Science.gov

Sample records for anticancer agent podophyllotoxin

  1. Synthesis and biological evaluation of a novel artesunate-podophyllotoxin conjugate as anticancer agent.

    PubMed

    Zhang, Lei; Chen, Fan; Zhang, Zeguo; Chen, Yongzheng; Wang, Jing

    2016-01-01

    A novel conjugate of artesunate-podophyllotoxin was prepared and evaluated for its cytotoxicity against diverse normal and multidrug resistance human cancer cell lines by CCK-8 assay. The conjugate exhibited good cytotoxicity on all the cell lines with IC50 values of 0.453±0.156-3.011±0.272?M and reduced the resistant factor. The conjugate was further found to disrupt the microtubule network and induce G2/M cell cycle arrest in multidrug resistance K562/ADR cells. Meanwhile, Hoechst staining analysis suggested that conjugate induced cell death by apoptosis. Furthermore, conjugate could downregulate the levels of P-glycoprotein (P-gp) in P-gp overexpressing K562/ADR cells. PMID:26615886

  2. Podophyllotoxin.

    PubMed

    Canel, C; Moraes, R M; Dayan, F E; Ferreira, D

    2000-05-01

    Podophyllin, an ethanolic extract of Podophyllum peltatum L. or P. emodi Wall (syn. P. hexandnum Royle), is a good source of the aryltetralin-type lignan, podophyllotoxin. The latter compound, as well as its congeners and derivatives exhibit pronounced biological activity mainly as strong antiviral agents and as antineoplastic drugs. The podophyllotoxin derivatives etoposide, etopophos (etoposide phosphate), and teniposide are thus successfully utilized in the treatment of a variety of malignant conditions. Continued research on the Podophyllum lignans is currently focused on structure optimization to generate derivatives with superior pharmacological profiles and broader therapeutic scope, and the development of alternative and renewable sources of podophyllotoxin. PMID:10872202

  3. The role of biotechnology in the production of the anticancer compound podophyllotoxin.

    PubMed

    Lata, Hemant; Mizuno, Cassia S; Moraes, Rita M

    2009-01-01

    Podophyllotoxin is a plant-derived compound found in Podophyllum sp. that is used to produce semi-synthetic anticancer pharmaceuticals such as etoposide, teniposide, and etoposide phosphate. This chapter describes the role of biotechnology to produce podophyllotoxin and our attempts to domesticate Podophyllum peltatum L., also known as the American mayapple. The domestication research on mayapple included surveys of the natural population, identification of high yielding genotypes, propagation, cultivation, sustainable harvest procedures and the development of protocols for in vitro germplasm bank. PMID:19521861

  4. A Synthetic Podophyllotoxin Derivative Exerts Anti-Cancer Effects by Inducing Mitotic Arrest and Pro-Apoptotic ER Stress in Lung Cancer Preclinical Models

    PubMed Central

    Chen, Jia-Yang; Tang, Yen-An; Li, Wen-Shan; Chiou, Yu-Ching; Shieh, Jiunn-Min; Wang, Yi-Ching

    2013-01-01

    Some potent chemotherapy drugs including tubulin-binding agents had been developed from nature plants, such as podophyllotoxin and paclitaxel. However, poor cytotoxic selectivity, serious side-effects, and limited effectiveness are still the major concerns in their therapeutic application. We developed a fully synthetic podophyllotoxin derivative named Ching001 and investigated its anti-tumor growth effects and mechanisms in lung cancer preclinical models. Ching001 showed a selective cytotoxicity to different lung cancer cell lines but not to normal lung cells. Ching001 inhibited the polymerization of microtubule resulting in mitotic arrest as evident by the accumulation of mitosis-related proteins, survivin and aurora B, thereby leading to DNA damage and apoptosis. Ching001 also activated pro-apoptotic ER stress signaling pathway. Intraperitoneal injection of 2 mg/kg Ching001 significantly inhibited the tumor growth of A549 xenograft, while injection of 0.2 mg/kg Ching001 decreased the lung colonization ability of A549 cells in experimental metastasis assay. These anti-tumor growth and lung colonization inhibition effects were stronger than those of paclitaxel treatment at the same dosage. The xenograft tumor tissue stains further confirmed that Ching001 induced mitosis arrest and tumor apoptosis. In addition, the hematology and biochemistry tests of blood samples as well as tissue examinations indicated that Ching001 treatment did not show apparent organ toxicities in tested animals. We provided preclinical evidence that novel synthetic microtubule inhibitor Ching001, which can trigger DNA damage and apoptosis by inducing mitotic arrest and ER stress, is a potential anti-cancer compound for further drug development. PMID:23646116

