB1, the peptide contains triptorelin sequence, present favorable anti-cancer activity as well as plasma stability. Further investigations disclosed that TB1 trigger apoptosis by activating the mitochondria-cytochrome c-caspase apoptotic pathway, it also exhibited the anti-migratory effect on cancer cells. PMID:26058357

  6. In Vivo Anti-Cancer Mechanism of Low-Molecular-Weight Fucosylated Chondroitin Sulfate (LFCS) from Sea Cucumber Cucumaria frondosa.

    PubMed

    Liu, Xiaoxiao; Liu, Yong; Hao, Jiejie; Zhao, Xiaoliang; Lang, Yinzhi; Fan, Fei; Cai, Chao; Li, Guoyun; Zhang, Lijuan; Yu, Guangli

    2016-01-01

    The low-molecular-weight fucosylated chondroitin sulfate (LFCS) was prepared from native fucosylated chondroitin sulfate (FCS), which was extracted and isolated from sea cucumber Cucumaria frondosa, and the anti-cancer mechanism of LFCS on mouse Lewis lung carcinoma (LLC) was investigated. The results showed that LFCS remarkably inhibited LLC growth and metastasis in a dose-dependent manner. LFCS induced cell cycle arrest by increasing p53/p21 expression and apoptosis through activation of caspase-3 activity in LLC cells. Meanwhile, LFCS suppressed the expression of vascular endothelial growth factor (VEGF), increased the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and downregulated the matrix metalloproteinases (MMPs) level. Furthermore, LFCS significantly suppressed the activation of ERK1/2/p38 MAPK/NF-κB pathway, which played a prime role in expression of MMPs. All of these data indicate LFCS may be used as anti-cancer drug candidates and deserve further study. PMID:27187337

  7. Aloe-emodin loaded solid lipid nanoparticles: formulation design and in vitro anti-cancer study.

    PubMed

    Chen, Ruie; Wang, Shengpeng; Zhang, Jinming; Chen, Meiwan; Wang, Yitao

    2015-01-01

    Aloe-emodin (AE) is a promising anti-tumor candidate for its significant activity against various tumors such as lung cancer, hepatic cancer, breast cancer and so on. Nevertheless, AE is clinically limited due to its poor water solubility and low bioavailability. This study was designed to prepare AE-loaded solid lipid nanoparticles (AE-SLNs) in an attempt to improve the anti-cancer efficacy of AE. The AE-SLNs were prepared with optimized prescription using high pressure homogenization (HPH) technique. Ultimately, the AE-SLNs showed stable particle size at 88.9 ± 5.2 nm, ideal drug entrapment efficiency (EE) of 97.71 ± 0.5% and good stability with regard to zeta-potential as high as -42.8 mV. The in vitro release profiles revealed that AE achieved sustained release by loading into SLNs. Moreover, AE-SLNs showed significantly higher in vitro cytotoxicity against human breast cancer MCF-7 cells and human hepatoma HepG2 cells as compared to the AE solution, while they showed no significant toxicity on human mammary epithelial MCF-10A cells. Hoechst 33342 staining and Annexin V/PI double staining indicated that AE-SLNs induced higher apoptotic rates in MCF-7 cells. Further study elucidated that the improved anti-cancer efficacy may be attributed to the increased cellular uptake of AE. Based on these findings, we believe that the development of AE-SLNs is an effective way for improving the anti-cancer efficacy of AE. PMID:24512431

  8. Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug

    PubMed Central

    Lam, Wing; Gullen, Elizabeth A.; Yu, Zhe; Wei, Ying; Wang, Lihui; Zeiss, Caroline; Beck, Amanda; Cheng, Ee-Chun; Wu, Chunfu; Cheng, Yung-Chi; Zhang, Yixuan

    2015-01-01

    Malformin C, a fungal cyclic pentapeptide, has been claimed to have anti-cancer potential, but no in vivo study was available to substantiate this property. Therefore, we conducted in vitro and in vivo experiments to investigate its anti-cancer effects and toxicity. Our studies showed Malformin C inhibited Colon 38 and HCT 116 cell growth dose-dependently with an IC50 of 0.27±0.07μM and 0.18±0.023μM respectively. This inhibition was explicated by Malformin C’s effect on G2/M arrest. Moreover, we observed up-regulated expression of phospho-histone H2A.X, p53, cleaved CASPASE 3 and LC3 after Malformin C treatment, while the apoptosis assay indicated an increased population of necrotic and late apoptotic cells. In vivo, the pathological study exhibited the acute toxicity of Malformin C at lethal dosage in BDF1 mice might be caused by an acute yet subtle inflammatory response, consistent with elevated IL-6 in the plasma cytokine assay. Further anti-tumor and toxicity experiments proved that 0.3mg/kg injected weekly was the best therapeutic dosage of Malformin C in Colon 38 xenografted BDF1 mice, whereas 0.1mg/kg every other day showed no effect with higher resistance, and 0.9mg/kg per week either led to fatal toxicity in seven-week old mice or displayed no advantage over 0.3mg/kg group in nine-week old mice. Overall, we conclude that Malformin C arrests Colon 38 cells in G2/M phase and induces multiple forms of cell death through necrosis, apoptosis and autophagy. Malformin C has potent cell growth inhibition activity, but the therapeutic index is too low to be an anti-cancer drug. PMID:26540166

  9. Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-cancer agents.

    PubMed

    Penthala, Narsimha Reddy; Thakkar, Shraddha; Crooks, Peter A

    2015-07-15

    Heteroaromatic analogs of DMU-212 (8-15) have been synthesized and evaluated for their anti-cancer activity against a panel of 60 human cancer cell lines. These novel analogs contain a trans-3,4,5-trimethoxystyryl moiety attached to the C2 position of indole, benzofuran, benzothiazole or benzothiophene ring (8, 11, 13 and 14, respectively) and showed potent growth inhibition in 85% of the cancer cell lines examined, with GI50 values <1 μM. Interestingly, trans-3,4- and trans-3,5-dimethoxystyryl DMU-212 analogs 9, 10, 12 and 15 exhibited significantly less growth inhibition than their 3,4,5-trimethoxystyryl counterparts, suggesting that the trans-3,4,5-trimethoxystyryl moiety is an essential structural element for the potent anti-cancer activity of these heterocyclic DMU-212 analogs. Molecular modeling studies showed that the four most active compounds (8, 11, 13 and 14) all bind to the colchicine binding site on tubulin, and that their binding modes are similar to that of DMU-212. PMID:26022840

  10. Repurposing Drugs in Oncology (ReDO)—itraconazole as an anti-cancer agent

    PubMed Central

    Pantziarka, Pan; Sukhatme, Vidula; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vikas P

    2015-01-01

    Itraconazole, a common triazole anti-fungal drug in widespread clinical use, has evidence of clinical activity that is of interest in oncology. There is evidence that at the clinically relevant doses, itraconazole has potent anti-angiogenic activity, and that it can inhibit the Hedgehog signalling pathway and may also induce autophagic growth arrest. The evidence for these anticancer effects, in vitro, in vivo, and clinical are summarised, and the putative mechanisms of their action outlined. Clinical trials have shown that patients with prostate, lung, and basal cell carcinoma have benefited from treatment with itraconazole, and there are additional reports of activity in leukaemia, ovarian, breast, and pancreatic cancers. Given the evidence presented, a case is made that itraconazole warrants further clinical investigation as an anti- cancer agent. Additionally, based on the properties summarised previously, it is proposed that itraconazole may synergise with a range of other drugs to enhance the anti-cancer effect, and some of these possible combinations are presented in the supplementary materials accompanying this paper. PMID:25932045

  11. Design, Synthesis, and Evaluation of Genistein Analogues as Anti-Cancer Agents

    PubMed Central

    Xiong, Pahoua; Wang, Rubing; Zhang, Xiaojie; Torre, Eduardo DeLa; Leon, Francisco; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong

    2016-01-01

    Genistein is a bioactive isoflavone derived from soybeans. The tie-in between the intake of genistein and the decreased incidence of some solid tumors (including prostate cancer) has been demonstrated by epidemiological studies. The potential of genistein in treating prostate cancer has also been displayed by in vitro cell-based and in vivo animal experiments. Genistein has entered clinical trials for both chemoprevention and potential treatment of prostate cancer. Even though the low oral bioavailability has presented the major challenges to genistein’s further clinical development, chemical modulation of genistein holds the promise to generate potential anti-prostate cancer agents with enhanced potency and/or better pharmacokinetic profiles than genistein. As part of our ongoing project to develop natural products-based anti-prostate cancer agents, the current study was undertaken to synthesize eight genistein analogues for cytotoxic evaluation in three prostate cancer cell lines (PC-3, DU-145, LNCaP; both androgen-sensitive and androgen-refractory cell lines), as well as one aggressive cervical cancer cell line (HeLa). Eight genistein analogues have been successfully synthesized with Suzuki-Miyaura coupling reaction as a key step. Their in vitro anti-cancer potential was evaluated by trypan blue exclusion assay and WST-1 cell proliferation assay against a panel of four human cancer cell lines. The acquired data suggest i) that the C-5 and C-7 hydroxyl groups in genistein are very important for the cytotoxicity and anti-proliferative activity; and ii) that 1-alkyl-1H-pyrazol-4-yl and pyridine-3-yl might act as good bioisosteres for the 4'-hydroxyphenyl moiety in genistein. PMID:25991428

  12. Design, Synthesis, and Evaluation of Genistein Analogues as Anti-Cancer Agents.

    PubMed

    Xiong, Pahoua; Wang, Rubing; Zhang, Xiaojie; DeLa Torre, Eduardo; Leon, Francisco; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong

    2015-01-01

    Genistein is a bioactive isoflavone derived from soybeans. The tie-in between the intake of genistein and the decreased incidence of some solid tumors (including prostate cancer) has been demonstrated by epidemiological studies. The potential of genistein in treating prostate cancer has also been displayed by in vitro cell-based and in vivo animal experiments. Genistein has entered clinical trials for both chemoprevention and potential treatment of prostate cancer. Even though the low oral bioavailability has presented the major challenges to genistein's further clinical development, chemical modulation of genistein holds the promise to generate potential anti-prostate cancer agents with enhanced potency and/or better pharmacokinetic profiles than genistein. As part of our ongoing project to develop natural products-based anti-prostate cancer agents, the current study was undertaken to synthesize eight genistein analogues for cytotoxic evaluation in three prostate cancer cell lines (PC-3, DU-145, LNCaP; both androgen-sensitive and androgen-refractory cell lines), as well as one aggressive cervical cancer cell line (HeLa). Eight genistein analogues have been successfully synthesized with Suzuki-Miyaura coupling reaction as a key step. Their in vitro anti-cancer potential was evaluated by trypan blue exclusion assay and WST-1 cell proliferation assay against a panel of four human cancer cell lines. The acquired data suggest i) that the C-5 and C-7 hydroxyl groups in genistein are very important for the cytotoxicity and anti-proliferative activity; and ii) that 1-alkyl-1H-pyrazol-4-yl and pyridine-3-yl might act as good bioisosteres for the 4'-hydroxyphenyl moiety in genistein. PMID:25991428

  13. New oleyl glycoside as anti-cancer agent that targets on neutral sphingomyelinase.

    PubMed

    Romero-Ramírez, Lorenzo; García-Álvarez, Isabel; Casas, Josefina; Barreda-Manso, M Asunción; Yanguas-Casás, Natalia; Nieto-Sampedro, Manuel; Fernández-Mayoralas, Alfonso

    2015-09-15

    We designed and synthesized two anomeric oleyl glucosaminides as anti-cancer agents where the presence of a trifluoroacetyl group close to the anomeric center makes them resistant to hydrolysis by hexosaminidases. The oleyl glycosides share key structural features with synthetic and natural oleyl derivatives that have been reported to exhibit anti-cancer properties. While both glycosides showed antiproliferative activity on cancer cell lines, only the α-anomer caused endoplasmic reticulum (ER) stress and cell death on C6 glioma cells. Analysis of sphingolipids and glycosphingolipds in cells treated with the glycosides showed that the α-anomer caused a drastic accumulation of ceramide and glucosylceramide and reduction of lactosylceramide and GM3 ganglioside at concentrations above a threshold of 20 μM. In order to understand how ceramide levels increase in response to α-glycoside treatment, further investigations were done using specific inhibitors of sphingolipid metabolic pathways. The pretreatment with 3-O-methylsphingomyelin (a neutral sphingomyelinase inhibitor) restored sphingomyelin levels together with the lactosylceramide and GM3 ganglioside levels and prevented the ER stress and cell death caused by the α-glycoside. The results indicated that the activation of neutral sphingomyelinase is the main cause of the alterations in sphingolipids that eventually lead to cell death. The new oleyl glycoside targets a key enzyme in sphingolipid metabolism with potential applications in cancer therapy. PMID:26206186

  14. Tumorsphere as an effective in vitro platform for screening anti-cancer stem cell drugs

    PubMed Central

    Lee, Che-Hsin; Yu, Cheng-Chia; Wang, Bing-Yen; Chang, Wen-Wei

    2016-01-01

    Cancer stem cells (CSCs) are a sub-population of cells within cancer tissues with tumor initiation, drug resistance and metastasis properties. CSCs also have been considered as the main cause of cancer recurrence. Targeting CSCs have been suggested as the key for successful treatment against cancer. Tumorsphere cultivation is based on culturing cancer cells onto ultralow attachment surface in serum-free media under the supplementation with growth factors such as epidermal growth factor and basic fibroblast growth factor. Tumorsphere cultivation is widely used to analyze the self-renewal capability of CSCs and to enrich these cells from bulk cancer cells. This method also provides a reliable platform for screening potential anti-CSC agents. The in vitro anti-proliferation activity of potential agents selected from tumorsphere assay is more translatable into in vivo anti-tumorigenic activity compared with general monolayer culture. Tumorsphere assay can also measure the outcome of clinical trials for potential anti-cancer agents. In addition, tumorsphere assay may be a promising strategy in the innovation of future cancer therapeutica and may help in the screening of anti-cancer small-molecule chemicals. PMID:26527320

  15. Synthesis and anti-cancer screening of novel heterocyclic-(2H)-1,2,3-triazoles as potential anti-cancer agents

    PubMed Central

    Penthala, Narsimha Reddy; Madhukuri, Leena; Thakkar, Shraddha; Madadi, Nikhil Reddy; Lamture, Gauri; Eoff, Robert L.; Crooks, Peter A.

    2015-01-01

    trans-Cyanocombretastatin A-4 (trans-CA-4) analogues have been structurally modified to afford their more stable CA-4-(2H)-1,2,3-triazole analogues. Fifteen novel, stable 4-heteroaryl-5-aryl-(2H)-1,2,3-triazole CA-4 analogues (8a–i, 9 and 11a–e) were evaluated for anti-cancer activity against a panel of 60 human cancer cell lines. These analogues displayed potent cytotoxic activity against both hematological and solid tumor cell lines with GI50 values in the low nanomolar range. The most potent compound, 8a, was a benzothiophen-2-yl analogue that incorporated a 3,4,5-trimethoxyphenyl moiety connected to the (2H)-1,2,3-triazole ring system. Compound 8a exhibited GI50 values of <10 nM against 80% of the cancer cell lines in the panel. Three triazole analogues, 8a, 8b and 8g, showed particularly potent growth inhibition against the triple negative Hs578T breast cancer cell line with GI50 values of 10.3 nM, 66.5 nM and 20.3 nM, respectively. Molecular docking studies suggest that these compounds bind to the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine and cis-CA-4, and are stabilized by Van der Waals’ interactions with surrounding amino acid residues. Compound 8a was found to inhibit tubulin polymerization in vitro with an IC50 value of 1.7 µM. The potent cytotoxicity of these novel compounds and their inhibition of tubulin dynamics make these triazole analogues promising candidates for development as anti-cancer drugs. PMID:27066215

  16. Repurposing Drugs in Oncology (ReDO)—nitroglycerin as an anti-cancer agent

    PubMed Central

    Sukhatme, Vidula; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vikas P; Pantziarka, Pan

    2015-01-01

    Nitroglycerin (NTG), a drug that has been in clinical use for more than a century, has a range of actions which make it of particular interest in an oncological setting. It is generally accepted that the main mechanism of action of NTG is via the production of nitric oxide (NO), which improves cardiac oxygenation via multiple mechanisms including improved blood flow (vasodilation), decreased platelet aggregation, increased erythrocyte O2 release and decreased mitochondrial utilization of oxygen. Its vasoactive properties mean that it has the potential to exploit more fully the enhanced permeability and retention effect in delivering anti-cancer drugs to tumour tissues. Moreover NTG can reduce HIF-1α levels in hypoxic tumour tissues and this may have anti-angiogenic, pro-apoptotic and anti-efflux effects. Additionally NTG may enhance anti-tumour immunity. Pre-clinical and clinical data on these anti-cancer properties of NTG are summarised and discussed. While there is evidence of a positive action as a monotherapy in prostate cancer, there are mixed results in NSCLC where initially positive results have yet to be fully replicated. Based on the evidence presented, a case is made that further exploration of the clinical benefits that may accrue to cancer patients is warranted. Additionally, it is proposed that NTG may synergise with a number of other drugs, including other repurposed drugs, and these are discussed in the supplementary material appended to this paper. PMID:26435741

  17. From COX-2 inhibitor nimesulide to potent anti-cancer agent: synthesis, in vitro, in vivo and pharmacokinetic evaluation

    PubMed Central

    Chennamaneni, Snigdha; Yi, Xin; Liu, lili; Pink, John J.; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; Su, Bin

    2014-01-01

    Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure–function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC50s around 100nM to 200nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC50s around 100nM to 500nM. Intraperitoneal injection with a dosage of 5mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound. PMID:22119125

  18. Identification of anti-cancer chemical compounds using Xenopus embryos.

    PubMed

    Tanaka, Masamitsu; Kuriyama, Sei; Itoh, Go; Kohyama, Aki; Iwabuchi, Yoshiharu; Shibata, Hiroyuki; Yashiro, Masakazu; Aiba, Namiko

    2016-06-01

    Cancer tissues have biological characteristics similar to those observed in embryos during development. Many types of cancer cells acquire pro-invasive ability through epithelial-mesenchymal transition (EMT). Similar processes (gastrulation and migration of cranial neural crest cells [CNCC]) are observed in the early stages of embryonic development in Xenopus during which cells that originate from epithelial sheets through EMT migrate to their final destinations. The present study examined Xenopus embryonic tissues to identify anti-cancer compounds that prevent cancer invasion. From the initial test of known anti-cancer drugs, AMD3100 (an inhibitor of CXCR4) and paclitaxel (a cytoskeletal drug targeting microtubules) effectively prevented migration during gastrulation or CNCC development. Blind-screening of 100 synthesized chemical compounds was performed, and nine candidates that inhibited migration of these embryonic tissues without embryonic lethality were selected. Of these, C-157 (an analog of podophyllotoxin) and D-572 (which is an indole alkaroid) prevented cancer cell invasion through disruption of interphase microtubules. In addition, these compounds affected progression of mitotic phase and induced apoptosis of SAS oral cancer cells. SAS tumors were reduced in size after intratumoral injection of C-157, and peritoneal dissemination of melanoma cells and intracranial invasion of glioma cells were inhibited by C-157 and D-572. When the other analogues of these chemicals were compared, those with subtle effect on embryos were not tumor suppressive. These results suggest that a novel chemical-screening approach based on Xenopus embryos is an effective method for isolating anti-cancer drugs and, in particular, targeting cancer cell invasion and proliferation. PMID:27019404

  19. Tandem Mass Spectrometry for Characterization of Covalent Adducts of DNA with Anti-cancer Therapeutics

    PubMed Central

    Silvestri, Catherine; Brodbelt, Jennifer S.

    2012-01-01

    The chemotherapeutic activities of many anticancer and antibacterial drugs arise from their interactions with nucleic acid substrates. Some of these ligands interact with DNA in a way that causes conformational changes or damage to the nucleic acid targets, ultimately altering recognition by key DNA-specific enzymes, interfering with DNA transcription or prohibiting replication, and terminating cell growth and proliferation. The design and synthesis of ligands that bind to nucleic acids remains a dynamic field in medicinal chemistry and pharmaceutical research. The quest for more selective and efficacious DNA-interactive anti-cancer chemotherapeutics has likewise catalyzed the need for sensitive analytical methods that can provide structural information about the nature of the resulting DNA adducts and provide insight into the mechanistic pathways of the DNA/drug interactions and the impact on the cellular processes in biological systems. This review focuses on the array of tandem mass spectrometric strategies developed and applied for characterization of covalent adducts formed between DNA and anti-cancer ligands. PMID:23150278

  20. Mitochondrial apoptosis contributes to the anti-cancer effect of Smilax glabra Roxb.

    PubMed

    Gao, Yujing; Su, Yahui; Qu, Like; Xu, Shuo; Meng, Lin; Cai, Shao-Qing; Shou, Chengchao

    2011-11-30

    Smilax glabra Roxb. (SGR), a member of the Smilacaceae family and a rhizome of the Liliaceae plant, has shown anti-inflammation and detoxification properties, and a few studies reported its anti-cancer effect. In this study, we showed that SGR inhibited growth of human breast cancer cell line MCF7, colon carcinoma cell line HT-29, and gastric cancer cell line BGC-823 in a dose-dependent manner. Furthermore, SGR could inhibit tumor growth of HT-29 in Balb/c nude mice and murine hepatoma H22 cells in ICR mice. SGR elicited apoptotic cell death, as confirmed by DNA ladder formation, changes in nuclear morphology, and the increased FITC-Annexin-V/PI staining. Permeabilization of mitochondrial membrane (MMP), production of reactive oxygen species (ROS), elevation of intracellular [Ca(2+)], relocation of cytochrome c, and the activation of caspase-3 were found to be associated with the initiation of apoptosis by SGR treatment. Using microarray analysis, we found the changes in expression profiles of genes related to apoptosis, proliferation and cell cycle control in the cells treated with SGR. Our results demonstrated the mitochondrial regulation of apoptosis by which SGR exerts the anti-cancer effect. PMID:21920417

  1. Knockdown of delta-5-desaturase promotes the anti-cancer activity of dihomo-γ-linolenic acid and enhances the efficacy of chemotherapy in colon cancer cells expressing COX-2.

    PubMed

    Xu, Yi; Yang, Xiaoyu; Zhao, Pinjing; Yang, Zhongyu; Yan, Changhui; Guo, Bin; Qian, Steven Y

    2016-07-01

    Cyclooxygenase (COX), commonly overexpressed in cancer cells, is a major lipid peroxidizing enzyme that metabolizes polyunsaturated fatty acids (ω-3s and ω-6s). The COX-catalyzed free radical peroxidation of arachidonic acid (ω-6) can produce deleterious metabolites (e.g. 2-series prostaglandins) that are implicated in cancer development. Thus, COX inhibition has been intensively investigated as a complementary therapeutic strategy for cancer. However, our previous study has demonstrated that a free radical-derived byproduct (8-hydroxyoctanoic acid) formed from COX-catalyzed peroxidation of dihomo-γ-linolenic acid (DGLA, the precursor of arachidonic acid) can inhibit colon cancer cell growth. We thus hypothesize that the commonly overexpressed COX in cancer (~90% of colon cancer patients) can be taken advantage to suppress cell growth by knocking down delta-5-desaturase (D5D, a key enzyme that converts DGLA to arachidonic acid). In addition, D5D knockdown along with DGLA supplement may enhance the efficacy of chemotherapeutic drugs. After knocking down D5D in HCA-7 colony 29 cells and HT-29 cells (human colon cancer cell lines with high and low COX levels, respectively), the antitumor activity of DGLA was significantly enhanced along with the formation of a threshold range (~0.5-1.0μM) of 8-hydroxyoctanoic acid. In contrast, DGLA treatment did not inhibit cell growth when D5D was not knocked down and only limited amount of 8-hydroxyoctanoic acid was formed. D5D knockdown along with DGLA treatment also enhanced the cytotoxicities of various chemotherapeutic drugs, including 5-fluorouracil, regorafenib, and irinotecan, potentially through the activation of pro-apoptotic proteins, e.g. p53 and caspase 9. For the first time, we have demonstrated that the overexpressed COX in cancer cells can be utilized in suppressing cancer cell growth. This finding may provide a new option besides COX inhibition to optimize cancer therapy. The outcome of this translational

  2. Knockdown of delta-5-desaturase promotes the anti-cancer activity of dihomo-γ-linolenic acid and enhances the efficacy of chemotherapy in colon cancer cells expressing COX-2

    PubMed Central

    Xu, Yi; Yang, Xiaoyu; Zhao, Pinjing; Yang, Zhongyu; Yan, Changhui; Guo, Bin; Qian, Steven Y.

    2016-01-01

    Cyclooxygenase (COX), commonly overexpressed in cancer cells, is a major lipid peroxidizing enzyme that metabolizes polyunsaturated fatty acids (ω-3s and ω-6s). The COX-catalyzed free radical peroxidation of arachidonic acid (ω-6) can produce deleterious metabolites (e.g. 2-series prostaglandins) that are implicated in cancer development. Thus, COX inhibition has been intensively investigated as a complementary therapeutic strategy for cancer. However, our previous study has demonstrated that a free radical-derived by product (8-hydroxyoctanoic acid) formed from COX-catalyzed peroxidation of dihomo-γ-linolenic acid (DGLA, the precursor of arachidonic acid) can inhibit colon cancer cell growth. We thus hypothesize that the commonly overexpressed COX in cancer (~90% of colon cancer patients) can be taken advantage to suppress cell growth by knocking down delta-5-desaturase (D5D, a key enzyme that converts DGLA to arachidonic acid). In addition, D5D knockdown along with DGLA supplement may enhance the efficacy of chemotherapeutic drugs. After knocking down D5D in HCA-7 colony 29 cells and HT-29 cells (human colon cancer cell lines with high and low COX levels, respectively), the antitumor activity of DGLA was significantly enhanced along with the formation of a threshold range (~0.5–1.0 µM) of 8-hydroxyoctanoic acid. In contrast, DGLA treatment did not inhibit cell growth when D5D was not knocked down and only limited amount of 8-hydroxyoctanoic acid was formed. D5D knockdown along with DGLA treatment also enhanced the cytotoxicities of various chemotherapeutic drugs, including 5-fluorouracil, regorafenib, and irinotecan, potentially through the activation of pro-apoptotic proteins, e.g. p53 and caspase 9. For the first time, we have demonstrated that the overexpressed COX in cancer cells can be utilized in suppressing cancer cell growth. This finding may provide a new option besides COX inhibition to optimize cancer therapy. The outcome of this translational

  3. Carboxyamidotriazole inhibits oxidative phosphorylation in cancer cells and exerts synergistic anti-cancer effect with glycolysis inhibition.

    PubMed

    Ju, Rui; Guo, Lei; Li, Juan; Zhu, Lei; Yu, Xiaoli; Chen, Chen; Chen, Wei; Ye, Caiying; Zhang, Dechang

    2016-01-28

    Targeting cancer cell metabolism is a promising strategy against cancer. Here, we confirmed that the anti-cancer drug carboxyamidotriazole (CAI) inhibited mitochondrial respiration in cancer cells for the first time and found a way to enhance its anti-cancer activity by further disturbing the energy metabolism. CAI promoted glucose uptake and lactate production when incubated with cancer cells. The oxidative phosphorylation (OXPHOS) in cancer cells was inhibited by CAI, and the decrease in the activity of the respiratory chain complex I could be one explanation. The anti-cancer effect of CAI was greatly potentiated when being combined with 2-deoxyglucose (2-DG). The cancer cells treated with the combination of CAI and 2-DG were arrested in G2/M phase. The apoptosis and necrosis rates were also increased. In a mouse xenograft model, this combination was well tolerated and retarded the tumor growth. The impairment of cancer cell survival was associated with significant cellular ATP decrease, suggesting that the combination of CAI and 2-DG could be one of the strategies to cause dual inhibition of energy pathways, which might be an effective therapeutic approach for a broad spectrum of tumors. PMID:26522259

  4. Mechanism of the induction of endoplasmic reticulum stress by the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT): Activation of PERK/eIF2α, IRE1α, ATF6 and calmodulin kinase.

    PubMed

    Merlot, Angelica M; Shafie, Nurul H; Yu, Yu; Richardson, Vera; Jansson, Patric J; Sahni, Sumit; Lane, Darius J R; Kovacevic, Zaklina; Kalinowski, Danuta S; Richardson, Des R

    2016-06-01

    The endoplasmic reticulum (ER) plays a major role in the synthesis, maturation and folding of proteins and is a critical calcium (Ca(2+)) reservoir. Cellular stresses lead to an overwhelming accumulation of misfolded proteins in the ER, leading to ER stress and the activation of the unfolded protein response (UPR). In the stressful tumor microenvironment, the UPR maintains ER homeostasis and enables tumor survival. Thus, a novel strategy for cancer therapeutics is to overcome chronically activated ER stress by triggering pro-apoptotic pathways of the UPR. Considering this, the mechanisms by which the novel anti-cancer agent, Dp44mT, can target the ER stress response pathways were investigated in multiple cell-types. Our results demonstrate that the cytotoxic chelator, Dp44mT, which forms redox-active metal complexes, significantly: (1) increased ER stress-associated pro-apoptotic signaling molecules (i.e., p-eIF2α, ATF4, CHOP); (2) increased IRE1α phosphorylation (p-IRE1α) and XBP1 mRNA splicing; (3) reduced expression of ER stress-associated cell survival signaling molecules (e.g., XBP1s and p58(IPK)); (4) increased cleavage of the transcription factor, ATF6, which enhances expression of its downstream targets (i.e., CHOP and BiP); and (5) increased phosphorylation of CaMKII that induces apoptosis. In contrast to Dp44mT, the iron chelator, DFO, which forms redox-inactive iron complexes, did not affect BiP, p-IRE1α, XBP1 or p58(IPK) levels. This study highlights the ability of a novel cancer therapeutic (i.e., Dp44mT) to target the pro-apoptotic functions of the UPR via cellular metal sequestration and redox stress. Assessment of ER stress-mediated apoptosis is fundamental to the understanding of the pharmacology of chelation for cancer treatment. PMID:27059255

  5. Everglades National Park Including Biscayne National Park. Activity Book.

    ERIC Educational Resources Information Center

    Ruehrwein, Dick

    Intended to help elementary school children learn about the resources of the Everglades and Biscayne National Parks, this activity book includes information, puzzles, games, and quizzes. The booklet deals with concepts related to: (1) the seasons; (2) fire ecology; (3) water; (4) fish; (5) mammals; (6) mosquitos; (7) birds; (8) venomous snakes;…

  6. Multifunctional liposomes for enhanced anti-cancer therapy

    NASA Astrophysics Data System (ADS)

    Falcao, Claudio Borges

    2011-12-01

    with half of the concentration needed for G3139 alone in CL to reduce the cell viability by 40%. Also, it was found greater apoptotic signal in cells treated with CLs containing D-(KLAKLAK)2/G3139 complexes than CLs with G3139 only. In vivo, D-(KLAKLAK) 2/G3139 complexes in CL significantly inhibited tumor growth compared to the saline treated group, through apoptosis induction. However, the mechanism involved in cell death by apoptosis seems to be independent of reduction of bcl-2 protein levels. PEG2000 at 1% mol could significantly reduce activity of PCL formulation towards B16(F10) cells compared to CLs. After pre-incubation at pH 7.4, PCL and pH-PCL had decreased activity compared to CL towards B16(F10) cells. After pre-incubation at pH 5.0, while CL and PCL had the same activity with the cells as in neutral pH, pH-PCL formulation had its PEG cleaved and its cytotoxicity was restored against the melanoma cells. Thus, D-(KLAKLAK)2/G3139 complexes in CL had enhanced anti-cancer therapy, through apoptosis, than G3139 alone in CL in vitro and in vivo. In vitro, PCL and pH-PCL particles obtained can have a prolonged blood residence time, and, once a tumor tissue is reached, pH-PCL can have its cytotoxicity restored because of hydrolysis of cleavable PEG at a lowered pH.

  7. The promising alliance of anti-cancer electrochemotherapy with immunotherapy.

    PubMed

    Calvet, Christophe Y; Mir, Lluis M

    2016-06-01

    Anti-tumor electrochemotherapy, which consists in increasing anti-cancer drug uptake by means of electroporation, is now implanted in about 140 cancer treatment centers in Europe. Its use is supported by the English National Institute for Health and Care Excellence for the palliative treatment of skin metastases, and about 13,000 cancer patients were treated by this technology by the end of 2015. Efforts are now focused on turning this local anti-tumor treatment into a systemic one. Electrogenetherapy, that is the electroporation-mediated transfer of therapeutic genes, is currently under clinical evaluation and has brought excitement to enlarge the anti-cancer armamentarium. Among the promising electrogenetherapy strategies, DNA vaccination and cytokine-based immunotherapy aim at stimulating anti-tumor immunity. We review here the interests and state of development of both electrochemotherapy and electrogenetherapy. We then emphasize the potent beneficial outcome of the combination of electrochemotherapy with immunotherapy, such as immune checkpoint inhibitors or strategies based on electrogenetherapy, to simultaneously achieve excellent local debulking anti-tumor responses and systemic anti-metastatic effects. PMID:26993326

  8. Structure-based drug design and potent anti-cancer activity of tricyclic 5:7:5-fused diimidazo[4,5-d:4′,5′-f][1,3]diazepines

    PubMed Central

    Kondaskar, Atul; Kondaskar, Shilpi; Fishbein, James C.; Carter-Cooper, Brandon A.; Lapidus, Rena G.; Sadowska, Mariola; Edelman, Martin J.

    2012-01-01

    Judicial structural modifications of 5:7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anticancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anticancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC50 values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anticancer compounds based on the diimidazo[4,5-d:4′,5′-f][1,3]diazepine structural skeleton of the lead compound 1. PMID:23290252

  9. Metformin may function as anti-cancer agent via targeting cancer stem cells: the potential biological significance of tumor-associated miRNAs in breast and pancreatic cancers

    PubMed Central

    Bao, Bin; Azmi, Asfar S.; Ali, Shadan; Zaiem, Feras

    2014-01-01

    Metformin is one of the most used diabetic drugs for the management of type II diabetes mellitus (DM) in the world. Increased numbers of epidemiological and clinical studies have provided convincing evidence supporting the role of metformin in the development and progression of a variety of human tumors including breast and pancreatic cancer. Substantial pre-clinical evidence from in vitro and in vivo experimental studies strongly suggests that metformin has an anti-cancer activity mediated through the regulation of several cell signaling pathways including activation of AMP kinase (AMPK), and other direct and indirect mechanisms; however, the detailed mechanism(s) has not yet been fully understood. The concept of cancer stem cells (CSCs) has gained significant attention in recent years due its identification and defining its clinical implications in many different tumors including breast cancer and pancreatic cancer. In this review, we will discuss the protective role of metformin in the development of breast and pancreatic cancers. We will further discuss the role of metformin as an anti-cancer agent, which is in part mediated through targeting CSCs. Finally, we will discuss the potential role of metformin in the modulation of tumor-associated or CSC-associated microRNAs (miRNAs) as part of the novel mechanism of action of metformin in the development and progression of breast and pancreatic cancers. PMID:25333034

  10. Metformin may function as anti-cancer agent via targeting cancer stem cells: the potential biological significance of tumor-associated miRNAs in breast and pancreatic cancers.

    PubMed

    Bao, Bin; Azmi, Asfar S; Ali, Shadan; Zaiem, Feras; Sarkar, Fazlul H

    2014-06-01

    Metformin is one of the most used diabetic drugs for the management of type II diabetes mellitus (DM) in the world. Increased numbers of epidemiological and clinical studies have provided convincing evidence supporting the role of metformin in the development and progression of a variety of human tumors including breast and pancreatic cancer. Substantial pre-clinical evidence from in vitro and in vivo experimental studies strongly suggests that metformin has an anti-cancer activity mediated through the regulation of several cell signaling pathways including activation of AMP kinase (AMPK), and other direct and indirect mechanisms; however, the detailed mechanism(s) has not yet been fully understood. The concept of cancer stem cells (CSCs) has gained significant attention in recent years due its identification and defining its clinical implications in many different tumors including breast cancer and pancreatic cancer. In this review, we will discuss the protective role of metformin in the development of breast and pancreatic cancers. We will further discuss the role of metformin as an anti-cancer agent, which is in part mediated through targeting CSCs. Finally, we will discuss the potential role of metformin in the modulation of tumor-associated or CSC-associated microRNAs (miRNAs) as part of the novel mechanism of action of metformin in the development and progression of breast and pancreatic cancers. PMID:25333034

  11. Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties.

    PubMed

    Krastel, Philipp; Roggo, Silvio; Schirle, Markus; Ross, Nathan T; Perruccio, Francesca; Aspesi, Peter; Aust, Thomas; Buntin, Kathrin; Estoppey, David; Liechty, Brigitta; Mapa, Felipa; Memmert, Klaus; Miller, Howard; Pan, Xuewen; Riedl, Ralph; Thibaut, Christian; Thomas, Jason; Wagner, Trixie; Weber, Eric; Xie, Xiaobing; Schmitt, Esther K; Hoepfner, Dominic

    2015-08-24

    Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti-fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF-1α) as the primary target for this compound class. Nannocystin A (1) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site of 1 with the anti-cancer compound didemnin B on EF-1α. This myxobacterial chemotype thus offers an interesting starting point for further investigations of the potential of therapeutics targeting elongation factor 1. PMID:26179970

  12. [Multifaceted Intervention to Explore the Appropriate Time of Anti-Cancer Treatment Cessation].

    PubMed

    Morita, Tatsuya; Okusaka, Takuji; Shimizu, Chikako

    2016-07-01

    When anti-cancer treatment should be ended is very controversial. This reviewprovides a narrative summary of recent empirical studies about the potential association between the timing of anti-cancer treatment cessation and patient quality of death and dying. Furthermore, we propose a multifaceted intervention model for Japanese oncology patients based on the evidence available. PMID:27431627

  13. Development of Lipid-Shell and Polymer Core Nanoparticles with Water-Soluble Salidroside for Anti-Cancer Therapy

    PubMed Central

    Fang, Dai-Long; Chen, Yan; Xu, Bei; Ren, Ke; He, Zhi-Yao; He, Li-Li; Lei, Yi; Fan, Chun-Mei; Song, Xiang-Rong

    2014-01-01

    Salidroside (Sal) is a potent antitumor drug with high water-solubility. The clinic application of Sal in cancer therapy has been significantly restricted by poor oral absorption and low tumor cell uptake. To solve this problem, lipid-shell and polymer-core nanoparticles (Sal-LPNPs) loaded with Sal were developed by a double emulsification method. The processing parameters including the polymer types, organic phase, PVA types and amount were systemically investigated. The obtained optimal Sal-LPNPs, composed of PLGA-PEG-PLGA triblock copolymers and lipids, had high entrapment efficiency (65%), submicron size (150 nm) and negatively charged surface (−23 mV). DSC analysis demonstrated the successful encapsulation of Sal into LPNPs. The core-shell structure of Sal-LPNPs was verified by TEM. Sal released slowly from the LPNPs without apparent burst release. MTT assay revealed that 4T1 and PANC-1 cancer cell lines were sensitive to Sal treatment. Sal-LPNPs had significantly higher antitumor activities than free Sal in 4T1 and PANC-1 cells. The data indicate that LPNPs are a promising Sal vehicle for anti-cancer therapy and worthy of further investigation. PMID:24573250

  14. The anti-cancer effect of probiotic Bacillus polyfermenticus on human colon cancer cells is mediated through ErbB2 and ErbB3 inhibition

    PubMed Central

    Ma, Elise L.; Choi, Yoon Jeong; Choi, Jinyoung; Pothoulakis, Charalabos; Rhee, Sang Hoon; Im, Eunok

    2015-01-01

    A wealth of data implicates that ErbB receptors have essential roles in tumor development. Probiotic bacteria are known to exert an anti-cancer activity in animal studies. Bacillus polyfermenticus (B.P.), a probiotic bacterium, has been clinically used for a variety of gastrointestinal disorders in East Asia. Here we investigated the effect of B.P. on the growth of tumors and its putative mechanism of actions. Conditioned medium of B.P. cultures (B.P. CM) inhibited the growth of human colon cancer cells including HT-29, DLD-1 and Caco-2 cells. Moreover, B.P. CM suppressed colony formation of HT-29 cells cultured on soft agar and reduced carcinogen-induced colony formation of normal colonocytes. Furthermore, data from the mouse xenograft model of human colon cancer cells showed reduced tumor size in B.P. CM-injected mice when compared to E.coli conditioned medium-injected mice. Exposure of B.P. CM to HT-29 cells for 24 h, 48 h and 2 weeks reduced ErbB2 and ErbB3 protein expression as well as mRNA levels. Moreover, cyclin D1 expression which is required for ErbB-dependent cell transformation was decreased by B.P. CM. Furthermore, transcription factor E2F-1 which regulates cyclin D1 expression was also decreased by B.P. CM. These results show that B.P. inhibits tumor growth and its anti-cancer activity occurs, at least in part, through suppressing ErbB2 and ErbB3. Taken together, our study suggests that this probiotic may be clinically used as a prophylactic treatment to prevent colon cancer development. PMID:19876926

  15. An Integrated Approach to Anti-Cancer Drug Sensitivity Prediction.

    PubMed

    Berlow, Noah; Haider, Saad; Wan, Qian; Geltzeiler, Mathew; Davis, Lara E; Keller, Charles; Pal, Ranadip

    2014-01-01

    A framework for design of personalized cancer therapy requires the ability to predict the sensitivity of a tumor to anticancer drugs. The predictive modeling of tumor sensitivity to anti-cancer drugs has primarily focused on generating functions that map gene expressions and genetic mutation profiles to drug sensitivity. In this paper, we present a new approach for drug sensitivity prediction and combination therapy design based on integrated functional and genomic characterizations. The modeling approach when applied to data from the Cancer Cell Line Encyclopedia shows a significant gain in prediction accuracy as compared to elastic net and random forest techniques based on genomic characterizations. Utilizing a Mouse Embryonal Rhabdomyosarcoma cell culture and a drug screen of 60 targeted drugs, we show that predictive modeling based on functional data alone can also produce high accuracy predictions. The framework also allows us to generate personalized tumor proliferation circuits to gain further insights on the individualized biological pathway. PMID:26357038

  16. Turning Tumor-Promoting Copper into an Anti-Cancer Weapon via High-Throughput Chemistry

    PubMed Central

    Wang, F.; Jiao, P.; Qi, M.; Frezza, M.; Dou, Q.P.; Yan, B.

    2013-01-01

    Copper is an essential element for multiple biological processes. Its concentration is elevated to a very high level in cancer tissues for promoting cancer development through processes such as angiogenesis. Organic chelators of copper can passively reduce cellular copper and serve the role as inhibitors of angiogenesis. However, they can also actively attack cellular targets such as proteasome, which plays a critical role in cancer development and survival. The discovery of such molecules initially relied on a step by step synthesis followed by biological assays. Today high-throughput chemistry and high-throughput screening have significantly expedited the copper-binding molecules discovery to turn “cancer-promoting” copper into anti-cancer agents. PMID:20586723

  17. Analogue-based approaches in anti-cancer compound modelling: the relevance of QSAR models

    PubMed Central

    2011-01-01

    Background QSAR is among the most extensively used computational methodology for analogue-based design. The application of various descriptor classes like quantum chemical, molecular mechanics, conceptual density functional theory (DFT)- and docking-based descriptors for predicting anti-cancer activity is well known. Although in vitro assay for anti-cancer activity is available against many different cell lines, most of the computational studies are carried out targeting insufficient number of cell lines. Hence, statistically robust and extensive QSAR studies against 29 different cancer cell lines and its comparative account, has been carried out. Results The predictive models were built for 266 compounds with experimental data against 29 different cancer cell lines, employing independent and least number of descriptors. Robust statistical analysis shows a high correlation, cross-validation coefficient values, and provides a range of QSAR equations. Comparative performance of each class of descriptors was carried out and the effect of number of descriptors (1-10) on statistical parameters was tested. Charge-based descriptors were found in 20 out of 39 models (approx. 50%), valency-based descriptor in 14 (approx. 36%) and bond order-based descriptor in 11 (approx. 28%) in comparison to other descriptors. The use of conceptual DFT descriptors does not improve the statistical quality of the models in most cases. Conclusion Analysis is done with various models where the number of descriptors is increased from 1 to 10; it is interesting to note that in most cases 3 descriptor-based models are adequate. The study reveals that quantum chemical descriptors are the most important class of descriptors in modelling these series of compounds followed by electrostatic, constitutional, geometrical, topological and conceptual DFT descriptors. Cell lines in nasopharyngeal (2) cancer average R2 = 0.90 followed by cell lines in melanoma cancer (4) with average R2 = 0.81 gave the

  18. Mitochondrial permeability transition pore as a selective target for anti-cancer therapy

    PubMed Central

    Suh, Dong H.; Kim, Mi-Kyung; Kim, Hee S.; Chung, Hyun H.; Song, Yong S.

    2012-01-01

    Mitochondrial outer membrane permeabilization (MOMP) is the ultimate step in dozens of lethal apoptotic signal transduction pathways which converge on mitochondria. One of the representative systems proposed to be responsible for the MOMP is the mitochondrial permeability transition pore (MPTP). Although the molecular composition of the MPTP is not clearly understood, the MPTP attracts much interest as a promising target for resolving two conundrums regarding cancer treatment: tumor selectivity and resistance to treatment. The regulation of the MPTP is closely related to metabolic reprogramming in cancer cells including mitochondrial alterations. Restoration of deregulated apoptotic machinery in cancer cells by tumor-specific modulation of the MPTP could therefore be a promising anti-cancer strategy. Currently, a number of MPTP-targeting agents are under pre-clinical and clinical studies. Here, we reviewed the structure and regulation of the MPTP as well as the current status of the development of promising MPTP-targeting drugs. PMID:23483560

  19. miR-30a Regulates the Expression of CAGE and p53 and Regulates the Response to Anti-Cancer Drugs

    PubMed Central

    Park, Deokbum; Kim, Hyuna; Kim, Youngmi; Jeoung, Dooil

    2016-01-01

    We have previously reported the role of miR-217 in anti-cancer drug-resistance. miRNA array and miRNA hybridization analysis predicted miR-30a-3p as a target of miR-217. miR-30a-3p and miR-217 formed a negative feedback loop and regulated the expression of each other. Ago1 immunoprecipitation and co-localization analysis revealed a possible interaction between miR-30a-3p and miR-217. miR-30a-3p conferred resistance to anti-cancer drugs and enhanced the invasion, migration, angiogenic, tumorigenic, and metastatic potential of cancer cells in CAGE-dependent manner. CAGE increased the expression of miR-30a-3p by binding to the promoter sequences of miR-30a-3p, suggesting a positive feedback loop between CAGE and miR-30a-3p. miR-30a-3p decreased the expression of p53, which showed the binding to the promoter sequences of miR-30a-3p and CAGE in anti-cancer drug-sensitive cancer cells. Luciferase activity assays showed that p53 serves as a target of miR-30a. Thus, the miR-30a-3p-CAGE-p53 feedback loop serves as a target for overcoming resistance to anti-cancer drugs. PMID:26912082

  20. In vitro anti-cancer effects of the actin-binding natural compound rhizopodin.

    PubMed

    Zhang, S; Menche, D; Zahler, S; Vollmar, A M; Liebl, J; Förster, F

    2015-09-01

    Several natural compound interfere with microtubules or the actin cytoskeleton. Compounds interfering with the microtubules like Vinca-alkaloids or taxanes, are extensively used for cancer therapy. In contrast, knowledge about pharmacological properties of actin binding drugs is poor and drugs interfering with actin are far from clinical use. Rhizopodin is a natural compound that strongly affects the actin cytoskeleton at nanomolar concentrations. Initial work revealed interesting anti-bacterial and cytotoxic effects, but the cellular effects and pharmacological properties of rhizopodin have not been characterized. We hypothesized that rhizopodin might exert anti-cancer activity. Therefore, the aim of this study was to characterize the cellular and pharmacological effects of rhizopodin in cancer. Effects of rhizopodin demonstrated prominent effects on the actin cytoskeleton as shown in the actin-pyrene assay and by immunostaining of cancer cells. To investigate cellular effects of rhizopodin, we analyzed cell proliferation, cell death induction by propidium iodide exclusion and western blot, as well as migration by impedance measurement using the xCELLligence device in MDA-MB-231 breast cancer and T24 bladder cancer cell lines. Rhizopodin inhibited proliferation and induced cell death of MDA-MB-231 and T24 cells at nanomolar concentrations. PARP cleavage by rhizopodin suggests caspase-dependent cell death induction. Importantly, rhizopodin potently inhibited MDA-MB-231 and T24 cancer cell migration at subtoxic doses where no actin aggregation was observed, indicating a specific underlying signaling of rhizopodin. In summary, our study elucidates rhizopodin as actin-binding natural compound that exerts potent anti-cancer effects. Therefore, our work provides the basis for further in depth characterization of rhizopodin as an antitumoral agent. PMID:26492647

  1. Quinones derived from plant secondary metabolites as anti-cancer agents.

    PubMed

    Lu, Jin-Jian; Bao, Jiao-Lin; Wu, Guo-Sheng; Xu, Wen-Shan; Huang, Ming-Qing; Chen, Xiu-Ping; Wang, Yi-Tao

    2013-03-01

    Quinones are plant-derived secondary metabolites that present some anti-proliferation and anti-metastasis effects in various cancer types both in vitro and in vivo. This review focuses on the anti-cancer prospects of plant-derived quinones, namely, aloe-emodin, juglone, β-lapachol, plumbagin, shikonin, and thymoquinone. We intend to summarize their anti-cancer effects and investigate the mechanism of actions to promote the research and development of anti-cancer agents from quinones. PMID:22931417

  2. Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components.