  5. Synthesis of novel spin-labeled podophyllotoxin derivatives as potential antineoplastic agents: Part XXV

    PubMed Central

    Yang, Liu; Nan, Xiang; Li, Wen-Qun; Wang, Mei-Juan; Zhao, Xiao-Bo; Zhang, Zhi-Jun

    2015-01-01

    A series of novel spin-labeled 4?-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin derivatives (17a–h) were firstly designed and synthesized with significant regioselectivity by employing Cu(I) catalyzed click approach, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU145, KB, and KBvin). Among them, compound 17h displayed the highest cytotoxic activity against the tumor cell lines tested. Significantly, compound 17h showed superior cytotoxic activity compared with etoposide (IC50 6.30 to>10 ?M), a clinically available anticancer drug. Significant activity toward the drug resistant KBvin cell line revealed promising future for compound 17h as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidate. PMID:25709376

  6. Recent Progress on C-4-Modified Podophyllotoxin Analogs as Potent Antitumor Agents

    PubMed Central

    Liu, Ying-Qian; Tian, Jing; Qian, Keduo; Zhao, Xiao-Bo; Morris-Natschke, Susan L.; Yang, Liu; Nan, Xiang; Tian, Xuan; Lee, Kuo-Hsiung

    2015-01-01

    Podophyllotoxin (PPT), as well as its congeners and derivatives, exhibits pronounced biological activities, especially antineoplastic effects. Its strong inhibitory effect on tumor cell growth led to the development of three of the most highly prescribed anticancer drugs in the world, etoposide, teniposide, and the water-soluble prodrug etoposide phosphate. Their clinical success as well as intriguing mechanism of action stimulated great interest in further modification of PPT for better antitumor activity. The C-4 position has been a major target for structural derivatization aimed at either producing more potent compounds or overcoming drug resistance. Accordingly, numerous PPT derivatives have been prepared via hemisynthesis and important structure–activity relationship (SAR) correlations have been identified. Several resulting compounds, including GL-331, TOP-53, and NK611, reached clinical trials. Some excellent reviews on the distribution, sources, applications, synthesis, and SAR of PPT have been published. This review focuses on a second generation of new etoposide-related drugs and provides detailed coverage of the current status and recent development of C-4-modified PPT analogs as anticancer clinical trial candidates. PMID:24827545

  7. Bacteriocins as Potential Anticancer Agents

    PubMed Central

    Kaur, Sumanpreet; Kaur, Sukhraj

    2015-01-01

    Cancer remains one of the leading causes of deaths worldwide, despite advances in its treatment and detection. The conventional chemotherapeutic agents used for the treatment of cancer have non-specific toxicity toward normal body cells that cause various side effects. Secondly, cancer cells are known to develop chemotherapy resistance in due course of treatment. Thus, the demand for novel anti-cancer agents is increasing day by day. Some of the experimental studies have reported the therapeutic potential of bacteriocins against various types of cancer cell lines. Bacteriocins are ribosomally-synthesized cationic peptides secreted by almost all groups of bacteria. Some bacteriocins have shown selective cytotoxicity toward cancer cells as compared to normal cells. This makes them promising candidates for further investigation and clinical trials. In this review article, we present the overview of the various cancer cell-specific cytotoxic bacteriocins, their mode of action and efficacies. PMID:26617524

  8. Novel antibodies as anticancer agents.

    PubMed

    Zafir-Lavie, I; Michaeli, Y; Reiter, Y

    2007-05-28

    In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents. PMID:17530025

  9. Anticancer agents derived from natural cinnamic acids.

    PubMed

    Su, Ping; Shi, Yaling; Wang, Jinfeng; Shen, Xiuxiu; Zhang, Jie

    2015-01-01

    Cancer is the most dangerous disease that causes deaths all over the world. Natural products have afforded a rich source of drugs in a number of therapeutic fields including anticancer agents. Many significant drugs have been derived from natural sources by structural optimization of natural products. Cinnamic acid has gained great interest due to its antiproliferative, antioxidant, antiangiogenic and antitumorigenic potency. Currently it has been observed that cinnamic acid and its analogs such as caffeic acid, sinapic acid, ferulic acid, and isoferulic acid display various pharmacological activities, such as immunomodulation, anti-inflammation, anticancer and antioxidant. They have served to be the major sources of potential leading anticancer compounds. In this review, we focus on the anticancer potency of cinnamic acid derivatives and novel strategies to design these derivatives. We hope this review will be useful for researchers who are interested in developing anticancer agents. PMID:25634446

  10. Multicomponent assembly of 4-aza-podophyllotoxins: A fast entry to highly selective and potent anti-leukemic agents.

    PubMed

    Jeedimalla, Nagalakshmi; Flint, Madison; Smith, Lyndsay; Haces, Alberto; Minond, Dmitriy; Roche, Stéphane P

    2015-12-01

    The aim of this study was the synthesis and lead structure selection of a best anti-leukemic agent from a library of aza-podophyllotoxin analogues (APTs). To this end, we report a scalable, modified multicomponent reaction using a "sacrificial" aniline partner as a more general route to rapidly construct the pivotal library of 50 APT analogues. Our preliminary structure activity relationship studies for anti-leukemic activity also address the innate toxicity of these compounds against non-malignant cells. As a result, we identified 2 novel compounds 2ca' and 2jc' more potent than etoposide 1 (25-60 fold) having high selectivity against the human THP-1 leukemia cell line and a minimal toxicity (IC50 of 9.3 ± 0.8 and 19.6 ± 1.4 nM respectively) which represent the best candidates for further pharmacological optimization. PMID:26547055

  11. Podophyllotoxin and essential oil profile of Juniperus and related species

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Podophyllotoxin is currently in high demand as the lead chemical precursor for the anti-cancer drugs etoposide and teniposide. The primary species in commercial bulk isolation of podophyllotoxin is an endangered medicinal plant gathered in the wild in the Himalayan region. Because of the threats t...

  12. Development of anticancer agents: wizardry with osmium.

    PubMed

    Hanif, Muhammad; Babak, Maria V; Hartinger, Christian G

    2014-10-01

    Platinum compounds are one of the pillars of modern cancer chemotherapy. The apparent disadvantages of existing chemotherapeutics have led to the development of novel anticancer agents with alternative modes of action. Many complexes of the heavy metal osmium (Os) are potent growth inhibitors of human cancer cells and are active in vivo, often superior or comparable to cisplatin, as the benchmark metal-based anticancer agent, or clinically tested ruthenium (Ru) drug candidates. Depending on the choice of ligand system, osmium compounds exhibit diverse modes of action, including redox activation, DNA targeting or inhibition of protein kinases. In this review, we highlight recent advances in the development of osmium anticancer drug candidates and discuss their cellular mechanisms of action. PMID:24955838

  13. Advances in cobalt complexes as anticancer agents.

    PubMed

    Munteanu, Catherine R; Suntharalingam, Kogularamanan

    2015-08-21

    The evolution of resistance to traditional platinum-based anticancer drugs has compelled researchers to investigate the cytostatic properties of alternative transition metal-based compounds. The anticancer potential of cobalt complexes has been extensively studied over the last three decades, and much time has been devoted to understanding their mechanisms of action. This perspective catalogues the development of antiproliferative cobalt complexes, and provides an in depth analysis of their mode of action. Early studies on simple cobalt coordination complexes, Schiff base complexes, and cobalt-carbonyl clusters will be documented. The physiologically relevant redox properties of cobalt will be highlighted and the role this plays in the preparation of hypoxia selective prodrugs and imaging agents will be discussed. The use of cobalt-containing cobalamin as a cancer specific delivery agent for cytotoxins will also be described. The work summarised in this perspective shows that the biochemical and biophysical properties of cobalt-containing compounds can be fine-tuned to produce new generations of anticancer agents with clinically relevant efficacies. PMID:26148776