    PubMed

    Rath, Emma M; Duff, Anthony P; Håkansson, Anders P; Vacher, Catherine S; Liu, Guo Jun; Knott, Robert B; Church, William Bret

    2015-01-01

    The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLET-like compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID:26626257

  3. Epigenetic mechanisms in anti-cancer actions of bioactive food components – the implications in cancer prevention

    PubMed Central

    Stefanska, B; Karlic, H; Varga, F; Fabianowska-Majewska, K; Haslberger, AG

    2012-01-01

    The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by both genetic and epigenetic modifications. Epigenetics refers to the changes in gene expression programming that alter the phenotype in the absence of a change in DNA sequence. Epigenetic modifications, which include amongst others DNA methylation, covalent modifications of histone tails and regulation by non-coding RNAs, play a significant role in normal development and genome stability. The changes are dynamic and serve as an adaptation mechanism to a wide variety of environmental and social factors including diet. A number of studies have provided evidence that some natural bioactive compounds found in food and herbs can modulate gene expression by targeting different elements of the epigenetic machinery. Nutrients that are components of one-carbon metabolism, such as folate, riboflavin, pyridoxine, cobalamin, choline, betaine and methionine, affect DNA methylation by regulating the levels of S-adenosyl-L-methionine, a methyl group donor, and S-adenosyl-L-homocysteine, which is an inhibitor of enzymes catalyzing the DNA methylation reaction. Other natural compounds target histone modifications and levels of non-coding RNAs such as vitamin D, which recruits histone acetylases, or resveratrol, which activates the deacetylase sirtuin and regulates oncogenic and tumour suppressor micro-RNAs. As epigenetic abnormalities have been shown to be both causative and contributing factors in different health conditions including cancer, natural compounds that are direct or indirect regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy. PMID:22536923

  4. SWCNT-Polymer Nanocomplexes for Anti-Cancer Drug Delivery

    NASA Astrophysics Data System (ADS)

    Withey, Paul; Momin, Zoya; Bommoju, Anvesh; Hoang, Trung; Rashid, Bazlur

    2015-03-01

    Utilization of single-walled carbon nanotubes (SWCNTs) as more effective drug-delivery agents are being considered due to their ability to easily cross cell membranes, while their high aspect ratio and large surface area provide multiple attachment sites for biocompatible drug complexes. However, excessive bundling of pristine SWCNTs caused by strong attractive Van der Walls forces between CNT sidewalls is a major obstacle. We have successfully dispersed SWCNTs with both polyvinyl alcohol and Pluronic biocompatible polymers, and attached anti-cancer drugs Camptothecin (CPT) and Doxorubicin to form non-covalent CNT-polymer-drug conjugates in aqueous solution. Polymeric dispersion of SWCNTs by both polymers is confirmed by clearly identifiable near-infrared (NIR) fluorescence emission peaks of individual (7,5) and (7,6) nanotubes, and drug attachment to form complete complexes verified by UV-Vis spectroscopy. These complexes, with varying SWCNT and drug concentrations, were tested for effectiveness by exposing them to a line of human embryonic kidney cancer cells and analyzed for cell viability. Preliminary results indicate significant improvement in drug effectiveness on the cancer cells, with more successful internalization due to unaltered SWCNTs as the drug carriers. Supported by the UHCL Faculty Research Support Fund.

  5. Death receptors as targets for anti-cancer therapy

    PubMed Central

    Papenfuss, Kerstin; Cordier, Stefanie M; Walczak, Henning

    2008-01-01

    Human tumour cells are characterized by their ability to avoid the normal regulatory mechanisms of cell growth, division and death. The classical chemotherapy aims to kill tumour cells by causing DNA damage-induced apoptosis. However, as many tumour cells posses mutations in intracellular apoptosis-sensing molecules like p53, they are not capable of inducing apoptosis on their own and are therefore resistant to chemotherapy. With the discovery of the death receptors the opportunity arose to directly trigger apoptosis from the outside of tumour cells, thereby circumventing chemotherapeutic resistance. Death receptors belong to the tumour necrosis factor receptor superfamily, with tumour necrosis factor (TNF) receptor-1, CD95 and TNF-related apoptosis-inducing ligand-R1 and -R2 being the most prominent members. This review covers the current knowledge about these four death receptors, summarizes pre-clinical approaches engaging these death receptors in anti-cancer therapy and also gives an overview about their application in clinical trials conducted to date. PMID:19210756

  6. Selective anti-cancer agents as anti-aging drugs

    PubMed Central

    Blagosklonny, Mikhail V

    2013-01-01

    Recent groundbreaking discoveries have revealed that IGF-1, Ras, MEK, AMPK, TSC1/2, FOXO, PI3K, mTOR, S6K, and NFκB are involved in the aging process. This is remarkable because the same signaling molecules, oncoproteins and tumor suppressors, are well-known targets for cancer therapy. Furthermore, anti-cancer drugs aimed at some of these targets have been already developed. This arsenal could be potentially employed for anti-aging interventions (given that similar signaling molecules are involved in both cancer and aging). In cancer, intrinsic and acquired resistance, tumor heterogeneity, adaptation, and genetic instability of cancer cells all hinder cancer-directed therapy. But for anti-aging applications, these hurdles are irrelevant. For example, since anti-aging interventions should be aimed at normal postmitotic cells, no selection for resistance is expected. At low doses, certain agents may decelerate aging and age-related diseases. Importantly, deceleration of aging can in turn postpone cancer, which is an age-related disease. PMID:24345884

  7. OLIGODEOXYNUCLEOTIDES AS ANTI-CANCER THERAPEUTICS AND DIAGNOSTICS | NCI Technology Transfer Center | TTC

    Cancer.gov

    The National Cancer Institute Laboratory of Experimental Immunology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-cancer oligodeoxynucleotides.  

  8. Antibody–drug conjugates as novel anti-cancer chemotherapeutics

    PubMed Central

    Peters, Christina; Brown, Stuart

    2015-01-01

    Over the past couple of decades, antibody–drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics. PMID:26182432

  9. Pro-Apoptotic Activity of 4-Isopropyl-2-(1-Phenylethyl) Aniline Isolated from Cordyceps bassiana

    PubMed Central

    Kim, Mi Seon; Lee, Yunmi; Sung, Gi-Ho; Kim, Ji Hye; Park, Jae Gwang; Kim, Han Gyung; Baek, Kwang Soo; Cho, Jae Han; Han, Jaegu; Lee, Kang-Hyo; Hong, Sungyoul; Kim, Jong-Hoon; Cho, Jae Youl

    2015-01-01

    Cordyceps species including Cordyceps bassiana are a notable anti-cancer dietary supplement. Previously, we identified several compounds with anti-cancer activity from the butanol fraction (Cb-BF) of Cordyceps bassiana. To expand the structural value of Cb-BF-derived anti-cancer drugs, we employed various chemical moieties to produce a novel Cb-BF-derived chemical derivative, KTH-13-amine-monophenyl [4-isopropyl-2-(1-phenylethyl) aniline (KTH-13-AMP)], which we tested for anti-cancer activity. KTH-13-AMP suppressed the proliferation of MDA-MB-231, HeLa, and C6 glioma cells. KTH-13-AMP also dose-dependently induced morphological changes in C6 glioma cells and time-dependently increased the level of early apoptotic cells stained with annexin V-FITC. Furthermore, the levels of the active full-length forms of caspase-3 and caspase-9 were increased. In contrast, the levels of total forms of caspases-3, caspase-8, caspase-9, and Bcl-2 were decreased in KTH-13-AMP treated-cells. We also confirmed that the phosphorylation of STAT3, Src, and PI3K/p85, which is linked to cell survival, was diminished by treatment with KTH-13-AMP. Therefore, these results strongly suggest that this compound can be used to guide the development of an anti-cancer drug or serve as a lead compound in forming another strong anti-proliferative agent. PMID:26157554

  10. Pro-Apoptotic Activity of 4-Isopropyl-2-(1-Phenylethyl) Aniline Isolated from Cordyceps bassiana.

    PubMed

    Kim, Mi Seon; Lee, Yunmi; Sung, Gi-Ho; Kim, Ji Hye; Park, Jae Gwang; Kim, Han Gyung; Baek, Kwang Soo; Cho, Jae Han; Han, Jaegu; Lee, Kang-Hyo; Hong, Sungyoul; Kim, Jong-Hoon; Cho, Jae Youl

    2015-07-01

    Cordyceps species including Cordyceps bassiana are a notable anti-cancer dietary supplement. Previously, we identified several compounds with anti-cancer activity from the butanol fraction (Cb-BF) of Cordyceps bassiana. To expand the structural value of Cb-BF-derived anti-cancer drugs, we employed various chemical moieties to produce a novel Cb-BF-derived chemical derivative, KTH-13-amine-monophenyl [4-isopropyl-2-(1-phenylethyl) aniline (KTH-13-AMP)], which we tested for anti-cancer activity. KTH-13-AMP suppressed the proliferation of MDA-MB-231, HeLa, and C6 glioma cells. KTH-13-AMP also dose-dependently induced morphological changes in C6 glioma cells and time-dependently increased the level of early apoptotic cells stained with annexin V-FITC. Furthermore, the levels of the active full-length forms of caspase-3 and caspase-9 were increased. In contrast, the levels of total forms of caspases-3, caspase-8, caspase-9, and Bcl-2 were decreased in KTH-13-AMP treated-cells. We also confirmed that the phosphorylation of STAT3, Src, and PI3K/p85, which is linked to cell survival, was diminished by treatment with KTH-13-AMP. Therefore, these results strongly suggest that this compound can be used to guide the development of an anti-cancer drug or serve as a lead compound in forming another strong anti-proliferative agent. PMID:26157554

  11. Liver Label Retaining Cancer Cells Are Relatively Resistant to the Reported Anti-Cancer Stem Cell Drug Metformin

    PubMed Central

    Xin, Hong-Wu; Ambe, Chenwi M.; Miller, Tyler C.; Chen, Jin-Qiu; Wiegand, Gordon W.; Anderson, Andrew J.; Ray, Satyajit; Mullinax, John E.; Hari, Danielle M.; Koizumi, Tomotake; Godbout, Jessica D.; Goldsmith, Paul K.; Stojadinovic, Alexander; Rudloff, Udo; Thorgeirsson, Snorri S.; Avital, Itzhak

    2016-01-01

    Background & Aims: Recently, we reported that liver Label Retaining Cancer Cells (LRCC) can initiate tumors with only 10 cells and are relatively resistant to the targeted drug Sorafenib, a standard of practice in advanced hepatocellular carcinoma (HCC). LRCC are the only cancer stem cells (CSC) isolated alive according to a stem cell fundamental function, asymmetric cell division. Metformin has been reported to preferentially target many other types of CSC of different organs, including liver. It's important to know if LRCC, a novel class of CSC, are relatively resistant to metformin, unlike other types of CSC. As metformin inhibits the Sorafenib-Target-Protein (STP) PI3K, and LRCC are newly described CSC, we undertook this study to test the effects of Metformin on Sorafenib-treated HCC and HCC-derived-LRCC. Methods: We tested various STP levels and phosphorylation status, associated genes' expression, proliferation, viability, toxicity, and apoptosis profiles, before and after treatment with Sorafenib with/without Metformin. Results: Metformin enhances the effects of Sorafenib on HCC, and significantly decreased viability/proliferation of HCC cells. This insulin-independent effect was associated with inhibition of multiple STPs (PKC, ERK, JNK and AKT). However, Metformin increased the relative proportion of LRCCs. Comparing LRCC vs. non-LRCC, this effect was associated with improved toxicity and apoptosis profiles, down-regulation of cell death genes and up-regulation of cell proliferation and survival genes in LRCC. Concomitantly, Metformin up-regulated pluripotency, Wnt, Notch and SHH pathways genes in LRCC vs. non-LRCC. Conclusions: Metformin and Sorafenib have enhanced anti-cancer effects. However, in contradistinction to reports on other types of CSC, Metformin is less effective against HCC-derived-CSC LRCC. Our results suggest that combining Metformin with Sorafenib may be able to repress the bulk of tumor cells, but as with other anti-cancer drugs, may

  12. Dynamic modeling of bone metastasis, microenvironment and therapy: Integrating parathyroid hormone (PTH) effect, anti-resorptive and anti-cancer therapy.

    PubMed

    Coelho, Rui Moura; Lemos, João Miranda; Alho, Irina; Valério, Duarte; Ferreira, Arlindo R; Costa, Luís; Vinga, Susana

    2016-02-21

    Bone is a common site for the development of metastasis, as its microenvironment provides the necessary conditions for the growth and proliferation of cancer cells. Several mathematical models to describe the bone remodeling process and how osteoclasts and osteoblasts coupled action ensures bone homeostasis have been proposed and further extended to include the effect of cancer cells. The model proposed here includes the influence of the parathyroid hormone (PTH) as capable of triggering and regulating the bone remodeling cycle. It also considers the secretion of PTH-related protein (PTHrP) by cancer cells, which stimulates the production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts that activates osteoclasts, increasing bone resorption and the subsequent release of growth factors entrapped in the bone matrix, which induce tumor growth, giving rise to a self-perpetuating cycle known as the vicious cycle of bone metastases. The model additionally describes how the presence of metastases contributes to the decoupling between bone resorption and formation. Moreover, the effects of anti-cancer and anti-resorptive treatments, through chemotherapy and the administration of bisphosphonates or denosumab, are also included, along with their corresponding pharmacokinetics (PK) and pharmacodynamics (PD). The simulated models, available at http://sels.tecnico.ulisboa.pt/software/, are able to describe bone remodeling cycles, the growth of bone metastases and how treatment can effectively reduce tumor burden on bone and prevent loss of bone strength. PMID:26657065

  13. Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment

    PubMed Central

    Friedman, Adam A.; Amzallag, Arnaud; Pruteanu-Malinici, Iulian; Baniya, Subash; Cooper, Zachary A.; Piris, Adriano; Hargreaves, Leeza; Igras, Vivien; Frederick, Dennie T.; Lawrence, Donald P.; Haber, Daniel A.; Flaherty, Keith T.; Wargo, Jennifer A.; Ramaswamy, Sridhar; Benes, Cyril H.; Fisher, David E.

    2015-01-01

    A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1) transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR) and platelet derived growth factor receptor (PDGFR) family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs), demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK) kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations. PMID:26461489

  14. Cardio-protective and anti-cancer therapeutic potential of Nigella sativa.

    PubMed

    Shafiq, Hammad; Ahmad, Asif; Masud, Tariq; Kaleem, Muhammad

    2014-12-01

    Nigella sativa is the miraculous plant having a lot of nutritional and medicinal benefits, and attracts large number of nutrition and pharmacological researchers. N. sativa seed composition shows that it is the blessing of nature and it contains and many bioactive compounds like thymoquinone, α-hederin, alkaloids, flavonoids, antioxidants, fatty acids many other compounds that have positive effects on curing of different diseases. Several medicinal properties of N. sativa like its anti-cancer, anti-inflammatory, anti-diabetic, antioxidant activities and many others are well acknowledged. However, this article focuses on activity of N. sativa against cardiovascular diseases and cancer. For gathering required data the authors went through vast number of articles using search engines like Science direct, ELSEVIER, Pub Med, Willey on Line Library and Google scholar and the findings were classified on the basis of relevance of the topic and were reviewed in the article. N. sativa is rich source of different biologically active compounds and is found effective in controlling number of cardiovascular diseases and various cancers both in vivo and in vitro studies. PMID:25859300

  15. Cardio-protective and anti-cancer therapeutic potential of Nigella sativa

    PubMed Central

    Shafiq, Hammad; Ahmad, Asif; Masud, Tariq; Kaleem, Muhammad

    2014-01-01

    Nigella sativa is the miraculous plant having a lot of nutritional and medicinal benefits, and attracts large number of nutrition and pharmacological researchers. N. sativa seed composition shows that it is the blessing of nature and it contains and many bioactive compounds like thymoquinone, α-hederin, alkaloids, flavonoids, antioxidants, fatty acids many other compounds that have positive effects on curing of different diseases. Several medicinal properties of N. sativa like its anti-cancer, anti-inflammatory, anti-diabetic, antioxidant activities and many others are well acknowledged. However, this article focuses on activity of N. sativa against cardiovascular diseases and cancer. For gathering required data the authors went through vast number of articles using search engines like Science direct, ELSEVIER, Pub Med, Willey on Line Library and Google scholar and the findings were classified on the basis of relevance of the topic and were reviewed in the article. N. sativa is rich source of different biologically active compounds and is found effective in controlling number of cardiovascular diseases and various cancers both in vivo and in vitro studies. PMID:25859300

  16. Targeting Cytochrome P450 Enzymes: A New Approach in Anti-cancer Drug Development

    PubMed Central

    Bruno, Robert D.; Njar, Vincent C.O.

    2007-01-01

    Cytochrome P450s (CYPs) represent a large class of heme-containing enzymes that catalyze the metabolism of multitudes of substrates both endogenous and exogenous. Until recently, however, CYPs have been largely overlooked in cancer drug development, acknowledged only for their role in Phase I metabolism of chemotherapeutics. The first successful strategy targeting CYP enzymes in cancer therapy was the development of potent inhibitors of CYP19 (aromatase) for the treatment of breast cancer. Aromatase inhibitors ushered in a new era in hormone ablation therapy for estrogen dependent cancers, and have paved the way for similar strategies (i.e. inhibition of CYP17) that combat androgen dependent prostate cancer. Identification of CYPs involved in the inactivation of anti-cancer metabolites of Vitamin D3 and Vitamin A has triggered development of agents that target these enzymes as well. The discovery of the over-expression of exogenous metabolizing CYPs, such as CYP1B1, in cancer cells has roused interest in the development of inhibitors for chemoprevention and of prodrugs designed to be activated by CYPs only in cancer cells. Finally, the expression of CYPs within tumors has been utilized in the development of bioreductive molecules that are activated by CYPs only under hypoxic conditions. This review offers the first comprehensive analysis of strategies in drug development that either inhibit or exploit CYP enzymes for the treatment of cancer. PMID:17544277

  17. From COX-2 inhibitor nimesulide to potent anti-cancer agent: synthesis, in vitro, in vivo and pharmacokinetic evaluation.

    PubMed

    Zhong, Bo; Cai, Xiaohan; Chennamaneni, Snigdha; Yi, Xin; Liu, Lili; Pink, John J; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; Su, Bin

    2012-01-01

    Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure-function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC(50)s around 100 nM-200 nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC(50)s around 100 nM-500 nM. Intraperitoneal injection with a dosage of 5  mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound. PMID:22119125

  18. Down-regulation of Bcl-2-interacting protein BAG-1 confers resistance to anti-cancer drugs.

    PubMed

    Takahashi, Noriko; Yanagihara, Miyako; Ogawa, Yuzi; Yamanoha, Banri; Andoh, Toshiwo

    2003-02-14

    BAG-1 was originally identified as a binding partner of anti-apoptotic factor Bcl-2 [Takayama et al., Cell 80 (1995) 279-284]. Exogenous expression of BAG-1 was reported to confer cells resistance to several stresses [Chen et al., Oncogene 21 (2002) 7050]. We have obtained human cervical cancer HeLa cells with down-regulated BAG-1 levels by using a highly specific and efficient RNA interference approach. Surprisingly, cells with down-regulated BAG-1 exhibited significantly lower sensitivity against several anti-cancer drugs than parental cells expressing normal levels of the protein. Furthermore, growth rate of the cells was reduced when BAG-1 was down-regulated. Activity of ERK pathway appeared to be decreased in BAG-1 down-regulated cells, as shown by the reduced phosphorylation of ERK1/2 proteins. Taken together resistance against anti-cancer drugs acquired by BAG-1 down-regulated cells may well be accounted for by the retardation of cell cycle progression, implicating the importance of BAG-1 in cell growth regulation. PMID:12565851

  19. Antitumor activity of fermented noni exudates (fNE) and its fractions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Noni (Morinda citrifolia) has been extensively used in folk medicine by Polynesians for over 2000 years and recent studies have shown that noni has a wide spectrum of therapeutic activities including inhibition of angiogenesis, anti-inflammatory effects, and anti-cancer activities. We recently repor...

  20. Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics.

    PubMed

    Burke, Russell T; Orth, James D

    2016-01-01

    The response of single cells to anti-cancer drugs contributes significantly in determining the population response, and therefore is a major contributing factor in the overall outcome. Immunoblotting, flow cytometry and fixed cell experiments are often used to study how cells respond to anti-cancer drugs. These methods are important, but they have several shortcomings. Variability in drug responses between cancer and normal cells, and between cells of different cancer origin, and transient and rare responses are difficult to understand using population averaging assays and without being able to directly track and analyze them longitudinally. The microscope is particularly well suited to image live cells. Advancements in technology enable us to routinely image cells at a resolution that enables not only cell tracking, but also the observation of a variety of cellular responses. We describe an approach in detail that allows for the continuous time-lapse imaging of cells during the drug response for essentially as long as desired, typically up to 96 hr. Using variations of the approach, cells can be monitored for weeks. With the employment of genetically encoded fluorescent biosensors numerous processes, pathways and responses can be followed. We show examples that include tracking and quantification of cell growth and cell cycle progression, chromosome dynamics, DNA damage, and cell death. We also discuss variations of the technique and its flexibility, and highlight some common pitfalls. PMID:27213923

  1. The Anti-Cancer Property of Proteins Extracted from Gynura procumbens (Lour.) Merr

    PubMed Central

    Hew, Chaw-Sen; Khoo, Boon-Yin; Gam, Lay-Harn

    2013-01-01

    Gynura procumbens (Lour.) Merr. belongs to the Asteraceae Family. The plant is a well-known traditional herb in South East Asia and it is widely used to treat inflammation, kidney discomfort, high cholesterol level, diabetic, cancer and high blood pressure. Our earlier study showed the presence of valuable plant defense proteins, such as peroxidase, thaumatin-like proteins and miraculin in the leaf of G. procumbens. However, the effects of these defense proteins on cancers have never been determined previously. In the present study, we investigated the bioactivity of gel filtration fractionated proteins of G. procumbens leaf extract. The active protein fraction, SN-F11/12, was found to inhibit the growth of a breast cancer cell line, MDA-MB-231, at an EC50 value of 3.8 µg/mL. The mRNA expressions of proliferation markers, Ki67 and PCNA, were reduced significantly in the MDA-MB-23 cells treated with SN-F11/12. The expression of invasion marker, CCL2, was also found reduced in the treated MDA-MB-231 cells. All these findings highlight the anti-cancer property of SN-F11/12, therefore, the proteins in this fraction can be a potential chemotherapeutic agent for breast cancer treatment. PMID:23874655

  2. The anti-cancer property of proteins extracted from Gynura procumbens (Lour.) Merr.

    PubMed

    Hew, Chaw-Sen; Khoo, Boon-Yin; Gam, Lay-Harn

    2013-01-01

    Gynura procumbens (Lour.) Merr. belongs to the Asteraceae Family. The plant is a well-known traditional herb in South East Asia and it is widely used to treat inflammation, kidney discomfort, high cholesterol level, diabetic, cancer and high blood pressure. Our earlier study showed the presence of valuable plant defense proteins, such as peroxidase, thaumatin-like proteins and miraculin in the leaf of G. procumbens. However, the effects of these defense proteins on cancers have never been determined previously. In the present study, we investigated the bioactivity of gel filtration fractionated proteins of G. procumbens leaf extract. The active protein fraction, SN-F11/12, was found to inhibit the growth of a breast cancer cell line, MDA-MB-231, at an EC50 value of 3.8 µg/mL. The mRNA expressions of proliferation markers, Ki67 and PCNA, were reduced significantly in the MDA-MB-23 cells treated with SN-F11/12. The expression of invasion marker, CCL2, was also found reduced in the treated MDA-MB-231 cells. All these findings highlight the anti-cancer property of SN-F11/12, therefore, the proteins in this fraction can be a potential chemotherapeutic agent for breast cancer treatment. PMID:23874655

  3. The anti-cancer agent nemorosone is a new potent protonophoric mitochondrial uncoupler.

    PubMed

    Pardo-Andreu, Gilberto L; Nuñez-Figueredo, Yanier; Tudella, Valeria G; Cuesta-Rubio, Osmany; Rodrigues, Fernando P; Pestana, Cezar R; Uyemura, Sérgio A; Leopoldino, Andréia M; Alberici, Luciane C; Curti, Carlos

    2011-03-01

    Nemorosone, a natural-occurring polycyclic polyprenylated acylphloroglucinol, has received increasing attention due to its strong in vitro anti-cancer action. Here, we have demonstrated the toxic effect of nemorosone (1-25 μM) on HepG2 cells by means of the MTT assay, as well as early mitochondrial membrane potential dissipation and ATP depletion in this cancer cell line. In mitochondria isolated from rat liver, nemorosone (50-500 nM) displayed a protonophoric uncoupling activity, showing potency comparable to the classic protonophore, carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Nemorosone enhanced the succinate-supported state 4 respiration rate, dissipated mitochondrial membrane potential, released Ca(2+) from Ca(2+)-loaded mitochondria, decreased Ca(2+) uptake and depleted ATP. The protonophoric property of nemorosone was attested by the induction of mitochondrial swelling in hyposmotic K(+)-acetate medium in the presence of valinomycin. In addition, uncoupling concentrations of nemorosone in the presence of Ca(2+) plus ruthenium red induced the mitochondrial permeability transition process. Therefore, nemorosone is a new potent protonophoric mitochondrial uncoupler and this property is potentially involved in its toxicity on cancer cells. PMID:21044702

  4. Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition.

    PubMed

    Wilson, Catherine; Nicholes, Katrina; Bustos, Daisy; Lin, Eva; Song, Qinghua; Stephan, Jean-Philippe; Kirkpatrick, Donald S; Settleman, Jeff

    2014-09-15

    Epithelial to mesenchymal transition (EMT) is a key process in embryonic development and has been associated with cancer metastasis and drug resistance. For example, in EGFR mutated non-small cell lung cancers (NSCLC), EMT has been associated with acquired resistance to the EGFR inhibitor erlotinib. Moreover, "EGFR-addicted" cancer cell lines induced to undergo EMT become erlotinib-resistant in vitro. To identify potential therapeutic vulnerabilities specifically within these mesenchymal, erlotinib-resistant cells, we performed a small molecule screen of ~200 established anti-cancer agents using the EGFR mutant NSCLC HCC827 cell line and a corresponding mesenchymal derivative line. The mesenchymal cells were more resistant to most tested agents; however, a small number of agents showed selective growth inhibitory activity against the mesenchymal cells, with the most potent being the Abl/Src inhibitor, dasatinib. Analysis of the tyrosine phospho-proteome revealed several Src/FAK pathway kinases that were differentially phosphorylated in the mesenchymal cells, and RNAi depletion of the core Src/FAK pathway components in these mesenchymal cells caused apoptosis. These findings reveal a novel role for Src/FAK pathway kinases in drug resistance and identify dasatinib as a potential therapeutic for treatment of erlotinib resistance associated with EMT. PMID:25193862

  5. Anti-cancer effect of rubropunctatin against human gastric carcinoma cells BGC-823.

    PubMed

    Zheng, Yunquan; Xin, Yanwen; Shi, Xianai; Guo, Yanghao

    2010-11-01

    The Monascus pigment, rubropunctatin, was extracted and purified from red mold rice (RMR) and its cytotoxic activities against human gastric adenocarcinoma BGC-823 cells were studied both in vitro and in vivo. Rubropunctatin inhibited the proliferation of BGC-823 cells with an inhibitory concentration (IC₅₀) of 12.57 μM, while it exhibited no significant toxicity to normal gastric epithelial cell GES-1 at the same concentration. Treatment of BGC-823 cells with rubropunctatin resulted in a dose- and time-dependent apoptosis, as validated by the increase in the percentage of cells in sub-G1 phase and phosphotidylserine externalization. The in vivo experimental data demonstrated that rubropunctatin could offer similar therapeutic benefits in comparison with the same dose of taxol. After five times of intravenous injection, tumor weight in BGC-823-bearing nude mice reduced 23.5% at the dose of 8 mg/kg and 37.7% at the dose of 32 mg/kg, respectively. The expressions of 30 genes related to induction of apoptosis were found up-regulated significantly. The two most expressed genes were tumor necrosis factor (TNF) and DNA-damage inducible transcript 3. TNF was considered as a major mediator of apoptosis induced by rubropunctatin. This is the first report describing the anti-proliferative effect of rubropunctatin and its apoptosis mechanism on BGC-823 cells. Rubropunctatin has potential to be developed as a new natural anti-cancer agent. PMID:20730532

  6. Dose critical in-vivo detection of anti-cancer drug levels in blood

    DOEpatents

    Miller, Holly H.; Hirschfeld, deceased, Tomas B.

    1991-01-01

    A method and apparatus are disclosed for the in vivo and in vitro detection and measurement of dose critical levels of DNA-binding anti-cancer drug levels in biological fluids. The apparatus comprises a laser based fiber optic sensor (optrode) which utilizes the secondary interactions between the drug and an intercalating fluorochrome bound to a probe DNA, which in turn is attached to the fiber tip at one end thereof. The other end of the optical fiber is attached to an illumination source, detector and recorder. The fluorescence intensity is measured as a function of the drug concentration and its binding constant to the probe DNA. Anticancer drugs which lend themselves to analysis by the use of the method and the optrode of the present invention include doxorubicin, daunorubicin, carminomycin, aclacinomycin, chlorambucil, cyclophosphamide, methotrexate, 5-uracil, arabinosyl cytosine, mitomycin, cis-platinum 11 diamine dichloride procarbazine, vinblastine vincristine and the like. The present method and device are suitable for the continuous monitoring of the levels of these and other anticancer drugs in biological fluids such as blood, serum, urine and the like. The optrode of the instant invention also enables the measurement of the levels of these drugs from a remote location and from multiple samples.

  7. Stoichiometric molecularly imprinted polymers for the recognition of anti-cancer pro-drug tegafur.

    PubMed

    Mattos Dos Santos, Paula; Hall, Andrew J; Manesiotis, Panagiotis

    2016-05-15

    Molecularly imprinted polymers (MIPs) targeting tegafur, an anti-cancer 5-fluorouracil pro-drug, have been prepared by stoichiometric imprinting using 2,6-bis(acrylamido)pyridine (BAAPy) as the functional monomer. Solution association between tegafur and BAAPy was studied by (1)H NMR titration, which confirmed the formation of 1:1 complexes with an affinity constant of 574±15M(-1) in CDCl3. Evaluation of the synthesised materials by HPLC and equilibrium rebinding experiments revealed high selectivity of the imprinted polymer for the pro-drug vs. 5-fluorouracil and other competing analytes, with maximum imprinting factors of 25.3 and a binding capacity of 45.1μmolg(-1). The synthesised imprinted polymer was employed in solid-phase extraction of the pro-drug using an optimised protocol that included a simple wash with the porogen used in the preparation of the material. Tegafur recoveries of up to 96% were achieved from aqueous samples and 92% from urine samples spiked with the template and three competing analytes. The results demonstrate the potential of the prepared polymers in the pre-concentration of tegafur from biological samples, which could be an invaluable tool in the monitoring of patient compliance and drug uptake and excretion. PMID:26711233

  8. Current Advances in Mathematical Modeling of Anti-Cancer Drug Penetration into Tumor Tissues

    PubMed Central

    Kim, MunJu; Gillies, Robert J.; Rejniak, Katarzyna A.

    2013-01-01

    Delivery of anti-cancer drugs to tumor tissues, including their interstitial transport and cellular uptake, is a complex process involving various biochemical, mechanical, and biophysical factors. Mathematical modeling provides a means through which to understand this complexity better, as well as to examine interactions between contributing components in a systematic way via computational simulations and quantitative analyses. In this review, we present the current state of mathematical modeling approaches that address phenomena related to drug delivery. We describe how various types of models were used to predict spatio-temporal distributions of drugs within the tumor tissue, to simulate different ways to overcome barriers to drug transport, or to optimize treatment schedules. Finally, we discuss how integration of mathematical modeling with experimental or clinical data can provide better tools to understand the drug delivery process, in particular to examine the specific tissue- or compound-related factors that limit drug penetration through tumors. Such tools will be important in designing new chemotherapy targets and optimal treatment strategies, as well as in developing non-invasive diagnosis to monitor treatment response and detect tumor recurrence. PMID:24303366

  9. Optimal design of active and semi-active suspensions including time delays and preview

    NASA Astrophysics Data System (ADS)

    Hac', A.; Youn, I.

    1993-10-01

    Several control laws for active and semi-active suspension based on a linear half car model are derived and investigated. The strategies proposed take full advantage of the fact that the road input to the rear wheels is a delayed version of that to the front wheels, which in turn can be obtained either from the measurements of the front wheels and body motions or by direct preview of road irregularities if preview sensors are available. The suspension systems are optimized with respect to ride comfort, road holding and suspension rattle space as expressed by the mean-square-values of body acceleration (including effects of heave and pitch), tire deflections and front and rear suspension travels. The optimal control laws that minimize the given performance index and include passivity constraints in the semi-active case are derived using calculus of variation. The optimal semi-active suspension becomes piecewise linear, varying between passive and fully active systems and combinations of them. The performances of active and semi-active systems with and without preview were evaluated by numerical simulation in the time and frequency domains. The results show that incorporation of time delay between the front and rear axles in controller design improves the dynamic behavior of the rear axle and control of body pitch motion, while additional preview improves front wheel dynamics and body heave.

  10. Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin

    PubMed Central

    Zhang, Li; Wang, Handong

    2015-01-01

    Astaxanthin (ATX) is a xanthophyll carotenoid which has been approved by the United States Food and Drug Administration (USFDA) as food colorant in animal and fish feed. It is widely found in algae and aquatic animals and has powerful anti-oxidative activity. Previous studies have revealed that ATX, with its anti-oxidative property, is beneficial as a therapeutic agent for various diseases without any side effects or toxicity. In addition, ATX also shows preclinical anti-tumor efficacy both in vivo and in vitro in various cancer models. Several researches have deciphered that ATX exerts its anti-proliferative, anti-apoptosis and anti-invasion influence via different molecules and pathways including signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and peroxisome proliferator-activated receptor gamma (PPARγ). Hence, ATX shows great promise as chemotherapeutic agents in cancer. Here, we review the rapidly advancing field of ATX in cancer therapy as well as some molecular targets of ATX. PMID:26184238

  11. Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I.

    PubMed Central

    Chowdhury, Arnab Roy; Sharma, Shalini; Mandal, Suparna; Goswami, Anindya; Mukhopadhyay, Sibabrata; Majumder, Hemanta K

    2002-01-01

    Luteolin, a naturally occurring flavonoid, is abundant in our daily dietary intake. It exhibits a wide spectrum of pharmacological properties, but little is known about its biochemical targets other than the fact that it induces topoisomerase II-mediated apoptosis. In the present study, we show that luteolin completely inhibits the catalytic activity of eukaryotic DNA topoisomerase I at a concentration of 40 microM, with an IC50 of 5 microM. Preincubation of enzyme with luteolin before adding a DNA substrate increases the inhibition of the catalytic activity (IC50=0.66 microM). Treatment of DNA with luteolin before addition of topoisomerase I reduces this inhibitory effect. Subsequent fluorescence tests show that luteolin not only interacts directly with the enzyme but also with the substrate DNA, and intercalates at a very high concentration (>250 microM) without binding to the minor groove. Direct interaction between luteolin and DNA does not affect the assembly of the enzyme-DNA complex, as evident from the electrophoretic mobility-shift assays. Here we show that the inhibition of topoisomerase I by luteolin is due to the stabilization of topoisomerase-I DNA-cleavable complexes. Hence, luteolin is similar to camptothecin, a class I inhibitor, with respect to its ability to form the topoisomerase I-mediated 'cleavable complex'. But, unlike camptothecin, luteolin interacts with both free enzyme and substrate DNA. The inhibitory effect of luteolin is translated into concanavalin A-stimulated mouse splenocytes, with the compound inducing SDS-K+-precipitable DNA-topoisomerase complexes. This is the first report on luteolin as an inhibitor of the catalytic activity of topoisomerase I, and our results further support its therapeutic potential as a lead anti-cancer compound that poisons topoisomerases. PMID:12027807

  12. Hsp90 Inhibitors and Drug Resistance in Cancer: The Potential Benefits of Combination Therapies of Hsp90 Inhibitors and Other Anti-Cancer Drugs

    PubMed Central

    Lu, Xiangyi; Xiao, Li; Wang, Luan; Ruden, Douglas M.

    2012-01-01

    Hsp90 is a chaperone protein that interacts with client proteins that are known to be in the cell cycle, signaling and chromatin-remodeling pathways. Hsp90 inhibitors act additively or synergistically with many other drugs in the treatment of both solid tumors and leukemias in murine tumor models and humans. Hsp90 inhibitors potentiate the actions of anti-cancer drugs that target Hsp90 client proteins, including trastuzumab (Herceptin™) which targets Her2/Erb2B, as Hsp90 inhibition elicits the drug effects in cancer cell lines that are otherwise resistant to the drug. A Phase II study of the Hsp90 inhibitor 17-AAG and trastuzumab showed that this combination therapy has anticancer activity in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. In this review, we discuss the results of Hsp90 inhibitors in combination with trastuzumab and other cancer drugs. We also discuss recent results from yeast focused on the genetics of drug resistance when Hsp90 is inhibited and the implications that this might have in understanding the effects of genetic variation in treating cancer in humans. PMID:22120678

  13. A ferromagnetic compound with anti-cancer proeprties for controlled drug delivery and imaging

    DOE PAGESBeta

    Eguchi, Haruki; Hirata, Kunio; Kurotani, Reiko; Singh, David J.; Fukumura, Hidenobu; Umemura, Masanari; Hoshino, Yujiro; Lee, Jin; Masuda, Takatsugu; Amemiya, Naoyuki; et al

    2015-03-17

    New anticancer agents and modalities for their use are of great interest. Recent studies have demonstrated the presence of anti-cancer properties in salen derivatives. We found that an iron salen derivative, i.e., [Fe(salen)]2O, displays ferromagnetic order above room temperature and shows spontaneous field-dependent magnetization and hysteresis. Understanding of this magnetic property is provided by first-principles calculations based on structures obtained by X-ray crystallography. [Fe(salen)]2O exhibited potent anti-cancer properties against various cancer cell types and was readily attracted by even moderate-strength permanent magnets in vitro. We demonstrated that the delivery of [Fe(salen)]2O to melanoma tissues transplanted into the tails of micemore » using a permanent magnet leads to a robust decrease in tumor size. The local accumulation of [Fe(salen)]2O was visualized by MRI. Thus, [Fe(salen)]2O acted as an anti-cancer and MRI contrast compound that has a pharmacological effect that is delivered in a controlled manner, suggesting new strategies for anti-cancer drug development.« less

  14. Double layered hydroxides as potential anti-cancer drug delivery agents.

    PubMed

    Riaz, Ufana; Ashraf, S M

    2013-04-01

    The emergence of nanotechnology has changed the scenario of the medical world by revolutionizing the diagnosis, monitoring and treatment of cancer. This nanotechnology has been proved miraculous in detecting cancer cells, delivering chemotherapeutic agents and monitoring treatment from non-specific to highly targeted killing of tumor cells. In the past few decades, a number of inorganic materials have been investigated such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide, and layered double hydroxide (LDH) for examining their efficacy in targeting drug delivery. The reason behind the selection of these inorganic materials was their versatile and unique features efficient in drug delivery, such as wide availability, rich surface functionality, good biocompatibility, potential for target delivery, and controlled release of the drug from these inorganic nanomaterials. Although, the drug-LDH hybrids are found to be quite instrumental because of their application as advanced anti-cancer drug delivery systems, there has not been much research on them. This mini review is set to highlight the advancement made in the use of layered double hydroxides (LDHs) as anti-cancer drug delivery agents. Along with the advantages of LDHs as anti-cancer drug delivery agents, the process of interaction of some of the common anti-cancer drugs with LDH has also been discussed. PMID:23170959

  15. A ferromagnetic compound with anti-cancer proeprties for controlled drug delivery and imaging

    SciTech Connect

    Eguchi, Haruki; Hirata, Kunio; Kurotani, Reiko; Singh, David J.; Fukumura, Hidenobu; Umemura, Masanari; Hoshino, Yujiro; Lee, Jin; Masuda, Takatsugu; Amemiya, Naoyuki; Yamamoto, Masahiro; Sato, Itaru; Feng, Xianfeng; Sato, Motohiko; Inoue, Seiichi; Yamamoto, Masaki; Aoki, Ichio; Tanigaki, Katsumi; Sato, Mamoru; Ishikawa, Yoshihiro

    2015-03-17

    New anticancer agents and modalities for their use are of great interest. Recent studies have demonstrated the presence of anti-cancer properties in salen derivatives. We found that an iron salen derivative, i.e., [Fe(salen)]2O, displays ferromagnetic order above room temperature and shows spontaneous field-dependent magnetization and hysteresis. Understanding of this magnetic property is provided by first-principles calculations based on structures obtained by X-ray crystallography. [Fe(salen)]2O exhibited potent anti-cancer properties against various cancer cell types and was readily attracted by even moderate-strength permanent magnets in vitro. We demonstrated that the delivery of [Fe(salen)]2O to melanoma tissues transplanted into the tails of mice using a permanent magnet leads to a robust decrease in tumor size. The local accumulation of [Fe(salen)]2O was visualized by MRI. Thus, [Fe(salen)]2O acted as an anti-cancer and MRI contrast compound that has a pharmacological effect that is delivered in a controlled manner, suggesting new strategies for anti-cancer drug development.

  16. Molecular modelling, synthesis, cytotoxicity and anti-tumour mechanisms of 2-aryl-6-substituted quinazolinones as dual-targeted anti-cancer agents

    PubMed Central

    Hour, M J; Lee, K H; Chen, T L; Lee, K T; Zhao, Yu; Lee, H Z

    2013-01-01

    Background and Purpose Our previous study demonstrated that 6-(pyrrolidin-1-yl)-2-(3-methoxyphenyl)quinazolin-4-one (HMJ38) was a potent anti-tubulin agent. Here, HMJ38 was used as a lead compound to develop more potent anti-cancer agents and to examine the anti-cancer mechanisms. Experimental Approach Using computer-aided drug design, 2-aryl-6-substituted quinazolinones (MJ compounds) were designed and synthesized by introducing substituents at C-2 and C-6 positions of HMJ38. The cytotoxicity of MJ compounds towards human cancer cells was examined by Trypan blue exclusion assay. Microtubule distribution was visualized using TubulinTracker™ Green reagent. Protein expression of cell cycle regulators and JNK was assessed by Western blot analysis. Key Results Compounds MJ65–70 exhibited strong anti-proliferative effects towards melanoma M21, lung squamous carcinoma CH27, lung non-small carcinoma H460, hepatoma Hep3B and oral cancer HSC-3 cells, with one compund MJ66 (6-(pyrrolidin-1-yl)-2-(naphthalen-1-yl)quinazolin-4-one) highly active against M21 cells (IC50 about 0.033 μM). Treatment of CH27 or HSC-3 cells with MJ65–70 resulted in significant mitotic arrest accompanied by increasing multiple asters of microtubules. JNK protein expression was involved in the MJ65–70-induced CH27 and M21 cell death. Consistent with the cell cycle arrest at G2/M phase, marked increases in cyclin B1 and Bcl-2 phosphorylation were also observed, after treatment with MJ65–70. Conclusions and Implication MJ65–70 are dual-targeted, tubulin- and JNK-binding, anti-cancer agents and induce cancer cell death through up-regulation of JNK and interfering in the dynamics of tubulin. Our work provides a new strategy and mechanism for developing dual-targeted anti-cancer drugs, contributing to clinical anti-cancer drug discovery and application. PMID:23638624

  17. Evidence to Support the Anti-Cancer Effect of Olive Leaf Extract and Future Directions

    PubMed Central

    Boss, Anna; Bishop, Karen S.; Marlow, Gareth; Barnett, Matthew P. G.; Ferguson, Lynnette R.

    2016-01-01

    The traditional Mediterranean diet (MD) is associated with long life and lower prevalence of cardiovascular disease and cancers. The main components of this diet include high intake of fruit, vegetables, red wine, extra virgin olive oil (EVOO) and fish, low intake of dairy and red meat. Olive oil has gained support as a key effector of health benefits and there is evidence that this relates to the polyphenol content. Olive leaf extract (OLE) contains a higher quantity and variety of polyphenols than those found in EVOO. There are also important structural differences between polyphenols from olive leaf and those from olive fruit that may improve the capacity of OLE to enhance health outcomes. Olive polyphenols have been claimed to play an important protective role in cancer and other inflammation-related diseases. Both inflammatory and cancer cell models have shown that olive leaf polyphenols are anti-inflammatory and protect against DNA damage initiated by free radicals. The various bioactive properties of olive leaf polyphenols are a plausible explanation for the inhibition of progression and development of cancers. The pathways and signaling cascades manipulated include the NF-κB inflammatory response and the oxidative stress response, but the effects of these bioactive components may also result from their action as a phytoestrogen. Due to the similar structure of the olive polyphenols to oestrogens, these have been hypothesized to interact with oestrogen receptors, thereby reducing the prevalence and progression of hormone related cancers. Evidence for the protective effect of olive polyphenols for cancer in humans remains anecdotal and clinical trials are required to substantiate these claims idea. This review aims to amalgamate the current literature regarding bioavailability and mechanisms involved in the potential anti-cancer action of olive leaf polyphenols. PMID:27548217

  18. Evidence to Support the Anti-Cancer Effect of Olive Leaf Extract and Future Directions.

    PubMed

    Boss, Anna; Bishop, Karen S; Marlow, Gareth; Barnett, Matthew P G; Ferguson, Lynnette R

    2016-01-01

    The traditional Mediterranean diet (MD) is associated with long life and lower prevalence of cardiovascular disease and cancers. The main components of this diet include high intake of fruit, vegetables, red wine, extra virgin olive oil (EVOO) and fish, low intake of dairy and red meat. Olive oil has gained support as a key effector of health benefits and there is evidence that this relates to the polyphenol content. Olive leaf extract (OLE) contains a higher quantity and variety of polyphenols than those found in EVOO. There are also important structural differences between polyphenols from olive leaf and those from olive fruit that may improve the capacity of OLE to enhance health outcomes. Olive polyphenols have been claimed to play an important protective role in cancer and other inflammation-related diseases. Both inflammatory and cancer cell models have shown that olive leaf polyphenols are anti-inflammatory and protect against DNA damage initiated by free radicals. The various bioactive properties of olive leaf polyphenols are a plausible explanation for the inhibition of progression and development of cancers. The pathways and signaling cascades manipulated include the NF-κB inflammatory response and the oxidative stress response, but the effects of these bioactive components may also result from their action as a phytoestrogen. Due to the similar structure of the olive polyphenols to oestrogens, these have been hypothesized to interact with oestrogen receptors, thereby reducing the prevalence and progression of hormone related cancers. Evidence for the protective effect of olive polyphenols for cancer in humans remains anecdotal and clinical trials are required to substantiate these claims idea. This review aims to amalgamate the current literature regarding bioavailability and mechanisms involved in the potential anti-cancer action of olive leaf polyphenols. PMID:27548217

  19. Characterization of the apoptotic response induced by the cyanine dye D112: a potentially selective anti-cancer compound.

    PubMed

    Yang, Ning; Gilman, Paul; Mirzayans, Razmik; Sun, Xuejun; Touret, Nicolas; Weinfeld, Michael; Goping, Ing Swie

    2015-01-01

    Chemotherapeutic drugs that are used in anti-cancer treatments often cause the death of both cancerous and noncancerous cells. This non-selective toxicity is the root cause of untoward side effects that limits the effectiveness of therapy. In order to improve chemotherapeutic options for cancer patients, there is a need to identify novel compounds with higher discrimination for cancer cells. In the past, methine dyes that increase the sensitivity of photographic emulsions have been investigated for anti-cancer properties. In the 1970's, Kodak Laboratories initiated a screen of approximately 7000 dye structural variants for selective toxicity. Among these, D112 was identified as a promising compound with elevated toxicity against a colon cancer cell line in comparison to a non-transformed cell line. Despite these results changing industry priorities led to a halt in further studies on D112. We decided to revive investigations on D112 and have further characterized D112-induced cellular toxicity. We identified that in response to D112 treatment, the T-cell leukemia cell line Jurkat showed caspase activation, mitochondrial depolarization, and phosphatidylserine externalization, all of which are hallmarks of apoptosis. Chemical inhibition of caspase enzymatic activity and blockade of the mitochondrial pathway through Bcl-2 expression inhibited D112-induced apoptosis. At lower concentrations, D112 induced growth arrest. To gain insight into the molecular mechanism of D112 induced mitochondrial dysfunction, we analyzed the intracellular localization of D112, and found that D112 associated with mitochondria. Interestingly, in the cell lines that we tested, D112 showed increased toxicity toward transformed versus non-transformed cells. Results from this work identify D112 as a potentially interesting molecule warranting further investigation. PMID:25927702

  20. Pharmacogenetics of resistance to cisplatin and other anti-cancer drugs and the role of sphingolipid metabolism

    PubMed Central

    Alexander, Stephen; Swatson, William S.; Alexander, Hannah

    2014-01-01

    Summary Dictyostelium discoideum has proven to be a useful lead genetic system for identifying novel genes and pathways responsible for the regulation of sensitivity to the widely used anti-cancer drug cisplatin. Resistance to cisplatin is a major factor limiting the efficacy of the drug in treating many types of cancer. Studies using unbiased insertional mutagenesis in D. discoideum have identified the pathway of sphingolipid metabolism as a key regulator in controlling sensitivity to cisplatin. Using the genetic tools including directed homologous recombination and ectopic gene expression available with D. discoideum has shown how pharmacological modulation of this pathway can increase sensitivity to cisplatin, and these results have been extensively translated to, and validated in, human cells. Strategies, experimental conditions and methods are presented to enable further study of resistance to cisplatin as well as other important drugs. PMID:23494308

  1. Anti-Cancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogs

    PubMed Central

    Beedie, Shaunna L.; Peer, Cody J.; Pisle, Steven; Gardner, Erin R.; Mahony, Chris; Barnett, Shelby; Ambrozak, Agnieszka; Gütschow, Michael; Chau, Cindy H.; Vargesson, Neil; Figg, William D.

    2015-01-01

    Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenesis pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogs (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the anti-angiogenic properties of these newly synthesized compounds. We examined the specific anti-angiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. Additionally, further in vitro efficacy was evaluated using HUVECs and PC3 cells treated with 5μM and 10μM doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The anti-angiogenic properties of the compounds was also examined in vivo in fli1:EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo:GFP zebrafish embryos, while Gu998 and Gu992 showed no difference. The compounds anti-tumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogs as a promising immunomodulatory class with anti-cancer effects that warrant further development to characterize their mechanisms of action. PMID:26269604

  2. Evaluation of Anti Cancer Effects of DPP-4 Inhibitors in Colon Cancer- An Invitro Study

    PubMed Central

    Kumaravelu, Punnagai; Chellathai, D. Darling

    2015-01-01

    Introduction Among the oral anti-diabetic drugs, Dipeptidyl peptidase - 4(DPP-4) inhibitor is an emerging class of drugs. Inhibitors of DPP-4 enzyme like Sitagliptin and Vildagliptin have shown Anti-oxidant properties in many studies, both invivo and invitro. It has also been characterized as an apoptotic agent on pancreatic cancer cells. In the following study, Anticancer effect of DPP 4 inhibitors on colon cell lines (HT-29) using MTT assay— {3 -4, 5-dimethyl (thiazol – 2 -yl) -3, 5- dimethyl tetrazolium bromide} assay was elucidated. Aim To elucidate and compare the anticancer potential of two DPP 4 inhibitors using in-vitro MTT assay on colorectal cell lines (HT-29). Materials and Methods We treated HT-29 cell lines with two DPP 4 inhibitors. HT-29 cells were incubated at 370C and drug samples were added in various concentrations and incubated for 24 hours. MTT dye was added to the sample and it was incubated for 4 hours. One ml of DMSO was added Using an Ultraviolet-Spectrophotometer, measurement of absorbance was done at 570nm following which the half maximal inhibitory concentration was graphically estimated in relation to the percentage of viability of the cell and the sample concentration. Results We found that both the drugs have shown anticancer activity starting from low to high concentrations when compared with the control using MTT assay. The IC 50 value of Sitagliptin is 31.2 mcg/ml and Vildagliptin is 125 mcg/ml. Conclusion: From this study, we found that the drugs have significant Anti-Cancer property, which would probably play a role as cytotoxic agent in tumour cells. Sitagliptin was found to be more potent than Vildagliptin in colon cancer cell lines. PMID:26816911

  3. Activation of human T-helper/inducer cell, T-cytotoxic/suppressor cell, B-cell, and natural killer (NK)-cells and induction of NK cell activity against K562 chronic myeloid leukemia cells with modified citrus pectin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background Modified citrus pectin (MCP) is known for its anti-cancer effects and its ability to be absorbed and circulated in the human body. In this report we tested the ability of MCP to induce the activation of human blood lymphocyte subsets including T-helper/inducer cell, Tcytotoxic/suppres...

  4. Colon-available raspberry polyphenols exhibit anti-cancer effects on in vitro models of colon cancer

    PubMed Central

    Coates, Emma M; Popa, Gina; Gill, Chris IR; McCann, Mark J; McDougall, Gordon J; Stewart, Derek; Rowland, Ian

    2007-01-01

    Background There is a probable association between consumption of fruit and vegetables and reduced risk of cancer, particularly cancer of the digestive tract. This anti-cancer activity has been attributed in part to anti-oxidants present in these foods. Raspberries in particular are a rich source of the anti-oxidant compounds, such as polyphenols, anthocyanins and ellagitannins. Methods A "colon-available" raspberry extract (CARE) was prepared that contained phytochemicals surviving a digestion procedure that mimicked the physiochemical conditions of the upper gastrointestinal tract. The polyphenolic-rich extract was assessed for anti-cancer properties in a series of in vitro systems that model important stages of colon carcinogenesis, initiation, promotion and invasion. Results The phytochemical composition of CARE was monitored using liquid chromatography mass spectrometry. The colon-available raspberry extract was reduced in anthocyanins and ellagitannins compared to the original raspberry juice but enriched in other polyphenols and polyphenol breakdown products that were more stable to gastrointestinal digestion. Initiation – CARE caused significant protective effects against DNA damage induced by hydrogen peroxide in HT29 colon cancer cells measured using single cell microgelelectrophoresis. Promotion – CARE significantly decreased the population of HT29 cells in the G1 phase of the cell cycle, effectively reducing the number of cells entering the cell cycle. However, CARE had no effect on epithelial integrity (barrier function) assessed by recording the trans-epithelial resistance (TER) of CACO-2 cell monolayers. Invasion – CARE caused significant inhibition of HT115 colon cancer cell invasion using the matrigel invasion assay. Conclusion The results indicate that raspberry phytochemicals likely to reach the colon are capable of inhibiting several important stages in colon carcinogenesis in vitro. PMID:17442116

  5. Lichen Secondary Metabolites in Flavocetraria cucullata Exhibit Anti-Cancer Effects on Human Cancer Cells through the Induction of Apoptosis and Suppression of Tumorigenic Potentials

    PubMed Central

    Nguyen, Thanh Thi; Yoon, Somy; Yang, Yi; Lee, Ho-Bin; Oh, Soonok; Jeong, Min-Hye; Kim, Jong-Jin; Yee, Sung-Tae; Crişan, Florin; Moon, Cheol; Lee, Kwang Youl; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2014-01-01

    Lichens are symbiotic organisms which produce distinct secondary metabolic products. In the present study, we tested the cytotoxic activity of 17 lichen species against several human cancer cells and further investigated the molecular mechanisms underlying their anti-cancer activity. We found that among 17 lichens species, F. cucullata exhibited the most potent cytotoxicity in several human cancer cells. High performance liquid chromatography analysis revealed that the acetone extract of F. cucullata contains usnic acid, salazinic acid, Squamatic acid, Baeomycesic acid, d-protolichesterinic acid, and lichesterinic acid as subcomponents. MTT assay showed that cancer cell lines were more vulnerable to the cytotoxic effects of the extract than non-cancer cell lines. Furthermore, among the identified subcomponents, usnic acid treatment had a similar cytotoxic effect on cancer cell lines but with lower potency than the extract. At a lethal dose, treatment with the extract or with usnic acid greatly increased the apoptotic cell population and specifically activated the apoptotic signaling pathway; however, using sub-lethal doses, extract and usnic acid treatment decreased cancer cell motility and inhibited in vitro and in vivo tumorigenic potentials. In these cells, we observed significantly reduced levels of epithelial-mesenchymal transition (EMT) markers and phosphor-Akt, while phosphor-c-Jun and phosphor-ERK1/2 levels were only marginally affected. Overall, the anti-cancer activity of the extract is more potent than that of usnic acid alone. Taken together, F. cucullata and its subcomponent, usnic acid together with additional component, exert anti-cancer effects on human cancer cells through the induction of apoptosis and the inhibition of EMT. PMID:25360754

  6. Lichen secondary metabolites in Flavocetraria cucullata exhibit anti-cancer effects on human cancer cells through the induction of apoptosis and suppression of tumorigenic potentials.

    PubMed

    Nguyen, Thanh Thi; Yoon, Somy; Yang, Yi; Lee, Ho-Bin; Oh, Soonok; Jeong, Min-Hye; Kim, Jong-Jin; Yee, Sung-Tae; Crişan, Florin; Moon, Cheol; Lee, Kwang Youl; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2014-01-01

    Lichens are symbiotic organisms which produce distinct secondary metabolic products. In the present study, we tested the cytotoxic activity of 17 lichen species against several human cancer cells and further investigated the molecular mechanisms underlying their anti-cancer activity. We found that among 17 lichens species, F. cucullata exhibited the most potent cytotoxicity in several human cancer cells. High performance liquid chromatography analysis revealed that the acetone extract of F. cucullata contains usnic acid, salazinic acid, Squamatic acid, Baeomycesic acid, d-protolichesterinic acid, and lichesterinic acid as subcomponents. MTT assay showed that cancer cell lines were more vulnerable to the cytotoxic effects of the extract than non-cancer cell lines. Furthermore, among the identified subcomponents, usnic acid treatment had a similar cytotoxic effect on cancer cell lines but with lower potency than the extract. At a lethal dose, treatment with the extract or with usnic acid greatly increased the apoptotic cell population and specifically activated the apoptotic signaling pathway; however, using sub-lethal doses, extract and usnic acid treatment decreased cancer cell motility and inhibited in vitro and in vivo tumorigenic potentials. In these cells, we observed significantly reduced levels of epithelial-mesenchymal transition (EMT) markers and phosphor-Akt, while phosphor-c-Jun and phosphor-ERK1/2 levels were only marginally affected. Overall, the anti-cancer activity of the extract is more potent than that of usnic acid alone. Taken together, F. cucullata and its subcomponent, usnic acid together with additional component, exert anti-cancer effects on human cancer cells through the induction of apoptosis and the inhibition of EMT. PMID:25360754

  7. MEK-ERK inhibition potentiates WAY-600-induced anti-cancer efficiency in preclinical hepatocellular carcinoma (HCC) models.

    PubMed

    Wang, Kaifeng; Fan, Yaohua; Chen, Gongying; Wang, Zhengrong; Kong, Dexin; Zhang, Peng

    2016-05-27

    The search for novel anti-hepatocellular carcinoma (HCC) agents is important. Mammalian target of rapamycin (mTOR) hyper-activation plays a pivotal role in promoting HCC tumorigenesis and chemoresistance. The current preclinical study evaluated the potential anti-HCC activity by a potent mTOR kinase inhibitor, WAY-600. We showed that WAY-600 inhibited survival and proliferation of HCC cell lines (HepG2 and Huh7) and primary human HCC cells. Caspase-dependent apoptosis was activated by WAY-600 in above HCC cells. Reversely, caspase inhibitors largely attenuated WAY-600's lethality against HCC cells. At the signaling level, WAY-600 blocked mTOR complex 1/2 (mTORC1/2) assemble and activation, yet activated MEK-ERK pathway in HCC cells. MEK-ERK inhibitors, PD-98059 and MEK-162, or MEK1/2 shRNA significantly potentiated WAY-600's cytotoxicity in HCC cells. Further studies showed that WAY-600 intraperitoneal (i.p.) administration in nude mice inhibited p-AKT Ser-473 and displayed significant anti-cancer activity against HepG2 xenografts. Remarkably, co-administration of MEK-162 further potentiated WAY-600's anti-HCC activity in vivo. These preclinical results demonstrate the potent anti-HCC activity by WAY-600, either alone or with MEK-ERK inhibitors. PMID:27107695

  8. Exploiting developments in nanotechnology for the preferential delivery of platinum-based anti-cancer agents to tumours: targeting some of the hallmarks of cancer.

    PubMed

    Parker, James P; Ude, Ziga; Marmion, Celine J

    2016-01-01

    Platinum drugs as anti-cancer therapeutics are held in extremely high regard. Despite their success, there are drawbacks associated with their use; their dose-limiting toxicity, their limited activity against an array of common cancers and patient resistance to Pt-based therapeutic regimes. Current investigations in medicinal inorganic chemistry strive to offset these shortcomings through selective targeting of Pt drugs and/or the development of Pt drugs with new or multiple modes of action. A comprehensive overview showcasing how liposomes, nanocapsules, polymers, dendrimers, nanoparticles and nanotubes may be employed as vehicles to selectively deliver cytotoxic Pt payloads to tumour cells is provided. PMID:26567482

  9. Anti-cancer flavonoids are mouse selective STING agonists

    PubMed Central

    Kim, Sujeong; Li, Lingyin; Maliga, Zoltan; Yin, Qian; Wu, Hao; Mitchison, Timothy J.

    2013-01-01

    The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice, but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor-specific vascular damage and other anti-tumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the anti-tumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy. PMID:23683494

  10. Controlled release of an anti-cancer drug from DNA structured nano-films

    NASA Astrophysics Data System (ADS)

    Cho, Younghyun; Lee, Jong Bum; Hong, Jinkee

    2014-02-01

    We demonstrate the generation of systemically releasable anti-cancer drugs from multilayer nanofilms. Nanofilms designed to drug release profiles in programmable fashion are promising new and alternative way for drug delivery. For the nanofilm structure, we synthesized various unique 3-dimensional anti cancer drug incorporated DNA origami structures (hairpin, Y, and X shaped) and assembled with peptide via layer-by-layer (LbL) deposition method. The key to the successful application of these nanofilms requires a novel approach of the influence of DNA architecture for the drug release from functional nano-sized surface. Herein, we have taken first steps in building and controlling the drug incorporated DNA origami based multilayered nanostructure. Our finding highlights the novel and unique drug release character of LbL systems in serum condition taken full advantages of DNA origami structure. This multilayer thin film dramatically affects not only the release profiles but also the structure stability in protein rich serum condition.

  11. Controlled release of an anti-cancer drug from DNA structured nano-films

    PubMed Central

    Cho, Younghyun; Lee, Jong Bum; Hong, Jinkee

    2014-01-01

    We demonstrate the generation of systemically releasable anti-cancer drugs from multilayer nanofilms. Nanofilms designed to drug release profiles in programmable fashion are promising new and alternative way for drug delivery. For the nanofilm structure, we synthesized various unique 3-dimensional anti cancer drug incorporated DNA origami structures (hairpin, Y, and X shaped) and assembled with peptide via layer-by-layer (LbL) deposition method. The key to the successful application of these nanofilms requires a novel approach of the influence of DNA architecture for the drug release from functional nano-sized surface. Herein, we have taken first steps in building and controlling the drug incorporated DNA origami based multilayered nanostructure. Our finding highlights the novel and unique drug release character of LbL systems in serum condition taken full advantages of DNA origami structure. This multilayer thin film dramatically affects not only the release profiles but also the structure stability in protein rich serum condition. PMID:24518218

  12. Viscum Album Var Hot Water Extract Mediates Anti-cancer Effects through G1 Phase Cell Cycle Arrest in SK-Hep1 Human Hepatocarcinoma cells.

    PubMed

    dela Cruz, Joseph Flores; Kim, Yeon Soo; Lumbera, Wenchie Marie Lara; Hwang, Seong Gu

    2015-01-01

    Viscum album var (VAV) also known as mistletoe, has long been categorized as a traditional herbal medicine in Asia. In addition to its immunomodulating activities, mistletoe has also been used in the treatment of chronic hepatic disorders in China and Korea. There are numerous reports showing that VAV possesses anti-cancer effects, however influence on human hepatocarcinoma has never been elucidated. In the present study, hot water extracts of VAV was evaluated for its potential anti-cancer effect in vitro. SK-Hep1 cells were treated with VAV (50-400 ug/ml) for both 24 and 48 hours then cell viability was measured by cell counting kit-8 (CCK-8). Flow cytometry analysis was used to measure the proportion of SK-Hep1 in the different stages of cell cycle. RT-PCR and Western blot analysis were conducted to measure expression of cell cycle arrest related genes and proteins respectively. VAV dose dependently inhibited the proliferation of SK-Hep1 cells without any cytotoxicity with normal Chang liver cell (CCL-13). Flow cytometry analysis showed that VAV extract inhibited the cell cycle of SK-Hep1 cells via G1 phase arrest. RT-PCR and Western blot analysis both revealed that cyclin dependent kinase 2 (Cdk2) and cyclin D1 gene expression were significantly down regulated while p21 was upregulated dose dependently by VAV treatment. Combined down regulation of Cdk2, Cyclin D1 and up regulation of p21 can result in cell death. These results indicate that VAV showed evidence of anti-cancer activity through G1 phase cell cycle arrest in SK-Hep1 cells. PMID:26434853

  13. Quantification of cell viability and rapid screening anti-cancer drug utilizing nanomechanical fluctuation.

    PubMed

    Wu, Shangquan; Liu, Xiaoli; Zhou, Xiarong; Liang, Xin M; Gao, Dayong; Liu, Hong; Zhao, Gang; Zhang, Qingchuan; Wu, Xiaoping

    2016-03-15

    Cancer is a serious threat to human health. Although numerous anti-cancer drugs are available clinically, many have shown toxic side effects due to poor tumor-selectivity, and reduced effectiveness due to cancers rapid development of resistance to treatment. The development of new highly efficient and practical methods to quantify cell viability and its change under drug treatment is thus of significant importance in both understanding of anti-cancer mechanism and anti-cancer drug screening. Here, we present an approach of utilizing a nanomechanical fluctuation based highly sensitive microcantilever sensor, which is capable of characterizing the viability of cells and quantitatively screening (within tens of minutes) their responses to a drug with the obvious advantages of a rapid, label-free, quantitative, noninvasive, real-time and in-situ assay. The microcantilever sensor operated in fluctuation mode was used in evaluating the paclitaxel effectiveness on breast cancer cell line MCF-7. This study demonstrated that the nanomechanical fluctuations of the microcantilever sensor are sensitive enough to detect the dynamic variation in cellular force which is provided by the cytoskeleton, using cell metabolism as its energy source, and the dynamic instability of microtubules plays an important role in the generation of the force. We propose that cell viability consists of two parts: biological viability and mechanical viability. Our experimental results suggest that paclitaxel has little effect on biological viability, but has a significant effect on mechanical viability. This new method provides a new concept and strategy for the evaluation of cell viability and the screening of anti-cancer drugs. PMID:26406457

  14. Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents.

    PubMed

    Huang, Wei-Chun; Tseng, Ting-Yuan; Chen, Ying-Ting; Chang, Cheng-Chung; Wang, Zi-Fu; Wang, Chiung-Lin; Hsu, Tsu-Ning; Li, Pei-Tzu; Chen, Chin-Tin; Lin, Jing-Jer; Lou, Pei-Jen; Chang, Ta-Chau

    2015-12-01

    G-quadruplex (G4) is a promising target for anti-cancer treatment. In this paper, we provide the first evidence supporting the presence of G4 in the mitochondrial DNA (mtDNA) of live cells. The molecular engineering of a fluorescent G4 ligand, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC), can change its major cellular localization from the nucleus to the mitochondria in cancer cells, while remaining primarily in the cytoplasm of normal cells. A number of BMVC derivatives with sufficient mitochondrial uptake can induce cancer cell death without damaging normal cells. Fluorescence studies of these anti-cancer agents in live cells and in isolated mitochondria from HeLa cells have demonstrated that their major target is mtDNA. In this study, we use fluorescence lifetime imaging microscopy to verify the existence of mtDNA G4s in live cells. Bioactivity studies indicate that interactions between these anti-cancer agents and mtDNA G4 can suppress mitochondrial gene expression. This work underlines the importance of fluorescence in the monitoring of drug-target interactions in cells and illustrates the emerging development of drugs in which mtDNA G4 is the primary target. PMID:26487635

  15. A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties

    PubMed Central

    Pitman, Melissa R.; Powell, Jason A.; Coolen, Carl; Moretti, Paul A.B.; Zebol, Julia R.; Pham, Duyen H.; Finnie, John W.; Don, Anthony S.; Ebert, Lisa M.; Bonder, Claudine S.; Gliddon, Briony L.; Pitson, Stuart M.

    2015-01-01

    The dynamic balance of cellular sphingolipids, the sphingolipid rheostat, is an important determinant of cell fate, and is commonly deregulated in cancer. Sphingosine 1-phosphate is a signaling molecule with anti-apoptotic, pro-proliferative and pro-angiogenic effects, while conversely, ceramide and sphingosine are pro-apoptotic. The sphingosine kinases (SKs) are key regulators of this sphingolipid rheostat, and are attractive targets for anti-cancer therapy. Here we report a first-in-class ATP-binding site-directed small molecule SK inhibitor, MP-A08, discovered using an approach of structural homology modelling of the ATP-binding site of SK1 and in silico docking with small molecule libraries. MP-A08 is a highly selective ATP competitive SK inhibitor that targets both SK1 and SK2. MP-A08 blocks pro-proliferative signalling pathways, induces mitochondrial-associated apoptosis in a SK-dependent manner, and reduces the growth of human lung adenocarcinoma tumours in a mouse xenograft model by both inducing tumour cell apoptosis and inhibiting tumour angiogenesis. Thus, this selective ATP competitive SK inhibitor provides a promising candidate for potential development as an anti-cancer therapy, and also, due to its different mode of inhibition to other known SK inhibitors, both validates the SKs as targets for anti-cancer therapy, and represents an important experimental tool to study these enzymes. PMID:25788259

  16. Optimizing drug development of anti-cancer drugs in children using modelling and simulation

    PubMed Central

    van Hasselt, Johan GC; van Eijkelenburg, Natasha KA; Beijnen, Jos H; Schellens, Jan HM; Huitema, Alwin DR

    2013-01-01

    Modelling and simulation (M&S)-based approaches have been proposed to support paediatric drug development in order to design and analyze clinical studies efficiently. Development of anti-cancer drugs in the paediatric population is particularly challenging due to ethical and practical constraints. We aimed to review the application of M&S in the development of anti-cancer drugs in the paediatric population, and to identify where M&S-based approaches could provide additional support in paediatric drug development of anti-cancer drugs. A structured literature search on PubMed was performed. The majority of identified M&S-based studies aimed to use population PK modelling approaches to identify determinants of inter-individual variability, in order to optimize dosing regimens and to develop therapeutic drug monitoring strategies. Prospective applications of M&S approaches for PK-bridging studies have scarcely been reported for paediatric oncology. Based on recent developments of M&S in drug development there are several opportunities where M&S could support more informative bridging between children and adults, and increase efficiency of the design and analysis of paediatric clinical trials, which should ultimately lead to further optimization of drug treatment strategies in this population. PMID:23216601

  17. Chemistry of potent anti-cancer compounds, amphidinolides.

    PubMed

    Chakraborty, T K; Das, S

    2001-08-01

    Amphidinolides A-V represent a family of cytotoxic marine natural products with diverse structural features and pronounced biological activities. Kobayashi and his research group have been reporting over the years the discoveries of these remarkable molecules, one after another, since 1986 when the first report of the series appeared. Thanks to their perseverance and painstaking research, the family is still expanding. The unique structural features and biological activity profiles of these macrolides have obviously attracted the attention of organic chemists worldwide. The total syntheses of three members of the family, amphidinolides J, K and P, have already been achieved. This review tries to chronicle the fascinating chemistries of amphidinolides, studies on the syntheses of some of these molecules and their biological activity profiles. PMID:12678763

  18. Screening of Drug Metabolizing Enzymes for the Ginsenoside Compound K In Vitro: An Efficient Anti-Cancer Substance Originating from Panax Ginseng

    PubMed Central

    Lin, Xiu-Xian; Peng, Shi-Fang; Xiao, Mei-Fang; Huang, Wei-Hua; Wang, Yi-Cheng; Peng, Jing-Bo; Zhang, Wei; Ouyang, Dong-Sheng; Chen, Yao

    2016-01-01

    Ginsenoside compound K (CK), a rare ginsenoside originating from Panax Ginseng, has been found to possess unique pharmacological activities specifically as anti-cancers. However, the role of cytochrome P450s (CYPs) in the metabolism of CK is unclear. In this study, we screened the CYPs for the metabolism of CK in vitro using human liver microsomes (HLMs) or human recombinant CYPs. The results showed that CK inhibited the enzyme activities of CYP2C9 and CYP3A4 in the HLMs. The Km and Vmax values of CK were 84.20±21.92 μM and 0.28±0.04 nmol/mg protein/min, respectively, for the HLMs; 34.63±10.48 μM and 0.45±0.05 nmol/nmol P450/min, respectively, for CYP2C9; and 27.03±5.04 μM and 0.68±0.04 nmol/nmol P450/min, respectively, for CYP3A4. The IC50 values were 16.00 μM and 9.83 μM, and Ki values were 14.92 μM and 11.42μM for CYP2C9 and CYP3A4, respectively. Other human CYP isoforms, including CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP2C19, showed minimal or no effect on CK metabolism. The results suggested that CK was a substrate and also inhibitors for both CYP2C9 and CYP3A4. Patients using CK in combination with therapeutic drugs that are substrates of CYP2C9 and CYP3A4 for different reasons should be careful, although the inhibiting potency of CK is much poorer than that of enzyme-specific inhibitors. PMID:26845774

  19. Exploratory studies of the potential anti-cancer effects of creatine.

    PubMed

    Campos-Ferraz, P L; Gualano, B; das Neves, W; Andrade, I T; Hangai, I; Pereira, R T S; Bezerra, R N; Deminice, R; Seelaender, M; Lancha, A H

    2016-08-01

    Two experiments were performed, in which male Wistar Walker 256 tumor-bearing rats were inoculated with 4 × 10(7) tumor cells subcutaneously and received either creatine (300 mg/kg body weight/day; CR) or placebo (water; PL) supplementation via intragastric gavage. In experiment 1, 50 rats were given PL (n = 22) or CR (n = 22) and a non-supplemented, non-inoculated group served as control CT (n = 6), for 40 days, and the survival rate and tumor mass were assessed. In experiment 2, 25 rats were given CR or PL for 15 days and sacrificed for biochemical analysis. Again, a non-supplemented, non-inoculated group served as control (CT; n = 6). Tumor and muscle creatine kinase (CK) activity and total creatine content, acidosis, inflammatory cytokines, and antioxidant capacity were assessed. Tumor growth was significantly reduced by approximately 30 % in CR when compared with PL (p = 0.03), although the survival rate was not significantly different between CR and PL (p = 0.65). Tumor creatine content tended to be higher in CR than PL (p = 0.096). Tumor CK activity in the cytosolic fraction was higher in CR than PL (p < 0.0001). Blood pCO2 was higher in CT and CR than PL (p = 0.0007 and p = 0.004, respectively). HCO3 was augmented in CT compared to PL (p = 0.03) and CR (p = 0.001). Plasma IL-6 was lower and IL-10 level was higher in CR than PL (p = 0.03 and p = 0.0007, respectively) and TNF-alpha featured a tendency of decrease in CR compared to PL (p = 0.08). Additionally, total antioxidant capacity tended to be lower in CT than PL (p = 0.07). Creatine supplementation was able to slow tumor growth without affecting the overall survival rate, probably due to the re-establishment of the CK-creatine system in cancer cells, leading to attenuation in acidosis, inflammation, and oxidative stress. These findings support the role of creatine as a putative anti-cancer agent as well as help in expanding our knowledge on its potential mechanisms

  20. Oxidative metabolism of the anti-cancer agent mitoxantrone by horseradish, lacto-and lignin peroxidase.

    PubMed

    Brück, Thomas B; Brück, Dieter W

    2011-02-01

    Mitoxantrone (MH(2)X), an anthraquinone-type anti-cancer agent used clinically in the treatment of human malignancies, is oxidatively activated by the peroxidase/H(2)O(2) enzyme system. In contrast to the enzymatic mechanisms of drug oxidation, the chemical transformations of MH(2)X are not well described. In this study, MH(2)X metabolites, produced by the horseradish, lacto- or lignin peroxidase (respectively HRP, LPO and LIP)/H(2)O(2) system, were investigated by steady-state spectrokinetic and HPLC-MS methods. At an equimolar mitoxantrone/H(2)O(2) ratio, the efficacy of the enzyme-catalyzed oxidation of mitoxantrone decreased in the following order: LPO > HRP > LIP, which accorded with the decreasing size of the substrate access channel in the enzyme panel examined. In all cases, the central drug oxidation product was the redox-active cyclic metabolite, hexahydronaphtho-[2,3-f]-quinoxaline-7,12-dione (MH(2)), previously identified in the urine of mitoxantrone-treated patients. As the reaction progressed, data gathered in this study suggests that further oxidation of the MH(2) side-chains occurred, yielding the mono- and dicarboxylic acid derivatives respectively. Based on the available data a further MH(2) derivative is proposed, in which the amino-alkyl side-chain(s) are cyclised. With increasing H(2)O(2) concentrations, these novel MH(2) derivatives were oxidised to additional metabolites, whose spectral properties and MS data indicated a stepwise destruction of the MH(2) chromophore due to an oxidative cleavage of the 9,10-anthracenedione moiety. The novel metabolites extend the known sequence of peroxidase-induced mitoxantrone metabolism, and may contribute to the cytotoxic effects of the drug in vivo. Based on the structural features of the proposed MH(2) oxidation products we elaborate on various biochemical mechanisms, which extend the understanding of mitoxantrone's pharmaceutical action and its clinical effectiveness with a particular focus on

  1. External influences and priority-setting for anti-cancer agents: a case study of media coverage in adjuvant trastuzumab for breast cancer

    PubMed Central

    Booth, Christopher M; Dranitsaris, George; Gainford, M Corona; Berry, Scott; Fralick, Michael; Fralick, John; Sue, Joanna; Clemons, Mark

    2007-01-01

    Background Setting priorities for the funding of new anti-cancer agents is becoming increasingly complex. The funding of adjuvant trastuzumab for breast cancer has brought this dilemma to the fore. In this paper we review external factors that may influence decision-making bodies and present a case study of media response in Ontario, Canada to adjuvant trastuzumab for breast cancer. Methods A comprehensive search of the databases of Canadian national and local newspapers and television was performed. Articles pertaining to trastuzumab in adjuvant breast cancer as well as 17 other anti-cancer drugs and indications were retrieved. The search period was from the date when individual trial results were announced to the date funding was made available in Ontario. Results During the 2.6 months between the release of the trastuzumab results to funding approval in Ontario, we identified 51 episodes of media coverage. For the 17 other drugs/indications (7 breast and 10 non-breast), the median time to funding approval was 31 months (range 14–46). Other recent major advances in oncology such as adjuvant vinorelbine/cisplatin for resected NSCLC and docetaxel for advanced prostate cancer received considerably less media attention (17 media reports for each) than trastuzumab. The median number of media reports for breast cancer drugs was 4.5 compared to 2.5 for non-breast cancer drugs (p = 0.56). Conclusion Priority-setting for novel anti-cancer agents is a complex process that tries to ensure fair use of constrained resources to fund therapies with the best evidence of clinical benefit. However, this process is subject to external factors including the influence of media, patient advocates, politicians, and industry. The data in this case study serve to illustrate the significant involvement one (or all) of these external factors may play in the debate over priority-setting. PMID:17598896

  2. Notoginseng enhances anti-cancer effect of 5-fluorouracil on human colorectal cancer cells

    PubMed Central

    Wang, Chong-Zhi; Luo, Xiaoji; Zhang, Bin; Song, Wen-Xin; Ni, Ming; Mehendale, Sangeeta; Xie, Jing-Tian; Aung, Han H.; He, Tong-Chuan

    2009-01-01

    Purpose Panax notoginseng is a commonly used Chinese herb. Although a few studies have found that notoginseng shows anti-tumor effects, the effect of this herb on colorectal cancer cells has not been investigated. 5-Fluorouracil (5-FU) is a chemotherapeutic agent for the treatment of colorectal cancer that interferes with the growth of cancer cells. However, this compound has serious side effects at high doses. In this study, using HCT-116 human colorectal cancer cell line, we investigated the possible synergistic anti-cancer effects between notoginseng flower extract (NGF) and 5-FU on colon cancer cells. Methods The anti-proliferation activity of these modes of treatment was evaluated by MTS cell proliferation assay. Apoptotic effects were analyzed by using Hoechst 33258 staining and Annexin-V/PI staining assays. The anti-proliferation effects of four major single compounds from NGF, ginsenosides Rb1, Rb3, Rc and Rg3 were also analyzed. Results Both 5-FU and NGF inhibited proliferation of HCT-116 cells. With increasing doses of 5-FU, the anti-proliferation effect was slowly increased. The combined usage of 5-FU 5 μM and NGF 0.25 mg/ml, significantly increased the anti-proliferation effect (59.4 ± 3.3%) compared with using the two medicines separately (5-FU 5 μM, 31.1 ± 0.4%; NGF 0.25 mg/ml, 25.3 ± 3.6%). Apoptotic analysis showed that at this concentration, 5-FU did not exert an apoptotic effect, while apoptotic cells induced by NGF were observed, suggesting that the anti-proliferation target(s) of NGF may be different from that of 5-FU, which is known to inhibit thymidilate synthase. Conclusions This study demonstrates that NGF can enhance the anti-proliferation effect of 5-FU on HCT-116 human colorectal cancer cells and may decrease the dosage of 5-FU needed for colorectal cancer treatment. PMID:17009031

  3. Mitosis as an anti-cancer drug target.

    PubMed

    Salmela, Anna-Leena; Kallio, Marko J

    2013-10-01

    Suppression of cell proliferation by targeting mitosis is one potential cancer intervention. A number of existing chemotherapy drugs disrupt mitosis by targeting microtubule dynamics. While efficacious, these drugs have limitations, i.e. neuropathy, unpredictability and development of resistance. In order to overcome these issues, a great deal of effort has been spent exploring novel mitotic targets including Polo-like kinase 1, Aurora kinases, Mps1, Cenp-E and KSP/Eg5. Here we summarize the latest developments in the discovery and clinical evaluation of new mitotic drug targets. PMID:23775312

  4. Curcumin AntiCancer Studies in Pancreatic Cancer.

    PubMed

    Bimonte, Sabrina; Barbieri, Antonio; Leongito, Maddalena; Piccirillo, Mauro; Giudice, Aldo; Pivonello, Claudia; de Angelis, Cristina; Granata, Vincenza; Palaia, Raffaele; Izzo, Francesco

    2016-01-01

    Pancreatic cancer (PC) is one of the deadliest cancers worldwide. Surgical resection remains the only curative therapeutic treatment for this disease, although only the minority of patients can be resected due to late diagnosis. Systemic gemcitabine-based chemotherapy plus nab-paclitaxel are used as the gold-standard therapy for patients with advanced PC; although this treatment is associated with a better overall survival compared to the old treatment, many side effects and poor results are still present. Therefore, new alternative therapies have been considered for treatment of advanced PC. Several preclinical studies have demonstrated that curcumin, a naturally occurring polyphenolic compound, has anticancer effects against different types of cancer, including PC, by modulating many molecular targets. Regarding PC, in vitro studies have shown potent cytotoxic effects of curcumin on different PC cell lines including MiaPaCa-2, Panc-1, AsPC-1, and BxPC-3. In addition, in vivo studies on PC models have shown that the anti-proliferative effects of curcumin are caused by the inhibition of oxidative stress and angiogenesis and are due to the induction of apoptosis. On the basis of these results, several researchers tested the anticancer effects of curcumin in clinical trials, trying to overcome the poor bioavailability of this agent by developing new bioavailable forms of curcumin. In this article, we review the results of pre-clinical and clinical studies on the effects of curcumin in the treatment of PC. PMID:27438851

  5. Curcumin AntiCancer Studies in Pancreatic Cancer

    PubMed Central

    Bimonte, Sabrina; Barbieri, Antonio; Leongito, Maddalena; Piccirillo, Mauro; Giudice, Aldo; Pivonello, Claudia; de Angelis, Cristina; Granata, Vincenza; Palaia, Raffaele; Izzo, Francesco

    2016-01-01

    Pancreatic cancer (PC) is one of the deadliest cancers worldwide. Surgical resection remains the only curative therapeutic treatment for this disease, although only the minority of patients can be resected due to late diagnosis. Systemic gemcitabine-based chemotherapy plus nab-paclitaxel are used as the gold-standard therapy for patients with advanced PC; although this treatment is associated with a better overall survival compared to the old treatment, many side effects and poor results are still present. Therefore, new alternative therapies have been considered for treatment of advanced PC. Several preclinical studies have demonstrated that curcumin, a naturally occurring polyphenolic compound, has anticancer effects against different types of cancer, including PC, by modulating many molecular targets. Regarding PC, in vitro studies have shown potent cytotoxic effects of curcumin on different PC cell lines including MiaPaCa-2, Panc-1, AsPC-1, and BxPC-3. In addition, in vivo studies on PC models have shown that the anti-proliferative effects of curcumin are caused by the inhibition of oxidative stress and angiogenesis and are due to the induction of apoptosis. On the basis of these results, several researchers tested the anticancer effects of curcumin in clinical trials, trying to overcome the poor bioavailability of this agent by developing new bioavailable forms of curcumin. In this article, we review the results of pre-clinical and clinical studies on the effects of curcumin in the treatment of PC. PMID:27438851

  6. Evolution of acquired resistance to anti-cancer therapy

    PubMed Central

    Foo, Jasmine; Michor, Franziska

    2014-01-01

    Acquired drug resistance is a major limitation for the successful treatment of cancer. Resistance can emerge due to a variety of reasons including host environmental factors as well as genetic or epigenetic alterations in the cancer cells. Evolutionary theory has contributed to the understanding of the dynamics of resistance mutations in a cancer cell population, the risk of resistance pre-existing before the initiation of therapy, the composition of drug cocktails necessary to prevent the emergence of resistance, and optimum drug administration schedules for patient populations at risk of evolving acquired resistance. Here we review recent advances towards elucidating the evolutionary dynamics of acquired drug resistance and outline how evolutionary thinking can contribute to outstanding questions in the field. PMID:24681298

  7. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... promotion activities, including paid advertising. (a) In order for a handler to receive credit for his/her own promotional activities from his/her pro rata portion of advertising assessment payments, pursuant... professional practices and rates for the type of activity conducted. In the case of claims for...

  8. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... promotion activities, including paid advertising. (a) In order for a handler to receive credit for his/her own promotional activities from his/her pro rata portion of advertising assessment payments, pursuant... professional practices and rates for the type of activity conducted. In the case of claims for...

  9. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... promotion activities, including paid advertising. (a) In order for a handler to receive credit for his/her own promotional activities from his/her pro rata portion of advertising assessment payments, pursuant... professional practices and rates for the type of activity conducted. In the case of claims for...

  10. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... promotion activities, including paid advertising. (a) In order for a handler to receive credit for his/her own promotional activities from his/her pro rata portion of advertising assessment payments, pursuant... professional practices and rates for the type of activity conducted. In the case of claims for...

  11. Human recombinant RNASET2: A potential anti-cancer drug

    PubMed Central

    Roiz, Levava; Smirnoff, Patricia; Lewin, Iris; Shoseyov, Oded; Schwartz, Betty

    2016-01-01

    The roles of cell motility and angiogenetic processes in metastatic spread and tumor aggressiveness are well established and must be simultaneously targeted to maximize antitumor drug potency. This work evaluated the antitumorigenic capacities of human recombinant RNASET2 (hrRNASET2), a homologue of the Aspergillus niger T2RNase ACTIBIND, which has been shown to display both antitumorigenic and antiangiogenic activities. hrRNASET2 disrupted intracellular actin filament and actin-rich extracellular extrusion organization in both CT29 colon cancer and A375SM melanoma cells and induced a significant dose-dependent inhibition of A375SM cell migration. hrRNASET2 also induced full arrest of angiogenin-induced tube formation and brought to a three-fold lower relative HT29 colorectal and A375SM melanoma tumor volume, when compared to Avastin-treated animals. In parallel, mean blood vessel counts were 36.9% lower in hrRNASET2-vs. Avastin-treated mice and survival rates of hrRNASET2-treated mice were 50% at 73 days post-treatment, while the median survival time for untreated animals was 22 days. Moreover, a 60-day hrRNASET2 treatment period reduced mean A375SM lung metastasis foci counts by three-fold when compared to untreated animals. Taken together, the combined antiangiogenic and antitumorigenic capacities of hrRNASET2, seemingly arising from its direct interaction with intercellular and extracellular matrices, render it an attractive anticancer therapy candidate. PMID:27014725

  12. Human recombinant RNASET2: A potential anti-cancer drug.

    PubMed

    Roiz, Levava; Smirnoff, Patricia; Lewin, Iris; Shoseyov, Oded; Schwartz, Betty

    2016-01-01

    The roles of cell motility and angiogenetic processes in metastatic spread and tumor aggressiveness are well established and must be simultaneously targeted to maximize antitumor drug potency. This work evaluated the antitumorigenic capacities of human recombinant RNASET2 (hrRNASET2), a homologue of the Aspergillus niger T2RNase ACTIBIND, which has been shown to display both antitumorigenic and antiangiogenic activities. hrRNASET2 disrupted intracellular actin filament and actin-rich extracellular extrusion organization in both CT29 colon cancer and A375SM melanoma cells and induced a significant dose-dependent inhibition of A375SM cell migration. hrRNASET2 also induced full arrest of angiogenin-induced tube formation and brought to a three-fold lower relative HT29 colorectal and A375SM melanoma tumor volume, when compared to Avastin-treated animals. In parallel, mean blood vessel counts were 36.9% lower in hrRNASET2-vs. Avastin-treated mice and survival rates of hrRNASET2-treated mice were 50% at 73 days post-treatment, while the median survival time for untreated animals was 22 days. Moreover, a 60-day hrRNASET2 treatment period reduced mean A375SM lung metastasis foci counts by three-fold when compared to untreated animals. Taken together, the combined antiangiogenic and antitumorigenic capacities of hrRNASET2, seemingly arising from its direct interaction with intercellular and extracellular matrices, render it an attractive anticancer therapy candidate. PMID:27014725

  13. ADAM10 as a target for anti-cancer therapy.

    PubMed

    Moss, Marcia L; Stoeck, Alexander; Yan, Wenbo; Dempsey, Peter J

    2008-02-01

    There is a great unmet medical need in the area of cancer treatment. A potential therapeutic target for intervention in cancer is ADAM10. ADAM10 is a disintegrin-metalloproteinase that processes membrane bound proteins from the cell surface to yield soluble forms. Pharmaceutical companies are actively seeking out inhibitors of ADAM10 for treatments in cancer as the enzyme is known to release the ErbB receptor, HER2/ErbB2 from the cell membrane, an event that is necessary for HER2 positive tumor cells to proliferate. ADAM10 is also capable of processing betacellulin indicating that an inhibitor could be used against EGFR/ErbB1 and/or HER4/ErbB4 receptor positive tumor cells that are betacellulin-dependent. ADAM10 is the principle sheddase for several other molecules associated with cancer proliferation, differentiation, adhesion and migration such as Notch, E-cadherin, CD44 and L1 adhesion molecule indicating that targeting ADAM10 with specific inhibitors could be beneficial. PMID:18289051

  14. Quantitative impedimetric monitoring of cell migration under the stimulation of cytokine or anti-cancer drug in a microfluidic chip

    PubMed Central

    Xiao, Xia; Lei, Kin Fong; Huang, Chia-Hao

    2015-01-01

    Cell migration is a cellular response and results in various biological processes such as cancer metastasis, that is, the primary cause of death for cancer patients. Quantitative investigation of the correlation between cell migration and extracellular stimulation is essential for developing effective therapeutic strategies for controlling invasive cancer cells. The conventional method to determine cell migration rate based on comparison of successive images may not be an objective approach. In this work, a microfluidic chip embedded with measurement electrodes has been developed to quantitatively monitor the cell migration activity based on the impedimetric measurement technique. A no-damage wound was constructed by microfluidic phenomenon and cell migration activity under the stimulation of cytokine and an anti-cancer drug, i.e., interleukin-6 and doxorubicin, were, respectively, investigated. Impedance measurement was concurrently performed during the cell migration process. The impedance change was directly correlated to the cell migration activity; therefore, the migration rate could be calculated. In addition, a good match was found between impedance measurement and conventional imaging analysis. But the impedimetric measurement technique provides an objective and quantitative measurement. Based on our technique, cell migration rates were calculated to be 8.5, 19.1, and 34.9 μm/h under the stimulation of cytokine at concentrations of 0 (control), 5, and 10 ng/ml. This technique has high potential to be developed into a powerful analytical platform for cancer research. PMID:26180566

  15. Surface functionalization of liposomes with proteins and carbohydrates for use in anti-cancer applications

    NASA Astrophysics Data System (ADS)

    Platt, Virginia M.

    Liposomes can be used to exploit the altered biology of cancer thereby increasing delivery of liposome-associated anti-cancer drugs. In this dissertation, I explore methods that utilize the unique cancer expression of the polymeric glycosaminoglycan hyaluronan (HA) and the HA receptor CD44 to target liposomes to tumors, using liposomes functionalized with proteins or oligosaccharides on their surface. To make it easier to prepare protein-functionalized liposomes, a non-covalent protein/liposome association method based upon metal chelation/his 6 interaction was devised and characterized. I evaluated non-covalent attachment of the prodrug converting enzyme yeast cytosine deaminase, the far-red fluorescent protein mKate, two antigens ovalbumin and the membrane proximal region of an HIV GAG and hyaluronidase, a HA-degrading enzyme. In Chapter 2, I describe the synthesis of hyaluronan-oligosaccharide (HA-O) lipid conjugates and their incorporation into liposomes to target CD44-overexpressing cancer cells. HA-O ligands of defined-length, up to 10 monosaccharides, were attached to lipids via various linkers by reductive amination. The HA-lipids were easily incorporated into liposomes but did not mediate binding of liposomes to CD44 overexpressing cells. In Chapter 3, I evaluate the capacity of tris-NTA-Ni-lipids incorporated within a liposome bilayer to associate with his6-tagged proteins. Tris-NTA-lipids of differing structures and avidities were used to associate yeast cytosine deaminase and mKate to the surface of liposomes. Two tris-NTA-lipids and a mono-NTA lipid associated his-tagged proteins to a 1:1 molar ratio in solution. The proteins remained active while associated with the liposome surface. When challenged in vitro with fetal calf serum, tris-NTA-containing liposomes retained his-tagged proteins longer than mono-NTA. However, the tris-NTA/his6 interaction was found to be in a dynamic state; free yeast cytosine deaminase rapidly competed with pre-bound m

  16. Utilizing hydrogen sulfide as a novel anti-cancer agent by targeting cancer glycolysis and pH imbalance

    PubMed Central

    Lee, Z-W; Teo, X-Y; Tay, E Y-W; Tan, C-H; Hagen, T; Moore, P K; Deng, L-W

    2014-01-01

    Background and Purpose Many disparate studies have reported the ambiguous role of hydrogen sulfide (H2S) in cell survival. The present study investigated the effect of H2S on the viability of cancer and non-cancer cells. Experimental Approach Cancer and non-cancer cells were exposed to H2S [using sodium hydrosulfide (NaHS) and GYY4137] and cell viability was examined by crystal violet assay. We then examined cancer cellular glycolysis by in vitro enzymatic assays and pH regulator activity. Lastly, intracellular pH (pHi) was determined by ratiometric pHi measurement using BCECF staining. Key Results Continuous, but not a single, exposure to H2S decreased cell survival more effectively in cancer cells, as compared to non-cancer cells. Slow H2S-releasing donor, GYY4137, significantly increased glycolysis, leading to overproduction of lactate. H2S also decreased anion exchanger and sodium/proton exchanger activity. The combination of increased metabolic acid production and defective pH regulation resulted in an uncontrolled intracellular acidification, leading to cancer cell death. In contrast, no significant intracellular acidification or cell death was observed in non-cancer cells. Conclusions and Implications Low and continuous exposure to H2S targets metabolic processes and pH homeostasis in cancer cells, potentially serving as a novel and selective anti-cancer strategy. PMID:24827113

  17. Evaluation of the toxic effects of four anti-cancer drugs in plant bioassays and its potency for screening in the context of waste water reuse for irrigation.