  14. Evaluation of Podophyllum peltatum accessions for podophyllotoxin production.

    PubMed

    Moraes, Rita M; Bedir, Ebru; Barrett, Holly; Burandt, Charles; Canel, Camilo; Khan, Ikhlas A

    2002-04-01

    In an effort to develop a sustainable source of podophyllotoxin for the production of anticancer drugs such as etoposide, teniposide and etopophos, Podophyllum peltatum accessions with podophyllotoxin-rich leaf biomass were identified and transplanted to different growing conditions by vegetative cuttings. Results indicate that the lignan profile in leaves does not change over time or due to environment conditions. Podophyllotoxin and alpha-peltatin content in the blades seems to be stable with an inverse relationship of concentration between these compounds. A podophyllotoxin-rich leaf accession showed low biosynthetic capability to synthesize alpha- and beta-peltatin and the converse was also true, indicating that selection and cultivation of high-yielding podophyllotoxin leaf biomass may reduce production costs. PMID:11988859

  15. Oral anticancer agent medication adherence by outpatients.

    PubMed

    Kimura, Michio; Usami, Eiseki; Iwai, Mina; Nakao, Toshiya; Yoshimura, Tomoaki; Mori, Hiromi; Sugiyama, Tadashi; Teramachi, Hitomi

    2014-11-01

    In the present study, medication adherence and factors affecting adherence were examined in patients taking oral anticancer agents. In June 2013, 172 outpatients who had been prescribed oral anticancer agents by Ogaki Municipal Hospital (Ogaki, Gifu, Japan) completed a questionnaire survey, with answers rated on a five-point Likert scale. The factors that affect medication adherence were evaluated using a customer satisfaction (CS) analysis. For patients with good and insufficient adherence to medication, the median ages were 66 years (range, 21-85 years) and 73 years (range, 30-90 years), respectively (P=0.0004), while the median dosing time was 131 days (range, 3-3,585 days) and 219 days (24-3,465 days), respectively (P=0.0447). In 36.0% (62 out of 172) of the cases, there was insufficient medication adherence; 64.5% of those cases (40 out of 62) showed good medication compliance (4-5 point rating score). However, these patients did not fully understand the effects or side-effects of the drugs, giving a score of three points or less. The percentage of patients with good medication compliance was 87.2% (150 out of 172). Through the CS analysis, three items, the interest in the drug, the desire to consult about the drug and the condition of the patient, were extracted as items for improvement. Overall, the medication compliance of the patients taking the oral anticancer agents was good, but the medication adherence was insufficient. To improve medication adherence, a better understanding of the effectiveness and necessity of drugs and their side-effects is required. In addition, the interest of patients in their medication should be encouraged and intervention should be tailored to the condition of the patient. These steps should lead to improved medication adherence. PMID:25295117

  16. 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

  17. Synthesis and bio-evaluation of novel quinolino-stilbene derivatives as potential anticancer agents.

    PubMed

    Srivastava, Vandana; Lee, Hoyun

    2015-12-15

    A series of 25 novel quinolino-stilbene derivatives were designed, synthesized and evaluated for their potential as anticancer agents. Three of them not only displayed quite potent antiproliferative activity with IC50 values<4?M but also showed approximately twofold selectivity against cancer cells, compared to non-cancerous cells. Three other compounds exhibited comparatively good activity with IC50 values in the range of 4-10?M, and the rest was moderately active or inactive. One of these viz. 3-[E-(4-fluorostyryl)]-2-chloroquinoline (compound 7B) caused substantial DNA damage and arrested cell cycle in S phase. Interestingly, 7B was very active against MDA-MB468 (IC50=0.12?M), but not against other cell lines examined. Compound 3-[Z-(3-(trifluoromethyl)styryl)]-2-chloroquinoline (12A), the most effective against all cancer cell lines examined, caused prolonged cell cycle arrest at mitosis and eventually apoptosis. Data from an in vitro study showed that compound 12A inhibited microtubule polymerization in a similar fashion to nocodazole. Further study using in silico molecular modeling revealed that 12A causes the impediment of microtubule polymerization by binding to tubulin at the same cavity where podophyllotoxin binds. PMID:26602827