    PubMed

    Lutterbeck, Carlos Alexandre; Kern, Deivid Ismael; Machado, Ênio Leandro; Kümmerer, Klaus

    2015-09-01

    Anti-cancer drugs are compounds that are of high environmental relevance because of their lack of specific mode of action. They can be extremely harmful to living organisms even at low concentrations. The present study evaluated the toxic effects of four frequently used anti-cancer drugs against plant seedlings, namely Cyclophosphamide (CP), Methotrexate (MTX), 5-Fluorouracil (5-FU) and Imatinib (IM). The phytotoxicity experiments were performed with Lactuca sativa seedlings whereas cytotoxicity, genotoxicity and mutagenicity investigations were performed with the well-established Allium cepa assays. MTX was the most phytotoxic compound, followed by 5-FU, CP and IM. Significant differences in the Mitotic Indexes (MI) were observed in three of the studied compounds (MTX, 5-FU and CP), indicating potential cytotoxic activity of these substances. Chromosome aberrations were registered in cells that were exposed to 5-FU, CP and IM. All the four compounds caused the formation of micronucleated cells indicating mutagenic potential. Besides, the assays performed with MTX samples presented a high number of cell apoptosis (cell death). Although it is unlikely that the pharmaceuticals concentrations measured in the environment could cause lethal effects in plants, the obtained results indicate that these compounds may affect the growth and normal development of these plants. So, both tests can constitute important tools for a fast screening of environmental contamination e.g. in the context of the reuse of treated wastewater and biosolids of agricultural purpose. PMID:26002047

  18. Transportation of Berberine into HepG2, HeLa and SY5Y Cells: A Correlation to Its Anti-Cancer Effect

    PubMed Central

    Pang, Yu-Nong; Liang, Yin-Wen; Feng, Tian-Shi; Zhao, Shuang; Wu, Hao; Chai, Yu-Shuang; Lei, Fan; Ding, Yi; Xing, Dong-Ming; Du, Li-Jun

    2014-01-01

    The anti-cancer activities of berberine (BBR) have been reported extensively in various cancer cell lines. However, the minimal inhibitory concentrations of BBR varied greatly among different cell lines and very few studies have been devoted to elucidate this aspect. In this study, we employed three cancer cell lines, HepG2, HeLa and SY5Y, to compare the transportation and distribution of BBR. HPLC results demonstrated that BBR was capable of penetrating all the cell lines whereas the cumulative concentrations were significantly different. HepG2 cells accumulated higher level of BBR for longer duration than the other two cell lines. Molecular docking studies revealed the BBR binding site on P-glycoprotein 1 (P-gp). In addition, we elucidated that BBR regulated P-gp at both mRNA and protein levels. BBR induced the transcription and translation of P-gp in HeLa and SY5Y cells, whereas BBR inhibited P-gp expression in HepG2 cells. Further study showed that BBR regulates P-gp expression depending on different mechanisms (or affected by different factors) in different cell lines. To summarize, our study has revealed several mechanistic aspects of BBR regulation on P-gp in different cancer cell lines and might shed some useful insights into the use of BBR in the anti-cancer drug development. PMID:25402492

  19. [Response of Pharmaceutical Companies to the Crisis of Post-Marketing Clinical Trials of Anti-Cancer Agents -- Results of Questionnaires to Pharmaceutical Companies].

    PubMed

    Nakajima, Toshifusa

    2016-04-01

    Investigator-oriented post-marketing clinical trials of anti-cancer agents are faced to financial crisis due to drastic decrease in research-funds from pharmaceutical companies caused by a scandal in 2013. In order to assess the balance of research funds between 2012 and 2014, we made queries to 26 companies manufacturing anti-cancer agents, and only 10 of 26 responded to our queries. Decrease in the fund was observed in 5 of 10, no change in 1, increase in 3 and no answer in 1. Companies showed passive attitude to carry out doctor-oriented clinical trials of off-patent drugs or unapproved drugs according to advanced medical care B program, though some companies answered to proceed approved routines of these drugs if clinical trials showed good results. Most companies declined to make comments on the activity of Japan Agency for Medical Research and Development (AMED), but some insisted to produce good corroboration between AMED and pharmaceutical companies in order to improve the quality of trials. Further corroboration must be necessary for this purpose among researchers, governmental administrative organs, pharmaceutical companies, patients' groups, and mass-media. PMID:27220801

  20. The zebrafish embryo as a tool for screening and characterizing pleurocidin host-defense peptides as anti-cancer agents

    PubMed Central

    Morash, Michael G.; Douglas, Susan E.; Robotham, Anna; Ridley, Christina M.; Gallant, Jeffrey W.; Soanes, Kelly H.

    2011-01-01

    SUMMARY The emergence of multidrug-resistant cancers and the lack of targeted therapies for many cancers underscore an unmet need for new therapeutics with novel modes of action towards cancer cells. Host-defense peptides often exhibit selective cytotoxicity towards cancer cells and show potential as anti-cancer therapeutics. Here, we screen 26 naturally occurring variants of the peptide pleurocidin for cytotoxic and anti-cancer activities, and investigate the underlying mechanism of action. Cytotoxicities were assessed in vitro using cell-based assays and in vivo using zebrafish embryos. Morphological changes were assessed by both transmission and scanning electron microscopy, and functional assays were performed on zebrafish embryos to investigate the mechanism of cell death. A total of 14 peptides were virtually inactive against HL60 human leukemia cells, whereas 12 caused >50% death at ≤32 μg/ml. Morphological changes characteristic of oncosis were evident by electron microscopy after only 1 minute of treatment with 32 μg/ml of variant NRC-03. Only two peptides were hemolytic. Four peptides showed no toxicity towards zebrafish embryos at the highest concentration tested (25 μM; ∼64 μg/ml) and one peptide was highly toxic, killing 4-hour-post-fertilization (hpf) embryos immediately after exposure to 1 μM peptide. Four other peptides killed embryos after 24 hours of exposure at 1 μM. Most peptides caused mortality at one or more developmental stages only after continuous exposure (24 hours) with higher lethal doses (≥5 μM). Pleurocidin NRC-03 bound to embryos and induced the release of superoxide, caused an increase in the number of TUNEL-positive nuclei, and caused membrane damage and the loss of embryonic epithelial integrity, marked by the exclusion of cells from the outer epithelium and the appearance of F-actin within the circumferential cells of the repair site. Our results indicate that specific pleurocidin variants are attractive cancer

  1. Anti-cancer glycosidase inhibitors from natural products: a computational and molecular modelling perspective.

    PubMed

    Singh, Ashona; Mhlongo, Ndumiso; Soliman, Mahmoud E S

    2015-01-01

    The implementation of computational tools in pharmaceutics has proven an effectual strategy in creating harmony between the physical and chemical aspects of proteins and potential inhibitors. This is achieved by bringing to life the three dimensional retrospect of biological systems, which takes into consideration computational approaches such as quantum mechanics and molecular dynamics to facilitate drug design and discovery. In this work, we aim to provide a summary of the computational aspects of naturally derived anti-cancer inhibitors targeting the enzyme family of glycosidases. Our study offers insight into the evolution of drug discovery, molecular modelling and molecular binding modes of natural product inhibitors associated with glycosidase enzymes. PMID:25706917

  2. Characteristics of pharmacogenomics/biomarker-guided clinical trials for regulatory approval of anti-cancer drugs in Japan.

    PubMed

    Ishiguro, Akihiro; Yagi, Satomi; Uyama, Yoshiaki

    2013-06-01

    Pharmacogenomics (PGx) or biomarker (BM) has the potential to facilitate the development of safer and more effective drugs in terms of their benefit/risk profiles by stratifying population into categories such as responders/non-responders and high-/low-risks to drug-induced serious adverse reactions. In the past decade, practical use of PGx or BM has advanced the field of anti-cancer drug development. To identify the characteristics of the PGx/BM-guided clinical trials for regulatory approval of anti-cancer drugs in Japan, we collected information on design features of 'key trials' in the review reports of anti-cancer drugs that were approved after the implementation of the 'Revised Guideline for the Clinical Evaluation of Anti-cancer drugs' in April 2006. On the basis of the information available on the regulatory review data for the newly approved anti-cancer drugs in Japan, this article aims to explain the limitations and points to consider in the study design of PGx/BM-guided clinical trials. PMID:23657427

  3. Improvements to the FATOLA computer program including added actively controlled landing gear subroutines

    NASA Technical Reports Server (NTRS)

    Mall, G. H.

    1983-01-01

    Modifications to a multi-degree-of-freedom flexible aircraft take-off and landing analysis (FATOLA) computer program, including a provision for actively controlled landing gears to expand the programs simulation capabilities, are presented. Supplemental instructions for preparation of data and for use of the modified program are included.

  4. An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery

    PubMed Central

    Willoughby, Lee F.; Schlosser, Tanja; Manning, Samuel A.; Parisot, John P.; Street, Ian P.; Richardson, Helena E.; Humbert, Patrick O.; Brumby, Anthony M.

    2013-01-01

    SUMMARY Anti-cancer drug development involves enormous expenditure and risk. For rapid and economical identification of novel, bioavailable anti-tumour chemicals, the use of appropriate in vivo tumour models suitable for large-scale screening is key. Using a Drosophila Ras-driven tumour model, we demonstrate that tumour overgrowth can be curtailed by feeding larvae with chemicals that have the in vivo pharmacokinetics essential for drug development and known efficacy against human tumour cells. We then develop an in vivo 96-well plate chemical screening platform to carry out large-scale chemical screening with the tumour model. In a proof-of-principle pilot screen of 2000 compounds, we identify the glutamine analogue, acivicin, a chemical with known activity against human tumour cells, as a potent and specific inhibitor of Drosophila tumour formation. RNAi-mediated knockdown of candidate acivicin target genes implicates an enzyme involved in pyrimidine biosynthesis, CTP synthase, as a possible crucial target of acivicin-mediated inhibition. Thus, the pilot screen has revealed that Drosophila tumours are glutamine-dependent, which is an emerging feature of many human cancers, and has validated the platform as a powerful and economical tool for in vivo chemical screening. The platform can also be adapted for use with other disease models, thus offering widespread applications in drug development. PMID:22996645

  5. Simulation Study of the Molecular Mechanism of Intercalation of the Anti-Cancer Drug Daunomycin into DNA

    NASA Astrophysics Data System (ADS)

    Mukherjee, Arnab; Lavery, Richard; Bagchi, Biman; Hynes, James T.

    Intercalation of anti-cancer drugs into DNA is the insertion of the planar aromatic portion of the drug molecules between a pair of DNA basepairs, inducing certain local structural changes in the DNA and subsequently stopping its replication. Despite its importance, a detailed mechanistic understanding of this process at the molecular level is lacking. Here we recount some of the key aspects of our recent extensive simulation study addressed to this issue [A. Mukherjee, R. Lavery, B. Bagchi, and J. T. Hynes, J. Am. Chem. Soc. 130, 9747 (2008)]. In particular, we discuss the molecular aspects of the intercalation mechanism of a well-known anticancer drug daunomycin into a twelve basepair DNA with the help of a free energy landscape of the process constructed using extensive computer simulations (>0:3 µsec) with umbrella sampling techniques. The results give an intercalation free energy change (-12.3 kcal/mol) in reasonable agreement with experiment (-9.4 kcal/mol). They also point to a mechanism in which the drug first binds to the minor groove and then intercalates into the DNA in an activated process, in general agreement with experimental kinetic results.

  6. Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity

    PubMed Central

    Koltai, Tomas

    2015-01-01

    Objective: To review the mechanisms of anti-cancer activity of nelfinavir and other protease inhibitors (PIs) based on evidences reported in the published literature. Methods: We extensively reviewed the literature concerning nelfinavir (NFV) as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed. Controversies regarding nelfinavir mode of action were also addressed. Conclusions: The two main mechanisms involved in anti-cancer activity are endoplasmic reticulum stress-unfolded protein response pathway and Akt inhibition. However there are many other effects, partially dependent and independent of those mentioned, that may be useful in cancer treatment, including MMP-9 and MMP-2 inhibition, down-regulation of CDK-2, VEGF, bFGF, NF-kB, STAT-3, HIF-1 alfa, IGF, EGFR, survivin, BCRP, androgen receptor, proteasome, fatty acid synthase (FAS), decrease in cellular ATP concentration and upregulation of TRAIL receptor DR5, Bax, increased radiosensitivity, and autophagy. The end result of all these effects is slower growth, decreased angiogenesis, decreased invasion and increased apoptosis, which means reduced proliferation and increased cancer cells death. PIs may be classified according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ER stressors. Beyond the phase I trials that have been recently completed, adequately powered and well-designed clinical trials are needed in the various cancer type settings, and specific trials where NFV is tested in association with other known anti-cancer pharmaceuticals should be sought, in order to find an appropriate place for NFV in cancer treatment. The analysis of controversies on the molecular mechanisms of NFV hints to the possibility that NFV works in a different way in tumor cells and in hepatocytes and adipocytes. PMID:26097685

  7. Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets.

    PubMed

    Lu, Junyan; Zeng, Hanlin; Liang, Zhongjie; Chen, Limin; Zhang, Liyi; Zhang, Hao; Liu, Hong; Jiang, Hualiang; Shen, Bairong; Huang, Ming; Geng, Meiyu; Spiegel, Sarah; Luo, Cheng

    2015-01-01

    The connection between inflammation and tumourigenesis has been well established. However, the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells. To obtain a more systematic understanding of inflammation-associated tumourigenesis as well as to identify novel therapeutic approaches, we constructed a knowledge-based network describing the development of colitis-associated colon cancer (CAC) by integrating the extracellular microenvironment and intracellular signalling pathways. Dynamic simulations of the CAC network revealed a core network module, including P53, MDM2, and AKT, that may govern the malignant transformation of colon epithelial cells in a pro-tumor inflammatory microenvironment. Furthermore, in silico mutation studies and experimental validations led to a novel finding that concurrently targeting ceramide and PI3K/AKT pathway by chemical probes or marketed drugs achieves synergistic anti-cancer effects. Overall, our network model can guide further mechanistic studies on CAC and provide new insights into the design of combinatorial cancer therapies in a rational manner. PMID:26446703

  8. Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets

    PubMed Central

    Lu, Junyan; Zeng, Hanlin; Liang, Zhongjie; Chen, Limin; Zhang, Liyi; Zhang, Hao; Liu, Hong; Jiang, Hualiang; Shen, Bairong; Huang, Ming; Geng, Meiyu; Spiegel, Sarah; Luo, Cheng

    2015-01-01

    The connection between inflammation and tumourigenesis has been well established. However, the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells. To obtain a more systematic understanding of inflammation-associated tumourigenesis as well as to identify novel therapeutic approaches, we constructed a knowledge-based network describing the development of colitis-associated colon cancer (CAC) by integrating the extracellular microenvironment and intracellular signalling pathways. Dynamic simulations of the CAC network revealed a core network module, including P53, MDM2, and AKT, that may govern the malignant transformation of colon epithelial cells in a pro-tumor inflammatory microenvironment. Furthermore, in silico mutation studies and experimental validations led to a novel finding that concurrently targeting ceramide and PI3K/AKT pathway by chemical probes or marketed drugs achieves synergistic anti-cancer effects. Overall, our network model can guide further mechanistic studies on CAC and provide new insights into the design of combinatorial cancer therapies in a rational manner. PMID:26446703

  9. Method development and validation for the analysis of a new anti-cancer infusion solution via HPLC.

    PubMed

    Donnarumma, Fabrizio; Schober, Margot; Greilberger, Joachim; Matzi, Veronika; Lindenmann, Jörg; Maier, Alfred; Herwig, Ralf; Wintersteiger, Reinhold

    2011-01-01

    A fast and simple HPLC method has been developed and validated for the quantification of a completely new anti-cancer drug during the manufacturing process. The combination of four compounds including α-ketoglutaric acid, hydroxymethylfurfural, N-acetyl-L-methionine and N-acetyl-L-selenomethionine, administered intravenously, is still in test phase but has already shown promising results in cancer therapy. HPLC separation was achieved on an RP-18 column with a gradient system. However, the highly different concentrations of the compounds required a variation in the detection wavelength within one run. In order to produce a chromatogram where peaks were comparable on a similar range scale, detection at absorption maxima for the two most concentrated components was avoided. After optimization of the gradient program it was possible to detect all four substances within 14 min in spite of their strongly different chemical structure. The method developed was validated for accuracy, repeatability, reproducibility and robustness in relation to temperature and pH of buffer. Linearity as well as the limit of detection and quantification were determined. This HPLC method was found to be precise, accurate and reproducible and can be easily used for in-line process control during the manufacture of the anti-tumour infusion solution. PMID:21246718

  10. Biofortification of oilseed Brassica juncea with the anti-cancer compound glucoraphanin by suppressing GSL-ALK gene family

    PubMed Central

    Augustine, Rehna; Bisht, Naveen C.

    2015-01-01

    Glucosinolates are amino acids derived secondary metabolites, invariably present in Brassicales, which have huge health and agricultural benefits. Sulphoraphane, the breakdown product of glucosinolate glucoraphanin is known to posses anti-cancer properties. AOP (2-oxoglutarate-dependent dioxygenases) or GSL-ALK enzyme catalyzes the conversion of desirable glucoraphanin to deleterious gluconapin and progoitrin, which are present in very high amounts in most of the cultivable Brassica species including Brassica juncea. In this study we showed that B. juncea encodes four functional homologs of GSL-ALK gene and constitutive silencing of GSL-ALK homologs resulted in accumulation of glucoraphanin up to 43.11 μmoles g−1 DW in the seeds with a concomitant reduction in the anti-nutritional glucosinolates. Glucoraphanin content was found remarkably high in leaves as well as sprouts of the transgenic lines. Transcript quantification of high glucoraphanin lines confirmed significant down-regulation of GSL-ALK homologs. Growth and other seed quality parameters of the transgenic lines did not show drastic difference, compared to the untransformed control. High glucoraphanin lines also showed higher resistance towards stem rot pathogen Sclerotinia sclerotiorum. Our results suggest that metabolic engineering of GSL-ALK has huge potential for enriching glucoraphanin content, and improve the oil quality and vegetable value of Brassica crops. PMID:26657321

  11. Biofortification of oilseed Brassica juncea with the anti-cancer compound glucoraphanin by suppressing GSL-ALK gene family.

    PubMed

    Augustine, Rehna; Bisht, Naveen C

    2015-01-01

    Glucosinolates are amino acids derived secondary metabolites, invariably present in Brassicales, which have huge health and agricultural benefits. Sulphoraphane, the breakdown product of glucosinolate glucoraphanin is known to posses anti-cancer properties. AOP (2-oxoglutarate-dependent dioxygenases) or GSL-ALK enzyme catalyzes the conversion of desirable glucoraphanin to deleterious gluconapin and progoitrin, which are present in very high amounts in most of the cultivable Brassica species including Brassica juncea. In this study we showed that B. juncea encodes four functional homologs of GSL-ALK gene and constitutive silencing of GSL-ALK homologs resulted in accumulation of glucoraphanin up to 43.11 μmoles g(-1) DW in the seeds with a concomitant reduction in the anti-nutritional glucosinolates. Glucoraphanin content was found remarkably high in leaves as well as sprouts of the transgenic lines. Transcript quantification of high glucoraphanin lines confirmed significant down-regulation of GSL-ALK homologs. Growth and other seed quality parameters of the transgenic lines did not show drastic difference, compared to the untransformed control. High glucoraphanin lines also showed higher resistance towards stem rot pathogen Sclerotinia sclerotiorum. Our results suggest that metabolic engineering of GSL-ALK has huge potential for enriching glucoraphanin content, and improve the oil quality and vegetable value of Brassica crops. PMID:26657321

  12. In vitro discovery of promising anti-cancer drug combinations using iterative maximisation of a therapeutic index

    PubMed Central

    Kashif, M.; Andersson, C.; Hassan, S.; Karlsson, H.; Senkowski, W.; Fryknäs, M.; Nygren, P.; Larsson, R.; Gustafsson, M.G.

    2015-01-01

    In vitro-based search for promising anti-cancer drug combinations may provide important leads to improved cancer therapies. Currently there are no integrated computational-experimental methods specifically designed to search for combinations, maximizing a predefined therapeutic index (TI) defined in terms of appropriate model systems. Here, such a pipeline is presented allowing the search for optimal combinations among an arbitrary number of drugs while also taking experimental variability into account. The TI optimized is the cytotoxicity difference (in vitro) between a target model and an adverse side effect model. Focusing on colorectal carcinoma (CRC), the pipeline provided several combinations that are effective in six different CRC models with limited cytotoxicity in normal cell models. Herein we describe the identification of the combination (Trichostatin A, Afungin, 17-AAG) and present results from subsequent characterisations, including efficacy in primary cultures of tumour cells from CRC patients. We hypothesize that its effect derives from potentiation of the proteotoxic action of 17-AAG by Trichostatin A and Afungin. The discovered drug combinations against CRC are significant findings themselves and also indicate that the proposed strategy has great potential for suggesting drug combination treatments suitable for other cancer types as well as for other complex diseases. PMID:26392291

  13. Toward Repurposing Metformin as a Precision Anti-Cancer Therapy Using Structural Systems Pharmacology

    PubMed Central

    Hart, Thomas; Dider, Shihab; Han, Weiwei; Xu, Hua; Zhao, Zhongming; Xie, Lei

    2016-01-01

    Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin’s molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification with network biology analysis by combining structural genomic, functional genomic, and interactomic data. Through searching the human structural proteome, we identified twenty putative metformin binding targets and their interaction models. We experimentally verified the interactions between metformin and our top-ranked kinase targets. Notably, kinases, particularly SGK1 and EGFR were identified as key molecular targets of metformin. Subsequently, we linked these putative binding targets to genes that do not directly bind to metformin but whose expressions are altered by metformin through protein-protein interactions, and identified network biomarkers of phenotypic response of metformin. The molecular targets and the key nodes in genetic networks are largely consistent with the existing experimental evidence. Their interactions can be affected by the observed cancer mutations. This study will shed new light into repurposing metformin for safe, effective, personalized therapies. PMID:26841718

  14. Toward Repurposing Metformin as a Precision Anti-Cancer Therapy Using Structural Systems Pharmacology.

    PubMed

    Hart, Thomas; Dider, Shihab; Han, Weiwei; Xu, Hua; Zhao, Zhongming; Xie, Lei

    2016-01-01

    Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin's molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification with network biology analysis by combining structural genomic, functional genomic, and interactomic data. Through searching the human structural proteome, we identified twenty putative metformin binding targets and their interaction models. We experimentally verified the interactions between metformin and our top-ranked kinase targets. Notably, kinases, particularly SGK1 and EGFR were identified as key molecular targets of metformin. Subsequently, we linked these putative binding targets to genes that do not directly bind to metformin but whose expressions are altered by metformin through protein-protein interactions, and identified network biomarkers of phenotypic response of metformin. The molecular targets and the key nodes in genetic networks are largely consistent with the existing experimental evidence. Their interactions can be affected by the observed cancer mutations. This study will shed new light into repurposing metformin for safe, effective, personalized therapies. PMID:26841718

  15. In Vitro and Ex Vivo Evaluations of Lipid Anti-Cancer Nanoformulations: Insights and Assessment of Bioavailability Enhancement.

    PubMed

    Jain, Ankitkumar S; Dhawan, Vivek V; Sarmento, Bruno; Nagarsenker, Mangal S

    2016-06-01

    Lipid-based nanoformulations have been extensively investigated for improving oral efficacy of plethora of drugs. Chemotherapeutic agents remain a preferred option for effective management of cancer; however, most chemotherapeutic agents suffer from limitation of poor oral bioavailability that is associated with their physicochemical properties. Drug delivery via lipid-based nanosystems possesses strong rational and potential for improving oral bioavailability of such anti-cancer molecules through various mechanisms, viz. improving their gut solubilisation owing to micellization, improving mucosal permeation, improving lymphatic uptake, inhibiting intestinal metabolism and/or inhibiting P-glycoprotein efflux of molecules in the gastrointestinal tract. Various in vitro characterization techniques have been reported in literature that aid in getting insights into mechanisms of lipid-based nanodevices in improving oral efficacy of anti-cancer drugs. The review focuses on different characterization techniques that can be employed for evaluation of lipid-based nanosystems and their role in effective anti-cancer drug delivery. PMID:27068527

  16. Anti-cancer-prostaglandin-induced cell-cycle arrest and its modulation by an inhibitor of the ATP-dependent glutathione S-conjugate export pump (GS-X pump).

    PubMed Central

    Ishikawa, T; Akimaru, K; Nakanishi, M; Tomokiyo, K; Furuta, K; Suzuki, M; Noyori, R

    1998-01-01

    The A and J series of prostaglandins (PGs) accumulate in the nuclei to suppress the proliferation of cancer cells. Here we report that Delta7-PGA1 methyl ester, a synthetic anti-cancer PG, increased the level of mRNA for the cyclin-dependent kinase inhibitor p21 in human leukaemia HL-60 cells. The induction of p21 was associated with the accumulation of hypophosphorylated retinoblastoma protein (pRB) and the suppression of c-myc gene expression. Since the p53 gene is deleted in HL-60 cells, the anti-cancer PG is suggested to inhibit cancer cell growth by inducing p21 via a p53-independent pathway. Unlike HL-60 cells, cisplatin-resistant HL-60/R-CP cells were insensitive to Delta7-PGA1 methyl ester. While c-myc expression was transiently suppressed, neither G1 arrest nor hypophosphorylation of pRB was observed with the anti-cancer PG. Plasma membrane vesicles from HL-60/R-CP cells showed an enhanced level of GS-X pump (ATP-dependent glutathione S-conjugate export pump) activity towards the glutathione S-conjugate of Delta7-PGA1 methyl ester (Km 110 nM). GIF-0019 ¿N-carbomethoxy-S-[5-(4-benzoylphenyl)pentyl]glutathione dimethyl ester¿, a specific inhibitor of the GS-X pump, dose-dependently enhanced the cellular sensitivity of HL-60/R-CP cells to Delta7-PGA1 methyl ester and induced G1 arrest. The GS-X pump is suggested to play a pivotal role in modulating the biological action of the anti-cancer PG. PMID:9841867

  17. Cucurbitacin IIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation

    PubMed Central

    Boykin, C; Zhang, G; Chen, Y-H; Zhang, R-W; Fan, X-E; Yang, W-M; Lu, Q

    2011-01-01

    Background: Cucurbitacin (Cuc) and triterpene-derived natural products exhibit anti-cancer potential in addition to their conspicuous anti-bacterial and anti-inflammatory activity. Recently, inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling was shown to underlie the effects of Cuc family on inducing cell death in cancer. Method: We purified Cuc IIa, the active component from the medicinal plant Hemsleya amalils Diels, which shows different structural modifications from other Cuc derivatives. We investigated the mechanisms of its inhibitory effects on cancer cells in vitro and tumour growth in vivo. Results: Cuc IIa induced the irreversible clustering of filamentous actin and arrested cell cycle by the increases in G2/M populations. Cuc IIa resulted in the reduced phospho-Histone H3 and markedly increased cleavage of poly-(ADP-ribose) polymerase or PARP, immediate upstream of DNA breakdown as the result of caspase activation, consistent with mitotic blockage-induced cell death. However, unlike other Cuc members, Cuc IIa did not suppress JAK2/STAT3 phosphorylation or alter phosphorylation of mitogen-activated protein kinases. Instead, the expression of the cell cycle-regulated Inhibitor of Apoptosis Protein (IAP) survivin was reduced. Introducing oncoprotein δ-catenin, which increased survivin expression and suppressed small GTPase RhoA, reduced efficacy of Cuc IIa to induce cell death. Supporting the effects of Cuc IIa on actin cytoskeletal signaling, RhoA phosphorylation was reduced suggesting its increased activity. Conclusion: Cuc IIa is a novel class of anti-cancer drug in suppression of cancer cell expansion by disrupting the actin cytoskeleton and directing the cell to undergo PARP-mediated apoptosis through the inhibition of survivin downstream of JAK2/STAT3. PMID:21304528

  18. Down-regulation of some miRNAs by degrading their precursors contributes to anti-cancer effect of mistletoe lectin-I

    PubMed Central

    Li, Lin-Na; Zhang, Hua-Dong; Zhi, Run; Yuan, Shou-Jun

    2011-01-01

    BACKGROUND AND PURPOSE Mistletoe lectin-I (ML-I), the main anti-cancer component of mistletoe extracts, was originally thought to act exclusively on 28S rRNA. Here, we investigate the down-regulating effect and mechanism of CM-1, an ML-I isolated from Chinese mistletoe, on some miRNAs. EXPERIMENTAL APPROACH The anti-cancer effects of CM-1 were assessed in vitro and in vivo in colorectal cancer cells. The miRNAs down-regulated by CM-1 were identified by miRNA microarray assay and validated by qRT-PCR analysis. The suppression of host gene transcription or by degradation of precursors was determined by qRT-PCR and enzyme activity assays respectively. The qRT-PCR, Western blot and immunohistochemistry were used to examine the expression of their target gene and related downstream effector. Cell proliferation was assayed in stably transfected HEK-293 cells with different levels of these miRNAs. KEY RESULTS CM-1 showed prominent anti-neoplastic activity towards CLY and HT-29 cells both in vitro and in vivo. The miR-135a&b were the miRNAs most down-regulated by CM-1. Their host gene transcription was largely up-regulated, while their precursors were degraded directly by CM-1. The expression of their target gene adenomatous polyposis coli and the phosphorylation of related effector β-catenin were both significantly up-regulated. The IC50 values of CM-1 on derivative HEK-293 cells with high miR-135a&b levels were 2–4 times lower than that of control cells. CONCLUSIONS AND IMPLICATIONS CM-1 down-regulated some miRNAs by degrading their precursors, which contributes to its prominent anti-cancer activity. LINKED ARTICLE This article is commented on by Rushworth, pp. 346–348 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.01075.x PMID:20955366

  19. Solar sail attitude control including active nutation damping in a fixed-momentum wheel satellite

    NASA Technical Reports Server (NTRS)

    Azor, Ruth

    1992-01-01

    In geostationary cruise of a momentum biased satellite, it is necessary to stabilize the roll/yaw attitude due to disturbances, caused mainly by solar radiation pressure. This work presents a roll/yaw control which is obtained by the use of solar arrays and fixed flaps as actuators, with a horizon sensor for roll measurement. The design also includes an active nutation damping.

  20. Population and Human Development: A Course Curriculum Including Lesson Plans, Activities, and Bibliography. Revised.

    ERIC Educational Resources Information Center

    Murphy, Elaine M.; Long, Alison T.

    This course outline suggests materials and learning activities on the interrelated causes and consequences of population growth and other population matters. The document describes 15 class sessions which integrate information for sociology, anthropology, psychology, biology, animal behavior, and education. Topics include the history of human…

  1. Translational Research in Oncology Research & Development and Its Impact on Early Development in China: report of the 5th Annual Meeting of the US Chinese Anti-Cancer Association (USCACA) at 2013 AACR Annual Meeting

    PubMed Central

    Guan, Lingjie; Dai, Yun; Luo, Roger

    2013-01-01

    In April 2013, the US Chinese Anti-Cancer Association (USCACA) held its 5th annual meeting in conjunction with the American Association for Cancer Research (AACR) 2013 Annual Meeting in Washington DC. The USCACA executive committee reported activities and programs and highlighted the partnership and collaboration between USCACA and other major organizations. The key initiatives and programs of USCACA included 1) USCACA-TIGM Esophageal Cancer Program that funds translational research of esophageal cancer prevention and treatment at the Xinxiang Medical University in Henan province, China; 2) the USCACA-NFCR-AFCR Scholarship Program, which has supported 10 young outstanding Chinese cancer researchers and will award 4 fellowships at the Guangzhou International Symposium on Oncology in November this year; 3) USCACA-Hengrui Training Program for Early Phase Clinical Research, which has supported the training of a Chinese scholar at two major cancer centers in the US; and 4) USCACA has continued its partnership with the Chinese Journal of Cancer, which has reached significant international impact. PMID:23823625

  2. miR-335 Targets SIAH2 and Confers Sensitivity to Anti-Cancer Drugs by Increasing the Expression of HDAC3

    PubMed Central

    Kim, Youngmi; Kim, Hyuna; Park, Deokbum; Jeoung, Dooil

    2015-01-01

    We previously reported the role of histone deacetylase 3 (HDAC3) in response to anti-cancer drugs. The decreased expression of HDAC3 in anti-cancer drug-resistant cancer cell line is responsible for the resistance to anti-cancer drugs. In this study, we investigated molecular mechanisms associated with regulation of HDAC3 expression. MG132, an inhibitor of proteasomal degradation, induced the expression of HDAC3 in various anti-cancer drug-resistant cancer cell lines. Ubiquitination of HDAC3 was observed in various anti-cancer drug-resistant cancer cell lines. HDAC3 showed an interaction with SIAH2, an ubiquitin E3 ligase, that has increased expression in various anti-cancer drug-resistant cancer cell lines. miRNA array analysis showed the decreased expression of miR-335 in these cells. Targetscan analysis predicted the binding of miR-335 to the 3′-UTR of SIAH2. miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs. PMID:25997740

  3. Extracellular control of intracellular drug release for enhanced safety of anti-cancer chemotherapy

    NASA Astrophysics Data System (ADS)

    Zhu, Qian; Qi, Haixia; Long, Ziyan; Liu, Shang; Huang, Zhen; Zhang, Junfeng; Wang, Chunming; Dong, Lei

    2016-06-01

    The difficulty of controlling drug release at an intracellular level remains a key challenge for maximising drug safety and efficacy. We demonstrate herein a new, efficient and convenient approach to extracellularly control the intracellular release of doxorubicin (DOX), by designing a delivery system that harnesses the interactions between the system and a particular set of cellular machinery. By simply adding a small-molecule chemical into the cell medium, we could lower the release rate of DOX in the cytosol, and thereby increase its accumulation in the nuclei while decreasing its presence at mitochondria. Delivery of DOX with this system effectively prevented DOX-induced mitochondria damage that is the main mechanism of its toxicity, while exerting the maximum efficacy of this anti-cancer chemotherapeutic agent. The present study sheds light on the design of drug delivery systems for extracellular control of intracellular drug delivery, with immediate therapeutic implications.

  4. Marine algal natural products with anti-oxidative, anti-inflammatory, and anti-cancer properties

    PubMed Central

    2013-01-01

    For their various bioactivities, biomaterials derived from marine algae are important ingredients in many products, such as cosmetics and drugs for treating cancer and other diseases. This mini-review comprehensively compares the bioactivities and biological functions of biomaterials from red, green, brown, and blue-green algae. The anti-oxidative effects and bioactivities of several different crude extracts of algae have been evaluated both in vitro and in vivo. Natural products derived from marine algae protect cells by modulating the effects of oxidative stress. Because oxidative stress plays important roles in inflammatory reactions and in carcinogenesis, marine algal natural products have potential for use in anti-cancer and anti-inflammatory drugs. PMID:23724847

  5. From taxol to Taxol: the changing identities and ownership of an anti-cancer drug.

    PubMed

    Walsh, Vivien; Goodman, Jordan

    2002-01-01

    This paper analyzes the emergence and evolution of taxol, the world's bestselling anti-cancer drug. Over the years taxol has changed its identity, its status as property, and its association with different places (from the old-growth forests of Washington State to the government agencies of Washington, D.C., to laboratories in France). Taxol is not only a profitable pharmaceutical commodity and a substance injected into women with breast and/or ovarian cancer; it is also a natural product found in the bark of Taxus brevifolia (the Pacific yew, which is native to the North American Pacific Northwest) and a chemical substance that was discovered and brought to the point of commercial production in the public sector. We explore its role in several controversies: the destruction of old-growth forests, public participation in policy making, and the privatization of intellectual property and its effect on the price of drugs. PMID:12458837

  6. Extracellular control of intracellular drug release for enhanced safety of anti-cancer chemotherapy

    PubMed Central

    Zhu, Qian; Qi, Haixia; Long, Ziyan; Liu, Shang; Huang, Zhen; Zhang, Junfeng; Wang, Chunming; Dong, Lei

    2016-01-01

    The difficulty of controlling drug release at an intracellular level remains a key challenge for maximising drug safety and efficacy. We demonstrate herein a new, efficient and convenient approach to extracellularly control the intracellular release of doxorubicin (DOX), by designing a delivery system that harnesses the interactions between the system and a particular set of cellular machinery. By simply adding a small-molecule chemical into the cell medium, we could lower the release rate of DOX in the cytosol, and thereby increase its accumulation in the nuclei while decreasing its presence at mitochondria. Delivery of DOX with this system effectively prevented DOX-induced mitochondria damage that is the main mechanism of its toxicity, while exerting the maximum efficacy of this anti-cancer chemotherapeutic agent. The present study sheds light on the design of drug delivery systems for extracellular control of intracellular drug delivery, with immediate therapeutic implications. PMID:27334142

  7. Multi-platinum anti-cancer agents. Substitution-inert compounds for tumor selectivity and new targets.

    PubMed

    Farrell, N P

    2015-12-21

    -action anti-cancer agents. PMID:25951946

  8. Specific repression of mutant K-RAS by 10-23 DNAzyme: Sensitizing cancer cell to anti-cancer therapies

    SciTech Connect

    Yu, S.-H.; Wang, T.-H.; Au, L.-C.

    2009-01-09

    Point mutations of the Ras family are frequently found in human cancers at a prevalence rate of 30%. The most common mutation K-Ras(G12V), required for tumor proliferation, survival, and metastasis due to its constitutively active GTPase activity, has provided an ideal target for cancer therapy. 10-23 DNAzyme, an oligodeoxyribonucleotide-based ribonuclease consisting of a 15-nucleotide catalytical domain flanked by two target-specific complementary arms, has been shown to effectively cleave the target mRNA at purine-pyrimidine dinucleotide. Taking advantage of this specific property, 10-23 DNAzyme was designed to cleave mRNA of K-Ras(G12V)(GGU {yields} GUU) at the GU dinucleotide while left the wild-type (WT) K-Ras mRNA intact. The K-Ras(G12V)-specific 10-23 DNAzyme was able to reduce K-Ras(G12V) at both mRNA and protein levels in SW480 cell carrying homozygous K-Ras(G12V). No effect was observed on the WT K-Ras in HEK cells. Although K-Ras(G12V)-specific DNAzymes alone did not inhibit proliferation of SW480 or HEK cells, pre-treatment of this DNAzyme sensitized the K-Ras(G12V) mutant cells to anti-cancer agents such as doxorubicin and radiation. These results offer a potential of using allele-specific 10-23 DNAzyme in combination with other cancer therapies to achieve better effectiveness on cancer treatment.

  9. Optimization of anti-cancer drugs and a targeting molecule on multifunctional gold nanoparticles

    NASA Astrophysics Data System (ADS)

    Rizk, Nahla; Christoforou, Nicolas; Lee, Sungmun

    2016-05-01

    Breast cancer is the most common and deadly cancer among women worldwide. Currently, nanotechnology-based drug delivery systems are useful for cancer treatment; however, strategic planning is critical in order to enhance the anti-cancer properties and reduce the side effects of cancer therapy. Here, we designed multifunctional gold nanoparticles (AuNPs) conjugated with two anti-cancer drugs, TGF-β1 antibody and methotrexate, and a cancer-targeting molecule, folic acid. First, optimum size and shape of AuNPs was selected by the highest uptake of AuNPs by MDA-MB-231, a metastatic human breast cancer cell line. It was 100 nm spherical AuNPs (S-AuNPs) that were used for further studies. A fixed amount (900 μl) of S-AuNP (3.8 × 108 particles/ml) was conjugated with folic acid-BSA or methotrexate-BSA. Methotrexate on S-AuNP induced cellular toxicity and the optimum amount of methotrexate-BSA (2.83 mM) was 500 μl. Uptake of S-AuNPs was enhanced by folate conjugation that binds to folate receptors overexpressed by MDA-MB-231 and the optimum uptake was at 500 μl of folic acid-BSA (2.83 mM). TGF-β1 antibody on S-AuNP reduced extracellular TGF-β1 of cancer cells by 30%. Due to their efficacy and tunable properties, we anticipate numerous clinical applications of multifunctional gold nanospheres in treating breast cancer.

  10. Optimization of anti-cancer drugs and a targeting molecule on multifunctional gold nanoparticles.

    PubMed

    Rizk, Nahla; Christoforou, Nicolas; Lee, Sungmun

    2016-05-01

    Breast cancer is the most common and deadly cancer among women worldwide. Currently, nanotechnology-based drug delivery systems are useful for cancer treatment; however, strategic planning is critical in order to enhance the anti-cancer properties and reduce the side effects of cancer therapy. Here, we designed multifunctional gold nanoparticles (AuNPs) conjugated with two anti-cancer drugs, TGF-β1 antibody and methotrexate, and a cancer-targeting molecule, folic acid. First, optimum size and shape of AuNPs was selected by the highest uptake of AuNPs by MDA-MB-231, a metastatic human breast cancer cell line. It was 100 nm spherical AuNPs (S-AuNPs) that were used for further studies. A fixed amount (900 μl) of S-AuNP (3.8 × 10(8) particles/ml) was conjugated with folic acid-BSA or methotrexate-BSA. Methotrexate on S-AuNP induced cellular toxicity and the optimum amount of methotrexate-BSA (2.83 mM) was 500 μl. Uptake of S-AuNPs was enhanced by folate conjugation that binds to folate receptors overexpressed by MDA-MB-231 and the optimum uptake was at 500 μl of folic acid-BSA (2.83 mM). TGF-β1 antibody on S-AuNP reduced extracellular TGF-β1 of cancer cells by 30%. Due to their efficacy and tunable properties, we anticipate numerous clinical applications of multifunctional gold nanospheres in treating breast cancer. PMID:27004512

  11. Novel epigallocatechin gallate (EGCG) analogs activate AMP-activated protein kinase pathway and target cancer stem cells

    PubMed Central

    Chen, Di; Pamu, Sreedhar; Cui, Qiuzhi; Chan, Tak Hang; Dou, Q. Ping

    2012-01-01

    AMP-activated protein kinase (AMPK) is a critical monitor of cellular energy status and also controls processes related to tumor development, including cell cycle progression, protein synthesis, cell growth and survival. Therefore AMPK as an anti-cancer target has received intensive attention recently. It has been reported that the anti-diabetic drug metformin and some natural compounds, such as quercetin, genistein, capsaicin and green tea polyphenol epigallocatechin gallate (EGCG), can activate AMPK and inhibit cancer cell growth. Indeed, natural products have been the most productive source of leads for the development of anti-cancer drugs but perceived disadvantages, such as low bioavailability and week potency, have limited their development and use in the clinic. In this study we demonstrated that synthetic EGCG analogs 4 and 6 were more potent AMPK activators than metformin and EGCG. Activation of AMPK by these EGCG analogs resulted in inhibition of cell proliferation, up-regulation of the cyclin-dependent kinase inhibitor p21, down-regulation of mTOR pathway, and suppression of stem cell population in human breast cancer cells. Our findings suggest that novel potent and specific AMPK activators can be discovered from natural and synthetic sources that have potential to be used for anti-cancer therapy in the clinic. PMID:22459208

  12. Dr. Josef Steiner Cancer Research Prize Lecture: the role of physiological cell death in neoplastic transformation and in anti-cancer therapy.

    PubMed

    Strasser, A

    1999-05-17

    Cell death is a physiological process which is required for normal development and existence of multi-cellular organisms. Physiological cell death, or apoptosis, is controlled by an evolutionarily conserved mechanism. Abnormalities in this process are implicated as a cause or contributing factor in a variety of diseases. Inhibition of apoptosis can promote neoplastic transformation, particularly in combination with dysregulated cell-cycle control, and can influence the response of tumour cells to anti-cancer therapy. Molecular biological and biochemical approaches are used to find missing cell-death regulators and to define signalling cascades, while experiments in genetically modified mice will identify the essential function of these molecules. Discoveries from cell death research should provide clues for designing therapies for a variety of diseases, including degenerative disorders, auto-immunity and cancer. PMID:10225436

  13. Histone Deacetylase-3/CAGE Axis Targets EGFR Signaling and Regulates the Response to Anti-Cancer Drugs

    PubMed Central

    Kim, Hyuna; Kim, Youngmi; Goh, Hyeonjung; Jeoung, Dooil

    2016-01-01

    We have previously reported the role of miR-326-HDAC3 loop in anti-cancer drug-resistance. CAGE, a cancer/testis antigen, regulates the response to anti-cancer drug-resistance by forming a negative feedback loop with miR-200b. Studies investigating the relationship between CAGE and HDAC3 revealed that HDAC3 negatively regulated the expression of CAGE. ChIP assays demonstrated the binding of HDAC3 to the promoter sequences of CAGE. However, CAGE did not affect the expression of HDAC3. We also found that EGFR signaling regulated the expressions of HDAC3 and CAGE. Anti-cancer drug-resistant cancer cell lines show an increased expression of pEGFRY845. HDAC3 was found to negatively regulate the expression of pEGFRY845. CAGE showed an interaction and co-localization with EGFR. It was seen that miR-326, a negative regulator of HDAC3, regulated the expression of CAGE, pEGFRY845, and the interaction between CAGE and EGFR. miR-326 inhibitor induced the binding of HDAC3 to the promoter sequences in anti-cancer drug-resistant Malme3MR cells, decreasing the tumorigenic potential of Malme3MR cells in a manner associated with its effect on the expression of HDAC3, CAGE and pEGFRY845. The down-regulation of HDAC3 enhanced the tumorigenic, angiogenic and invasion potential of the anti-cancer drug-sensitive Malme3M cells in CAGE-dependent manner. Studies revealed that PKCδ was responsible for the increased expression of pEGFRY845 and CAGE in Malme3MR cells. CAGE showed an interaction with PKCδ in Malme3MR cells. Our results show that HDAC3-CAGE axis can be employed as a target for overcoming resistance to EGFR inhibitors. PMID:26883907

  14. Histone Deacetylase-3/CAGE Axis Targets EGFR Signaling and Regulates the Response to Anti-Cancer Drugs.

    PubMed

    Kim, Hyuna; Kim, Youngmi; Goh, Hyeonjung; Jeoung, Dooil

    2016-03-31

    We have previously reported the role of miR-326-HDAC3 loop in anti-cancer drug-resistance. CAGE, a cancer/testis antigen, regulates the response to anti-cancer drug-resistance by forming a negative feedback loop with miR-200b. Studies investigating the relationship between CAGE and HDAC3 revealed that HDAC3 negatively regulated the expression of CAGE. ChIP assays demonstrated the binding of HDAC3 to the promoter sequences of CAGE. However, CAGE did not affect the expression of HDAC3. We also found that EGFR signaling regulated the expressions of HDAC3 and CAGE. Anti-cancer drug-resistant cancer cell lines show an increased expression of pEGFR(Y845). HDAC3 was found to negatively regulate the expression of pEGFR(Y845). CAGE showed an interaction and co-localization with EGFR. It was seen that miR-326, a negative regulator of HDAC3, regulated the expression of CAGE, pEGFR(Y845), and the interaction between CAGE and EGFR. miR-326 inhibitor induced the binding of HDAC3 to the promoter sequences in anti-cancer drug-resistant Malme3M(R) cells, decreasing the tumorigenic potential of Malme3M(R) cells in a manner associated with its effect on the expression of HDAC3, CAGE and pEGFR(Y845). The down-regulation of HDAC3 enhanced the tumorigenic, angiogenic and invasion potential of the anti-cancer drug-sensitive Malme3M cells in CAGE-dependent manner. Studies revealed that PKCδ was responsible for the increased expression of pEGFR(Y845) and CAGE in Malme3M(R) cells. CAGE showed an interaction with PKCδ in Malme3M(R) cells. Our results show that HDAC3-CAGE axis can be employed as a target for overcoming resistance to EGFR inhibitors. PMID:26883907

  15. ΔPK oncolytic activity includes modulation of the tumour cell milieu.