  18. Efficient synthesis of benzamide riboside, a potential anticancer agent.

    PubMed

    Bonnac, Laurent F; Gao, Guang-Yao; Chen, Liqiang; Patterson, Steven E; Jayaram, Hiremagalur N; Pankiewicz, Krzysztof W

    2007-01-01

    An efficient five step synthesis of benzamide riboside (BR) amenable for a large scale synthesis has been developed. It allows for extensive pre-clinical studies of BR as a potential anticancer agent. PMID:18066762

  19. Determination of picropodophyllin and its isomer podophyllotoxin in human serum samples with electrospray ionization of hexylamine adducts by liquid chromatography-tandem mass spectrometry.

    PubMed

    Rönquist-Nii, Yuko; Eksborg, Staffan; Axelson, Magnus; Harmenberg, Johan; Ekman, Simon; Bergqvist, Michael; Beck, Olof

    2011-02-15

    A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of the new anticancer agent picropodophyllin (AXL1717) and its isomer podophyllotoxin levels in human serum has been developed. Monitoring of hexylamine adducts rather than proton adducts was used to optimize sensitivity. The chromatography system was an Acquity BEH C18, 2.1 mm × 50 mm 1.7 ?m column with gradient elution (mobile phase A: 2.5 mM hexylamine and 5 mM formic acid in Milli-Q water and mobile phase B: methanol). The retention times were 1.4 min for picropodophyllin, 1.5 min for podophyllotoxin and 1.9 min for internal standard deoxypodophyllotoxin. The isomers were base-line separated. The analytes were detected after electrospray ionization in positive mode with selected reaction monitoring (SRM) with ion transitions m/z 516?102 for picropodophyllin and podophyllotoxin and m/z 500?102 for internal standard. The sample preparation was protein precipitation with acetonitrile (1:3) containing internal standard followed by dilution of the supernatant with mobile phase A (1:1). The limit of quantification (LOQ) was 0.01 ?mol/L for picropodophyllin and podophyllotoxin. The limit of detection (LOD) at 3 times the signal to noise (S/N) was estimated below 0.001 ?mol/L for picropodophyllin and podophyllotoxin. The quantification range of the method was between 0.01 ?mol/L and 5 ?mol/L for both isomers. The accuracy was within ±15% of the theoretical value for both picropodophyllin and podophyllotoxin and inter-assay precision did not exceed ±15%, except for the 0.016 ?mol/L level of podophyllotoxin, which was 18%. The selectivity of the method was verified by analysis of two different product ions for each analyte and by analysis for interference of seven different batches of blank human serum. The combined recovery and matrix effects were about 83% for picropodophyllin and podophyllotoxin. The new LC-MS/MS method showed sufficient sensitivity and selectivity for determination of picropodophyllin and its isomer podophyllotoxin levels in human serum from subjects receiving therapeutic doses of AXL1717. PMID:21251888