    PubMed

    Bollino, Dominique; Colunga, Aric; Li, Baiquan; Aurelian, Laure

    2016-02-01

    Oncolytic virotherapy is a unique cancer therapeutic that encompasses tumour cell lysis through both virus replication and programmed cell death (PCD) pathways. Nonetheless, clinical efficacy is relatively modest, likely related to the immunosuppressive tumour milieu. Our studies use the herpes simplex virus type 2 (HSV-2)-based oncolytic virus ΔPK that has documented anti-tumour activity associated with virus replication, PCD and cancer stem cell lysis. They are designed to examine whether ΔPK-mediated oncolysis includes the ability to reverse the immunosuppressive tumour microenvironment by altering the balance of cytokines directly secreted by the melanoma cells and to define its mechanism. Here, we show that melanoma cells secreted the immunosuppressive cytokine IL-10, and that secretion was inhibited by ΔPK through virus replication and c-Jun N-terminal kinase/c-Jun activation. ΔPK-induced IL-10 inhibition upregulated surface expression of MHC class I chain-related protein A, the ligand for the activating NKG2D receptor expressed on NK- and cytotoxic T-cells. Concomitantly, ΔPK also upregulated the secretion of inflammatory cytokines TNF-α, granulocyte macrophage colony-stimulating factor and IL-1β through autophagy-mediated activation of Toll-like receptor 2 pathways and pyroptosis, and it inhibited the expression of the negative immune checkpoint regulator cytotoxic T-lymphocyte antigen 4. Pharmacologic inhibition of these processes significantly reduces the oncolytic activity of ΔPK. PMID:26602205

  16. Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4

    PubMed Central

    Chang, Bo Yoon; Kim, Seon Beom; Lee, Mi Kyeong; Park, Hyun; Kim, Sung Yeon

    2015-01-01

    Morus alba L. fruits have long been used in traditional medicine by many cultures. Their medicinal attributes include cardiovascular, hepatoprotective, neuroprotective and immunomodulatory actions. However, their mechanism of macrophage activation and anti-cancer effects remain unclear. The present study investigated the molecular mechanisms of immune stimulation and improved chemotherapeutic effect of M. alba L. fruit extract (MFE). MFE stimulated the production of cytokines, nitric oxide (NO) and tumor necrosis factor-α (TNF-α) and tumoricidal properties of macrophages. MFE activated macrophages through the mitogen-activated protein kinase (MAPKinase) and nuclear factor-κB (NF-κB) signaling pathways downstream from toll-like receptor (TLR) 4. MFE was shown to exhibit cytotoxicity of CT26 cells via the activated macrophages, even though MFE did not directly affect CT26 cells. In a xenograft mouse model, MFE significantly enhanced anti-cancer activity combined with 5-fluorouracil and markedly promoted splenocyte proliferation, natural killer (NK) cell activity, cytotoxic T lymphocyte (CTL) activity and IFN-γ production. Immunoglobulin G (IgG) antibody levels were significantly increased. These results indicate the indirect anti-cancer activity of MFE through improved immune response mediated by TLR4 signaling. M. alba L. fruit extract might be a potential anti-tumor immunomodulatory candidate chemotherapy agent. PMID:26473845

  17. A role for cytochrome b5 in the in vivo disposition of anti-cancer and cytochrome P450 probe drugs in mice

    PubMed Central

    Henderson, Colin J.; McLaughlin, Lesley A.; Finn, Robert D.; Ronseaux, Sebastien; Kapelyukh, Yury; Wolf, C. Roland

    2014-01-01

    The role of microsomal cytochrome b5 (Cyb5) in defining the rate of drug metabolism and disposition has been intensely debated for several decades. Recently we described mouse models involving the hepatic or global deletion of Cyb5, demonstrating its central role in in vivo drug disposition. We have now used the cytochrome b5 complete null (BCN) model to determine the role of Cyb5 in the metabolism of ten pharmaceuticals metabolised by a range of cytochrome P450s, including five anti-cancer drugs, in vivo and in vitro. The extent to which metabolism was significantly affected by the absence of Cyb5 was substrate-dependent, with AUC increased (75-245%), and clearance decreased (35-72%), for phenacetin, metoprolol and chlorzoxazone. Tolbutamide disposition was not significantly altered by Cyb5 deletion, while for midazolam clearance was decreased by 66%. The absence of Cyb5 had no effect on gefitinib and paclitaxel disposition, while significant changes in the in vivo pharmacokinetics of cyclophosphamide were measured (Cmax and terminal half-life increased 55% and 40%, respectively), tamoxifen (AUClast and Cmax increased 370% and 233%, respectively) and anastrozole (AUC and terminal half-life increased 125% and 62%, respectively; clearance down 80%). These data from provide strong evidence that both hepatic and extra-hepatic Cyb5 levels are an important determinant of in vivo drug disposition catalysed by a range of cytochrome P450s, including currently-prescribed anti-cancer agents, and that individuality in Cyb5 expression could be a significant determinant in rates of drug disposition in man. PMID:24115751

  18. Active seat suspension for a small vehicle: considerations for control system including observer

    NASA Astrophysics Data System (ADS)

    Katsumata, Hiroyuki; Shiino, Hiroshi; Oshinoya, Yasuo; Ishibashi, Kazuhisa; Ozaki, Koichi; Ogino, Hirohiko

    2007-12-01

    We have examined the improvement of ride quality and the reduction of riding fatigue brought about by the active control of the seat suspension of small vehicles such as one-seater electric automobiles. A small active seat suspension, which is easy to install, was designed and manufactured for one-seater electric automobiles. For the actuator, a maintenance-free voice coil motor used as a direct drive was adopted. For fundamental considerations, we designed a one-degree-of-freedom model for the active seat suspension system. Then, we designed a disturbance cancellation control system that includes the observer for a two-degree-of-freedom model. In an actual driving test, a test road, in which the concavity and convexity of an actual road surface were simulated using hard rubber, was prepared and the control performance of vertical vibrations of the seat surface during driving was examined. As a result, in comparison with the one-degree-of-freedom control system, it was confirmed that the control performance was improved by the two-degree-of-freedom control system that includes the observer.

  19. Production of anti-cancer triterpene (betulinic acid) from callus cultures of different Ocimum species and its elicitation.

    PubMed

    Pandey, Harshita; Pandey, Pallavi; Singh, Sailendra; Gupta, Ruby; Banerjee, Suchitra

    2015-03-01

    Betulinic acid (BA), a pentacyclic triterpenoid, is gaining unmatched attention owing to its unique anti-cancer activity with selective melanoma growth inhibition without damaging normal cells. It is also well-known for its multifaceted pharmacokinetics, entailing antibacterial, antimalarial, anti-HIV and antioxidant merits. Considering the escalating demand with diminishing bioresource of this molecule, the present study was undertaken that revealed the untapped potentials of Ocimum calli, contrasting to that in the in vitro derived leaves, as effective production alternative of BA in three out of four tested species (i.e. Ocimum basilicum, Ocimum kilimandscharicum, Ocimum sanctum excluding Ocimum grattisimum). Callus inductions were obtained in all the four species with different 2,4-dichlorophenoxyacetic acid (2,4-D)/α-naphthaleneacetic acid (NAA) concentrations with kinetin. Notably, 2,4-D favoured maximum callus growth in all whereas NAA proved beneficial for the highest metabolite yield in the calli of each BA-producing species. The O. basilicum calli demonstrated the maximum growth (growth index (GI) 678.7 ± 24.47) and BA yield (2.59 ± 0.55 % dry weight [DW]), whereas those in O. kilimandscharicum (GI 533.33 ± 15.87; BA 1.87 ± 0.6 % DW) and O. sanctum (GI 448 ± 16.07; BA 0.39 ± 0.12 % DW) followed a descending order. The O. gratissimum calli revealed minimum growth (GI 159 ± 13.25) with no BA accumulation. Elicitation with methyl jasmonate at 200-μM concentration after 48-h exposure doubled the BA yield (5.10 ± 0.18 % DW) in NAA-grown O. basilicum calli compared to that in the untreated counterpart (2.61 ± 0.19 % DW), which further enthused its future application. PMID:25308098

  20. Are language-based activities in science effective for all students, including low achievers?

    NASA Astrophysics Data System (ADS)

    Rivard, Léonard P.

    2004-05-01

    The study investigated achievement status as a factor determining the use of language-based activities for learning science. A total of 154 eighth-grade students were randomly assigned to four groups, all stratified for gender and achievement level. The treatments involved various combinations of talk and writing, and descriptive and explanatory tasks. The dependent measures included scores on multiple choice tests obtained at three times during the study. Records of student talk and writing were also analyzed to identify patterns of differences between groups of achievers. The findings suggested that low achievers complete more problems, and develop better understanding and comprehension of ecology concepts when they have engaged in peer discussions of explanatory tasks. In comparison, high achievers benefit more from writing than talking, and writing explanations enhances comprehension more than restricted writing activities.

  1. Gelam honey and ginger potentiate the anti cancer effect of 5-FU against HCT 116 colorectal cancer cells.

    PubMed

    Hakim, Luqman; Alias, Ekram; Makpol, Suzana; Ngah, Wan Zurinah Wan; Morad, Nor Azian; Yusof, Yasmin Anum Mohd

    2014-01-01

    The development of chemopreventive approaches using a concoction of phytochemicals is potentially viable for combating many types of cancer including colon carcinogenesis. This study evaluated the anti-proliferative effects of ginger and Gelam honey and its efficacy in enhancing the anti-cancer effects of 5-FU (5-fluorouracil) against a colorectal cancer cell line, HCT 116. Cell viability was measured via MTS (3-(4,5-dimethylthiazol-2- yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphenyl)-2H-tetrazolium) assay showing ginger inhibiting the growth of HCT 116 cells more potently (IC50 of 3mg/mL) in comparison to Gelam honey (IC50 of 75 mg/mL). Combined treatment of the two compounds (3mg/mL ginger+75 mg/mL Gelam honey) synergistically lowered the IC50 of Gelam honey to 22 mg/mL. Combination with 35 mg/mL Gelam honey markedly enhanced 5-FU inhibiting effects on the growth of HCT 116 cells. Subsequent analysis on the induction of cellular apoptosis suggested that individual treatment of ginger and Gelam honey produced higher apoptosis than 5-FU alone. In addition, treatment with the combination of two natural compounds increased the apoptotic rate of HCT 116 cells dose- dependently while treatment of either ginger or Gelam honey combined with 5-FU only showed modest changes. Combination index analysis showed the combination effect of both natural compounds to be synergistic in their inhibitory action against HCT 116 colon cancer cells (CI 0.96 < 1). In conclusion, combined treatment of Gelam honey and ginger extract could potentially enhance the chemotherapeutic effect of 5-FU against colorectal cancer. PMID:24969899

  2. Phytochemical Analysis and Anti-cancer Investigation of Boswellia serrata Bioactive Constituents In Vitro.

    PubMed

    Ahmed, Hanaa H; Abd-Rabou, Ahmed A; Hassan, Amal Z; Kotob, Soheir E

    2015-01-01

    presence of pent-2-ene-1,4-dione, 2-methyl- levulinic acid methyl ester, 3,5- dimethyl- 1- hexane, methyl-1-methylpentadecanoate, 1,1- dimethoxy cyclohexane, 1-methoxy-4-(1-propenyl)benzene and 17a-hydroxy-17a-cyano, preg-4-en-3-one. GC/MS analysis of volatile oils of B. Serrata oleo gum resin revealed the presence of sabinene (19.11%), terpinen-4-ol (14.64%) and terpinyl acetate (13.01%) as major constituents. The anti-cancer effect of two extracts (1 and 2) and four fractions (I, II, III and IV) as well as volatile oils of B. Serrata oleo gum resin on HepG2 and HCT 116 cell lines was investigated using SRB assay. Regarding HepG2 cell line, extracts 1 and 2 elicited the most pronounced cytotoxic activity with IC50 values equal 1.58 and 5.82 μg/mL at 48 h, respectively which were comparable to doxorubicin with an IC50 equal 4.68 μg/mL at 48 h. With respect to HCT 116 cells, extracts 1 and 2 exhibited the most obvious cytotoxic effect; with IC50 values equal 0.12 and 6.59 μg/mL at 48 h, respectively which were comparable to 5-fluorouracil with an IC50 equal 3.43 μg/ mL at 48 h. In conclusion, total extracts, fractions and volatile oils of B. Serrata oleo gum resin proved their usefulness as cytotoxic mediators against HepG2 and HCT 116 cell lines with different potentiality (extracts > fractions > volatile oil). In the two studied cell lines the cytotoxic acivity of each of extract 1 and 2 was comparable to doxorubicin and 5-fluorouracil, respectively. Extensive in vivo research is warranted to explore the precise molecular mechanisms of these bioactive natural products in cytotoxicity against HCC and CRC cells. PMID:26514509

  3. Measuring and Reducing Off-Target Activities of Programmable Nucleases Including CRISPR-Cas9.

    PubMed

    Koo, Taeyoung; Lee, Jungjoon; Kim, Jin-Soo

    2015-06-01

    Programmable nucleases, which include zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and RNA-guided engineered nucleases (RGENs) repurposed from the type II clustered, regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system are now widely used for genome editing in higher eukaryotic cells and whole organisms, revolutionising almost every discipline in biological research, medicine, and biotechnology. All of these nucleases, however, induce off-target mutations at sites homologous in sequence with on-target sites, limiting their utility in many applications including gene or cell therapy. In this review, we compare methods for detecting nuclease off-target mutations. We also review methods for profiling genome-wide off-target effects and discuss how to reduce or avoid off-target mutations. PMID:25985872

  4. Investigation of the biological and anti-cancer properties of ellagic acid-encapsulated nano-sized metalla-cages.

    PubMed

    Dubey, Abhishek; Park, Dae Won; Kwon, Jung Eun; Jeong, Yong Joon; Kim, Taegeun; Kim, Inhye; Kang, Se Chan; Chi, Ki-Whan

    2015-01-01

    Three new large hexanuclear metalla-prisms 9-11 incorporating 1,3, 5-tris(pyridin-4-ylethynyl)benzene (tpeb) 4 and one of the dinuclear arene ruthenium clips [Ru2(p-iPrC6H4Me)2(OO∩OO)][CF3SO3]2 (OO∩OO =2,5-dioxydo-1,4-benzoquinonato [dobq] 1, 5,8-dihydroxy-1,4-naphthaquinonato (donq) 2, and 6,11-dihydroxy-5,12-naphthacenedionato [dotq] 3), which encapsulate the guest molecule ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione, 5) were prepared. All complexes were isolated as triflate salts in good yields and were fully characterized by (1)H NMR spectroscopy and electrospray ionization mass spectrometry. The photophysical properties of these metalla-prisms were also investigated. Compounds 9 and 10 showed potent antioxidant activity, but 10 had the superior ORACPE value (1.30 ± 0.020). Ellagic acid (5) and compound 11 showed weaker activity than that of Trolox. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the metalla-prism compounds exhibit anticancer properties in vitro. Compound 10 inhibited the growth of all cancer cell lines at micromolar concentrations, with the highest cytotoxicity observed against A549 human lung cancer cells (IC50 =25.9 μM). However, these compounds had a lower anti-cancer activity than that of doxorubicin. In a tumoricidal assay, ellagic acid (5) and compound 10 induced cytotoxicity in tumor cells, while doxorubicin did not. While free ellagic acid had no effect on the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein, the encapsulated metalla-prism 10 stimulated granulocyte-colony stimulating factor and reduced regulated on activation normal T cell expressed and secreted protein expression in the RAW264.7 macrophage line. Our results show that ellagic acid encapsulated in metalla-prisms inhibited cancer cells via the modulation of mRNA induction and protein expression levels of the granulocyte-colony stimulating

  5. Investigation of the biological and anti-cancer properties of ellagic acid-encapsulated nano-sized metalla-cages

    PubMed Central

    Dubey, Abhishek; Park, Dae Won; Kwon, Jung Eun; Jeong, Yong Joon; Kim, Taegeun; Kim, Inhye; Kang, Se Chan; Chi, Ki-Whan

    2015-01-01

    Three new large hexanuclear metalla-prisms 9–11 incorporating 1,3, 5-tris(pyridin-4-ylethynyl)benzene (tpeb) 4 and one of the dinuclear arene ruthenium clips [Ru2(p-iPrC6H4Me)2(OO∩OO)][CF3SO3]2 (OO∩OO =2,5-dioxydo-1,4-benzoquinonato [dobq] 1, 5,8-dihydroxy-1,4-naphthaquinonato (donq) 2, and 6,11-dihydroxy-5,12-naphthacenedionato [dotq] 3), which encapsulate the guest molecule ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione, 5) were prepared. All complexes were isolated as triflate salts in good yields and were fully characterized by 1H NMR spectroscopy and electrospray ionization mass spectrometry. The photophysical properties of these metalla-prisms were also investigated. Compounds 9 and 10 showed potent antioxidant activity, but 10 had the superior ORACPE value (1.30±0.020). Ellagic acid (5) and compound 11 showed weaker activity than that of Trolox. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the metalla-prism compounds exhibit anticancer properties in vitro. Compound 10 inhibited the growth of all cancer cell lines at micromolar concentrations, with the highest cytotoxicity observed against A549 human lung cancer cells (IC50 =25.9 μM). However, these compounds had a lower anti-cancer activity than that of doxorubicin. In a tumoricidal assay, ellagic acid (5) and compound 10 induced cytotoxicity in tumor cells, while doxorubicin did not. While free ellagic acid had no effect on the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein, the encapsulated metalla-prism 10 stimulated granulocyte-colony stimulating factor and reduced regulated on activation normal T cell expressed and secreted protein expression in the RAW264.7 macrophage line. Our results show that ellagic acid encapsulated in metalla-prisms inhibited cancer cells via the modulation of mRNA induction and protein expression levels of the granulocyte-colony stimulating

  6. Should Cost-Effectiveness Analysis Include the Cost of Consumption Activities? AN Empirical Investigation.

    PubMed

    Adarkwah, Charles Christian; Sadoghi, Amirhossein; Gandjour, Afschin

    2016-02-01

    There has been a debate on whether cost-effectiveness analysis should consider the cost of consumption and leisure time activities when using the quality-adjusted life year as a measure of health outcome under a societal perspective. The purpose of this study was to investigate whether the effects of ill health on consumptive activities are spontaneously considered in a health state valuation exercise and how much this matters. The survey enrolled patients with inflammatory bowel disease in Germany (n = 104). Patients were randomized to explicit and no explicit instruction for the consideration of consumption and leisure effects in a time trade-off (TTO) exercise. Explicit instruction to consider non-health-related utility in TTO exercises did not influence TTO scores. However, spontaneous consideration of non-health-related utility in patients without explicit instruction (60% of respondents) led to significantly lower TTO scores. Results suggest an inclusion of consumption costs in the numerator of the cost-effectiveness ratio, at least for those respondents who spontaneously consider non-health-related utility from treatment. Results also suggest that exercises eliciting health valuations from the general public may include a description of the impact of disease on consumptive activities. PMID:25684073

  7. Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex.

    PubMed Central

    Katz, D H; Marcelletti, J F; Khalil, M H; Pope, L E; Katz, L R

    1991-01-01

    This article reports that 1-docosanol, a 22-carbon-long saturated alcohol, exerts a substantial inhibitory effect on replication of certain viruses (e.g., herpes simplex virus and respiratory syncytial virus) within primary target cells in vitro. To study the basis for its viral inhibitory activity, a suspension of 1-docosanol was formulated in an inert and nontoxic surfactant, Pluronic F-68; this suspension exerted potent inhibitory activity on the ability of susceptible viruses to infect cultured target cells. Susceptible viruses included wild-type herpes simplex viruses 1 and 2 as well as acyclovir-resistant herpes simplex virus 2 and also respiratory syncytial virus--all of which are lipid-enveloped. In contrast, nonenveloped poliovirus was not susceptible to the inhibitory action of 1-docosanol. Although the precise mechanism has yet to be defined, current evidence suggests that 1-docosanol inhibits viral replication by interfering with the early intracellular events surrounding viral entry into target cells. It is possible that interaction between the highly lipophilic compound and components of target cell membranes renders such target cells less susceptible to viral fusion and/or entry. If this mechanism proves to be correct, 1-docosanol may provide a broad spectrum activity against many different viruses, especially those with lipid-containing envelopes. Images PMID:1660151

  8. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... interpretative signs; (4) Provision for non-motorized trail activities including pedestrians and bicycles; (5) Provision for motorized trail activities including all terrain vehicles, motorcycles, snowmobiles, etc.; (6...; (8) Maintenance and restoration of existing recreational trails; (9) Development and...

  9. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... interpretative signs; (4) Provision for non-motorized trail activities including pedestrians and bicycles; (5) Provision for motorized trail activities including all terrain vehicles, motorcycles, snowmobiles, etc.; (6...; (8) Maintenance and restoration of existing recreational trails; (9) Development and...

  10. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... interpretative signs; (4) Provision for non-motorized trail activities including pedestrians and bicycles; (5) Provision for motorized trail activities including all terrain vehicles, motorcycles, snowmobiles, etc.; (6...; (8) Maintenance and restoration of existing recreational trails; (9) Development and...

  11. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... interpretative signs; (4) Provision for non-motorized trail activities including pedestrians and bicycles; (5) Provision for motorized trail activities including all terrain vehicles, motorcycles, snowmobiles, etc.; (6...; (8) Maintenance and restoration of existing recreational trails; (9) Development and...

  12. Monitoring active volcanoes and mitigating volcanic hazards: the case for including simple approaches

    NASA Astrophysics Data System (ADS)

    Stoiber, Richard E.; Williams, Stanley N.

    1990-07-01

    Simple approaches to problems brought about eruptions and their ensuing hazardous effects should be advocated and used by volcanologists while awaiting more sophisticated remedies. The expedients we advocate have all or many of the following attributes: only locally available materials are required; no extensive training of operators or installation is necessary; they are affordable and do not require foreign aid or exports; they are often labor intensive and are sustainable without outside assistance. Where appropriate, the involvement of local residents is advocated. Examples of simple expedients which can be used in forecasting or mitigating the effects of crises emphasize the relative ease and the less elaborate requirements with which simple approaches can be activated. Emphasis is on visual observations often by untrained observers, simple meteorogical measurements, observations of water level in lakes, temperature and chemistry of springs and fumaroles, new springs and collapse areas and observations of volcanic plumes. Simple methods are suggested which can be applied to mitigating damage from mudflows, nuées ardentes, tephra falls and gas discharge. A review in hindsight at Ruiz includes the use of both chemical indicators and simple mudflow alarms. Simple expedients are sufficiently effective that any expert volcanologist called to aid in a crisis must include them in the package of advice offered. Simple approaches are a critical and logical complement to highly technical solutions to hazardous situations.

  13. Challenges in pre-clinical testing of anti-cancer drugs in cell culture and in animal models

    PubMed Central

    HogenEsch, Harm; Yu Nikitin, Alexander

    2012-01-01

    Experiments with cultures of human tumor cell lines, xenografts of human tumors into immunodeficient mice, and mouse models of human cancer are important tools in the development and testing of anti-cancer drugs. Tumors are complex structures composed of genetically and phenotypically heterogeneous cancer cells that interact in a reciprocal manner with the stromal microenvironment and the immune system. Modeling the complexity of human cancers in cell culture and in mouse models for preclinical testing is a challenge that has not yet been met although tremendous advances have been made. A combined approach of cell culture and mouse models of human cancer is most likely to predict the efficacy of novel anti-cancer treatments in human clinical trials. PMID:22446384

  14. Anti-Cancer Effects of Protein Extracts from Calvatia lilacina, Pleurotus ostreatus and Volvariella volvacea.

    PubMed

    Wu, Jin-Yi; Chen, Chi-Hung; Chang, Wen-Huei; Chung, King-Thom; Liu, Yi-Wen; Lu, Fung-Jou; Chen, Ching-Hsein

    2011-01-01

    Calvatia lilacina (CL), Pleurotus ostreatus (PO) and Volvariella volvacea (VV) are widely distributed worldwide and commonly eaten as mushrooms. In this study, cell viabilities were evaluated for a human colorectal adenocarcinoma cell line (SW480 cells) and a human monocytic leukemia cell line (THP-1 cells). Apoptotic mechanisms induced by the protein extracts of PO and VV were evaluated for SW480 cells. The viabilities of THP-1 and SW480 cells decreased in a concentration-dependent manner after 24 h of treatment with the protein extracts of CL, PO or VV. Apoptosis analysis revealed that the percentage of SW480 cells in the SubG(1) phase (a marker of apoptosis) was increased upon PO and VV protein-extract treatments, indicating that oligonucleosomal DNA fragmentation existed concomitantly with cellular death. The PO and VV protein extracts induced reactive oxygen species (ROS) production, glutathione (GSH) depletion and mitochondrial transmembrane potential (ΔΨ(m)) loss in SW480 cells. Pretreatment with N-acetylcysteine, GSH or cyclosporine A partially prevented the apoptosis induced by PO protein extracts, but not that induced by VV extracts, in SW480 cells. The protein extracts of CL, PO and VV exhibited therapeutic efficacy against human colorectal adenocarcinoma cells and human monocytic leukemia cells. The PO protein extracts induced apoptosis in SW480 cells partially through ROS production, GSH depletion and mitochondrial dysfunction. Therefore, the protein extracts of these mushrooms could be considered an important source of new anti-cancer drugs. PMID:21792367

  15. MicroRNAs Used in Combination with Anti-Cancer Treatments Can Enhance Therapy Efficacy

    PubMed Central

    Mognato, Maddalena; Celotti, Lucia

    2015-01-01

    MicroRNAs (miRNAs), a recently discovered class of small non-coding RNAs, constitute a promising approach to anti-cancer treatments when they are used in combination with other agents. MiRNAs are evolutionarily conserved non-coding RNAs that negatively regulate gene expression by binding to the complementary sequence in the 3’-untranslated region (UTR) of target genes. MiRNAs typically suppress gene expression by direct association with target transcripts, thus decreasing the expression levels of target proteins. The delivery to cells of synthetic miRNAs that mimic endogenous miRNA targeting genes involved in the DNA-Damage Response (DDR) can perturb the process, making cells more sensitive to chemotherapy or radiotherapy. This review examines how cells respond to combined therapy and it provides insights into the role of miRNAs in targeting the DDR repair pathway when they are used in combination with chemical compounds or ionizing radiation to enhance cellular sensitivity to treatments. PMID:26156420

  16. Mitochondrial DNA is a direct target of anti-cancer anthracycline drugs

    SciTech Connect

    Ashley, Neil Poulton, Joanna

    2009-01-16

    The anthracyclines, such as doxorubicin (DXR), are potent anti-cancer drugs but they are limited by their clinical toxicity. The mechanisms involved remain poorly understood partly because of the difficulty in determining sub-cellular drug localisation. Using a novel method utilising the fluorescent DNA dye PicoGreen, we found that anthracyclines intercalated not only into nuclear DNA but also mitochondrial DNA (mtDNA). Intercalation of mtDNA by anthracyclines may thus contribute to the marked mitochondrial toxicity associated with these drugs. By contrast, ethidium bromide intercalated exclusively into mtDNA, without interacting with nuclear DNA, thereby explaining why mtDNA is the main target for ethidium. By exploiting PicoGreen quenching we also developed a novel assay for quantification of mtDNA levels by flow-cytometry, an approach which should be useful for studies of mitochondrial dysfunction. In summary our PicoGreen assay should be useful to study drug/DNA interactions within live cells, and facilitate therapeutic drug monitoring and kinetic studies in cancer patients.

  17. Reducing Both Pgp Overexpression and Drug Efflux with Anti-Cancer Gold-Paclitaxel Nanoconjugates

    PubMed Central

    Li, Fei; Zhou, Xiaofei; Zhou, Hongyu; Jia, Jianbo; Li, Liwen; Zhai, Shumei; Yan, Bing

    2016-01-01

    Repeated administrations of anti-cancer drugs to patients often induce drug resistance. P-glycoprotein (Pgp) facilitates an efficient drug efflux, preventing cellular accumulation of drugs and causing multi-drug resistance (MDR). In this study, we developed a gold-paclitaxel nanoconjugate system to overcome MDR. Gold nanoparticles (GNPs) were conjugated with β-cyclodextrin enclosing paclitaxel (PTX) molecules and PEG molecules. GNP conjugates were effectively endocytosed by both drug-sensitive human lung cancer H460 cells and Pgp-overexpressed drug-resistant H460PTX cells. Compared with PTX, PGNPs did not induce the Pgp overexpression in drug-sensitive H460 cells after long-term treatment and also avoided being pumped out of cells by overexpressed Pgp molecules in H460PTX with a 17-fold lower EC50 compared to PTX. Fluorescent microscopy and flow cytometry further confirmed that fluorescent labeled PGNPs (f-PGNPs) maintained a high cellular PTX level in both H460 and H460PTX cells. These results demonstrated that nano-drug conjugates were able to avoid the development of drug resistance in sensitive cells and evade Pgp-mediated drug resistance and to maintain a high cytotoxicity in drug-resistant cancer cells. These findings exemplify a powerful nanotechnological approach to the long-lasting issue of chemotherapy-induced drug resistance. PMID:27467397

  18. Spectral and structural studies of the anti-cancer drug Flutamide by density functional theoretical method

    NASA Astrophysics Data System (ADS)

    Mariappan, G.; Sundaraganesan, N.

    2014-01-01

    A comprehensive screening of the more recent DFT theoretical approach to structural analysis is presented in this section of theoretical structural analysis. The chemical name of 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide is usually called as Flutamide (In the present study it is abbreviated as FLT) and is an important and efficacious drug in the treatment of anti-cancer resistant. The molecular geometry, vibrational spectra, electronic and NMR spectral interpretation of Flutamide have been studied with the aid of density functional theory method (DFT). The vibrational assignments of the normal modes were performed on the basis of the PED calculations using the VEDA 4 program. Comparison of computational results with X-ray diffraction results of Flutamide allowed the evaluation of structure predictions and confirmed B3LYP/6-31G(d,p) as accurate for structure determination. Application of scaling factors for IR and Raman frequency predictions showed good agreement with experimental values. This is supported the assignment of the major contributors of the vibration modes of the title compound. Stability of the molecule arising from hyperconjugative interactions leading to its bioactivity, charge delocalization have been analyzed using natural bond orbital (NBO) analysis. NMR chemical shifts of the molecule were calculated using the gauge independent atomic orbital (GIAO) method. The comparison of measured FTIR, FT-Raman, and UV-Visible data to calculated values allowed assignment of major spectral features of the title molecule. Besides, Frontier molecular orbital analyze was also investigated using theoretical calculations.

  19. Anti-Cancer Effects of Protein Extracts from Calvatia lilacina, Pleurotus ostreatus and Volvariella volvacea

    PubMed Central

    Wu, Jin-Yi; Chen, Chi-Hung; Chang, Wen-Huei; Chung, King-Thom; Liu, Yi-Wen; Lu, Fung-Jou; Chen, Ching-Hsein

    2011-01-01

    Calvatia lilacina (CL), Pleurotus ostreatus (PO) and Volvariella volvacea (VV) are widely distributed worldwide and commonly eaten as mushrooms. In this study, cell viabilities were evaluated for a human colorectal adenocarcinoma cell line (SW480 cells) and a human monocytic leukemia cell line (THP-1 cells). Apoptotic mechanisms induced by the protein extracts of PO and VV were evaluated for SW480 cells. The viabilities of THP-1 and SW480 cells decreased in a concentration-dependent manner after 24 h of treatment with the protein extracts of CL, PO or VV. Apoptosis analysis revealed that the percentage of SW480 cells in the SubG1 phase (a marker of apoptosis) was increased upon PO and VV protein-extract treatments, indicating that oligonucleosomal DNA fragmentation existed concomitantly with cellular death. The PO and VV protein extracts induced reactive oxygen species (ROS) production, glutathione (GSH) depletion and mitochondrial transmembrane potential (ΔΨm) loss in SW480 cells. Pretreatment with N-acetylcysteine, GSH or cyclosporine A partially prevented the apoptosis induced by PO protein extracts, but not that induced by VV extracts, in SW480 cells. The protein extracts of CL, PO and VV exhibited therapeutic efficacy against human colorectal adenocarcinoma cells and human monocytic leukemia cells. The PO protein extracts induced apoptosis in SW480 cells partially through ROS production, GSH depletion and mitochondrial dysfunction. Therefore, the protein extracts of these mushrooms could be considered an important source of new anti-cancer drugs. PMID:21792367

  20. Bacterial Biosynthetic Gene Clusters Encoding the Anti-cancer Haterumalide Class of Molecules

    PubMed Central

    Matilla, Miguel A.; Stöckmann, Henning; Leeper, Finian J.; Salmond, George P. C.

    2012-01-01

    Haterumalides are halogenated macrolides with strong antitumor properties, making them attractive targets for chemical synthesis. Unfortunately, current synthetic routes to these molecules are inefficient. The potent haterumalide, oocydin A, was previously identified from two plant-associated bacteria through its high bioactivity against plant pathogenic fungi and oomycetes. In this study, we describe oocydin A (ooc) biosynthetic gene clusters identified by genome sequencing, comparative genomics, and chemical analysis in four plant-associated enterobacteria of the Serratia and Dickeya genera. Disruption of the ooc gene cluster abolished oocydin A production and bioactivity against fungi and oomycetes. The ooc gene clusters span between 77 and 80 kb and encode five multimodular polyketide synthase (PKS) proteins, a hydroxymethylglutaryl-CoA synthase cassette and three flavin-dependent tailoring enzymes. The presence of two free-standing acyltransferase proteins classifies the oocydin A gene cluster within the growing family of trans-AT PKSs. The amino acid sequences and organization of the PKS domains are consistent with the chemical predictions and functional peculiarities associated with trans-acyltransferase PKS. Based on extensive in silico analysis of the gene cluster, we propose a biosynthetic model for the production of oocydin A and, by extension, for other members of the haterumalide family of halogenated macrolides exhibiting anti-cancer, anti-fungal, and other interesting biological properties. PMID:23012376

  1. Structural characterization and anti-cancerous potential of gallium bioactive glass/hydrogel composites.

    PubMed

    Keenan, T J; Placek, L M; Coughlan, A; Bowers, G M; Hall, M M; Wren, A W

    2016-11-20

    A bioactive glass series (0.42SiO2-0.10Na2O-0.08CaO-(0.40-X)ZnO-(X)Ga2O3) was incorporated into carboxymethyl cellulose (CMC)/dextran (Dex) hydrogels in three different amounts (0.05, 0.10, and 0.25m(2)), and the resulting composites were characterized using transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and (13)C Cross Polarization Magic Angle Spinning Nuclear Magnetic Resonance (CP MAS-NMR). Composite extracts were also evaluated in vitro against MG-63 osteosarcoma cells. TEM confirmed glass distribution throughout the composites, although some particle agglomeration was observed. DSC revealed that glass composition and content did have small effects on both Tg and Tm. MAS-NMR revealed that both CMC and Dex were successfully functionalized, that cross-linking occurred, and that glass addition did slightly alter bonding environments. Cell viability analysis suggested that extracts of the glass and composites with the largest Ga-content significantly decreased MG-63 osteosarcoma viability after 30days. This study successfully characterized this composite series, and demonstrated their potential for anti-cancerous applications. PMID:27561520

  2. Supersonic Shear Wave Elastography of Response to Anti-cancer Therapy in a Xenograft Tumor Model.

    PubMed

    Chamming's, Foucauld; Le-Frère-Belda, Marie-Aude; Latorre-Ossa, Heldmuth; Fitoussi, Victor; Redheuil, Alban; Assayag, Franck; Pidial, Laetitia; Gennisson, Jean-Luc; Tanter, Mickael; Cuénod, Charles-André; Fournier, Laure S

    2016-04-01

    Our objective was to determine if supersonic shear wave elastography (SSWE) can detect changes in stiffness of a breast cancer model under therapy. A human invasive carcinoma was implanted in 22 mice. Eleven were treated with an anti-angiogenic therapy and 11 with glucose for 24 d. Tumor volume and stiffness were assessed during 2 wk before treatment and 0, 7, 12, 20 and 24 d after the start of therapy using SSWE. Pathology was assessed after 12 and 24 d of treatment. We found that response to therapy was associated with early softening of treated tumors only, resulting in a significant difference from non-treated tumors after 12 d of treatment (p = 0.03). On pathology, large areas of necrosis were observed at 12 d in treated tumors. Although treatment was still effective, treated tumors subsequently stiffened during a second phase of the treatment (days 12-24), with a small amount of necrosis observed on pathology on day 24. In conclusion, SSWE was able to measure changes in the stiffness of tumors in response to anti-cancer treatment. However, stiffness changes associated with good response to treatment may change over time, and increased stiffness may also reflect therapy efficacy. PMID:26746382

  3. Bridging academic science and clinical research in the search for novel targeted anti-cancer agents

    PubMed Central

    Matter, Alex

    2015-01-01

    This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials. PMID:26779369

  4. Enhanced osteoblast adhesion on nanostructured selenium compacts for anti-cancer orthopedic applications

    PubMed Central

    Tran, Phong; Webster, Thomas J

    2008-01-01

    Metallic bone implants possess numerous problems limiting their long-term efficacy, such as poor prolonged osseointegration, stress shielding, and corrosion under in vivo environments. Such problems are compounded for bone cancer patients since numerous patients receive orthopedic implants after cancerous bone resection. Unfortunately, current orthopedic materials were not originally developed to simultaneously increase healthy bone growth (as in traditional orthopedic implant applications) while inhibiting cancerous bone growth. The long-term objective of the present research is to investigate the use of nano-rough selenium to prevent bone cancer from re-occurring while promoting healthy bone growth for this select group of cancer patients. Selenium is a well known anti-cancer chemical. However, what is not known is how healthy bone cells interact with selenium. To determine this, selenium, spherical or semispherical shots, were pressed into cylindrical compacts and these compacts were then etched using 1N NaOH to obtain various surface structures ranging from the micron, submicron to nano scales. Changes in surface chemistry were also analyzed. Through these etching techniques, results of this study showed that biologically inspired surface roughness values were created on selenium compacts to match that of natural bone roughness. Moreover, results showed that healthy bone cell adhesion increased with greater nanometer selenium roughness (more closely matching that of titanium). In this manner, this study suggests that nano-rough selenium should be further tested for orthopedic applications involving bone cancer treatment. PMID:18990948

  5. Analysis of FDA-Approved Anti-Cancer Agents in the NCI60 Panel of Human Tumor Cell Lines

    PubMed Central

    Holbeck, Susan L.; Collins, Jerry M.; Doroshow, James H.

    2010-01-01

    Since the early 1990's the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) has utilized a panel of 60 human tumor cell lines representing 9 tissue types to screen for potential new anti-cancer agents. To date, about 100,000 compounds and 50,000 natural product extracts have been screened. Early in this program it was discovered that the pattern of growth inhibition in these cell lines was similar for compounds of similar mechanism. The development of the COMPARE algorithm provided a means by which investigators, starting with a compound of interest, could identify other compounds whose pattern of growth inhibition was similar. With extensive molecular characterization of these cell lines, COMPARE and other user-defined algorithms have been used to link patterns of molecular expression and drug sensitivity. We describe here results of screening current FDA-approved anti-cancer agents in the NCI60 screen, with an emphasis on those agents that target signal transduction. We have analyzed results from agents with mechanisms of action presumed to be similar; we have also performed hierarchical clustering of all of these agents. The addition of data from recently approved anti-cancer agents will increase the utility of the NCI60 databases to the cancer research community. These data are freely accessible to the public on the DTP web site (http://dtp.cancer.gov/). The FDA-approved anti-cancer agents are themselves available from the NCI as a plated set of compounds for research use. PMID:20442306

  6. Rod-shaped and fluorine-substituted hydroxyapatite free of molecular immunopotentiators stimulates anti-cancer immunity in vivo.

    PubMed

    Wang, Xiupeng; Li, Xia; Ito, Atsuo; Watanabe, Yohei; Tsuji, Noriko M

    2016-06-01

    Herein, rod-shaped and fluorine-substituted hydroxyapatite nanoparticles (FHA) were synthesized using a facile hydrothermal method. The rod-shaped FHA significantly increased the cellular uptake of a model antigen by bone marrow dentritic cells in vitro, improved antigen presentation in vivo, stimulated immune-related cytokine secretion in vitro and ex vivo, and enhanced the anti-cancer immunity in vivo. PMID:27121009

  7. Be BOLD: Encouraging Girls to Include Unstructured Bouts of Physical Activity into Daily Routines

    ERIC Educational Resources Information Center

    Hill, Kory; Williams, Gwynne M.

    2014-01-01

    Adolescent girls are less active than their male counterparts and physical activity levels tend to decline as one ages. One of the goals of concerned physical educators is to promote a physically active lifestyle and to teach skills and promote behaviors that will allow students to be active both in and out of school. This article presents a…

  8. 1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: Anti-cancer agents that target nucleophosmin 1 (NPM1).

    PubMed

    Penthala, Narsimha Reddy; Ketkar, Amit; Sekhar, Konjeti R; Freeman, Michael L; Eoff, Robert L; Balusu, Ramesh; Crooks, Peter A

    2015-11-15

    In the present study, we have designed and synthesized a series of 1-benzyl-2-methyl-3-indolylmethylene barbituric acid analogs (7a-7h) and 1-benzyl-2-methyl-3-indolylmethylene thiobarbituric acid analogs (7 i-7 l) as nucleophosmin 1 (NPM1) inhibitors and have evaluated them for their anti-cancer activity against a panel of 60 different human cancer cell lines. Among these analogs 7 i, 7 j, and 7 k demonstrated potent growth inhibitory effects in various cancer cell types with GI50 values <2 μM. Compound 7 k exhibited growth inhibitory effects on a sub-panel of six leukemia cell lines with GI50 values in the range 0.22-0.35 μM. Analog 7 i also exhibited GI50 values <0.35 μM against three of the leukemia cell lines in the sub-panel. Analogs 7 i, 7 j, 7 k and 7 l were also evaluated against the mutant NPM1 expressing OCI-AML3 cell line and compounds 7 k and 7 l were found to cause dose-dependent apoptosis (AP50 = 1.75 μM and 3.3 μM, respectively). Compound 7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: that is, A498 renal cancer (GI50 = 0.19 μM), HOP-92 and NCI-H522 lung cancer (GI50 = 0.25 μM), COLO 205 and HCT-116 colon cancer (GI50 = 0.20 and 0.26 μM, respectively), CNS cancer SF-539 (GI50 = 0.22 μM), melanoma MDA-MB-435 (GI50 = 0.22 μM), and breast cancer HS 578T (GI50 = 0.22 μM) cell lines. Molecular docking studies suggest that compounds 7 k and 7 l exert their anti-leukemic activity by binding to a pocket in the central channel of the NPM1 pentameric structure. These results indicate that the small molecule inhibitors 7 i, 7 j, 7 k, and 7 l could be potentially developed into anti-NPM1 drugs for the treatment of a variety of hematologic malignancies and solid tumors. PMID:26602084

  9. Synthesis, structural investigations, and anti-cancer activity of new methyl indole-3-carboxylate derivatives

    NASA Astrophysics Data System (ADS)

    Niemyjska, Maria; Maciejewska, Dorota; Wolska, Irena; Truszkowski, Paweł

    2012-10-01

    Two new methyl indole-3-carboxylate derivatives: methyl 1-(3'-indolylmethane)-indole-3-carboxylate (1), and methyl 1-(1'-benzenosulfonyl-3'-indolylmethane)-indole-3-carboxylate (2) were synthesized. They are interesting as the analogs of 3,3'-diindolylmethane, which is intensively tested as a potent antitumor agent. Their solid-state structure was characterized using 13C CP/MAS NMR or X-ray diffraction measurements. Molecular modeling was used as a help in the structure elucidation. The solid-state NMR spectroscopy showed only one stable conformer of 1, but the X-ray diffraction results indicate that compound 2 crystallizes in the triclinic space group P-1 with two molecules, A and B, in the asymmetric unit. Both compounds inhibited the growth of melanoma, renal and breast cancers cell lines.

  10. Preparation and anti-cancer activity of polymer-encapsulated curcumin nanoparticles

    NASA Astrophysics Data System (ADS)

    Thu Ha, Phuong; Huong Le, Mai; Nhung Hoang, Thi My; Thu Huong Le, Thi; Quang Duong, Tuan; Tran, Thi Hong Ha; Tran, Dai Lam; Phuc Nguyen, Xuan

    2012-09-01

    Curcumin (Cur) is a yellow compound isolated from rhizome of the herb curcuma longa. Curcumin possesses antioxidant, anti-inflammatory, anti-carcinogenic and antimicrobial properties, and suppresses proliferation of many tumor cells. However, the clinical application of curcumin in cancer treatment is considerably limited due to its serious poor delivery characteristics. In order to increase the hydrophilicity and drug delivery capability, we encapsulated curcumin into copolymer PLA-TPGS, 1,3-beta-glucan (Glu), O-carboxymethyl chitosan (OCMCs) and folate-conjugated OCMCs (OCMCs-Fol). These polymer-encapsulated curcumin nanoparticles (Cur-PLA-TPGS, Cur-Glu, Cur-OCMCs and Cur-OCMCs-Fol) were characterized by infrared (IR), fluorescence (FL), photoluminescence (PL) spectra, field emission scanning electron microscopy (FE-SEM), and found to be spherical particles with an average size of 50–100 nm, being suitable for drug delivery applications. They were much more soluble in water than not only free curcumin but also other biodegradable polymer-encapsulated curcumin nanoparticles. The anti-tumor promoting assay was carried out, showing the positive effects of Cur-Glu and Cur-PLA-TPGS on tumor promotion of Hep-G2 cell line in vitro. Confocal microscopy revealed that the nano-sized curcumin encapsulated by polymers OCMCs and OCMCs-Fol significantly enhanced the cellular uptake (cancer cell HT29 and HeLa).

  11. Inhibition on Proteasome β1 Subunit Might Contribute to the Anti-Cancer Effects of Fangchinoline in Human Prostate Cancer Cells

    PubMed Central

    Sun, Peng; Feng, Li-Xing; Liu, Miao; Hu, Li-Hong; Wu, Wan-Ying; Jiang, Bao-Hong; Yang, Min; Qu, Xiao-Bo; Guo, De-An; Liu, Xuan

    2015-01-01

    Fangchinoline is a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae S. Moore. Fangchinoline and its structure analogue, tetrandrine, exhibited direct binding affinity with recombinant human proteasome β1 subunit and also inhibited its activity in vitro. In cultured prostate PC-3 cells and LnCap cells, fangchinoline could dose-dependently inhibit cell proliferation and caspase-like activity of cellular proteasome which was mediated by proteasome β1 subunit. The inhibitive effect of fangchinoline on caspase-like activity of proteasome was also observed in purified human erythrocyte 20S proteasome. In PC-3 cells, fangchinoline induced cell cycle arrest at G0/G1 phase and apoptosis. Treatment of PC-3 tumor-bearing nude mice with fangchinoline inhibited tumor growth, induced apoptosis and also caused decrease in proteasome activities in tumor xenografts. Dose-dependent and time-dependent accumulation of ubiquitinated proteins and important proteasome substrates such as p27, Bax and IκB-α were observed in fangchinoline-treated cells. Over-expression of proteasome β1 subunit by plasmid transfection increased sensitivity of cells to the cytotoxicity of fangchinoline while knockdown of proteasome β1 subunit ameliorated cytotoxicity of fangchinoline in PC-3 cells. Results of the present study suggested that proteasome inhibition was involved in the anti-cancer effects of fangchinoline. Fangchinoline and its structure analogues might be new natural proteasome inhibitors targeting β1 subunit. PMID:26512898

  12. Inhibition on Proteasome β1 Subunit Might Contribute to the Anti-Cancer Effects of Fangchinoline in Human Prostate Cancer Cells.