  20. Podophyllotoxins: current status and recent developments.

    PubMed

    Damayanthi, Y; Lown, J W

    1998-06-01

    Podophyllotoxin is a natural product isolated from Podophyllum peltatum and Podophyllum emodi and has long been known to possess medicinal properties. Etoposide (VP-16), a podophyllotoxin derivative, is currently in clinical use in the treatment of many cancers, particularly small cell lung carcinoma and testicular cancer. This compound arrests cell growth by inhibiting DNA topo-isomerase II, which causes double strand breaks in DNA. VP-16 does not inhibit tubulin polymerization, however, its parent compound, podophyllotoxin, which has no inhibitory activity against DNA topoisomerase II, is a potent inhibitor of microtubule assembly. In addition to these two mechanisms of action, an unknown third mechanism of action has also been proposed for some of the recent modifications of podophyllotoxins. Owing to its severe toxic side effects a number of modifications have been done on podophyllotoxin structure. Some of the congeners exhibited potent antitumor actiivity, of which etoposide and teniposide are in clinical use, NK 611 is in phase II clinical trials and many compounds are in the same line. Recent developments on podophyllotoxins have led structure-activity correlations which have assisted in the design and synthesis of new podophyllotoxin derivatives of potential antitumor activity. Modification of the A-ring gave compounds having significant activity but less than that of etoposide, whereas modification of the B-ring resulted in the loss of activity. One of the modifications in the D-ring produced GP-11 which is almost equipotent with etoposide. E-ring oxygenation did not affect the DNA cleavage which led to the postulation of the third mechanism of action. It has also been observed that free rotation of E-ring is necessary for the antitumor activity. The C4-substituted aglycones have a significant place in these recent developments. Epipodophyllotoxin conjugates with DNA cleaving agents such as distamycin increased the number of sites of cleavage. The substitution of a glycosidic moiety with arylamines produced enhanced activity. Modification in the sugar ring resulted in the development of the agent, NK 611 which is in clinical trial at present. This article review, the progress of podophyllotoxins from its early applications in folk medicine to the most recent modifications and the mechanism(s) of action, pharmacology and the structure-activity relationships. PMID:9562603

  1. Plant Antimicrobial Peptides as Potential Anticancer Agents

    PubMed Central

    Guzmán-Rodríguez, Jaquelina Julia; López-Gómez, Rodolfo

    2015-01-01

    Antimicrobial peptides (AMPs) are part of the innate immune defense mechanism of many organisms and are promising candidates to treat infections caused by pathogenic bacteria to animals and humans. AMPs also display anticancer activities because of their ability to inactivate a wide range of cancer cells. Cancer remains a cause of high morbidity and mortality worldwide. Therefore, the development of methods for its control is desirable. Attractive alternatives include plant AMP thionins, defensins, and cyclotides, which have anticancer activities. Here, we provide an overview of plant AMPs anticancer activities, with an emphasis on their mode of action, their selectivity, and their efficacy. PMID:25815333

  2. Renal toxicity of anticancer agents targeting HER2 and EGFR.

    PubMed

    Cosmai, Laura; Gallieni, Maurizio; Porta, Camillo

    2015-12-01

    EGFR and HER2 are found overexpressed and/or activated in many different human malignancies (e.g. breast and colon cancer), and a number of drugs specifically targeting these two tyrosine kinases have been developed over the years as anticancer agents. In the present review, the renal safety profile of presently available agents targeting either HER2 or EGFR will be discussed, together with the peculiarities related to their clinical use in patients with impaired renal function, or even in dialysis. Indeed, even though renal toxicity is not so common with these agents, it may nevertheless happen, especially when these agents are combined with traditional chemotherapeutic agents. As a whole, kidney impairment or dialysis should not be regarded per se as reasons not to administer or to stop an active anti-HER or anti-EGFR anticancer treatment, especially given the possibility of significantly improving the life expectancy of many cancer patients with the use of these agents. PMID:26341657

  3. Development of anticancer agents targeting the Wnt/?-catenin signaling

    PubMed Central

    Zhang, Xiangqian; Hao, Jijun

    2015-01-01

    Wnt/?-catenin signaling plays indispensable roles in both embryonic development and adult homeostasis. Abnormal regulation of this pathway is implicated in many types of cancer. Consequently, substantial efforts have made to develop therapeutic agents as anticancer drugs by specifically targeting the Wnt/?-catenin pathway. Here we systematically review the potential therapeutic agents that have been developed to date for inhibition of the Wnt/?-catenin cascade as well as current status of clinical trials of some of these agents. PMID:26396911

  4. The use of cannabinoids as anticancer agents.

    PubMed

    Velasco, Guillermo; Hernández-Tiedra, Sonia; Dávila, David; Lorente, Mar

    2016-01-01

    It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumor growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumor angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored. In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area. PMID:26071989

  5. Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy

    PubMed Central

    CHOI, JAE YEON; HONG, WAN GI; CHO, JEONG HYUN; KIM, EUN MI; KIM, JONGDOO; JUNG, CHAN-HUN; HWANG, SANG-GU; UM, HONG-DUCK; PARK, JONG KUK