    PubMed

    Li, Dong; Lu, Yu; Sun, Peng; Feng, Li-Xing; Liu, Miao; Hu, Li-Hong; Wu, Wan-Ying; Jiang, Bao-Hong; Yang, Min; Qu, Xiao-Bo; Guo, De-An; Liu, Xuan

    2015-01-01

    Fangchinoline is a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae S. Moore. Fangchinoline and its structure analogue, tetrandrine, exhibited direct binding affinity with recombinant human proteasome β1 subunit and also inhibited its activity in vitro. In cultured prostate PC-3 cells and LnCap cells, fangchinoline could dose-dependently inhibit cell proliferation and caspase-like activity of cellular proteasome which was mediated by proteasome β1 subunit. The inhibitive effect of fangchinoline on caspase-like activity of proteasome was also observed in purified human erythrocyte 20S proteasome. In PC-3 cells, fangchinoline induced cell cycle arrest at G0/G1 phase and apoptosis. Treatment of PC-3 tumor-bearing nude mice with fangchinoline inhibited tumor growth, induced apoptosis and also caused decrease in proteasome activities in tumor xenografts. Dose-dependent and time-dependent accumulation of ubiquitinated proteins and important proteasome substrates such as p27, Bax and IκB-α were observed in fangchinoline-treated cells. Over-expression of proteasome β1 subunit by plasmid transfection increased sensitivity of cells to the cytotoxicity of fangchinoline while knockdown of proteasome β1 subunit ameliorated cytotoxicity of fangchinoline in PC-3 cells. Results of the present study suggested that proteasome inhibition was involved in the anti-cancer effects of fangchinoline. Fangchinoline and its structure analogues might be new natural proteasome inhibitors targeting β1 subunit. PMID:26512898

  13. Loading of Gemcitabine on chitosan magnetic nanoparticles increases the anti-cancer efficacy of the drug.

    PubMed

    Parsian, Maryam; Unsoy, Gozde; Mutlu, Pelin; Yalcin, Serap; Tezcaner, Aysen; Gunduz, Ufuk

    2016-08-01

    Targeted delivery of anti-cancer drugs increase the efficacy, while decreasing adverse effects. Among various delivery systems, chitosan coated iron oxide nanoparticles (CsMNPs) gained attention with their biocompatibility, biodegradability, low toxicity and targetability under magnetic field. This study aimed to increase the cellular uptake and efficacy of Gemcitabine. CsMNPs were synthesized by in situ co-precipitation and Gemcitabine was loaded onto the nanoparticles. Nanoparticle characterization was performed by TEM, FTIR, XPS, and zeta potential. Gemcitabine release and stability was analyzed. The cellular uptake was shown. Cytotoxicity of free-Gemcitabine and Gem-CsMNPs were examined on SKBR and MCF-7 breast cancer cells by XTT assay. Gemcitabine loading was optimized as 30µM by spectrophotometric analyses. Drug release was highest (65%) at pH 4.2, while it was 8% at pH 7.2. This is a desired release characteristic since pH of tumor-tissue and endosomes are acidic, while the blood-stream and healthy-tissues are neutral. Peaks reflecting the presence of Gemcitabine were observed in FTIR and XPS. At neutral pH, zeta potential increased after Gemcitabine loading. TEM images displayed, Gem-CsMNPs were 4nm with uniform size-distribution and have spherical shape. The cellular uptake and targetability of CsMNPs was studied on MCF-7 breast cancer cell lines. IC50 value of Gem-CsMNPs was 1.4 fold and 2.6 fold lower than free-Gem on SKBR-3 and MCF-7 cell lines respectively, indicating the increased efficacy of Gemcitabine when loaded onto nanoparticles. Targetability by magnetic field, stability, size distribution, cellular uptake and toxicity characteristics of CsMNPs in this study provides a useful targeted delivery system for Gemcitabine in cancer therapy. PMID:27181067

  14. Using Assistive Technology Adaptations To Include Students with Learning Disabilities in Cooperative Learning Activities.

    ERIC Educational Resources Information Center

    Bryant, Diane Pedrotty; Bryant, Brian R.

    1998-01-01

    Discusses a process for integrating technology adaptations for students with learning disabilities into cooperative-learning activities in terms of three components: (1) selecting adaptations; (2) monitoring use of adaptations during cooperative-learning activities; and (3) evaluating the adaptations' effectiveness. Barriers to and support systems…

  15. Interest Inventory. [Includes Academic Interest Measure, Pupil Activity Inventory, and Semantic Differential].

    ERIC Educational Resources Information Center

    Harvard Univ., Cambridge, MA. Harvard Project Physics.

    This Interest Inventory contains three inventories: Academic Interest Measure (AIM), Pupil Activity Inventory (PAI), and Semantic Differential test (SD). The AIM measures six subscales of academic interests; the PAI measures non-school activities in science; and the SD measures attitudes toward science and physics. The inventories are designed for…

  16. 3-Bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective "small molecule" anti-cancer agent taken from labside to bedside: introduction to a special issue.

    PubMed

    Pedersen, Peter L

    2012-02-01

    . Significantly, in subsequent experiments with rodents (19 animals with advanced cancer) Ko led a project in which 3BP was shown in a short treatment period to eradicate all (100%). Ko's and co-author's findings once published attracted global attention leading world-wide to many other studies and publications related to 3BP and its potent anti-cancer effect. This Issue of the Journal of Bioenergetics and Biomembranes (JOBB 44-1) captures only a sampling of research conducted to date on 3BP as an anticancer agent, and includes also a Case Report on the first human patient known to the author to be treated with specially formulated 3BP. Suffice it to say in this bottom line, "3BP, a small molecule, results in a remarkable therapeutic effect when it comes to treating cancers exhibiting a "Warburg effect". This includes most cancer types. PMID:22382780

  17. Survivin knockdown increased anti-cancer effects of (-)-epigallocatechin-3-gallate in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells

    SciTech Connect

    Hossain, Md. Motarab; Banik, Naren L.; Ray, Swapan K.

    2012-08-01

    network formation ability of cells was significantly inhibited by survivin silencing and completely by combination of survivin silencing and EGCG treatment. Collectively, survivin silencing potentiated anti-cancer effects of EGCG in human malignant neuroblastoma cells having survivin overexpression. -- Highlights: Black-Right-Pointing-Pointer Survivin shRNA + EGCG controlled growth of human malignant neuroblastoma cells. Black-Right-Pointing-Pointer Survivin knockdown induced neuronal differentiation in neuroblastoma cells. Black-Right-Pointing-Pointer Survivin shRNA + EGCG induced morphological and biochemical features of apoptosis. Black-Right-Pointing-Pointer Combination therapy inhibited invasion, proliferation, and angiogenesis as well. Black-Right-Pointing-Pointer So, combination therapy showed multiple anti-cancer mechanisms in neuroblastoma.

  18. The 26S proteasome is a multifaceted target for anti-cancer therapies.

    PubMed

    Grigoreva, Tatyana A; Tribulovich, Vyacheslav G; Garabadzhiu, Alexander V; Melino, Gerry; Barlev, Nickolai A

    2015-09-22

    Proteasomes play a critical role in the fate of proteins that are involved in major cellular processes, including signal transduction, gene expression, cell cycle, replication, differentiation, immune response, cellular response to stress, etc. In contrast to non-specific degradation by lysosomes, proteasomes are highly selective and destroy only the proteins that are covalently labelled with small proteins, called ubiquitins. Importantly, many diseases, including neurodegenerative diseases and cancers, are intimately connected to the activity of proteasomes making them an important pharmacological target. Currently, the vast majority of inhibitors are aimed at blunting the proteolytic activities of proteasomes. However, recent achievements in solving structures of proteasomes at very high resolution provided opportunities to design new classes of small molecules that target other physiologically-important enzymatic activities of proteasomes, including the de-ubiquitinating one. This review attempts to catalog the information available to date about novel classes of proteasome inhibitors that may have important pharmacological ramifications. PMID:26295307

  19. The 26S proteasome is a multifaceted target for anti-cancer therapies

    PubMed Central

    Grigoreva, Tatyana A; Tribulovich, Vyacheslav G.; Garabadzhiu, Alexander V.; Melino, Gerry; Barlev, Nickolai A.

    2015-01-01

    Proteasomes play a critical role in the fate of proteins that are involved in major cellular processes, including signal transduction, gene expression, cell cycle, replication, differentiation, immune response, cellular response to stress, etc. In contrast to non-specific degradation by lysosomes, proteasomes are highly selective and destroy only the proteins that are covalently labelled with small proteins, called ubiquitins. Importantly, many diseases, including neurodegenerative diseases and cancers, are intimately connected to the activity of proteasomes making them an important pharmacological target. Currently, the vast majority of inhibitors are aimed at blunting the proteolytic activities of proteasomes. However, recent achievements in solving structures of proteasomes at very high resolution provided opportunities to design new classes of small molecules that target other physiologically-important enzymatic activities of proteasomes, including the de-ubiquitinating one. This review attempts to catalog the information available to date about novel classes of proteasome inhibitors that may have important pharmacological ramifications. PMID:26295307

  20. Intracellular activity of clinical concentrations of phenothiazines including thioridiazine against phagocytosed Staphylococcus aureus.

    PubMed

    Ordway, Diane; Viveiros, Miguel; Leandro, Clara; Arroz, Maria Jorge; Amaral, Leonard

    2002-07-01

    The effect of thioridazine (TZ) was studied on the killing activity of human peripheral blood monocyte derived macrophages (HPBMDM) and of human macrophage cell line THP-1 at extracellular concentrations below those achievable clinically. These macrophages have nominal killing activity against bacteria and therefore, would not influence any activity that the compounds may have against intracellular localised Staphylococcus aureus. The results indicated that whereas TZ has an in vitro minimum inhibitory concentration (MIC) against the strains of S. aureus of 18, 0.1 mg/l of TZ in the medium completely inhibits the growth of S. aureus that has been phagocytosed by macrophages. The latter concentration was non-toxic to macrophages, did not cause cellular expression of activation marker CD69 nor induction of CD3+ T cell production of IFN-gamma, but blocked cellular proliferation and down-regulated the production of T cell-derived cytokines (IFN-gamma, IL-5). These results suggest that TZ induces intracellular bactericidal activities independent of the capacity to generate Type 1 responses against S. aureus. PMID:12127709

  1. Diffractive laser beam homogenizer including a photo-active material and method of fabricating the same

    DOEpatents

    Bayramian, Andy J; Ebbers, Christopher A; Chen, Diana C

    2014-05-20

    A method of manufacturing a plurality of diffractive optical elements includes providing a partially transmissive slide, providing a first piece of PTR glass, and directing first UV radiation through the partially transmissive slide to impinge on the first piece of PTR glass. The method also includes exposing predetermined portions of the first piece of PTR glass to the first UV radiation and thermally treating the exposed first piece of PTR glass. The method further includes providing a second piece of PTR glass and directing second UV radiation through the thermally treated first piece of PTR glass to impinge on the second piece of PTR glass. The method additionally includes exposing predetermined portions of the second piece of PTR glass to the second UV radiation, thermally treating the exposed second piece of PTR glass, and repeating providing and processing of the second piece of PTR glass using additional pieces of PTR glass.

  2. Electrode including porous particles with embedded active material for use in a secondary electrochemical cell

    DOEpatents

    Vissers, Donald R.; Nelson, Paul A.; Kaun, Thomas D.; Tomczuk, Zygmunt

    1978-04-25

    Particles of carbonaceous matrices containing embedded electrode active material are prepared for vibratory loading within a porous electrically conductive substrate. In preparing the particles, active materials such as metal chalcogenides, solid alloys of alkali or alkaline earth metals along with other metals and their oxides in powdered or particulate form are blended with a thermosetting resin and particles of a volatile to form a paste mixture. The paste is heated to a temperature at which the volatile transforms into vapor to impart porosity at about the same time as the resin begins to cure into a rigid, solid structure. The solid structure is then comminuted into porous, carbonaceous particles with the embedded active material.

  3. Sixty Minutes of Physical Activity per Day Included within Preschool Academic Lessons Improves Early Literacy

    ERIC Educational Resources Information Center

    Kirk, Stacie M.; Kirk, Erik P.

    2016-01-01

    Background: The effects of increases in physical activity (PA) on early literacy skills in preschool children are not known. Methods: Fifty-four African-American preschool children from a low socioeconomic urban Head Start participated over 8 months. A 2-group, quasi-experimental design was used with one preschool site participating in the PA…

  4. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AGRICULTURE ALMONDS GROWN IN CALIFORNIA Administrative Rules and Regulations § 981.441 Credit for market... each activity shall be to promote the sale, consumption or use of California almonds, and nothing... in California almond growing counties with more than 1,000 bearing acres: Provided, That...

  5. Observing a fictitious stressful event: haematological changes, including circulating leukocyte activation.

    PubMed

    Mian, Rubina; Shelton-Rayner, Graham; Harkin, Brendan; Williams, Paul

    2003-03-01

    The aim of this study was to assess the effect of watching a psychological stressful event on the activation of leukocytes in healthy human volunteers. Blood samples were obtained from 32 healthy male and female subjects aged between 20 and 26 years before, during and after either watching an 83-minute horror film that none of the subjects had previously seen (The Texas Chainsaw Massacre, 1974) or by sitting quietly in a room (control group). Total differential cell counts, leukocyte activation as measured by the nitroblue tetrazolium (NBT) test, heart rate and blood pressure (BP) measurements were taken at defined time points. There were significant increases in peripheral circulating leukocytes, the number of activated circulating leukocytes, haemoglobin (Hb) concentration and haematocrit (Hct) in response to the stressor. These were accompanied by significant increases in heart rate, systolic and diastolic BP (P<0.05 from baseline). This is the first reported study on the effects of observing a psychologically stressful, albeit fictitious event on circulating leukocyte numbers and the state of leukocyte activation as determined by the nitrotetrazolium test. PMID:12637206

  6. Backyards and Butterflies: Ways to Include Children with Disabilities in Outdoor Activities.

    ERIC Educational Resources Information Center

    Greenstein, Doreen; And Others

    This sourcebook is designed for children, parents, and families, detailing ideas for outdoor play and learning activities, with emphasis on involving children with disabilities in outdoor play. A rural perspective permeates the guide, although each chapter contains ideas for making outdoor environments more accessible and safer for all children,…

  7. Beyond Right or Wrong: Challenges of Including Creative Design Activities in the Classroom

    ERIC Educational Resources Information Center

    Brennan, Karen

    2015-01-01

    In this article, we explore challenges encountered by K-12 educators in establishing classroom cultures that support creative learning activities with the Scratch programming language. Providing opportunities for students to understand and to build capacities for creative work was described by many of the teachers that we interviewed as a central…

  8. Physical Activity Programs in Higher Education: Modifying Net/Wall Games to Include Individuals with Disabilities

    ERIC Educational Resources Information Center

    Braga, Luciana; Tracy, Julia F.; Taliaferro, Andrea R.

    2015-01-01

    The growing number of students with disabilities in higher education settings has presented challenges for instructors with regards to appropriate inclusion. Concerning physical activity courses in higher education, instructors may not have the knowledge or resources to make modifications and accommodations that will ultimately result in…

  9. Population and Human Development: A Course Curriculum Including Lesson Plans, Activities and Bibliography.

    ERIC Educational Resources Information Center

    Murphy, Elaine M.

    This course outline suggests materials and learning activities on the interrelated causes and consequences of population growth and other population concerns. Designed to educate general college audiences, it is also intended for use as a preservice course for teachers. In addition, the course can be modified for high school students. The course…

  10. A novel peptide inhibitor of classical and lectin complement activation including ABO incompatibility

    PubMed Central

    Mauriello, Clifford T.; Pallera, Haree K.; Sharp, Julia A.; Woltmann, Jon L.; Qian, Shizhi; Hair, Pamela S.; van der Pol, Pieter; van Kooten, Cees; Thielens, Nicole M.; Lattanzio, Frank A.; Cunnion, Kenji M.; Krishna, Neel K.

    2012-01-01

    Previous experiments from our laboratories have identified peptides derived from the human astrovirus coat protein (CP) that bind C1q and mannose binding lectin (MBL) inhibiting activation of the classical and lectin pathways of complement, respectively. The purpose of this study was to evaluate the function of these coat protein peptides (CPPs) in an in vitro model of complement-mediated disease (ABO incompatibility), preliminarily assess their in vivo complement suppression profile and develop more highly potent derivatives of these molecules. E23A, a 30 amino acid CPP derivative previously demonstrated to inhibit classical pathway activation was able to dose-dependently inhibit lysis of AB erythrocytes treated with mismatched human O serum. Additionally, when injected into rats, E23A inhibited the animals’ serum from lysing antibody-sensitized erythrocytes, providing preliminary in vivo functional evidence that this CPP can cross the species barrier to inhibit serum complement activity in rodents. A rational drug design approach was implemented to identify more potent CPP derivatives, resulting in the identification and characterization of a 15 residue peptide (Polar Assortant (PA)), which demonstrated both superior inhibition of classical complement pathway activation and robust binding to C1q collagen-like tails. PA also inhibited ABO incompatibility in vitro and demonstrated in vivo complement suppression up to 24 hours post-injection. CPP’s ability to inhibit ABO incompatibility in vitro, proof of concept in vivo inhibitory activity in rats and the development of the highly potent PA derivative set the stage for preclinical testing of this molecule in small animal models of complement-mediated disease. PMID:22906481

  11. An Updated Review of Interventions that Include Promotion of Physical Activity for Adult Men.

    PubMed

    Bottorff, Joan L; Seaton, Cherisse L; Johnson, Steve T; Caperchione, Cristina M; Oliffe, John L; More, Kimberly; Jaffer-Hirji, Haleema; Tillotson, Sherri M

    2015-06-01

    The marked disparity in life expectancy between men and women suggests men are a vulnerable group requiring targeted health promotion programs. As such, there is an increasing need for health promotion strategies that effectively engage men with their health and/or illness management. Programs that promote physical activity could significantly improve the health of men. Although George et al. (Sports Med 42(3):281, 30) reviewed physical activity programs involving adult males published between 1990 and 2010, developments in men's health have prompted the emergence of new sex- and gender-specific approaches targeting men. The purpose of this review was to: (1) extend and update the review undertaken by George et al. (Sports Med 42(3):281, 30) concerning the effectiveness of physical activity programs in males, and (2) evaluate the integration of gender-specific influences in the content, design, and delivery of men's health promotion programs. A search of MEDLINE, CINAHL, ScienceDirect, Web of Science, PsycINFO, the Cochrane Library, and the SPORTDiscus databases for articles published between January 2010 and August 2014 was conducted. In total, 35 studies, involving evaluations of 31 programs, were identified. Findings revealed that a variety of techniques and modes of delivery could effectively promote physical activity among men. Though the majority of programs were offered exclusively to men, 12 programs explicitly integrated gender-related influences in male-specific programs in ways that recognized men's interests and preferences. Innovations in male-only programs that focus on masculine ideals and gender influences to engage men in increasing their physical activity hold potential for informing strategies to promote other areas of men's health. PMID:25430599

  12. Enhancing the in vitro anti-cancer efficacy of artesunate by loading into poly-D,L-lactide-co-glycolide (PLGA) nanoparticles.

    PubMed

    Nguyen, Hanh Thuy; Tran, Tuan Hiep; Kim, Jong Oh; Yong, Chul Soon; Nguyen, Chien Ngoc

    2015-01-01

    Artesunate (ART)-a well-known anti-malarial agent is also known to have potential anti-proliferative activities but its instability, poor aqueous solubility, and lack of relevant studies have limited its application as an effective anti-cancer drug. To overcome these problems, ART was loaded in poly (lactic-co-glycolic) acid (PLGA) nanoparticles using oil/water emulsion evaporation method. PLGA nanoparticles with small particle size and high entrapment efficiency were obtained. The PLGA nanoparticles were optimized by evaluating the effects of several formulation parameters on physicochemical properties of nanoparticles. The in vitro cytotoxicity of blank PLGA, free ART, and ART-PLGA on 3 human cancer cell lines viz. A549, SCC-7, and MCF-7 was conducted using MTT assay. The particles showed nanometric size (~170 nm), large entrapment efficiency (up to 83.4%), and excellent stability (evaluated for 1 month) after lyophilization with 5% mannitol. ART was dispersed inside particle core allowing a sustained release up to 48 h. The in vitro cytotoxicity results demonstrated strong activity of ART against cancer cell lines. The ART-PLGA formulation significantly reduced cell viability than the free ART. The formulation of ART loaded PLGA nanoparticles supported a potential application of ART as an anticancer agent. PMID:24968925

  13. Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate

    PubMed Central

    Lis, Paweł; Jurkiewicz, Paweł; Cal-Bąkowska, Magdalena; Ko, Young H.; Pedersen, Peter L.; Goffeau, Andre; Ułaszewski, Stanisław

    2016-01-01

    In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of yeast cells to 3-BP, possibly due to the non-functional system of mitophagy of damaged mitochondria through the Ras-cAMP-PKA pathway. Single deletions of genes encoding glycolytic enzymes, the TCA cycle enzymes and mitochondrial carriers result in multiple effects after 3-BP treatment. However, it can be concluded that activity of the pentose phosphate pathway is necessary to prevent the toxicity of 3-BP, probably due to the fact that large amounts of NADPH are produced by this pathway, ensuring the reducing force needed for glutathione reduction, crucial to cope with the oxidative stress. Moreover, single deletions of genes encoding the TCA cycle enzymes and mitochondrial carriers generally cause sensitivity to 3-BP, while totally inactive mitochondrial respiration in the rho0 mutant resulted in increased resistance to 3-BP. PMID:26862728

  14. Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate.

    PubMed

    Lis, Paweł; Jurkiewicz, Paweł; Cal-Bąkowska, Magdalena; Ko, Young H; Pedersen, Peter L; Goffeau, Andre; Ułaszewski, Stanisław

    2016-03-01

    In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of yeast cells to 3-BP, possibly due to the non-functional system of mitophagy of damaged mitochondria through the Ras-cAMP-PKA pathway. Single deletions of genes encoding glycolytic enzymes, the TCA cycle enzymes and mitochondrial carriers result in multiple effects after 3-BP treatment. However, it can be concluded that activity of the pentose phosphate pathway is necessary to prevent the toxicity of 3-BP, probably due to the fact that large amounts of NADPH are produced by this pathway, ensuring the reducing force needed for glutathione reduction, crucial to cope with the oxidative stress. Moreover, single deletions of genes encoding the TCA cycle enzymes and mitochondrial carriers generally cause sensitivity to 3-BP, while totally inactive mitochondrial respiration in the rho0 mutant resulted in increased resistance to 3-BP. PMID:26862728

  15. Traf2- and Nck-interacting kinase (TNIK) is involved in the anti-cancer mechanism of dovitinib in human multiple myeloma IM-9 cells.

    PubMed

    Chon, Hae Jung; Lee, Yura; Bae, Kyoung Jun; Byun, Byung Jin; Kim, Soon Ae; Kim, Jiyeon

    2016-07-01

    Traf2- and Nck-interacting kinase (TNIK) is a member of the germinal center kinase family. TNIK was first identified as a kinase that is involved in regulating cytoskeletal organization in many types of cells, and it was recently proposed as a novel therapeutic target in several types of human cancers. Although previous studies suggest that TNIK plays a pivotal role in cancer cell survival and prognosis, its function in hematological cancer cell survival has not been investigated. Here we investigated the relationship between TNIK function and cell viability in multiple myeloma IM-9 cells using TNIK small interfering RNA (siRNA) transfection and dovitinib treatment. Treatment of IM-9 cells with TNIK siRNA and dovitinib treatment reduced cell proliferation. The ATP competing kinase assay and western blot analysis showed that dovitinib strongly inhibited both the interaction of TNIK with ATP (K i, 13 nM) and the activation of Wnt signaling effectors such as β-catenin and TCF4. Dovitinib also induced caspase-dependent apoptosis in IM-9 cells without significant cytotoxicity in PBMCs. Our results provide new evidence that TNIK may be involved in the proliferation of multiple myeloma IM-9 cells and in the anti-cancer activity of dovitinib via inhibition of the endogenous Wnt signaling pathway. PMID:26995282

  16. Simultaneous determination of the novel thiosemicarbazone anti-cancer agent, Bp4eT, and its main phase I metabolites in plasma: application to a pilot pharmacokinetic study in rats.

    PubMed

    Stariat, Ján; Suprunová, Vlasta; Roh, Jaroslav; Šesták, Vít; Eisner, Tomáš; Filipský, Tomáš; Mladěnka, Přemysl; Nobilis, Milan; Šimůnek, Tomáš; Klimeš, Jiří; Kalinowski, Danuta S; Richardson, Des R; Kovaříková, Petra

    2014-05-01

    Novel thiosemicarbazone metal chelators are extensively studied anti-cancer agents with marked and selective activity against a wide variety of cancer cells, as well as human tumor xenografts in mice. This study describes the first validated LC-MS/MS method for the simultaneous quantification of 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT) and its main metabolites (E/Z isomers of the semicarbazone structure, M1-E and M1-Z, and the amidrazone metabolite, M2) in plasma. Separation was achieved using a C18 column with ammonium formate/acetonitrile mixture as the mobile phase. Plasma samples were treated using solid-phase extraction on 96-well plates. This method was validated over the concentration range of 0.18-2.80 μM for Bp4eT, 0.02-0.37 μM for both M1-E and M1-Z, and 0.10-1.60 μM for M2. This methodology was applied to the analysis of samples from in vivo experiments, allowing for the concentration-time profile to be simultaneously assessed for the parent drug and its metabolites. The current study addresses the lack of knowledge regarding the quantitative analysis of thiosemicarbazone anti-cancer drugs and their metabolites in plasma and provides the first pharmacokinetic data on a lead compound of this class. PMID:24254882

  17. Functional characterization and anti-cancer action of the clinical phase II cardiac Na+/K+ ATPase inhibitor istaroxime: in vitro and in vivo properties and cross talk with the membrane androgen receptor.

    PubMed

    Alevizopoulos, Konstantinos; Dimas, Konstantinos; Papadopoulou, Natalia; Schmidt, Eva-Maria; Tsapara, Anna; Alkahtani, Saad; Honisch, Sabina; Prousis, Kyriakos C; Alarifi, Saud; Calogeropoulou, Theodora; Lang, Florian; Stournaras, Christos

    2016-04-26

    Sodium potassium pump (Na+/K+ ATPase) is a validated pharmacological target for the treatment of various cardiac conditions. Recent published data with Na+/K+ ATPase inhibitors suggest a potent anti-cancer action of these agents in multiple indications. In the present study, we focus on istaroxime, a Na+/K+ ATPase inhibitor that has shown favorable safety and efficacy properties in cardiac phase II clinical trials. Our experiments in 22 cancer cell lines and in prostate tumors in vivo proved the strong anti-cancer action of this compound. Istaroxime induced apoptosis, affected the key proliferative and apoptotic mediators c-Myc and caspase-3 and modified actin cystoskeleton dynamics and RhoA activity in prostate cancer cells. Interestingly, istaroxime was capable of binding to mAR, a membrane receptor mediating rapid, non-genomic actions of steroids in prostate and other cells. These results support a multi-level action of Na+/K+ ATPase inhibitors in cancer cells and collectively validate istaroxime as a strong re-purposing candidate for further cancer drug development. PMID:27027435

  18. Space Resources for Teachers: Biology, Including Suggestions for Classroom Activities and Laboratory Experiments.

    ERIC Educational Resources Information Center

    Lee, Tom E.; And Others

    This compilation of resource units concerns the latest developments in space biology. Some of the topics included are oxygen consumption, temperature, radiation, rhythms, weightlessness, acceleration and vibration stress, toxicity, and sensory and perceptual problems. Many of the topics are interdisciplinary and relate biology, physiology,…

  19. Combined cetuximab and genistein treatment shows additive anti-cancer effect on oral squamous cell carcinoma.

    PubMed

    Park, Sung-Jin; Kim, Myung-Jin; Kim, Yu-Kyoung; Kim, Soung-Min; Park, Ju-Yong; Myoung, Hoon

    2010-06-01

    The purpose of this study was to evaluate the potency of EGFR pathway inhibition achieved by combining cetuximab, an anti-EGFR monoclonal antibody, and genistein, a tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively, in oral squamous cell carcinoma (OSCC) in vitro and in vivo. Two OSCC cell lines, HSC3 and KB, were treated with cetuximab (C, 0-400mug/ml), genistein (G, 0-80muM), or a combination of both at a range of concentrations. Downstream protein expression of EGFR, p-EGFR, and p-Akt were evaluated by Western blot. Cell proliferation and apoptosis indices were calculated to assess anti-cancer effects in vitro. The in vivo effects of cetuximab and genistein on tumor cell growth were examined using an OSCC xenografted nude mouse model and immunohistochemical analyses of proliferation (PCNA) and microvessel density (CD31). Treatment of cells with dual anti-EGFR agents reduced the expressions of p-EGFR, and p-Akt in HSC3 cell line, but there was no significant difference in downregulation between cetuximab alone and in combination with genistein in KB cells. Both HSC3 and KB cells showed a dose-dependent decrease in cell proliferation significantly with single agent treatment and combination (p<0.05). In low concentration, combined cetuximab and genistein therapy resulted in additive growth inhibition and more apoptosis compared to that achieved with single-agent exposure in both cell lines. A combination of cetuximab and genistein significantly inhibited tumor growth and caused a substantial growth delay in in vivo models of both cell lines while each single-agent exposure caused no delay of tumor growth. Immunohistochemical staining with PCNA revealed that the group receiving combined cetuximab and genistein exhibited the lowest number of proliferating cells and microvessel density (p<0.05). Combined therapy with genistein and cetuximab can add the potency of EGFR signaling inhibition. Because not all

  20. LGR5 expressing cells of hair follicle as potential targets for antibody mediated anti-cancer laser therapy

    NASA Astrophysics Data System (ADS)

    Popov, Boris V.

    2013-02-01

    Near infrared laser immunotherapy becomes now a new promising research field to cure the patients with cancers. One of the critical limitation in medical application of this treatment is availability of the specific markers for delivery of laser-sensitive nanoparticles. When coupled to antibodies to the cancer stem cells markers these nanoparticles may be delivered to the cancer tissue and mediate the laser induced thermolysis of the cancer stem cells that initiate and drive growth of cancer. This paper addresses the Lgr5 cell surface marker mediating the Wnt/β-catenin signal transduction as a potential target for anti-cancer laser immunotherapy of skin cancers.

  1. DNA strand breaks induced by nuclear hijacking of neuronal NOS as an anti-cancer effect of 2-methoxyestradiol

    PubMed Central

    Gorska, Magdalena; Kuban-Jankowska, Alicja; Zmijewski, Michal; Gammazza, Antonella Marino; Cappello, Francesco; Wnuk, Maciej; Gorzynik, Monika; Rzeszutek, Iwona; Daca, Agnieszka; Lewinska, Anna; Wozniak, Michal

    2015-01-01

    2-Methoxyestradiol (2-ME) is a physiological metabolite of 17β-estradiol. At pharmacological concentrations, 2-ME inhibits colon, breast and lung cancer in tumor models. Here we investigated the effect of physiologically relevant concentrations of 2-ME in osteosarcoma cell model. We demonstrated that 2-ME increased nuclear localization of neuronal nitric oxide synthase, resulting in nitro-oxidative DNA damage. This in turn caused cell cycle arrest and apoptosis in osteosarcoma cells. We suggest that 2-ME is a naturally occurring hormone with potential anti-cancer properties. PMID:25972363

  2. Development of an Optimized Protocol for NMR Metabolomics Studies of Human Colon Cancer Cell Lines and First Insight from Testing of the Protocol Using DNA G-Quadruplex Ligands as Novel Anti-Cancer Drugs

    PubMed Central

    Lauri, Ilaria; Savorani, Francesco; Iaccarino, Nunzia; Zizza, Pasquale; Pavone, Luigi Michele; Novellino, Ettore; Engelsen, Søren Balling; Randazzo, Antonio

    2016-01-01

    The study of cell lines by nuclear magnetic resonance (NMR) spectroscopy metabolomics represents a powerful tool to understand how the local metabolism and biochemical pathways are influenced by external or internal stimuli. In particular, the use of adherent mammalian cells is emerging in the metabolomics field in order to understand the molecular mechanism of disease progression or, for example, the cellular response to drug treatments. Hereto metabolomics investigations for this kind of cells have generally been limited to mass spectrometry studies. This study proposes an optimized protocol for the analysis of the endo-metabolome of human colon cancer cells (HCT116) by NMR. The protocol includes experimental conditions such as washing, quenching and extraction. In order to test the proposed protocol, it was applied to an exploratory study of cancer cells with and without treatment by anti-cancer drugs, such as DNA G-quadruplex binders and Adriamycin (a traditional anti-cancer drug). The exploratory NMR metabolomics analysis resulted in NMR assignment of all endo-metabolites that could be detected and provided preliminary insights about the biological behavior of the drugs tested. PMID:26784246

  3. Activity of faropenem tested against Neisseria gonorrhoeae isolates including fluoroquinolone-resistant strains.

    PubMed

    Jones, Ronald N; Critchley, Ian A; Whittington, William L H; Janjic, Nebojsa; Pottumarthy, Sudha

    2005-12-01

    We evaluated the anti-gonococcal potency of faropenem along with 7 comparator reference antimicrobials against a preselected collection of clinical isolates. The 265 isolates were inclusive of 2 subsets: 1) 76 well-characterized resistant phenotypes of gonococcal strains (53 quinolone-resistant strains--31 with documented quinolone resistance-determining region changes from Japan, 15 strains resistant to penicillin and tetracycline, and 8 strains with intermediate susceptibility to penicillin) and 2) 189 recent isolates from clinical specimens in 2004 from 6 states across the United States where quinolone resistance is prevalent. Activity of faropenem was adversely affected by l-cysteine hydrochloride in IsoVitaleX (4-fold increase in [minimal inhibitory concentration] MIC50; 0.06 versus 0.25 microg/mL). The rank order of potency of the antimicrobials for the entire collection was ceftriaxone (MIC90, 0.06 microg/mL) > faropenem (0.25 microg/mL) > azithromycin (0.5 microg/mL) > cefuroxime (1 microg/mL) > tetracycline (2 microg/mL) > penicillin = ciprofloxacin = levofloxacin (4 microg/mL). Using MIC90 for comparison, faropenem was 4-fold more potent than cefuroxime (0.25 versus 1 microg/mL), but was 4-fold less active than ceftriaxone (0.25 versus 0.06 microg/mL). Although the activity of faropenem was not affected by either penicillinase production (MIC90, 0.12 microg/mL, penicillinase-positive) or increasing ciprofloxacin MIC (0.25 microg/mL, ciprofloxacin-resistant), increasing penicillin MIC was associated with an increase in MIC90 values (0.016 microg/mL for penicillin-susceptible to 0.25 microg/mL for penicillin-resistant strains). Among the recent (2004) clinical gonococcal isolates tested, reduced susceptibility to penicillins, tetracycline, and fluoroquinolones was high (28.0-94.2%). Geographic distribution of the endemic resistance rates of gonococci varied considerably, with 16.7-66.7% of the gonococcal isolates being ciprofloxacin-resistant in Oregon

  4. Phytophthora infestans Has a Plethora of Phospholipase D Enzymes Including a Subclass That Has Extracellular Activity

    PubMed Central

    Meijer, Harold J. G.; Hassen, Hussen Harrun; Govers, Francine

    2011-01-01

    In eukaryotes phospholipase D (PLD) is involved in many cellular processes. Currently little is known about PLDs in oomycetes. Here we report that the oomycete plant pathogen Phytophthora infestans has a large repertoire of PLDs divided over six subfamilies: PXPH-PLD, PXTM-PLD, TM-PLD, PLD-likes, and type A and B sPLD-likes. Since the latter have signal peptides we developed a method using metabolically labelled phospholipids to monitor if P. infestans secretes PLD. In extracellular medium of ten P. infestans strains PLD activity was detected as demonstrated by the production of phosphatidic acid and the PLD specific marker phosphatidylalcohol. PMID:21423760

  5. Evaluation of school-based dental health activities including fluoride mouth-rinsing in Hiraizumi, Japan.

    PubMed

    Ohara, S; Kawaguchi, Y; Shinada, K; Sasaki, Y

    2000-06-01

    School-based dental health activities conducted in Hiraizumi over the past 20 years have remarkably improved the dental health status of schoolchildren. For example, DMFT index of 12-year-old children decreased to 1.5 in 1998, one-half that of the national average. School dental health activities, which were focused on dental health education, resulted in an increase of filled teeth rates, a decrease in the number of missing teeth, and a decline in incisor caries (1979-1986). In addition, the introduction of a school-based fluoride mouth-rinsing program (1986 - ) showed a positive effect on the prevention of dental caries; a significant decrease was observed in the overall prevalence of dental caries, particularly in the molars. In Japan it seems advantageous to promote the dental health of schoolchildren by school-based programs that combine dental health examination, dental health education and fluoride mouth-rinsing program. Especially, to prevent dental caries in the mandibular first molars more effectively, it is recommended to start fluoride mouth-rinsing at age 5. PMID:12160185

  6. A Methodology for Post Operational Clean Out of a Highly Active Facility Including Solids Behaviour - 12386

    SciTech Connect

    Edmondson, Michael J.; Ward, Tracy R.; Maxwell, Lisa J.

    2012-07-01

    The Highly Active Liquor Evaporation and Storage (HALES) plant at Sellafield handles acidic fission product containing liquor with typical activities of the order of 18x10{sup 9} Bq/ml. A strategy experimental feedback approach has been used to establish a wash regime for the Post Operational Clean Out (POCO) of the oldest storage tanks for this liquor. Two different wash reagents have been identified as being potentially suitable for removal of acid insoluble fission product precipitates. Ammonium carbamate and sodium carbonate yield similar products during the proposed wash cycle. The proposed wash reagents provide dissolution of caesium phosphomolybdate (CPM) and zirconium molybdate (ZM) solid phases but yields a fine, mobile precipitate of metal carbonates from the Highly Active Liquor (HAL) supernate. Addition of nitric acid to the wash effluent can cause CPM to precipitate where there is sufficient caesium and phosphorous available. Where they are not present (from ZM dissolution) the nitric acid addition initially produces a nitrate precipitate which then re-dissolves, along with the metal carbonates, to give a solid-free solution. The different behaviour of the two solids during the wash cycle has led to the proposal for an amended flowsheet. Additional studies on the potential to change the morphology of crystallising ZM have presented opportunities for changing the rheology of ZM sediments through doping with tellurium or particular organic acids. Two different wash reagents have been identified as being potentially suitable for the POCO of HALES Oldside HASTs. AC and SC both yield similar products during the proposed wash cycle. However, the different behaviour of the two principle HAL solids, CPM and ZM, during the wash cycle has led to the proposal for an amended flowsheet. Additional studies on the potential to change the morphology of crystallising ZM have presented opportunities for changing its rheology through doping with tellurium or certain

  7. Steady-state analysis of activated sludge processes with a settler model including sludge compression.

    PubMed

    Diehl, S; Zambrano, J; Carlsson, B

    2016-01-01

    A reduced model of a completely stirred-tank bioreactor coupled to a settling tank with recycle is analyzed in its steady states. In the reactor, the concentrations of one dominant particulate biomass and one soluble substrate component are modelled. While the biomass decay rate is assumed to be constant, growth kinetics can depend on both substrate and biomass concentrations, and optionally model substrate inhibition. Compressive and hindered settling phenomena are included using the Bürger-Diehl settler model, which consists of a partial differential equation. Steady-state solutions of this partial differential equation are obtained from an ordinary differential equation, making steady-state analysis of the entire plant difficult. A key result showing that the ordinary differential equation can be replaced with an approximate algebraic equation simplifies model analysis. This algebraic equation takes the location of the sludge-blanket during normal operation into account, allowing for the limiting flux capacity caused by compressive settling to easily be included in the steady-state mass balance equations for the entire plant system. This novel approach grants the possibility of more realistic solutions than other previously published reduced models, comprised of yet simpler settler assumptions. The steady-state concentrations, solids residence time, and the wastage flow ratio are functions of the recycle ratio. Solutions are shown for various growth kinetics; with different values of biomass decay rate, influent volumetric flow, and substrate concentration. PMID:26476681

  8. Nuclear Rocket Test Facility Decommissioning Including Controlled Explosive Demolition of a Neutron-Activated Shield Wall

    SciTech Connect

    Michael Kruzic

    2007-09-01

    Located in Area 25 of the Nevada Test Site, the Test Cell A Facility was used in the 1960s for the testing of nuclear rocket engines, as part of the Nuclear Rocket Development Program. The facility was decontaminated and decommissioned (D&D) in 2005 using the Streamlined Approach For Environmental Restoration (SAFER) process, under the Federal Facilities Agreement and Consent Order (FFACO). Utilities and process piping were verified void of contents, hazardous materials were removed, concrete with removable contamination decontaminated, large sections mechanically demolished, and the remaining five-foot, five-inch thick radiologically-activated reinforced concrete shield wall demolished using open-air controlled explosive demolition (CED). CED of the shield wall was closely monitored and resulted in no radiological exposure or atmospheric release.

  9. Quasielastic neutron scattering experiments including activation energies and mathematical modeling of methyl halide dynamics

    NASA Astrophysics Data System (ADS)

    Kirstein, O.; Prager, M.; Grimm, H.; Buchsteiner, A.; Wischnewski, A.

    2007-09-01

    Quasielastic neutron scattering experiments were carried out using the multichopper time-of-flight spectrometer V3 at the Hahn-Meitner Institut, Germany and the backscattering spectrometer at Forschungszentrum Jülich, Germany. Activation energies for CH3X, X =F, Cl, Br, and I, were obtained. In combination with results from previous inelastic neutron scattering experiments the data were taken to describe the dynamics of the halides in terms of two different models, the single particle model and the coupling model. Coupled motions of methyl groups seem to explain the dynamics of the methyl fluoride and chloride; however, the coupling vanishes with the increase of the mass of the halide atom in CH3Br and CH3I.

  10. LIPID PEROXIDATION GENERATES BIOLOGICALLY ACTIVE PHOSPHOLIPIDS INCLUDING OXIDATIVELY N-MODIFIED PHOSPHOLIPIDS

    PubMed Central

    Davies, Sean S.; Guo, Lilu

    2014-01-01

    Peroxidation of membranes and lipoproteins converts “inert” phospholipids into a plethora of oxidatively modified phospholipids (oxPL) that can act as signaling molecules. In this review, we will discuss four major classes of oxPL: mildly oxygenated phospholipids, phospholipids with oxidatively truncated acyl chains, phospholipids with cyclized acyl chains, and phospholipids that have been oxidatively N-modified on their headgroups by reactive lipid species. For each class of oxPL we will review the chemical mechanisms of their formation, the evidence for their formation in biological samples, the biological activities and signaling pathways associated with them, and the catabolic pathways for their elimination. We will end by briefly highlighting some of the critical questions that remain about the role of oxPL in physiology and disease. PMID:24704586

  11. Preferential binding of anti-cancer drug adriamycin to the Sp1 binding site in c-met promoter region: A spectroscopic and molecular modeling study

    NASA Astrophysics Data System (ADS)

    Singhal, Garima; Rajeswari, Moganty R.

    2009-02-01

    The c-met gene encodes a transmembrane glycoprotein receptor with tyrosine kinase activity and overexpression of MET receptor is found in a number of common human malignancies. Regulation of c-met oncogene expression in general can be controlled by several DNA binding anti-cancer drugs. Interaction of adriamycin with a short oligonucleotide (24RY), which is part of the positive regulatory element (-233 to -68) in c-met gene was studied using UV-Vis absorption and fluorescence spectroscopy, UV-thermal melting, and molecular modeling. Strong binding of adriamycin to 24RY (overall binding constant K, 1- 3 × 10 5 M -1) is thermodynamically favored and is accompanied by the following: a marked increase in the melting temperature of 24RY by +15 °C and ˜60% decrease in absorption at 480 nm, ˜80% quenching of fluorescence at 555 nm along with a blue shift of the λemimax to 522 nm of adriamycin. Present data reveals that adriamycin binds to ˜ 5 bp (GCGGG) of the Sp1 binding site in 24RY and thus competes with Sp1 binding to the promoter site which results in down-regulation of kinase. Therefore, targeting c-met is a promising approach as it is an attractive novel oncogene for cancer therapeutics.

  12. Attenuation of nucleoside and anti-cancer nucleoside analog drug uptake in prostate cancer cells by Cimicifuga racemosa extract BNO-1055.

    PubMed

    Dueregger, Andrea; Guggenberger, Fabian; Barthelmes, Jan; Stecher, Günther; Schuh, Markus; Intelmann, Daniel; Abel, Gudrun; Haunschild, Jutta; Klocker, Helmut; Ramoner, Reinhold; Sampson, Natalie

    2013-11-15

    This study aimed to investigate the mechanisms underlying the anti-proliferative effects of the ethanolic Cimicifuga racemosa extract BNO-1055 on prostate cells and evaluate its therapeutic potential. BNO-1055 dose-dependently attenuated cellular uptake and incorporation of thymidine and BrdU and significantly inhibited cell growth after long-time exposure. Similar results were obtained using saponin-enriched sub-fractions of BNO-1055. These inhibitory effects of BNO-1055 could be mimicked using pharmacological inhibitors and isoform-specific siRNAs targeting the equilibrative nucleoside transporters ENT1 and ENT2. Moreover, BNO-1055 attenuated the uptake of clinically relevant nucleoside analogs, e.g. the anti-cancer drugs gemcitabine and fludarabine. Consistent with inhibition of the salvage nucleoside uptake pathway BNO-1055 potentiated the cytotoxicity of the de novo nucleotide synthesis inhibitor 5-FU without significantly altering its uptake. Collectively, these data show for the first time that the anti-proliferative effects of BNO-1055 result from hindered nucleoside uptake due to impaired ENT activity and demonstrate the potential therapeutic use of BNO-1055 for modulation of nucleoside transport. PMID:23972793

  13. Fatty acid-releasing activities in Sinorhizobium meliloti include unusual diacylglycerol lipase.

    PubMed

    Sahonero-Canavesi, Diana X; Sohlenkamp, Christian; Sandoval-Calderón, Mario; Lamsa, Anne; Pogliano, Kit; López-Lara, Isabel M; Geiger, Otto

    2015-09-01

    Phospholipids are well known for their membrane-forming properties and thereby delimit any cell from the exterior world. In addition, membrane phospholipids can act as precursors for signals and other biomolecules during their turnover. Little is known about phospholipid signalling, turnover and remodelling in bacteria. Recently, we showed that a FadD-deficient mutant of Sinorhizobium meliloti, unable to convert free fatty acids to their coenzyme A derivatives, accumulates free fatty acids during the stationary phase of growth. Enzymatic activities responsible for the generation of these free fatty acids were unknown in rhizobia. Searching the genome of S. meliloti, we identified a potential lysophospholipase (SMc04041) and two predicted patatin-like phospholipases A (SMc00930, SMc01003). Although SMc00930 as well as SMc01003 contribute to the release of free fatty acids in S. meliloti, neither one can use phospholipids as substrates. Here we show that SMc01003 converts diacylglycerol to monoacylglycerol and a fatty acid, and that monoacylglycerol can be further degraded by SMc01003 to another fatty acid and glycerol. A SMc01003-deficient mutant of S. meliloti transiently accumulates diacylglycerol, suggesting that SMc01003 also acts as diacylglycerol lipase (DglA) in its native background. Expression of the DglA lipase in Escherichia coli causes lysis of cells in stationary phase of growth. PMID:25711932

  14. Ozone control of biological activity during Earth's history, including the KT catastrophe

    NASA Technical Reports Server (NTRS)

    Sheldon, W. R.

    1994-01-01

    There have been brief periods since the beginning of the Cambrian some 600 m.y. ago when mass extinctions destroyed a significant fraction of living species. The most widely studied of these events is the catastrophe at the KT boundary that ended the long dominance of the dinosaurs. In addition to mass extinctions, there is another profound discontinuity in the history of Earth's biota, the explosion of life at the end of the Precambrian era which is an episode that is not explained well at all. For some 3 b.y. before the Cambrian, life had been present on Earth, but maintained a low level of activity which is an aspect of the biota that is puzzling, especially during the last two-thirds of that period. During the last 2 b.y. before the Cambrian, conditions at the Earth's surface were suitable for a burgeoning of the biota, according to most criteria: the oceans neither boiled nor were fozen solid during this time, and the atmosphere contained sufficient O for the development of animals. The purpose of this paper is to suggest that mass extinctions and the lackluster behavior of the Precambrian biota share a common cause: an inadequate amount of ozone in the atmosphere.

  15. Design of a high-lift experiment in water including active flow control

    NASA Astrophysics Data System (ADS)

    Beutel, T.; Sattler, S.; El Sayed, Y.; Schwerter, M.; Zander, M.; Büttgenbach, S.; Leester-Schädel, M.; Radespiel, R.; Sinapius, M.; Wierach, P.

    2014-07-01

    This paper describes the structural design of an active flow-control experiment. The aim of the experiment is to investigate the increase in efficiency of an internally blown Coanda flap using unsteady blowing. The system uses tailor-made microelectromechanical (MEMS) pressure sensors to determine the state of the oncoming flow and an actuated lip to regulate the mass flow and velocity of a stream near a wall over the internally blown flap. Sensors and actuators are integrated into a highly loaded system that is extremely compact. The sensors are connected to a bus system that feeds the data into a real-time control system. The piezoelectric actuators using the d 33 effect at a comparable low voltage of 120 V are integrated into a lip that controls the blowout slot height. The system is designed for closed-loop control that efficiently avoids flow separation on the Coanda flap. The setup is designed for water-tunnel experiments in order to reduce the free-stream velocity and the system’s control frequency by a factor of 10 compared with that in air. This paper outlines the function and verification of the system’s main components and their development.