    2015-01-01

    We previously reported that podophyllotoxin acetate (PA) radiosensitizes NCI-H460 cells. Here, we confirmed that PA treatment also induces cell death among two other non-small cell lung cancer (NSCLC) cell lines: NCI-H1299 and A549 cells (IC50 values = 7.6 and 16.1 nM, respectively). Our experiments further showed that PA treatment was able to induce cell death via various mechanisms. First, PA dose-dependently induced cell cycle arrest at G2/M phase, as shown by accumulation of the mitosis-related proteins, p21, survivin and Aurora B. This G2/M phase arrest was due to the PA-induced inhibition of microtubule polymerization. Together, the decreased microtubule polymerization and increased cell cycle arrest induced DNA damage (reflected by accumulation of ?-H2AX) and triggered the induction of intrinsic and extrinsic apoptotic pathways, as shown by the time-dependent activations of caspase-3, -8 and -9. Second, PA time-dependently activated the pro-apoptotic ER stress pathway, as evidenced by increased expression levels of BiP, CHOP, IRE1-?, phospho-PERK, and phospho-JNK. Third, PA activated autophagy, as reflected by time-dependent increases in the expression levels of beclin-1, Atg3, Atg5 and Atg7, and the cleavage of LC3. Collectively, these results suggest a model wherein PA decreases microtubule polymerization and increases cell cycle arrest, thereby inducing apoptotic cell death via the activation of DNA damage, ER stress and autophagy. PMID:26314270

  6. Insight into the reactive form of the anticancer agent iproplatin.

    PubMed

    Volckova, Erika; Weaver, Evelyne; Bose, Rathindra N

    2008-05-01

    The reaction of iproplatin with reduced glutathione at different mole ratios yielded cis-di(isopropylamine)chloro-glutathionatoplatinum(II), not the expected cis-dichloro- species, indicating a mode of action of this anticancer agent that is different from that of cis-diamminedichloroplatinum(II). PMID:17707553

  7. Natural compounds as anticancer agents: Experimental evidence

    PubMed Central

    Wang, Jiao; Jiang, Yang-Fu

    2012-01-01

    Cancer prevention research has drawn much attention worldwide. It is believed that some types of cancer can be prevented by following a healthy life style. Cancer chemoprevention by either natural or synthetic agents is a promising route towards lowering cancer incidence. In recent years, the concept of cancer chemoprevention has evolved greatly. Experimental studies in animal models demonstrate that the reversal or suppression of premalignant lesions by chemopreventive agents is achievable. Natural occurring agents such as dietary phytochemicals, tea polyphenols and resveratrol show chemopreventive activity in animal models. Moreover, clinical trials for testing the safety and efficacy of a variety of natural agents in preventing or treating human malignancy have been ongoing. Here, we summarize experimental data on the chemopreventive or tumor suppressive effects of several natural compounds including curcumin, (-)-epigallocatechin-3-gallate, resveratrol, indole-3-carbinol, and vitamin D. PMID:24520533

  8. Underestimated potential of organometallic rhenium complexes as anticancer agents.

    PubMed

    Leonidova, Anna; Gasser, Gilles

    2014-10-17

    In the recent years, organometallic compounds have become recognized as promising anti-cancer drug candidates. While radioactive (186/188)Re compounds are already used in clinics for cancer treatment, cold Re organometallic compounds have mostly been explored as luminescent probes for cell imaging and photosensitizers in photocatalysis. However, a growing number of studies have recently revealed the potential of Re organometallic complexes as anti-cancer agents. Several compounds have displayed cytotoxicity equaling or exceeding that of the well-established anti-cancer drug cisplatin. In this review, we present the currently known Re organometallic complexes that have shown anti-proliferative activity on cancer cell lines. A particular emphasis is placed on their cellular uptake and localization as well as their potential mechanism of action. PMID:25137157