  16. Differences in Lifestyles Including Physical Activity According to Sexual Orientation among Korean Adolescents

    PubMed Central

    YOON, Jin-Ho; SO, Wi-Young

    2013-01-01

    Abstract Background The purpose of the present study was to examine differences in lifestyle factors such as physical activity among homosexual (gay or lesbian), bisexual, and heterosexual Korean adolescents. Methods The sample consisted of 74,186 adolescents from grades 7—12 (ages 12—18) who participated in the 8th annual Korea Youth Risk Behavior Web-based Survey in 2012. Of this sample, only 11,829 provided enough information regarding their romantic and sexual experiences to define them as gay, lesbian, bisexual, or heterosexual. From this information, males were divided into gay (n = 323), bisexual (n = 243), and heterosexual (n = 6,501) groups, and females were divided into lesbian (n = 208), bisexual (n = 113), and heterosexual (n = 4,441) groups. Differences in lifestyle factors according to sexual orientation were analyzed using one-way analysis of variance. Results Males showed significant differences by sexual orientation group in terms of frequency of smoking (P = 0.029), alcohol consumption (P < 0.001), muscular strength exercises (P = 0.020), and walking for at least 10 minutes per week (P < 0.001). Females showed significant differences by sexual orientation group in terms of frequency of smoking (P < 0.001), alcohol consumption (P < 0.001), vigorous physical exercise (P < 0.001), moderate physical exercise (P < 0.001), and muscular strength exercises (P < 0.001), as well as for self-reported mental stress (P < 0.001). Conclusion We concluded those gay and bisexual males and lesbian and bisexual females had significant lifestyle differences as compared with heterosexual adolescents. This effect was stronger for females than for males. PMID:26060636

  17. RADIO PROPERTIES OF LOW-REDSHIFT BROAD-LINE ACTIVE GALACTIC NUCLEI INCLUDING EXTENDED RADIO SOURCES

    SciTech Connect

    Rafter, Stephen E.; Crenshaw, D. Michael; Wiita, Paul J.

    2011-03-15

    We present a study of the extended radio emission in a sample of 8434 low-redshift (z < 0.35) broad-line active galactic nuclei (AGNs) from the Sloan Digital Sky Survey. To calculate the jet and lobe contributions to the total radio luminosity, we have taken the 846 radio core sources detected in our previous study of this sample and performed a systematic search in the FIRST database for extended radio emission that is likely associated with the optical counterparts. We found that 51 out of 846 radio core sources have extended emission (>4'' from the optical AGN) that is positively associated with the AGN, and we have identified an additional 12 AGNs with extended radio emission but no detectable radio core emission. Among these 63 AGNs, we found 6 giant radio galaxies, with projected emission exceeding 750 kpc in length, and several other AGNs with unusual radio morphologies also seen in higher redshift surveys. The optical spectra of many of the extended sources are similar to those of typical broad-line radio galaxy spectra, having broad H{alpha} emission lines with boxy profiles and large M{sub BH}. With extended emission taken into account, we find strong evidence for a bimodal distribution in the radio-loudness parameter R ({identical_to}{nu}{sub radio} L{sub radio}/{nu}{sub opt} L{sub opt}), where the lower radio luminosity core-only sources appear as a population separate from the extended sources, with a dividing line at log(R) {approx}1.75. This dividing line ensures that these are indeed the most radio-loud AGNs, which may have different or extreme physical conditions in their central engines when compared to the more numerous radio-quiet AGNs.

  18. 45 CFR 287.130 - Can NEW Program activities include job market assessments, job creation and economic development...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... assessments, job creation and economic development activities? 287.130 Section 287.130 Public Welfare... creation and economic development activities? (a) A Tribe may conduct job market assessments within its NEW Program. These might include the following: (1) Consultation with the Tribe's economic development...

  19. 45 CFR 287.130 - Can NEW Program activities include job market assessments, job creation and economic development...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... assessments, job creation and economic development activities? 287.130 Section 287.130 Public Welfare... creation and economic development activities? (a) A Tribe may conduct job market assessments within its NEW Program. These might include the following: (1) Consultation with the Tribe's economic development...

  20. 45 CFR 287.130 - Can NEW Program activities include job market assessments, job creation and economic development...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... assessments, job creation and economic development activities? 287.130 Section 287.130 Public Welfare... creation and economic development activities? (a) A Tribe may conduct job market assessments within its NEW Program. These might include the following: (1) Consultation with the Tribe's economic development...

  1. 45 CFR 287.130 - Can NEW Program activities include job market assessments, job creation and economic development...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... assessments, job creation and economic development activities? 287.130 Section 287.130 Public Welfare... creation and economic development activities? (a) A Tribe may conduct job market assessments within its NEW Program. These might include the following: (1) Consultation with the Tribe's economic development...

  2. 45 CFR 287.130 - Can NEW Program activities include job market assessments, job creation and economic development...

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... assessments, job creation and economic development activities? 287.130 Section 287.130 Public Welfare... creation and economic development activities? (a) A Tribe may conduct job market assessments within its NEW Program. These might include the following: (1) Consultation with the Tribe's economic development...

  3. Synthesis and biological evaluation of some novel 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazin-3(2H)-ones as anti-cancer, antimicrobial, and anti-inflammatory agents.

    PubMed

    Ahmad, Shamim; Rathish, I G; Bano, Sameena; Alam, M S; Javed, Kalim

    2010-04-01

    A series of 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazin-3(2H)-ones (2a-j) were synthesized by condensation of the appropriate beta-aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol and tested for anti-cancer, anti-inflammatory, and antimicrobial actions. According to the protocol of the National Cancer Institute (NCI) in vitro disease-oriented human cells screening panel assay, compound 2g showed high activity against HL-60 (TB) (leukemia), SR (leukemia), NCI-H522 (non-small-cell lung cancer), and BT-549 (breast cancer) with a GI(50) value of less than 2 microM. Two compounds (2c and 2f) were found to have promising anti-inflammatory activity, while a fair number of compounds showed good antifungal activity. PMID:20038271

  4. Anti-cancer drug loaded iron-gold core-shell nanoparticles (Fe@Au) for magnetic drug targeting.

    PubMed

    Kayal, Sibnath; Ramanujan, Raju Vijayaraghavan

    2010-09-01

    Magnetic drug targeting, using core-shell magnetic carrier particles loaded with anti-cancer drugs, is an emerging and significant method of cancer treatment. Gold shell-iron core nanoparticles (Fe@Au) were synthesized by the reverse micelle method with aqueous reactants, surfactant, co-surfactant and oil phase. XRD, XPS, TEM and magnetic property measurements were utilized to characterize these core-shell nanoparticles. Magnetic measurements showed that the particles were superparamagnetic at room temperature and that the saturation magnetization decreased with increasing gold concentration. The anti-cancer drug doxorubicin (DOX) was loaded onto these Fe@Au nanoparticle carriers and the drug release profiles showed that upto 25% of adsorbed drug was released in 80 h. It was found that the amine (-NH2) group of DOX binds to the gold shell. An in vitro apparatus simulating the human circulatory system was used to determine the retention of these nanoparticle carriers when exposed to an external magnetic field. A high percentage of magnetic carriers could be retained for physiologically relevant flow speeds of fluid. The present findings show that DOX loaded gold coated iron nanoparticles are promising for magnetically targeted drug delivery. PMID:21133071

  5. Nano-mechanical Phenotype as a Promising Biomarker to Evaluate Cancer Development, Progression, and Anti-cancer Drug Efficacy

    PubMed Central

    Park, Soyeun

    2016-01-01

    Since various bio-mechanical assays have been introduced for studying mechanical properties of biological samples, much progress has been made in cancer biology. It has been noted that enhanced mechanical deformability can be used as a marker for cancer diagnosis. The relation between mechanical compliances and the metastatic potential of cancer cells has been suggested to be a promising prognostic marker. Although it is yet to be conclusive about its clinical application due to the complexity in the tissue integrity, the nano-mechanical compliance of human cell samples has been evaluated by several groups as a promising marker in diagnosing cancer development and anticipating its progression. In this review, we address the mechanical properties of diverse cancer cells obtained by atomic force microscopy-based indentation experiments and reiterate prognostic relations between the nano-mechanical compliance and cancer progression. We also review the nano-mechanical responses of cancer cells to the anti-cancer drug treatment in order to interrogate a possible use of nano-mechanical compliance as a means to evaluate the effectiveness of anti-cancer drugs. PMID:27390735

  6. Technology whitespaces India should focus: a comparative anti-cancer patent rational analysis of Indian and international public funded universities.

    PubMed

    Dara, Ajay; Sangamwar, Abhay T

    2015-01-01

    The article reported an in-depth comparative technology analysis of 1708 Anti-cancer patents from top 20 international universities and leading 10 Indian public funded organization and research institutes. The study segregated pioneer universities vs. technologies used in the field of Anticancer research at a level of drug discovery, development, diagnosis and treatment, which are illustrated in the form of novel substantive patent landscape maps. The reported competitive intelligent maps identified genetics, composition and synthetic compounds as dominating technologies; followed by natural extracts, combination and drug delivery systems as upcoming technologies. The least number of patents were reported by surgical apparatus, targeted therapy and animal models. In addition, the study analysed the key technologies followed by Indian universities in comparison to the international universities, to identify the overlooked technologies by the Indian public funded institutes. In an ever changing competitive world, it is essential for every university to have their own research plan and thrust areas; but at the same time, it is equally important for any organisation to have an idea of their competitor's research plan as well. So, the article suggested Indian institutes to focus on the latest emerging Anti-cancer technology trends, which are in practice by the international universities. Concurrently, this study may be a landmark indication for Indian public funded universities and institutes, calling for a U-turn from their traditional approaches. PMID:25751276

  7. Pharmacological Modulation of Cytotoxicity and Cellular Uptake of Anti-cancer Drugs by PDE5 Inhibitors in Lung Cancer Cells

    PubMed Central

    LI, QING; SHU, YAN

    2013-01-01

    Purpose Previous research has led to the recognition of a cGMP signaling pathway governing drug transport. This study is to investigate whether inhibitors of phosphodiesterase type 5 (PDE5), which increase intracellular cGMP levels, modulate the cytotoxicity and uptake of anti-cancer drugs in cancer cells. Methods The experiments were conducted with and without PDE5 inhibitors: dipyridamole, vardenafil, and/or sildenafil. The cytotoxicity of doxorubicin, cisplatin and oxaliplatin was determined in multiple cancer cell lines derived from different tissues. The cellular uptake of structurally diverse compounds was further examined in lung cancer cells with and without various endocytotic inhibitors. The tumor accumulation and the anti-tumor effect of trastuzumab were examined in a lung cancer xenograft mouse model. Results Dipyridamole could modulate the cytotoxicity of doxorubicin, cisplatin, and oxaliplatin in cancer cells. Particularly, PDE5 inhibitors increased cellular uptake of structurally diverse compounds into lung cancer cells both in vitro and in vivo. The effect of vardenafil on drug uptake could be blocked by endocytotic inhibitors. The growth of lung cancer xenograft in nude mice was significantly suppressed by addition of vardenafil to trastuzumab treatment. Conclusion PDE5 inhibitors may increase the efficacy of anti-cancer drugs by increasing endocytosis-mediated cellular drug uptake, and thus serve as adjuvant therapy for certain cancers such as lung cancer. PMID:23884568

  8. Activity of tigecycline tested against a global collection of Enterobacteriaceae, including tetracycline-resistant isolates.

    PubMed

    Fritsche, Thomas R; Strabala, Patty A; Sader, Helio S; Dowzicky, Michael J; Jones, Ronald N

    2005-07-01

    Steadily increasing resistance among the Enterobacteriaceae to beta-lactams, fluoroquinolones, aminoglycosides, tetracyclines, and trimethoprim/sulfamethoxazole has compromised the utility of these commonly used antimicrobial classes for many community- or hospital-acquired infections. The development of tigecycline, the sentinel representative of a novel class of broad-spectrum agents (the glycylcyclines), represents an important milestone in addressing this critical need. Resistance to tigecycline might be expected to occur via the same mechanisms that produce tetracycline resistance; however, tigecycline remains stable and largely unaffected by the commonly occurring efflux and ribosomal protection resistance mechanisms. In this study, an international collection of Enterobacteriaceae (11327 isolates; 32.8% tetracycline-resistant) from global surveillance studies (2000-2004) were evaluated against tigecycline and other comparator antimicrobials. Although the most active agents were the carbapenems and aminoglycosides (97.5-99.7% susceptible), tigecycline displayed high potency (MIC50 and MIC90, 0.25 and 1 microg/mL) with 95.7% of all strains being inhibited at < or =2 microg/mL. Despite higher MIC values observed with Serratia spp. and Proteae, between 90.5% and 97.5% of isolates were inhibited by < or =4 microg/mL of tigecycline. Tetracycline-resistant populations demonstrated only modest decreases in potency to tigecycline, which appeared to be species-dependent (up to 2-fold only for Escherichia coli, Salmonella spp., Shigella spp., and Panteoa agglomerans; and up to 4-fold for Klebsiella spp., Enterobacter spp., and Citrobacter spp.). Among E. coli (263 isolates) and Klebsiella spp. (356) that meet recognized screening definitions for extended-spectrum beta-lactamase production, 100.0% and 94.4% were inhibited by tigecycline at 2 microg/mL, respectively. These findings confirm that tigecycline exhibits potency, breadth of spectrum, and stability to the

  9. Prospects in the development of natural radioprotective therapeutics with anti-cancer properties from the plants of Uttarakhand region of India.

    PubMed

    Painuli, Sakshi; Kumar, Navin

    2016-03-01

    Radioprotective agents are substances those reduce the effects of radiation in healthy tissues while maintaining the sensitivity to radiation damage in tumor cells. Due to increased awareness about radioactive substances and their fatal effects on human health, radioprotective agents are now the topic of vivid research. Scavenging of free radicals is the most common mechanism in oncogenesis that plays an important role in protecting tissues from lethal effect of radiation exposure therefore radioprotectors are also good anti-cancer agents. There are numerous studies indicating plant-based therapeutics against cancer and radioprotection. Such plants could be further explored for developing them as promising natural radioprotectors with anti-cancer properties. This review systematically presents information on plants having radioprotective and anti-cancer properties. PMID:27240731

  10. Should Physical Activity Be Included in Nutrition Education? A Comparison of Nutrition Outcomes with and without In-Class Activities

    ERIC Educational Resources Information Center

    Palmer-Keenan, Debra M.; Corda, Kirsten

    2014-01-01

    Limited-resource adults' dietary intakes and nutrition behaviors improve as a result of Expanded Food and Nutrition Education Program (EFNEP)/Supplemental Nutrition Assistance Program Education (SNAP-Ed) participation; however, physical activity education is needed for improved health. The experimental study reported here assessed if spending…

  11. Engineering of a disulfide loop instead of a Zn binding loop restores the anti-proliferative, anti-angiogenic and anti-tumor activities of the N-terminal fragment of endostatin: Mechanistic and therapeutic insights.

    PubMed

    Chamani, Reyhane; Asghari, S Mohsen; Alizadeh, Ali Mohammad; Eskandari, Sedigheh; Mansouri, Kamran; Khodarahmi, Reza; Taghdir, Majid; Heidari, Zahra; Gorji, Ali; Aliakbar, Alireza; Ranjbar, Bijan; Khajeh, Khosro

    2015-09-01

    Although considerable effort has been devoted to understanding the molecular mechanism of endostatin's anti-cancer activity, the role of its Zn bound N-terminal loop has not been completely clarified. To investigate whether Zn binding or the N-terminal loop is involved in the anti-cancer properties of endostatin, we compared the structure and biological activity of a native Zn binding endostatin peptide (ES-Zn) with three variants: a Zn free variant (ES), a variant containing both a Zn binding site and a disulfide bond (ES-SSZn), and a variant including a disulfide loop but incapable of Zn binding (ES-SS). Spectroscopic studies indicated that ES-Zn and ES-SS consist of random coil and β structures, whereas ES-SSZn and ES fold into random coils. Theoretical analysis proposed that ES-Zn and ES-SS have a similar binding site to αVβ3 integrin. The anti-proliferative activity of endostatin was retained by all peptides except ES, and the in vitro anti-angiogenic property was preserved in ES-Zn and ES-SS. Remarkably, breast tumor growth and CD31 activity were inhibited more effectively by ES-SS than by ES-Zn. Therefore, a correlation exists between the N-terminal loop and anti-cancer properties of endostatin fragment and a disulfide loop may be more promising than a Zn binding loop for inhibiting tumor growth. PMID:26187352

  12. In Vitro Characterization of the Pharmacological Properties of the Anti-Cancer Chelator, Bp4eT, and Its Phase I Metabolites

    PubMed Central

    Potůčková, Eliška; Roh, Jaroslav; Macháček, Miloslav; Sahni, Sumit; Stariat, Ján; Šesták, Vít; Jansová, Hana; Hašková, Pavlína; Jirkovská, Anna; Vávrová, Kateřina; Kovaříková, Petra; Kalinowski, Danuta S.; Richardson, Des R.; Šimůnek, Tomáš

    2015-01-01

    Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma), non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts) and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1) promote the redox cycling of iron; (2) bind and mobilize iron from labile intracellular pools; and (3) prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents. PMID:26460540

  13. Anti-Cancer Effect of Lambertianic Acid by Inhibiting the AR in LNCaP Cells

    PubMed Central

    Lee, Myoung-Sun; Lee, Seon-Ok; Kim, Sung-Hoon; Lee, Eun-Ok; Lee, Hyo-Jeong

    2016-01-01

    Lambertianic acid (LA) is known to have anti-allergic and antibacterial effects. However, the anticancer activities and mechanism of action of LA have not been investigated. Therefore, the anticancer effects and mechanism of LA are investigated in this study. LA decreased not only AR protein levels, but also cellular and secretory levels of PSA. Furthermore, LA inhibited nuclear translocation of the AR induced by mibolerone. LA suppressed cell proliferation by inducing G1 arrest, downregulating CDK4/6 and cyclin D1 and activating p53 and its downstream molecules, p21 and p27. LA induced apoptosis and the expression of related proteins, including cleaved caspase-9 and -3, c-PARP and BAX, and inhibited BCl-2. The role of AR in LA-induced apoptosis was assessed by using siRNA. Collectively, these findings suggest that LA exerts the anticancer effect by inhibiting AR and is a valuable therapeutic agent in prostate cancer treatment. PMID:27399684

  14. Current developments of coumarin-based anti-cancer agents in medicinal chemistry.

    PubMed

    Emami, Saeed; Dadashpour, Sakineh

    2015-09-18

    Cancer is one of the leading health hazards and the prominent cause of death in the world. A number of anticancer agents are currently in clinical practice and used for treatment of various kinds of cancers. There is no doubt that the existing arsenal of anticancer agents is insufficient due to the high incidence of side effects and multidrug resistance. In the efforts to develop suitable anticancer drugs, medicinal chemists have focused on coumarin derivatives. Coumarin is a naturally occurring compound and a versatile synthetic scaffold possessing wide spectrum of biological effects including potential anticancer activity. This review article covers the current developments of coumarin-based anticancer agents and also discusses the structure-activity relationship of the most potent compounds. PMID:26318068

  15. Virtual Dual inhibition of COX-2 / 5-LOX enzymes based on binding properties of alpha-amyrins, the anti-inflammatory compound as a promising anti-cancer drug.

    PubMed

    Ranjbar, Mohammad Mehdi; Assadolahi, Vahideh; Yazdani, Mohsen; Nikaein, Donya; Rashidieh, Behnam

    2016-01-01

    Hydro-alcoholic fruit extract of Cordia myxa was considerably effective on curing acute inflammation in mouse model. Previous studies suggested significant anti-inflammatory activities as well as potential anticancer agent of α-amyrins in seeds. Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX) is significant in cancer prevention and therapeutics although this inhibition with chemo-drugs has its own side-effects. It is shown that these enzymes pathways are related to several cancers including colon, breast and lung cancer. This study was conducted based on Cordia species' α-amyrins as a safer natural anti-cancer compound for inhibition of COX-2 and 5-LOX enzymes by molecular docking. The X-ray crystal structure of COX2 / 5-LOX enzymes and α-amyrins was retrieved and energetically minimized respectively. The binding site and surface of enzymes were detected. Docking studies were performed by AutoDock 4.2 using Lamarckian genetic algorithm (LGA). Finally drug likeness, molecular pharmacokinetic properties and toxicity of α-amyrins was calculated. Molecular Docking revealed hydrogen and hydrophobic interactions between α-amyrins with both active sites of COX-2 and 5-LOX enzymes. Interestingly, it covalently bonded to Fe cofactor of 5-LOX enzyme and chelated this molecule. Base on binding energies (∆G) α-amyrin has more inhibitory effects on 5-LOX (-10.45 Kcal/mol) than COX-2 (-8.02 Kcal/mol). Analysis of molecular pharmacokinetic parameters suggested that α-amyrins complied with most sets of Lipinski's rules, and so it could be a suitable ligand for docking studies. Eventually, bioactivity score showed α-amyrins possess considerable biological activities as nuclear receptor, enzyme inhibitor, GPCR and protease inhibitor ligand. These results clearly demonstrate that α-amyrins could act as potential highly selective COX-/5-LOX inhibitor. Also, it is a safe compound in comparison with classical non-steroidal anti-inflammatory drugs (NSAIDs

  16. Virtual Dual inhibition of COX-2 / 5-LOX enzymes based on binding properties of alpha-amyrins, the anti-inflammatory compound as a promising anti-cancer drug

    PubMed Central

    Ranjbar, Mohammad Mehdi; Assadolahi, Vahideh; Yazdani, Mohsen; Nikaein, Donya; Rashidieh, Behnam

    2016-01-01

    Hydro-alcoholic fruit extract of Cordia myxa was considerably effective on curing acute inflammation in mouse model. Previous studies suggested significant anti-inflammatory activities as well as potential anticancer agent of α-amyrins in seeds. Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX) is significant in cancer prevention and therapeutics although this inhibition with chemo-drugs has its own side-effects. It is shown that these enzymes pathways are related to several cancers including colon, breast and lung cancer. This study was conducted based on Cordia species' α-amyrins as a safer natural anti-cancer compound for inhibition of COX-2 and 5-LOX enzymes by molecular docking. The X-ray crystal structure of COX2 / 5-LOX enzymes and α-amyrins was retrieved and energetically minimized respectively. The binding site and surface of enzymes were detected. Docking studies were performed by AutoDock 4.2 using Lamarckian genetic algorithm (LGA). Finally drug likeness, molecular pharmacokinetic properties and toxicity of α-amyrins was calculated. Molecular Docking revealed hydrogen and hydrophobic interactions between α-amyrins with both active sites of COX-2 and 5-LOX enzymes. Interestingly, it covalently bonded to Fe cofactor of 5-LOX enzyme and chelated this molecule. Base on binding energies (∆G) α-amyrin has more inhibitory effects on 5-LOX (-10.45 Kcal/mol) than COX-2 (-8.02 Kcal/mol). Analysis of molecular pharmacokinetic parameters suggested that α-amyrins complied with most sets of Lipinski's rules, and so it could be a suitable ligand for docking studies. Eventually, bioactivity score showed α-amyrins possess considerable biological activities as nuclear receptor, enzyme inhibitor, GPCR and protease inhibitor ligand. These results clearly demonstrate that α-amyrins could act as potential highly selective COX-/5-LOX inhibitor. Also, it is a safe compound in comparison with classical non-steroidal anti-inflammatory drugs (NSAIDs

  17. Anti-cancer effect of metformin by suppressing signaling pathway of HER2 and HER3 in tamoxifen-resistant breast cancer cells.

    PubMed

    Kim, Jinkyoung; Lee, Jiyun; Kim, Chungyeul; Choi, Jinhyuk; Kim, Aeree

    2016-05-01

    Development of new therapeutic strategies is becoming increasingly important to overcome tamoxifen resistance. Recently, much interest has been focused on anti-tumor effects of metformin commonly used to treat type II diabetes. Increased protein expression and signaling of epidermal growth factor receptor (EGFR) family is a possible mechanism involved in tamoxifen resistance. Since HER2/HER3 heterodimers are able to induce strong downstream signaling and activate various biological responses such as cellular proliferation and growth, we investigated the anti-cancer effect of metformin by inhibition of signaling pathway via downregulation of HER2 and HER3 using tamoxifen-resistant MCF-7 (TR MCF-7) cells. Compared to MCF-7 cells, TR MCF-7 cells showed increased expression of EGFR, HER2, and HER3, and metformin inhibited the expression of these proteins in a dose- and time-dependent manner. Metformin inhibited activation of HER2 (Tyr1248)/HER3 (Tyr1289)/Akt (Ser473) as well as cell proliferation and colony formation by estrogenic promotion in MCF-7 and TR MCF-7 cells. Known as a HER3 ligand, heregulin (HRG)-β1-induced phosphorylation of HER2, HER3 and Akt, and protein interaction of HER2/HER3 and colony formation were inhibited by metformin in both cells. Consistent with the results in the two cell lines, we identified that metformin inhibited HER2/HER3/Akt signaling axis activated by HRG-β1 using the HER2 and HER3-overexpressing breast cancer cell line SK-BR-3. Lastly, lapatinib-induced HER3 upregulation was significantly inhibited by treatment of metformin in HER3 siRNA-transfected TR MCF-7 cells. These data suggest that metformin might overcome tamoxifen resistance through the inhibition of expression and signaling of receptor tyrosine kinase HER2 and HER3. PMID:26581908

  18. Fulvic acid promotes extracellular anti-cancer mediators from RAW 264.7 cells, causing to cancer cell death in vitro.

    PubMed

    Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Dilshara, Matharage Gayani; Kang, Chang-Hee; Lee, Seungheon; Choi, Yung Hyun; Jeong, Yong Kee; Kim, Gi-Young

    2016-07-01

    Fulvic acid (FA) is known to promote electrochemical balance as a donor or a receptor possessing many biomedical functions. Nevertheless, the effect of FA on the anti-cancer activity has not been elucidated. In the current study, we first isolated FA from humus and investigated whether FA regulates immune-stimulating functions, such as production of nitric oxide (NO), in RAW 264.7 cells. Our data showed that FA slightly enhances cell viability in a dose-dependent manner and secretion of NO from RAW 264.7 cells. It upregulated the protein and mRNA expression of inducible NO synthesis (iNOS). In addition, FA enhanced the DNA-binding activity of nuclear factor-κB (NF-κB) in RAW 264.7 cells; the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC) effectively attenuated the expression of FA-stimulated iNOS, suggesting that FA stimulates NF-κB to promote iNOS and NO production. Finally, FA-stimulated culture media (FA-CM) from RAW 264.7 cells were collected and MCA-102 fibrosarcoma cells were cultured in this media. The FA-CM augmented MCA-102 fibrosarcoma cell apoptosis; however, an NO inhibitor N(G)-monomethyl-l-arginine (NMMA) slightly inhibited the FA-CM-mediated MCA-102 fibrosarcoma cell apoptosis, which was accompanied by low levels of NO. In the present study, we found that FA induces the generation of NO and iNOS in RAW 264.7 cells by inducing NF-κB activation; however, NO did not significantly stimulate MCA-102 fibrosarcoma cell apoptosis in the current study. In addition, FA-CM enhanced cell death in various human cancer cells such as Hep3B, LNCaP, and HL60. Taken together, FA most likely stimulates immune-modulating molecules such as NO and induces cancer cell apoptosis. PMID:27177083

  19. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... other information required under 25 CFR 1000 subpart K. ... self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  20. Effects of Leisure Education Programme Including Sportive Activities on Perceived Freedom in Leisure of Adolescents with Intellectual Disabilities

    ERIC Educational Resources Information Center

    Ertuzun, Ezgi

    2015-01-01

    The objective of this experimental study is to determine the effect of leisure education programme including sportive activities on the perceived freedom in leisure of adolescents with mild intellectual disabilities. The research was designed with an experimental group (n = 37) and a control group (n = 34), and was conducted among a total of 71…

  1. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false What types of activities can a recreation, tourism, and trails program include? 170.137 Section 170.137 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and Eligibility Recreation, Tourism and Trails...

  2. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... other information required under 25 CFR 1000 subpart K. ... self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  3. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... other information required under 25 CFR 1000 subpart K. ... self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  4. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... other information required under 25 CFR 1000 subpart K. ... self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  5. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... other information required under 25 CFR 1000 subpart K. ... self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  6. Stabilization of the Nitric Oxide (NO) Prodrugs and Anti-Cancer Leads, PABA/NO and Double JS-K through Incorporation into PEG-Protected Nanoparticles

    PubMed Central

    Kumar, Varun; Hong, Sam Y.; Maciag, Anna E.; Saavedra, Joseph E.; Adamson, Douglas H.; Prud'homme, Robert K.; Keefer, Larry K.; Chakrapani, Harinath

    2009-01-01

    Here we report the stabilization of the nitric oxide (NO) prodrugs and anti-cancer lead compounds, PABA/NO (O2-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) and “Double JS-K” (1,5-bis{[1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diol-2-ato]-2,4-dinitrobenzene), through their incorporation into polymer-protected nanoparticles. The prodrugs were formulated in block copolymer-stabilized nanoparticles with sizes from 220 to 450 nm by a novel rapid precipitation process. The block copolymers, with polyethylene glycol (PEG) soluble blocks, provide a steric barrier against NO prodrug activation by glutathione. Too rapid activation and NO release has been a major barrier to effective administration of this class of compounds. The nanoparticle stabilized PABA/NO from attack by glutathione as evidenced by a significant increase in time taken for 50% decomposition from 15 min (unformulated) to 5 h (formulated); in the case of Double JS-K, the 50% decomposition time was extended from 4.5 min (unformulated) to 40 min (formulated). The more hydrophobic PABA/NO produced more stable nanoparticles and correspondingly more extended release times in comparison with Double JS-K. The hydrophobic blocks of the polymer were either polystyrene or polylactide. Both blocks produced nanoparticles of approximately the same size and release kinetics. This combination of PEG-protected nanoparticles with sizes appropriate for cancer targeting by enhanced permeation and retention (EPR) and delayed release of NO may afford enhanced therapeutic benefit. PMID:20000791

  7. Ceftaroline versus isolates from animal bite wounds: comparative in vitro activities against 243 isolates, including 156 Pasteurella species isolates.

    PubMed

    Goldstein, Ellie J C; Citron, Diane M; Merriam, C Vreni; Tyrrell, Kerin L

    2012-12-01

    More than 5 million Americans are bitten by animals, usually dogs, annually. Bite patients comprise ∼1% of all patients who visit emergency departments (300,000/year), and approximately 10,000 require hospitalization and intravenous antibiotics. Ceftaroline is the bioactive component of the prodrug ceftaroline fosamil, which is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs), including those containing methicillin-resistant Staphylococcus aureus (MRSA). There are no in vitro data about the activity of ceftaroline against Pasteurella multocida subsp. multocida and Pasteurella multocida subsp. septica, other Pasteurella spp., or other bite wound isolates. We therefore studied the in vitro activity of ceftaroline against 243 animal bite isolates. MICs were determined using the broth microdilution method according to CLSI guidelines. Comparator drugs included cefazolin, ceftriaxone, ertapenem, ampicillin-sulbactam, azithromycin, doxycycline, and sulfamethoxazole-trimethoprim (SMX-TMP). Ceftaroline was the most active agent against all 5 Pasteurella species, including P. multocida subsp. multocida and P. multocida subsp. septica, with a maximum MIC of ≤0.008 μg/ml; more active than ceftriaxone and ertapenem (MIC(90)s, ≤0.015 μg/ml); and more active than cefazolin (MIC(90), 0.5 μg/ml) doxycycline (MIC(90), 0.125 μg/ml), azithromycin (MIC(90), 0.5 μg/ml), ampicillin-sulbactam (MIC(90), 0.125 μg/ml), and SMX-TMP (MIC(90), 0.125 μg/ml). Ceftaroline was also very active against all S. aureus isolates (MIC(90), 0.125 μg/ml) and other Staphylococcus and Streptococcus species, with a maximum MIC of 0.125 μg/ml against all bite isolates tested. Ceftaroline has potential clinical utility against infections involving P. multocida, other Pasteurella species, and aerobic Gram-positive isolates, including S. aureus. PMID:23027193

  8. Ceftaroline versus Isolates from Animal Bite Wounds: Comparative In Vitro Activities against 243 Isolates, Including 156 Pasteurella Species Isolates

    PubMed Central

    Citron, Diane M.; Merriam, C. Vreni; Tyrrell, Kerin L.

    2012-01-01

    More than 5 million Americans are bitten by animals, usually dogs, annually. Bite patients comprise ∼1% of all patients who visit emergency departments (300,000/year), and approximately 10,000 require hospitalization and intravenous antibiotics. Ceftaroline is the bioactive component of the prodrug ceftaroline fosamil, which is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs), including those containing methicillin-resistant Staphylococcus aureus (MRSA). There are no in vitro data about the activity of ceftaroline against Pasteurella multocida subsp. multocida and Pasteurella multocida subsp. septica, other Pasteurella spp., or other bite wound isolates. We therefore studied the in vitro activity of ceftaroline against 243 animal bite isolates. MICs were determined using the broth microdilution method according to CLSI guidelines. Comparator drugs included cefazolin, ceftriaxone, ertapenem, ampicillin-sulbactam, azithromycin, doxycycline, and sulfamethoxazole-trimethoprim (SMX-TMP). Ceftaroline was the most active agent against all 5 Pasteurella species, including P. multocida subsp. multocida and P. multocida subsp. septica, with a maximum MIC of ≤0.008 μg/ml; more active than ceftriaxone and ertapenem (MIC90s, ≤0.015 μg/ml); and more active than cefazolin (MIC90, 0.5 μg/ml) doxycycline (MIC90, 0.125 μg/ml), azithromycin (MIC90, 0.5 μg/ml), ampicillin-sulbactam (MIC90, 0.125 μg/ml), and SMX-TMP (MIC90, 0.125 μg/ml). Ceftaroline was also very active against all S. aureus isolates (MIC90, 0.125 μg/ml) and other Staphylococcus and Streptococcus species, with a maximum MIC of 0.125 μg/ml against all bite isolates tested. Ceftaroline has potential clinical utility against infections involving P. multocida, other Pasteurella species, and aerobic Gram-positive isolates, including S. aureus. PMID:23027193

  9. Development of LSPR and SPR sensor for the detection of an anti-cancer drug for chemotherapy

    NASA Astrophysics Data System (ADS)

    Zhao, Sandy Shuo; Bolduc, Olivier R.; Colin, Damien Y.; Pelletier, Joelle N.; Masson, Jean-François

    2012-03-01

    The anti-cancer drug, methotrexate (MTX) as a strong inhibitor of human dihydrofolate reductase (hDHFR) has been studied in localized surface plasmon resonance (LSPR) and surface plasmon resonance (SPR) competitive binding assays with folic acid stabilized gold nanoparticles (FA AuNP). The latter with a diameter of 15 nm were prepared in a simple step with sequential characterization using UV-Vis, FTIR, and Raman. A LSPR competitive binding assay between different concentrations of MTX and FA AuNP for hDHFR in solution was designed to quantify MTX by using UV-Vis spectroscopy. Sensitivity of the assay was optimized with respect to both concentrations of the enzyme and FA. The detection and quantification of spiked MTX was demonstrated in phosphate buffer saline and in fetal bovine serum accompanied by solid-phase extraction treatment of the serum. In addition, this assay could also provide as a screening tool for potential inhibitors of hDHFR. In another perspective, MTX was measured in a competitive binding assay with FA AuNP for histidine-tagged hDHFR immobilized on a SPR sensitive surface. In this case, FA AuNP offer a secondary amplification of the analytical response which is indirectly proportional to the concentration of MTX. This alternative approach could contribute to the realization of direct detection of MTX in complex biological fluids. A comparison of characteristics and analytical parameters such as sensitivity, dynamic range and limit of detection between the LSPR and SPR sensing platforms will also be presented. Both assays offer potential in tackling real biological samples for the purpose of monitoring and validating anti-cancer drug levels in human serum during chemotherapy.

  10. The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: Ensuing energetic and oxidative stress implications

    SciTech Connect

    Pardo-Andreu, Gilberto L.; Tudella, Valeria G.

    2011-06-15

    Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 {mu}M) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca{sup 2+} efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP{sup +} transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds. - Graphical abstract: Guttiferone-A permeabilizes mitochondrial membrane and induces cancer cell death Display Omitted Highlights: > We addressed the involvement of mitochondria in guttiferone (GA) toxicity toward cancer cells. > GA promoted membrane permeabilization, membrane potential dissipation, NAD(P)H depletion, ROS accumulation and ATP depletion. > These actions

  11. Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN-007 in Orthotopic Mouse Xenografts

    PubMed Central

    Coutinho de Souza, Patricia; Mallory, Samantha; Smith, Nataliya; Saunders, Debra; Li, Xiao-Nan; McNall-Knapp, Rene Y.; Fung, Kar-Ming; Towner, Rheal A.

    2015-01-01

    Pediatric glioblastomas (pGBM), although rare, are one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. Here, we describe the use of conventional and advanced in vivo magnetic resonance imaging (MRI) techniques to assess a novel orthotopic xenograft pGBM mouse (IC-3752GBM patient-derived culture) model, and to monitor the effects of the anti-cancer agent OKN-007 as an inhibitor of pGBM tumor growth. Immunohistochemistry support data is also presented for cell proliferation and tumor growth signaling. OKN-007 was found to significantly decrease tumor volumes (p<0.05) and increase animal survival (p<0.05) in all OKN-007-treated mice compared to untreated animals. In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05). OKN-007 also significantly reduced lipid tumor metabolism in responsive animals [(Lip1.3 and Lip0.9)-to-creatine ratio (p<0.05)], as well as significantly decrease tumor cell proliferation (p<0.05) and microvessel density (p<0.05). Furthermore, in relationship to the PDGFRα pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-α (platelet-derived growth factor receptor-α) (p<0.05) immunoexpression, and significantly increase decorin expression (p<0.05) in responsive mice. This study indicates that OKN-007 may be an effective anti-cancer agent for some patients with pGBMs by inhibiting cell proliferation and angiogenesis, possibly via the PDGFRα pathway, and could be considered as an additional therapy for pediatric brain tumor patients. PMID:26248280

  12. Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN-007 in Orthotopic Mouse Xenografts.

    PubMed

    Coutinho de Souza, Patricia; Mallory, Samantha; Smith, Nataliya; Saunders, Debra; Li, Xiao-Nan; McNall-Knapp, Rene Y; Fung, Kar-Ming; Towner, Rheal A

    2015-01-01

    Pediatric glioblastomas (pGBM), although rare, are one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. Here, we describe the use of conventional and advanced in vivo magnetic resonance imaging (MRI) techniques to assess a novel orthotopic xenograft pGBM mouse (IC-3752GBM patient-derived culture) model, and to monitor the effects of the anti-cancer agent OKN-007 as an inhibitor of pGBM tumor growth. Immunohistochemistry support data is also presented for cell proliferation and tumor growth signaling. OKN-007 was found to significantly decrease tumor volumes (p<0.05) and increase animal survival (p<0.05) in all OKN-007-treated mice compared to untreated animals. In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05). OKN-007 also significantly reduced lipid tumor metabolism in responsive animals [(Lip1.3 and Lip0.9)-to-creatine ratio (p<0.05)], as well as significantly decrease tumor cell proliferation (p<0.05) and microvessel density (p<0.05). Furthermore, in relationship to the PDGFRα pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-α (platelet-derived growth factor receptor-α) (p<0.05) immunoexpression, and significantly increase decorin expression (p<0.05) in responsive mice. This study indicates that OKN-007 may be an effective anti-cancer agent for some patients with pGBMs by inhibiting cell proliferation and angiogenesis, possibly via the PDGFRα pathway, and could be considered as an additional therapy for pediatric brain tumor patients. PMID:26248280

  13. Optimization of Aqueous Biphasic Tumor Spheroid Microtechnology for Anti-Cancer Drug Testing in 3D Culture

    PubMed Central

    Lemmo, Stephanie; Atefi, Ehsan; Luker, Gary D.; Tavana, Hossein

    2014-01-01

    Tumor spheroids are three-dimensional clusters of cancer cells that exhibit characteristics of poorly perfused tumors and hence present a relevant model for testing the efficacy of anti-cancer compounds. The use of spheroids for drug screening is hindered by technological complexities for high throughput generation of consistent size spheroids individually addressable by drug compounds. Here we present and optimize a simple spheroid technology based on the use of an aqueous two-phase system. Cancer cells confined in a drop of the denser aqueous dextran phase are robotically dispensed into a microwell containing the immersion aqueous polyethylene glycol phase. Cells remain within the drop and form a viable spheroid, without a need for any external stimuli. The size of resulting spheroids is sensitive to volume variations of dispensed drops from the air displacement pipetting head of a commercial liquid handling robot. Therefore, we parametrically optimize the process of dispensing of dextran phase drops. For a given cell density, this optimization reproducibly generates consistent size spheroids in standard 96-well plates. In addition, we evaluate the use of a commercial biochemical assay to examine cellular viability of cancer cell spheroids. Spheroids show a dose-dependent response to cisplatin similar to a monolayer culture. However unlike their two-dimensional counterpart, spheroids exhibit resistance to paclitaxel treatment. This technology, which uses only commercially-available reagents and equipment, can potentially expedite anti-cancer drug discovery. Although the use of robotics makes the ATPS spheroid technology particularly useful for drug screening applications, this approach is compatible with simpler liquid handling techniques such as manual micropipetting and offers a straightforward method of 3D cell culture in research laboratories. PMID:25221631

  14. Isolation, biology and chemistry of the disorazoles: new anti-cancer macrodiolides

    PubMed Central

    Hopkins, Chad D.; Wipf, Peter

    2009-01-01

    The disorazoles comprise a family of 29 closely related macrocyclic polyketides isolated in 1994 from the fermentation broth of the gliding myxobacterium Sorangium cellulosum. Disorazoles A1, E and C1 have shown exceptional biological activities toward inhibiting the proliferation of human cancer cell lines in picomolar and nanomolar concentrations through the disruption of microtubule polymerization. This review gives a brief introduction describing the biosynthesis and the significance of the disorazoles as a new class of microtubulin disruptors. Another portion of the review focuses on the biology of the disorazoles, specifically disorazole A1 and C1, and their antiproliferative efficacy against animal and human tumor cell lines, as well as the available SAR data. The majority of the discussion addresses synthetic efforts, including partial syntheses of various disorazoles and a summary of the total synthesis of disorazole C1. PMID:19387496

  15. Use of the Rad51 promoter for targeted anti-cancer therapy.

    PubMed

    Hine, Christopher M; Seluanov, Andrei; Gorbunova, Vera

    2008-12-30

    Rad51 protein, involved in homologous recombination, is overexpressed in a variety of tumors, and its expression is correlated with a poor prognosis. Here we propose to exploit the overexpression of Rad51 in cancer cells to design a Rad51 promoter-based anticancer therapy. On average, Rad51 mRNA and protein levels are increased in cancer cells four- and sixfold, respectively. Serendipitously, we discovered that when the Rad51 ORF is replaced with another ORF, the difference in promoter activity between normal and cancer cells increases to an average of 840-fold with a maximum difference of 12,500-fold. This dramatic difference in activity has high therapeutic potential. We demonstrate that the fusion of Rad51 promoter to diphtheria toxin A (DTA) gene kills a variety of cancer cell types, including breast cancer, fibrosarcoma, and cervical cancer cells, with minimal effect on normal breast epithelial cells and normal fibroblasts. Our results suggest that therapies based on the Rad51 promoter will be highly tumor specific and open new avenues for targeting a broad range of cancers. PMID:19106292

  16. IGF-1R as an anti-cancer target—trials and tribulations

    PubMed Central

    Chen, Helen X.; Sharon, Elad

    2013-01-01

    Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF-2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R–targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non–small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development. PMID:23601239

  17. Human Lipocalin-Type Prostaglandin D Synthase-Based Drug Delivery System for Poorly Water-Soluble Anti-Cancer Drug SN-38

    PubMed Central

    Nakatsuji, Masatoshi; Inoue, Haruka; Kohno, Masaki; Saito, Mayu; Tsuge, Syogo; Shimizu, Shota; Ishida, Atsuko; Ishibashi, Osamu; Inui, Takashi

    2015-01-01

    Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily, which is composed of secretory transporter proteins, and binds a wide variety of small hydrophobic molecules. Using this function, we have reported the feasibility of using L-PGDS as a novel drug delivery vehicle for poorly water-soluble drugs. In this study, we show the development of a drug delivery system using L-PGDS, one that enables the direct clinical use of 7-ethyl-10-hydroxy-camptothecin (SN-38), a poorly water-soluble anti-cancer drug. In the presence of 2 mM L-PGDS, the concentration of SN-38 in PBS increased 1,130-fold as compared with that in PBS. Calorimetric experiments revealed that L-PGDS bound SN-38 at a molecular ratio of 1:3 with a dissociation constant value of 60 μM. The results of an in vitro growth inhibition assay revealed that the SN-38/L-PGDS complexes showed high anti-tumor activity against 3 human cancer cell lines, i.e., Colo201, MDA-MB-231, and PC-3 with a potency similar to that of SN-38 used alone. The intravenous administration of SN-38/L-PGDS complexes to mice bearing Colo201 tumors showed a pronounced anti-tumor effect. Intestinal mucositis, which is one of the side effects of this drug, was not observed in mice administered SN-38/L-PGDS complexes. Taken together, L-PGDS enables the direct usage of SN-38 with reduced side effects. PMID:26529243

  18. Anti-cancer Effects of Novel Flavonoid Vicenin-2 as a Single Agent and in Synergistic Combination with Docetaxel in Prostate Cancer

    PubMed Central

    Nagaprashantha, Lokesh Dalasanur; Vatsyayan, Rit; Singhal, Jyotsana; Fast, Spence; Roby, Rhonda; Awasthi, Sanjay; Singhal, Sharad S.

    2011-01-01

    The present study was conducted to determine the efficacy of novel flavonoid vicenin-2 (VCN-2), an active constituent of the medicinal herb Ocimum Sanctum Linn or Tulsi, as a single agent and in combination with docetaxel (DTL) in carcinoma of prostate (CaP). VCN-2 effectively induced anti-proliferative, anti-angiogenic and pro-apoptotic effect in CaP cells (PC-3, DU-145 and LNCaP) irrespective of their androgen responsiveness or p53 status. VCN-2 inhibited EGFR/Akt/mTOR/ p70S6K pathway along with decreasing c-Myc, cyclin D1, cyclin B1, CDK4, PCNA and hTERT in vitro. VCN-2 reached a level of 2.6 ± 0.3 micromol/L in serum after oral administration in mice which reflected that VCN-2 is orally absorbed. The i.v. administration of docetaxel (DTL), current drug of choice in androgen-independent CaP, is associated with dose-limiting toxicities like febrile neutropenia which has lead to characterization of alternate routes of administration and potential combinatorial regimens. In this regard, VCN-2 in combination with DTL synergistically inhibited the growth of prostate tumors in vivo with a greater decrease in the levels of AR, pIGF1R, pAkt, PCNA, cyclin D1, Ki67, CD31, and increase in E-cadherin. VCN-2 has been investigated for radioprotection and anti-inflammatory properties. This is the first study on the anti-cancer effects of VCN-2. In conclusion, our investigations collectively provide strong evidence that VCN-2 is effective against CaP progression along with indicating that VCN-2 and DTL co-administration is more effective than either of the single agents in androgen-independent prostate cancer. PMID:21803027

  19. The Anti-cancer Drug Chlorambucil as a Substrate for the Human Polymorphic Enzyme Glutathione Transferase P1-1: Kinetic Properties and Crystallographic Characterisation of Allelic Variants

    SciTech Connect

    Parker, Lorien J.; Ciccone, Sarah; Italiano, Louis C.; Primavera, Alessandra; Oakley, Aaron J.; Morton, Craig J.; Hancock, Nancy C.; Bello, Mario Lo; Parker, Michael W.

    2008-08-04

    The commonly used anti-cancer drug chlorambucil is the primary treatment for patients with chronic lymphocytic leukaemia. Chlorambucil has been shown to be detoxified by human glutathione transferase Pi (GST P1-1), an enzyme that is often found over-expressed in cancer tissues. The allelic variants of GST P1-1 are associated with differing susceptibilities to leukaemia and differ markedly in their efficiency in catalysing glutathione (GSH) conjugation reactions. Here, we perform detailed kinetic studies of the allelic variants with the aid of three representative co-substrates. We show that the differing catalytic properties of the variants are highly substrate-dependent. We show also that all variants exhibit the same temperature stability in the range 10 C to 45 C. We have determined the crystal structures of GST P1-1 in complex with chlorambucil and its GSH conjugate for two of these allelic variants that have different residues at positions 104 and 113. Chlorambucil is found to bind in a non-productive mode to the substrate-binding site (H-site) in the absence of GSH. This result suggests that under certain stress conditions where GSH levels are low, GST P1-1 can inactivate the drug by sequestering it from the surrounding medium. However, in the presence of GSH, chlorambucil binds in the H-site in a productive mode and undergoes a conjugation reaction with GSH present in the crystal. The crystal structure of the GSH-chlorambucil complex bound to the *C variant is identical with the *A variant ruling out the hypothesis that primary structure differences between the variants cause structural changes at the active site. Finally, we show that chlorambucil is a very poor inhibitor of the enzyme in contrast to ethacrynic acid, which binds to the enzyme in a similar fashion but can act as both substrate and inhibitor.

  20. Anti-cancer effects of novel flavonoid vicenin-2 as a single agent and in synergistic combination with docetaxel in prostate cancer.

    PubMed

    Nagaprashantha, Lokesh Dalasanur; Vatsyayan, Rit; Singhal, Jyotsana; Fast, Spence; Roby, Rhonda; Awasthi, Sanjay; Singhal, Sharad S

    2011-11-01

    The present study was conducted to determine the efficacy of novel flavonoid vicenin-2 (VCN-2), an active constituent of the medicinal herb Ocimum Sanctum Linn or Tulsi, as a single agent and in combination with docetaxel (DTL) in carcinoma of prostate (CaP). VCN-2 effectively induced anti-proliferative, anti-angiogenic and pro-apoptotic effect in CaP cells (PC-3, DU-145 and LNCaP) irrespective of their androgen responsiveness or p53 status. VCN-2 inhibited EGFR/Akt/mTOR/p70S6K pathway along with decreasing c-Myc, cyclin D1, cyclin B1, CDK4, PCNA and hTERT in vitro. VCN-2 reached a level of 2.6±0.3μmol/l in serum after oral administration in mice which reflected that VCN-2 is orally absorbed. The i.v. administration of docetaxel (DTL), current drug of choice in androgen-independent CaP, is associated with dose-limiting toxicities like febrile neutropenia which has lead to characterization of alternate routes of administration and potential combinatorial regimens. In this regard, VCN-2 in combination with DTL synergistically inhibited the growth of prostate tumors in vivo with a greater decrease in the levels of AR, pIGF1R, pAkt, PCNA, cyclin D1, Ki67, CD31, and increase in E-cadherin. VCN-2 has been investigated for radioprotection and anti-inflammatory properties. This is the first study on the anti-cancer effects of VCN-2. In conclusion, our investigations collectively provide strong evidence that VCN-2 is effective against CaP progression along with indicating that VCN-2 and DTL co-administration is more effective than either of the single agents in androgen-independent prostate cancer. PMID:21803027

  1. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway

    SciTech Connect

    Jo, Miran; Park, Mi Hee; Kollipara, Pushpa Saranya; An, Byeong Jun; Song, Ho Sueb; Han, Sang Bae; Kim, Jang Heub; Song, Min Jong; Hong, Jin Tae

    2012-01-01

    We investigated whether bee venom and melittin, a major component of bee venom, inhibit cell growth through enhancement of death receptor expressions in the human ovarian cancer cells, SKOV3 and PA-1. Bee venom (1–5 μg/ml) and melittin (0.5–2 μg/ml) inhibited the growth of SKOV3 and PA-1 ovarian cancer cells by the induction of apoptotic cell death in a dose dependent manner. Consistent with apoptotic cell death, expression of death receptor (DR) 3 and DR6 was increased in both cancer cells, but expression of DR4 was increased only in PA-1 cells. Expression of DR downstream pro-apoptotic proteins including caspase-3, 8, and Bax was concomitantly increased, but the phosphorylation of JAK2 and STAT3 and the expression of Bcl-2 were inhibited by treatment with bee venom and melittin in SKOV3 and PA-1 cells. Expression of cleaved caspase-3 was increased in SKOV3, but cleaved caspase-8 was increased in PA-1 cells. Moreover, deletion of DR3, DR4, and DR6 by small interfering RNA significantly reversed bee venom and melittin-induced cell growth inhibitory effect as well as down regulation of STAT3 by bee venom and melittin in SKOV3 and PA-1 ovarian cancer cell. These results suggest that bee venom and melittin induce apoptotic cell death in ovarian cancer cells through enhancement of DR3, DR4, and DR6 expression and inhibition of STAT3 pathway. -- Highlights: ► Some studies have showed that bee venom and/or melittin have anti-cancer effects. ► We found that bee venom and melittin inhibited cell growth in ovarian cancer cells. ► Bee venom and melittin induce apoptosis in SKOV3 and PA-1.

  2. Repurposing Drugs in Oncology (ReDO)-clarithromycin as an anti-cancer agent.

    PubMed

    Van Nuffel, An Mt; Sukhatme, Vidula; Pantziarka, Pan; Meheus, Lydie; Sukhatme, Vikas P; Bouche, Gauthier

    2015-01-01

    Clarithromycin (CAM) is a well-known macrolide antibiotic available as a generic drug. CAM is traditionally used for many types of bacterial infections, treatment of Lyme disease and eradication of gastric infection with Helicobacter pylori. Extensive preclinical and clinical data demonstrate a potential role for CAM to treat various tumours in combination with conventional treatment. The mechanisms of action underlying the anti-tumour activity of CAM are multiple and include prolonged reduction of pro-inflammatory cytokines, autophagy inhibition, and anti-angiogenesis. Here, we present an overview of the current preclinical (in vitro and in vivo) and clinical evidence supporting the role of CAM in cancer. Overall these findings justify further research with CAM in many tumour types, with multiple myeloma, lymphoma, chronic myeloid leukaemia (CML), and lung cancer having the highest level of evidence. Finally, a series of proposals are being made to further investigate the use of CAM in clinical trials which offer the greatest prospect of clinical benefit to patients. PMID:25729426

  3. Repurposing Drugs in Oncology (ReDO)—clarithromycin as an anti-cancer agent

    PubMed Central

    Van Nuffel, An MT; Sukhatme, Vidula; Pantziarka, Pan; Meheus, Lydie; Sukhatme, Vikas P; Bouche, Gauthier

    2015-01-01

    Clarithromycin (CAM) is a well-known macrolide antibiotic available as a generic drug. CAM is traditionally used for many types of bacterial infections, treatment of Lyme disease and eradication of gastric infection with Helicobacter pylori. Extensive preclinical and clinical data demonstrate a potential role for CAM to treat various tumours in combination with conventional treatment. The mechanisms of action underlying the anti-tumour activity of CAM are multiple and include prolonged reduction of pro-inflammatory cytokines, autophagy inhibition, and anti-angiogenesis. Here, we present an overview of the current preclinical (in vitro and in vivo) and clinical evidence supporting the role of CAM in cancer. Overall these findings justify further research with CAM in many tumour types, with multiple myeloma, lymphoma, chronic myeloid leukaemia (CML), and lung cancer having the highest level of evidence. Finally, a series of proposals are being made to further investigate the use of CAM in clinical trials which offer the greatest prospect of clinical benefit to patients. PMID:25729426

  4. Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines: clinical results.

    PubMed

    Cluff, Christopher W

    2010-01-01

    As technological advances allow for the identification of tumor-associated antigens (TAAs) against which adaptive immune responses can be raised, efforts to develop vaccines for the treatment of cancer continue to gain momentum. Some of these vaccines target differentiation antigens that are expressed by tumors derived from one particular tissue (e. g., Melan-A/ MART-1, tyrosinase, gp 100). Some target antigens are specifically expressed in tumors of different types but not in normal tissues (e. g., MAGE-3), while other possible targets are antigens that are expressed at low level in normal tissues and are over-expressed in tumors of different types (e. g., HER2, Muc 1). Oncogenes (HER2/neu, Ras, E7 HPV 16), tumor suppressor genes (pS3) or tumor-specific post-translational modified proteins (under glycosylated Muc 1) can also be used as cancer vaccine candidates. In either case, these antigens tend to be poorly inmmunogenic by themselves and vaccines containing them generally require the inclusion of potent immunological adjuvants in order to generate robust anti-tumor immune responses in humans. Many adjuvants currently under evaluation for use in cancer vaccines activate relevant antigen presenting cells, such as dendritic cells and macrophages, via toll-like receptors (TLRs) and promote effective uptake, processing and presentation of antigen to T-cells in draining lymph nodes.Lipid A, the biologically active portion of the gram-negative bacterial cell wall constituent lipopolysaccharide (LPS), is known to possess strong immunostimulatory properties and has been evaluated for more than two decades as an adjuvant for promoting immune responses to minimally immunogenic antigens, including TAAs. The relatively recent discovery of TLRs and the identification of TLR4 as the signaling receptor for lipid A have allowed for a better understanding of how this immunostimulant functions with regard to induction of innate and adaptive immune responses.Although several lipid

  5. Aptamers as targeting delivery devices or anti-cancer drugs for fighting tumors.

    PubMed

    Scaggiante, Bruna; Dapas, Barbara; Farra, Rossella; Grassi, Mario; Pozzato, Gabriele; Giansante, Carlo; Fiotti, Nicola; Tamai, Elisa; Tonon, Federica; Grassi, Gabriele

    2013-06-01

    Aptamer researches applied to the treatment of human cancers have increased since their discovery in 1990. This is due to different factors including: 1) the technical possibility to select, by SELEX-based procedures, specific aptamers targeting virtually any given molecule, 2) the aptamer favorable bio-activity in vivo, 3) the low production costs and 4) the ease synthesis and storage for the marketing. In the field of cancer treatments, aptamers have been studied as tumor-specific agents driving drugs into cancer cells; additionally they have been used as anti-neoplastic agents, able to inhibit tumor cell growth and dissemination when administered alone or in combination with conventional anti-neoplastic drugs. Aptamers are gaining an increased interest for pharmaceutical companies and some of them are under clinical evaluation trials. In this review we update the findings about the use of aptamers as "escort" molecules able to drive drugs into the cells and as antineoplastic drugs. Current anti-neoplastic treatments suffer from the intrinsic toxicity related to the un-specific targeting of both normal and tumorigenic proliferating cells. The aptamers could be useful to improve: 1) the selective targeting of molecules essential for the viability and expansion of tumor cells and/or the selective driving of chemotherapies into tumor cells, thus resulting in higher effectiveness and lower systemic side-effects compared to conventional anti-neoplastic drugs alone and 2) to improve the therapeutic index of currently used chemotherapies. Even if some problems related to the in vivo stability and pharmacokinetic/dynamics of aptamers remain to be improved, their potential use in the treatment of different human cancers is getting closer and closer to a practical therapeutic use. PMID:23687927

  6. Improving Outcomes in Cancer Patients on Oral Anti-Cancer Medications Using a Novel Mobile Phone-Based Intervention: Study Design of a Randomized Controlled Trial

    PubMed Central

    Flanagan, Clare; Searl, Meghan; Elfiky, Aymen; Kvedar, Joseph; Jethwani, Kamal

    2014-01-01

    Background The widespread and increasing use of oral anti-cancer medications has been ushered in by a rapidly increasing understanding of cancer pathophysiology. Furthermore, their popular ease of administration and potential cost savings has highlighted their central position in the health care system as a whole. These facts have heightened appreciation of the unique challenges associated with the use of oral anti-cancer medications; especially in the long-term use of these medications and the associated side effects that may impede optimal adherence to their use. Therefore, we developed ChemOtheRapy Assistant, CORA, a personalized mobile phone–based self-management application to help cancer patients on oral anti-cancer medications. Objective Our objective is to evaluate the effect of CORA on adherence to oral anti-cancer medications and other clinically relevant outcomes in the management of patients with renal and prostate cancer. Methods The study will be implemented as a 2-parallel group randomized controlled trial in 104 patients with renal or prostate cancer on oral anti-cancer medications over a 3-month study period. The intervention group will use CORA in addition to usual care for self-management while the control group will continue care as usual. Medication adherence will be measured objectively by a Medication Event Monitoring System device and is defined as the percentage of prescribed doses taken. We will also assess the effect of the intervention on cancer-related symptoms measured by the MD Anderson Symptom Inventory and unplanned hospital utilizations. Other outcomes that will be measured at study start, midpoint, and endpoint are health-related quality of life, cancer-related fatigue, and anxiety. Group differences in medication adherence will be examined by t tests or by non-parametric Mann-Whitney tests if the data are not normally distributed. Logistic regression will be used to identify potential predictors of adherence. Results We expect

  7. Activity of Eravacycline against Enterobacteriaceae and Acinetobacter baumannii, Including Multidrug-Resistant Isolates, from New York City

    PubMed Central

    Abdallah, Marie; Olafisoye, Olawole; Cortes, Christopher; Urban, Carl; Landman, David

    2014-01-01

    Eravacycline demonstrated in vitro activity against a contemporary collection of more than 4,000 Gram-negative pathogens from New York City hospitals, with MIC50/MIC90 values, respectively, for Escherichia coli of 0.12/0.5 μg/ml, Klebsiella pneumoniae of 0.25/1 μg/ml, Enterobacter aerogenes of 0.25/1 μg/ml, Enterobacter cloacae 0.5/1 μg/ml, and Acinetobacter baumannii of 0.5/1 μg/ml. Activity was retained against multidrug-resistant isolates, including those expressing KPC and OXA carbapenemases. For A. baumannii, eravacycline MICs correlated with increased expression of the adeB gene. PMID:25534744

  8. Modified agar dilution susceptibility testing method for determining in vitro activities of antifungal agents, including azole compounds.

    PubMed Central

    Yoshida, T; Jono, K; Okonogi, K

    1997-01-01

    In vitro activities of antifungal agents, including azole compounds, against yeasts were easily determined by using RPMI-1640 agar medium and by incubating the plates in the presence of 20% CO2. The end point of inhibition was clear by this method, even in the case of azole compounds, because of the almost complete inhibition of yeast growth at high concentrations which permitted weak growth of some Candida strains by traditional methods. MICs obtained by the agar dilution method were similar to those obtained by the broth dilution method proposed by the National Committee for Clinical Laboratory Standards. PMID:9174197

  9. Increasing resource allocation and research into tobacco control activities: a comprehensive approach including primary prevention, treatment and brief intervention.

    PubMed

    Richmond, R

    1993-01-01

    The range of tobacco control activities should be viewed as essential parts of a complex multi-component puzzle. Intervention strategies designed to address tobacco control should be comprehensive and include both primary and secondary prevention activities and be multi-faceted and capable of bringing about change at both the individual and broader social and cultural levels. In this paper I argue for a mutually inclusive framework in which the various components contribute in important and different ways. I examine the prevalence of smoking and identify the high risk groups, then I examine the range of available strategies and present the evidence for their success. I discuss the primary prevention approaches such as warning labels, taxes, price increases, workplace bans, education in schools, mass media and self-help materials, as well as brief interventions and treatment strategies which are conducted at the worksite, general practice and specialized cessation clinics. The areas for future research are delineated for increased resource allocation and include: the best ways to disseminate brief interventions to smokers, methods to motivate smokers; training of health professionals to deliver brief interventions; enhancing quitting and access to existing treatment resources among specific disadvantaged minority groups, e.g. migrants, unemployed youth, the effect on smoking prevalence of warning labels on cigarette packets and price rises on cigarettes. PMID:16818330

  10. Type I interferons: ancient peptides with still under-discovered anti-cancer properties.

    PubMed

    Caraglia, Michele; Dicitore, Alessandra; Marra, Monica; Castiglioni, Sara; Persani, Luca; Sperlongano, Pasquale; Tagliaferri, Pierosandro; Abbruzzese, Alberto; Vitale, Giovanni

    2013-04-01

    Type I interferons (IFNs) represent a group of cytokines that act through a common receptor composed by two chains (IFNAR-1 and IFNAR-2). Several in vitro and in vivo studies showed a potent antitumor activity induced by these cytokines. IFN-α, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of cancer cell growth and differentiation, affecting cellular communication and signal transduction pathways. IFN-α, is currently the most used cytokine in the treatment of cancer. However, the potential anti-tumour activity of IFN-α is limited by the activation of tumour resistance mechanisms. This article reviews the current knowledge about the antitumor activity of type I IFNs, focusing on new potential strategies able to strengthen the antitumor activity of these cytokines. PMID:23016588

  11. An Antimicrobial Metabolite from Bacillus sp.: Significant Activity Against Pathogenic Bacteria Including Multidrug-Resistant Clinical Strains

    PubMed Central

    Chalasani, Ajay G.; Dhanarajan, Gunaseelan; Nema, Sushma; Sen, Ramkrishna; Roy, Utpal

    2015-01-01

    In this study, the cell free modified tryptone soya broth (pH 7.4 ± 0.2) of Bacillus subtilis URID 12.1 showed significant antimicrobial activity against multidrug-resistant strains of Staphylococcus aureus, S. epidermidis, Streptococcus pyogenes and Enterococcus faecalis. The partially purified antimicrobial molecule was found to be resistant to extremes of pH and temperatures and also to higher concentrations of trypsin and proteinase K. The antimicrobial molecule was purified by a three-step method that included reversed-phase high performance liquid chromatography (RP-HPLC). The minimum inhibitory concentration (MIC) values were determined for 14 species of bacteria using a microbroth dilution technique. The HPLC-purified fraction showed the MICs ranging from 0.5 to 16 μg/ml for methicillin and vancomycin-resistant Staphylococcus aureus (MVRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) strains. The molecular mass of the antimicrobial compound was determined to be 842.37 Da. The same antimicrobial fraction showed negligible haemolytic activity against human red blood cells even at a concentration as high as 100 μg/ml. Because of its significant antimicrobial activity at low MIC values coupled with its non-haemolytic property, it may prove to be a novel antimicrobial lead molecule. PMID:26696963

  12. Meta analysis of gene expression changes upon treatment of A549 cells with anti-cancer drugs to identify universal responses.

    PubMed

    Agrawal, Megha; Gadgil, Mugdha

    2012-11-01

    A meta-analysis of publicly available gene expression changes in A549 cells upon treatment with anti-cancer drugs is reported. To reduce false positives, both fold-change and significance level cutoffs were used. Simulated datasets and permutation analysis were used to guide choice of ratio cutoff. Of the genes identified, FDXR is the only gene differentially expressed in six of the seven drug treatments. Though FDXR has been reported to be differentially expressed upon treatment with 5-fluorouracil and its expression correlated to long term disease survival, to our knowledge this is a first study implicating a wide effect of anti-cancer drug treatment on FDXR expression. The other genes identified which are differentially expressed in four out of the seven drug treatments are CDKN1A and PARVB which are upregulated and MYC, HBP1, LDLR, SIM2, ALX1 and GPHN which are downregulated. PMID:23063289

  13. The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: ensuing energetic and oxidative stress implications.

    PubMed

    Pardo-Andreu, Gilberto L; Nuñez-Figueredo, Yanier; Tudella, Valeria G; Cuesta-Rubio, Osmany; Rodrigues, Fernando P; Pestana, Cezar R; Uyemura, Sérgio A; Leopoldino, Andreia M; Alberici, Luciane C; Curti, Carlos

    2011-06-15

    Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 μM) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca²⁺ efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP+ transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds. PMID:21549140

  14. Immunotherapy with methyl gallate, an inhibitor of Treg cell migration, enhances the anti-cancer effect of cisplatin therapy

    PubMed Central

    Kim, Hyunseong; Lee, Gihyun; Sohn, Sung-Hwa; Lee, Chanju; Kwak, Jung Won

    2016-01-01

    Foxp3+ CD25+CD4+ regulatory T (Treg) cells are crucial for the maintenance of immunological self-tolerance and are abundant in tumors. Most of these cells are chemo-attracted to tumor tissues and suppress anti-tumor responses inside the tumor. Currently, several cancer immunotherapies targeting Treg cells are being clinically tested. Cisplatin is one of the most potent chemotherapy drugs widely used for cancer treatment. While cisplatin is a powerful drug for the treatment of multiple cancers, there are obstacles that limit its use, such as renal dysfunction and the development of cisplatin-resistant cancer cells after its use. To minimize these barriers, combinatorial therapies of cisplatin with other drugs have been developed and have proven to be more effective to treat cancer. In the present study, we evaluated the eff ect of the combination therapy using methyl gallate with cisplatin in EL4 murine lymphoma bearing C57BL/6 mice. The combinatorial therapy of methyl gallate and cisplatin showed stronger anti-cancer eff ects than methyl gallate or cisplatin as single treatments. In Treg cell-depleted mice, however, the eff ect of methyl gallate vanished. It was found that methyl gallate treatment inhibited Treg cell migration into the tumor regardless of cisplatin treatment. Additionally, in both the normal and cisplatin-treated tumor-bearing mice, there was no renal toxicity attributed to methyl gallate treatment. These findings suggest that methyl gallate treatment could be useful as an adjuvant method accompanied with cisplatin therapy. PMID:27162480

  15. Surface modified multifunctional ZnFe2O4 nanoparticles for hydrophobic and hydrophilic anti-cancer drug molecule loading.

    PubMed

    Maiti, Debabrata; Saha, Arindam; Devi, Parukuttyamma Sujatha

    2016-01-21

    Multifunctional ZnFe2O4 nanoparticles were successfully synthesized via thermolysis of Fe-oleate and Zn-oleate precursors. Monodisperse, single phase ZnFe2O4 nanoparticles with an average particle size of ∼22 nm, exhibiting green emission (λmax∼ 480 nm) and ferromagnetism at room temperature (saturation magnetization of 48.46 emu gm(-1)) have been formed by this novel approach. By appropriate surface functionalization, these materials have been converted into smart carriers of hydrophobic (water insoluble) drug molecule-curcumin and hydrophilic (water soluble) drug molecule-daunorubicin. The in vitro cytotoxicity of both the hydrophobic and hydrophilic drug loaded ZnFe2O4 nanoparticles was studied using the conventional MTT assay which revealed that the drug loaded nanoparticles induce significant death of the carcinoma cells (HeLa). Interestingly, this appears to be a significant development towards the capability of surface functionalized multifunctional ZnFe2O4 nanoparticles as carriers for both water soluble and insoluble drugs for anti-cancer therapy. PMID:26524183

  16. Synthesis and restriction enzyme analysis of oligodeoxyribonucleotides containing the anti-cancer drug 2',2'-difluoro-2'-deoxycytidine.

    PubMed Central

    Richardson, F C; Richardson, K K; Kroin, J S; Hertel, L W

    1992-01-01

    The anti-cancer drug 2',2'-difluoro-2'-deoxycytidine (dFdC) is internally incorporated into DNA in vitro. To determine the effects of this incorporation on DNA structure and function, the beta-cyanoethyl phosphoramidite of dFdC was synthesized and oligodeoxyribonucleotides containing dFdC were made using automated solid phase DNA synthesis techniques. Extension of the coupling time was required to achieve high coupling efficiency, suggesting a significant reduction in the rate of phosphotriester formation. Insertion of dFdC 5' into the recognition sequence of restriction enzymes HpaII and KpnI reduced the rate of cutting by 4% and 14% over 60 minutes. This reduction is similar to the effects seen with arabinofuranosylcytidine (ara-C) but small compared to the reductions caused by base analogues and phosphothioates. Insertion of dFdC into the BamHI recognition sequence, but not 5' to the cut site, did not alter the rate of cutting/recognition. The presence of a single dFdC reduced the Tm's of oligomers by 2-4 degrees C, depending on sequence and location. These results demonstrate that, once incorporated into DNA, dFdC does not greatly alter recognition between DNA and restriction enzymes; however, it does significantly alter duplex stability. Images PMID:1579470

  17. A New Approach to Reduce Toxicities and to Improve Bioavailabilities of Platinum-Containing Anti-Cancer Nanodrugs

    PubMed Central

    Liu, Li; Ye, Qing; Lu, Maggie; Lo, Ya-Chin; Hsu, Yuan-Hung; Wei, Ming-Cheng; Chen, Yu-Hsiang; Lo, Shen-Chuan; Wang, Shian-Jy; Bain, Daniel J.; Ho, Chien

    2015-01-01

    Platinum (Pt) drugs are the most potent and commonly used anti-cancer chemotherapeutics. Nanoformulation of Pt drugs has the potential to improve the delivery to tumors and reduce toxic side effects. A major challenge for translating nanodrugs to clinical settings is their rapid clearance by the reticuloendothelial system (RES), hence increasing toxicities on off-target organs and reducing efficacy. We are reporting that an FDA approved parenteral nutrition source, Intralipid 20%, can help this problem. A dichloro (1, 2-diaminocyclohexane) platinum (II)-loaded and hyaluronic acid polymer-coated nanoparticle (DACHPt/HANP) is used in this study. A single dose of Intralipid (2 g/kg, clinical dosage) is administrated [intravenously (i. v.), clinical route] one hour before i.v. injection of DACHPt/HANP. This treatment can significantly reduce the toxicities of DACHPt/HANP in liver, spleen, and, interestingly, kidney. Intralipid can decrease Pt accumulation in the liver, spleen, and kidney by 20.4%, 42.5%, and 31.2% at 24-hr post nanodrug administration, respectively. The bioavailability of DACHPt/HANP increases by 18.7% and 9.4% during the first 5 and 24 hr, respectively. PMID:26039249

  18. A new approach to reduce toxicities and to improve bioavailabilities of platinum-containing anti-cancer nanodrugs.

    PubMed

    Liu, Li; Ye, Qing; Lu, Maggie; Lo, Ya-Chin; Hsu, Yuan-Hung; Wei, Ming-Cheng; Chen, Yu-Hsiang; Lo, Shen-Chuan; Wang, Shian-Jy; Bain, Daniel J; Ho, Chien

    2015-01-01

    Platinum (Pt) drugs are the most potent and commonly used anti-cancer chemotherapeutics. Nanoformulation of Pt drugs has the potential to improve the delivery to tumors and reduce toxic side effects. A major challenge for translating nanodrugs to clinical settings is their rapid clearance by the reticuloendothelial system (RES), hence increasing toxicities on off-target organs and reducing efficacy. We are reporting that an FDA approved parenteral nutrition source, Intralipid 20%, can help this problem. A dichloro (1, 2-diaminocyclohexane) platinum (II)-loaded and hyaluronic acid polymer-coated nanoparticle (DACHPt/HANP) is used in this study. A single dose of Intralipid (2 g/kg, clinical dosage) is administrated [intravenously (i. v.), clinical route] one hour before i.v. injection of DACHPt/HANP. This treatment can significantly reduce the toxicities of DACHPt/HANP in liver, spleen, and, interestingly, kidney. Intralipid can decrease Pt accumulation in the liver, spleen, and kidney by 20.4%, 42.5%, and 31.2% at 24-hr post nanodrug administration, respectively. The bioavailability of DACHPt/HANP increases by 18.7% and 9.4% during the first 5 and 24 hr, respectively. PMID:26039249

  19. Bridging the US and China together to conquer cancer: report of the 4th annual meeting of the US Chinese Anti-Cancer Association (USCACA)

    PubMed Central

    Yang, Wancai; Guan, Lingjie

    2012-01-01

    A global collaborative effort is pivotal to conquer cancer. Themed “Emerging role of China in global clinical development of novel anti-cancer drugs”, the US Chinese Anti-Cancer Association (USCACA) held its 4th annual meeting in Chicago on June 2, 2012, in conjunction with the American Society of Clinical Oncology (ASCO) annual meeting to further bridge the US and China together to outsmart cancer. Although a young organization, USCACA has made significant contributions to this goal in the 3 years since its inception through extensive collaboration with academic organizations, the pharmaceutical industry, and governmental agencies. USCACA has engaged various stakeholders in developing translational and personalized medical strategies to facilitate new anti-cancer drug development and clinical trials in China. USCACA has initiated and implemented the USCACA-National Foundation for Cancer Research (NFCR) scholarship to encourage overseas returnees to continue cancer research in China. USCACA announced the Hengrui-USCACA scholarship to fund clinical trial staff from China to conduct the observation of early oncologic clinical trials in the US. During the annual meeting, distinguished panelists and the audience discussed the following critical topics: (1) oncologic translational research and early development capabilities in China; (2) novel chemical entity development and partnership with Chinese companies; and (3) Chinese participation in global anti-cancer drug development. USCACA will continue to promote collaborations among cancer researchers and clinicians in the US and China by engaging in more frequent communications and joint efforts across fields, disciplines, and countries, diligently working together toward curing and eliminating cancers. PMID:22739264

  20. PITBUL: a physics-based modeling package for imaging and tracking of airborne targets for HEL applications including active illumination

    NASA Astrophysics Data System (ADS)

    Van Zandt, Noah R.; McCrae, Jack E.; Fiorino, Steven T.

    2013-05-01

    Aimpoint acquisition and maintenance is critical to high energy laser (HEL) system performance. This study demonstrates the development by the AFIT/CDE of a physics-based modeling package, PITBUL, for tracking airborne targets for HEL applications, including atmospheric and sensor effects and active illumination, which is a focus of this work. High-resolution simulated imagery of the 3D airborne target in-flight as seen from the laser position is generated using the HELSEEM model, and includes solar illumination, laser illumination, and thermal emission. Both CW and pulsed laser illumination are modeled, including the effects of illuminator scintillation, atmospheric backscatter, and speckle, which are treated at a first-principles level. Realistic vertical profiles of molecular and aerosol absorption and scattering, as well as optical turbulence, are generated using AFIT/CDE's Laser Environmental Effects Definition and Reference (LEEDR) model. The spatially and temporally varying effects of turbulence are calculated and applied via a fast-running wave optical method known as light tunneling. Sensor effects, for example blur, sampling, read-out noise, and random photon arrival, are applied to the imagery. Track algorithms, including centroid and Fitts correlation, as a part of a closed loop tracker are applied to the degraded imagery and scored, to provide an estimate of overall system performance. To gauge performance of a laser system against a UAV target, tracking results are presented as a function of signal to noise ratio. Additionally, validation efforts to date involving comparisons between simulated and experimental tracking of UAVs are presented.

  1. Anti-cancer effect of Cassia auriculata leaf extract in vitro through cell cycle arrest and induction of apoptosis in human breast and larynx cancer cell lines.

    PubMed

    Prasanna, R; Harish, C C; Pichai, R; Sakthisekaran, D; Gunasekaran, P

    2009-02-01

    The in vitro anti-cancer effect of Cassia auriculata leaf extract (CALE) was evaluated in human breast adenocarcinoma MCF-7 and human larynx carcinoma Hep-2 cell lines. CALE preferentially inhibited the growth of both the cell lines in a dose-dependent manner with IC(50) values of 400 and 500 microg for MCF-7 and Hep-2 cells, respectively. The results showed the anti-cancer action is due to nuclear fragmentation and condensation, associated with the appearance of A(0) peak in cell cycle analysis that is indicative of apoptosis. In addition, CALE treated MCF-7 and Hep-2 cells had decreased expression of anti-apoptotic Bcl-2 protein and increased expression of pro-apoptotic Bax protein, eventually leading a decrease in the Bcl-2/Bax ratio. These results demonstrated that CALE inhibits the proliferation of MCF-7 and Hep-2 cells through induction of apoptosis, making CALE a candidate as new anti-cancer drug. PMID:18996213

  2. Antimicrobial characterisation of CEM-101 activity against respiratory tract pathogens, including multidrug-resistant pneumococcal serogroup 19A isolates.

    PubMed

    Farrell, David J; Sader, Helio S; Castanheira, Mariana; Biedenbach, Douglas J; Rhomberg, Paul R; Jones, Ronald N

    2010-06-01

    CEM-101 is a novel fluorinated macrolide-ketolide with potent activity against bacterial pathogens that are susceptible or resistant to other macrolide-lincosamide-streptogramin B (MLS(B))-ketolide agents. CEM-101 is being developed for oral and parenteral use in moderate to moderately severe community-acquired bacterial pneumonia. The objective of this study was to assess the activity of CEM-101 and comparators against contemporary respiratory tract infection (RTI) isolates. A worldwide sample of organisms was used, including Streptococcus pneumoniae [n=168; 59.3% erythromycin-resistant and 18 multidrug-resistant (MDR) serogroup 19A strains], Moraxella catarrhalis (n=21; 11 beta-lactamase positive), Haemophilus influenzae (n=100; 48 beta-lactamase positive), Haemophilus parainfluenzae and Haemophilus haemolyticus (n=12), and Legionella pneumophila (n=30). Testing and interpretation were performed using reference Clinical and Laboratory Standards Institute methods. CEM-101 was very potent against S. pneumoniae [minimum inhibitory concentration for 90% of the organisms (MIC90)=0.25 mg/L; highest MIC at 0.5 mg/L] and was 2- and > or =32-fold more active than telithromycin and clindamycin, respectively. CEM-101 also demonstrated potent activity against S. pneumoniae MDR-19A strains (MIC90=0.5 mg/L). CEM-101 was the most potent antimicrobial agent tested against L. pneumophila, with all MIC values at < or = 0.015 mg/L (telithromycin MIC90=0.03 mg/L). CEM-101 was as potent as azithromycin against Haemophilus spp. RTI pathogens (MIC90=2 mg/L), with no variations for beta-lactamase production. CEM-101 MIC values against M. catarrhalis were all at < or =0.5mg/L. Interestingly, CEM-101 potency was ca. 6 log(2) dilutions greater than telithromycin MIC results among 44 beta-haemolytic streptococci having telithromycin MICs > or = 2 mg/L. CEM-101 exhibited the greatest potency and widest spectrum of activity against RTI pathogens among the tested MLS(B)-ketolide agents

  3. Anti-cancer effects of celecoxib on nasopharyngeal carcinoma HNE-1 cells expressing COX-2 oncoprotein

    PubMed Central

    Chen, Jiongyu; Ran, Yonggang; Hong, Chaoqun; Chen, Zhijian

    2010-01-01

    Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor with antitumor and antiangiogenic activities. To investigate the effects of celecoxib on nasopharyngeal carcinoma (NPC), HNE-1 cells were treated with celecoxib at various concentrations. MTT assay, migration assay and invasion assay were performed to observe the inhibitory activity of celecoxib on HNE-1 cells. Additionally, VEGF-A expression and radiation survival of NPC cell were also examined after treatment with celecoxib. Celecoxib treatment presented an anti-proliferation function in a time and dose-dependent manner on HNE-1 cells which highly express COX-2 protein. Celecoxib also displayed an obvious inhibitory activity on invasive capacity of NPC cells. Moreover, the celecoxib’s effects to suppress VEGF-A expression and enhance radiosensitivity were detected in HNE-1 cells. These findings implicate that application of celecoxib may be an effective strategy for NPC therapy. PMID:20809260

  4. Bio-assay Guided Isolation of Anti-cancer Compounds from Anthocephalus cadamba Bark.

    PubMed

    Kumar, Deepak; Tejaswi, Chilukuri; Rasamalla, Saiprasanna; Mallick, Sumana; Pala, Bikas C

    2015-08-01

    Anthocephalus cadamba, an important plant in the traditional system of medicine in India, is reported to possess anticancer activity. Guided by bio-assay tests using human colorectal (HCT116) and hepatocellular carcinoma (HepG2) cell lines, it has been shown to contain three active constituents, the triterpenoid saponins 3-O-[α-L-rhamnopyranosyl]-quinovic acid (1) and 3-O-[α-L-rhamnopyranosyl]-quinovic acid 28-O-[β-D-glucopyranosyl] ester (2), and the alkaloid cadambine (3). The structures of the isolated compounds were established using spectroscopic techniques. The isolated compounds demonstrated concentration dependent inhibition of both the cell lines, where compound 3 proved to be the most potent inhibitor of cell line HCT116 (IC50 45 +/- 4 μg/mL) and compound 2 demonstrated maximum inhibitory activity against HepG2 cell line with an IC50 value of 89 +/- 7 μg/mL. PMID:26434112

  5. Anti-Cancer Effect of Thiacremonone through Down Regulation of Peroxiredoxin 6

    PubMed Central

    Park, Kyung-Ran; Park, Mi Hee; Lee, Dong Hun; Cho, Seung Hee; Yoo, Hwan-Soo; Lee, Yong-Moon; Jeong, Heon Sang; Kim, Youngsoo; Jung, Jae Kyung; Hwang, Bang Yeon; Lee, Mi Kyeong; Kim, Nam Doo; Han, Sang Bae; Hong, Jin Tae

    2014-01-01

    Thiacremonone (2, 4-dihydroxy-2, 5-dimethyl-thiophene-3-one) is an antioxidant substance as a novel sulfur compound generated from High-Temperature-High-Pressure-treated garlic. Peroxiredoxin 6 (PRDX6) is a member of peroxidases, and has glutathione peroxidase and calcium-independent phospholipase A2 (iPLA2) activities. Several studies have demonstrated that PRDX6 stimulates lung cancer cell growth via an increase of glutathione peroxidase activity. A docking model study and pull down assay showed that thiacremonone completely fits on the active site (cys-47) of glutathione peroxidase of PRDX6 and interacts with PRDX6. Thus, we investigated whether thiacremonone inhibits cell growth by blocking glutathione peroxidase of PRDX6 in the human lung cancer cells, A549 and NCI-H460. Thiacremonone (0–50 μg/ml) inhibited lung cancer cell growth in a concentration dependent manner through induction of apoptotic cell death accompanied by induction of cleaved caspase-3, -8, -9, Bax, p21 and p53, but decrease of xIAP, cIAP and Bcl2 expression. Thiacremonone further inhibited glutathione peroxidase activity in lung cancer cells. However, the cell growth inhibitory effect of thiacremonone was not observed in the lung cancer cells transfected with mutant PRDX6 (C47S) and in the presence of dithiothreitol and glutathione. In an allograft in vivo model, thiacremonone (30 mg/kg) also inhibited tumor growth accompanied with the reduction of PRDX6 expression and glutathione peroxidase activity, but increased expression of cleaved caspase-3, -8, -9, Bax, p21 and p53. These data indicate that thiacremonone inhibits tumor growth via inhibition of glutathione peroxidase activity of PRDX6 through interaction. These data suggest that thiacremonone may have potentially beneficial effects in lung cancer. PMID:24618722

  6. Selective inhibitors of nuclear export (SINE)--a novel class of anti-cancer agents.

    PubMed

    Parikh, Kaushal; Cang, Shundong; Sekhri, Arunabh; Liu, Delong

    2014-01-01

    Dysregulation of the nucleo-cytoplasmic transport of proteins plays an important role in carcinogenesis. The nuclear export of proteins depends on the activity of transport proteins, exportins. Exportins belong to the karyopherin β superfamily. Exportin-1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), mediates transport of around 220 proteins. In this review, we summarized the development of a new class of antitumor drugs, collectively known as selective inhibitors of nuclear export (SINE). KPT-330 (selinexor) as an oral agent is showing activities in early clinical trials in both solid tumors and hematological malignancies. PMID:25316614

  7. [The action of decorin in anti-fibrosis and anti-cancer].

    PubMed

    Ma, Weifeng; Tan, Yi; Cai, Shaohui; Chen, Hongyuan; Du, Jun; Cai, Shaoxi

    2007-02-01

    Decorin (DCN) is a member of the small leucine-rich proteoglycan gene family. Many studies indicated that DCN inhibited fibrosis and scar-formation by neutralization of TGF-P and interfering the binding of TGF-beta with its receptor, which induced ectopic deposition of extracellular matrix. Additionally, DCN can prevent the proliferation and metastasis of tumor cells by activating EGFR/MAPK/p21 signal pathway and inhibiting the cell proliferation pathway mediated by EGF-EGFR. It is suggested that the recombinant DCN had potential pharmaceutical potency in treatment of chronic fibrosis and neoplasm for its critical biological activities and low immunogenicity. PMID:17333927

  8. Recent progress in the identification of BRAF inhibitors as anti-cancer agents.

    PubMed

    El-Nassan, Hala Bakr

    2014-01-24

    The "RAS/BRAF/MEK/ERK" pathway has been associated with human cancers due to the frequent oncogenic mutations identified in its members. In particular, BRAF is mutated at high frequency in many cancers especially melanoma. This mutation leads to activation of the MAPK signaling pathway, inducing uncontrolled cell proliferation, and facilitating malignant transformation. All these facts make BRAF an ideal target for antitumor therapeutic development. Many BRAF inhibitors have been discovered during the last decade and most of them exhibit potent antitumor activity especially on tumors that harbor BRAF(V600E) mutations. Some of these compounds have entered clinical trials and displayed encouraged results. The present review highlights the progress in identification and development of BRAF inhibitors especially during the last five years. PMID:24424304

  9. Novel hederagenin-triazolyl derivatives as potential anti-cancer agents.

    PubMed

    Rodríguez-Hernández, Diego; Demuner, Antonio J; Barbosa, Luiz C A; Heller, Lucie; Csuk, René

    2016-06-10

    A series of novel aryl-1H-1,2,3-triazol-4-yl methylester and amide derivatives of the natural product hederagenin was synthesized aiming to develop new antitumor agents, using Huisgen 1,3-dipolar cycloaddition reactions, with yields between 35% and 95%. The structures of all derivatives (2-31) were confirmed by MS, IR, (1)H NMR and (13)C NMR spectroscopic data. The cytotoxic activities of all compounds were screened against a panel of six human cancer cell lines using SRB assay. It was found that most of the compounds displayed higher levels of antitumor activities as compared to parent hederagenin. Compounds 4, 8 and 15 were the most potent against all human cancer cell lines. Furthermore, compound 11 was the most cytotoxic against cell HT29 showing EC50 = 1.6 μM and a selectivity index of 5.4. PMID:27017553

  10. Synthesis and Investigation of Novel Spiro-isoxazolines as Anti-Cancer Agents

    PubMed Central

    Das, Prasanta; Omollo, Ann O.; Sitole, Lungile J.; McClendon, Eric; Valente, Edward J.; Raucher, Drazen; Walker, Leslie R.; Hamme, Ashton T.

    2015-01-01

    A series of structurally diverse 4-bromo spiro-isoxazolines possessing a variety of aromatic and aliphatic substituents at the 3 position, were synthesized through a 1,3-dipolar cycloaddition followed by intramolecular cyclization of a pendant hydroxyl or carboxylic acid group. The biochemical antiproliferative activity was evaluated in vitro by using two breast cancer cell lines (MCF-7 and MDA-MB-231) and two prostate cancer cell lines (PC-3 and DU-145) using the MTT viability assay, and the IC50 values were obtained. Spiro-isoxazoline derivatives bearing a p-chloro or an o-dichloro aromatic substituent at the 3-position of the isoxazoline showed considerable antitumor activities in all four cell lines with IC50 value ranging from 43μM to 56μM. PMID:25821250

  11. Dendritic Cells in Oncolytic Virus-Based Anti-Cancer Therapy.

    PubMed

    Kim, Youra; Clements, Derek R; Sterea, Andra M; Jang, Hyun Woo; Gujar, Shashi A; Lee, Patrick W K

    2015-12-01

    Dendritic cells (DCs) are specialized antigen-presenting cells that have a notable role in the initiation and regulation of innate and adaptive immune responses. In the context of cancer, appropriately activated DCs can induce anti-tumor immunity by activating innate immune cells and tumor-specific lymphocytes that target cancer cells. However, the tumor microenvironment (TME) imposes different mechanisms that facilitate the impairment of DC functions, such as inefficient antigen presentation or polarization into immunosuppressive DCs. These tumor-associated DCs thus fail to initiate tumor-specific immunity, and indirectly support tumor progression. Hence, there is increasing interest in identifying interventions that can overturn DC impairment within the TME. Many reports thus far have studied oncolytic viruses (OVs), viruses that preferentially target and kill cancer cells, for their capacity to enhance DC-mediated anti-tumor effects. Herein, we describe the general characteristics of DCs, focusing on their role in innate and adaptive immunity in the context of the TME. We also examine how DC-OV interaction affects DC recruitment, OV delivery, and anti-tumor immunity activation. Understanding these roles of DCs in the TME and OV infection is critical in devising strategies to further harness the anti-tumor effects of both DCs and OVs, ultimately enhancing the efficacy of OV-based oncotherapy. PMID:26690204

  12. Synthesis and evaluation of polymeric gold glyco-conjugates as anti-cancer agents.

    PubMed

    Ahmed, Marya; Mamba, Saul; Yang, Xiao-Hong; Darkwa, James; Kumar, Piyush; Narain, Ravin

    2013-06-19

    The antitumor activity of organo-gold compounds is a focus of research from the past two decades. A variety of gold stabilizing ligands such as vitamins and xanthanes have been prepared and explored for their 'chelating effect' as well as for their antitumor activity. Dithiocarbamates (DTC) compounds and their metallic conjugates have been well explored for their antiproliferative activities. In this study, glycopolymer based DTC-conjugates are prepared by reversible addition-fragmentation chain transfer polymerization (RAFT) and subsequently modified with gold(I) phosphine. These polymer-DTC derivatives and their gold compounds are tested for their in vitro toxicity in both normal and cancer cell lines. The Au(I) phosphine conjugated cationic glycopolymers of 10 kDa and 30 kDa are evaluated for their cytotoxicity profiles using MTT assay. Au(I) compounds are well-known for their mitochondrial toxicity, hence hypoxic cell lines bearing unusually enlarged mitochondria are subjected to these anticancer compounds. It is concluded that these polymeric DTC derivatives and their gold conjugates indeed show higher accumulation as well as cytotoxicity to cancer cells under hypoxic conditions in comparison to the normoxic ones. Hypoxic MCF-7 cells showed significant sensitivity toward the low molecular weight (10 kDa) glycopolymer-Au(I) complexes. PMID:23631753

  13. Dendritic Cells in Oncolytic Virus-Based Anti-Cancer Therapy

    PubMed Central

    Kim, Youra; Clements, Derek R.; Sterea, Andra M.; Jang, Hyun Woo; Gujar, Shashi A.; Lee, Patrick W. K.

    2015-01-01

    Dendritic cells (DCs) are specialized antigen-presenting cells that have a notable role in the initiation and regulation of innate and adaptive immune responses. In the context of cancer, appropriately activated DCs can induce anti-tumor immunity by activating innate immune cells and tumor-specific lymphocytes that target cancer cells. However, the tumor microenvironment (TME) imposes different mechanisms that facilitate the impairment of DC functions, such as inefficient antigen presentation or polarization into immunosuppressive DCs. These tumor-associated DCs thus fail to initiate tumor-specific immunity, and indirectly support tumor progression. Hence, there is increasing interest in identifying interventions that can overturn DC impairment within the TME. Many reports thus far have studied oncolytic viruses (OVs), viruses that preferentially target and kill cancer cells, for their capacity to enhance DC-mediated anti-tumor effects. Herein, we describe the general characteristics of DCs, focusing on their role in innate and adaptive immunity in the context of the TME. We also examine how DC-OV interaction affects DC recruitment, OV delivery, and anti-tumor immunity activation. Understanding these roles of DCs in the TME and OV infection is critical in devising strategies to further harness the anti-tumor effects of both DCs and OVs, ultimately enhancing the efficacy of OV-based oncotherapy. PMID:26690204

  14. Fluorescence studies of anti-cancer drugs--analytical and biomedical applications.

    PubMed

    Aaron, Jean-Jacques; Trajkovska, Snezana

    2006-09-01

    The fluorescence properties of anticancer drugs (ACDs), including steady-state native fluorescence, time-resolved fluorescence, fluorescence polarization, excimer and exciplex emission, laser-induced fluorescence (LIF) with one- or two-photon excitation are reviewed, as well as the use of fluorogenic labels and fluorescent probes for the non-fluorescent ACDs. The interest of monitoring the fluorescence spectral changes to study the interactions of ACDs with biomolecules, such as DNA, proteins, vesicles, and the formation of complexes is discussed. The fluorescence methodologies used for ACDs studies, including fluorescence with two-photon excitation, liquid chromatography and capillary electrophoresis with fluorescence and laser-induced fluorescence (LIF) detection, and fluorescence microscopy, are also surveyed. Analytical and bioanalytical applications of fluorescence, indicating good selectivity and very low limits of detection at the nanomolar and picomolar level for most ACDs, are described. Biomedical and clinical applications of the fluorescence methods, mostly oriented towards the evaluation of the cytoxicity and anti-tumor potential of ACDs in single cells as well as in biological fluids, including blood, serum, plasma, cerebrospinal fluid, urine and feces, are also discussed in detail. This review is based on selected literature published in the last decade (1994-2003). PMID:17017886

  15. Selecte