  9. Alkaloids Isolated from Natural Herbs as the Anticancer Agents

    PubMed Central

    Lu, Jin-Jian; Bao, Jiao-Lin; Chen, Xiu-Ping; Huang, Min; Wang, Yi-Tao

    2012-01-01

    Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation and antimetastasis effects on various types of cancers both in vitro and in vivo. Alkaloids, such as camptothecin and vinblastine, have already been successfully developed into anticancer drugs. This paper focuses on the naturally derived alkaloids with prospective anticancer properties, such as berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine, and summarizes the mechanisms of action of these compounds. Based on the information in the literature that is summarized in this paper, the use of alkaloids as anticancer agents is very promising, but more research and clinical trials are necessary before final recommendations on specific alkaloids can be made. PMID:22988474

  10. Rational Design, Synthesis, and Biological Evaluation of Third Generation ?-Noscapine Analogues as Potent Tubulin Binding Anti-Cancer Agents

    PubMed Central

    Manchukonda, Naresh Kumar; Naik, Pradeep Kumar; Santoshi, Seneha; Lopus, Manu; Joseph, Silja; Sridhar, Balasubramanian; Kantevari, Srinivas

    2013-01-01

    Systematic screening based on structural similarity of drugs such as colchicine and podophyllotoxin led to identification of noscapine, a microtubule-targeted agent that attenuates the dynamic instability of microtubules without affecting the total polymer mass of microtubules. We report a new generation of noscapine derivatives as potential tubulin binding anti-cancer agents. Molecular modeling experiments of these derivatives 5a, 6a-j yielded better docking score (-7.252 to -5.402 kCal/mol) than the parent compound, noscapine (-5.505 kCal/mol) and its existing derivatives (-5.563 to -6.412 kCal/mol). Free energy (?Gbind) calculations based on the linear interaction energy (LIE) empirical equation utilizing Surface Generalized Born (SGB) continuum solvent model predicted the tubulin-binding affinities for the derivatives 5a, 6a-j (ranging from -4.923 to -6.189 kCal/mol). Compound 6f showed highest binding affinity to tubulin (-6.189 kCal/mol). The experimental evaluation of these compounds corroborated with theoretical studies. N-(3-brormobenzyl) noscapine (6f) binds tubulin with highest binding affinity (KD, 38 ± 4.0 µM), which is ~ 4.0 times higher than that of the parent compound, noscapine (KD, 144 ± 1.0 µM) and is also more potent than that of the first generation clinical candidate EM011, 9-bromonoscapine (KD, 54 ± 9.1 µM). All these compounds exhibited substantial cytotoxicity toward cancer cells, with IC50 values ranging from 6.7 µM to 72.9 µM; compound 6f showed prominent anti-cancer efficacy with IC50 values ranging from 6.7 µM to 26.9 µM in cancer cells of different tissues of origin. These compounds perturbed DNA synthesis, delayed the cell cycle progression at G2/M phase, and induced apoptotic cell death in cancer cells. Collectively, the study reported here identified potent, third generation noscapinoids as new anti-cancer agents. PMID:24205049

  11. Rational design, synthesis, and biological evaluation of third generation ?-noscapine analogues as potent tubulin binding anti-cancer agents.

    PubMed

    Manchukonda, Naresh Kumar; Naik, Pradeep Kumar; Santoshi, Seneha; Lopus, Manu; Joseph, Silja; Sridhar, Balasubramanian; Kantevari, Srinivas

    2013-01-01

    Systematic screening based on structural similarity of drugs such as colchicine and podophyllotoxin led to identification of noscapine, a microtubule-targeted agent that attenuates the dynamic instability of microtubules without affecting the total polymer mass of microtubules. We report a new generation of noscapine derivatives as potential tubulin binding anti-cancer agents. Molecular modeling experiments of these derivatives 5a, 6a-j yielded better docking score (-7.252 to -5.402 kCal/mol) than the parent compound, noscapine (-5.505 kCal/mol) and its existing derivatives (-5.563 to -6.412 kCal/mol). Free energy (?G bind ) calculations based on the linear interaction energy (LIE) empirical equation utilizing Surface Generalized Born (SGB) continuum solvent model predicted the tubulin-binding affinities for the derivatives 5a, 6a-j (ranging from -4.923 to -6.189 kCal/mol). Compound 6f showed highest binding affinity to tubulin (-6.189 kCal/mol). The experimental evaluation of these compounds corroborated with theoretical studies. N-(3-brormobenzyl) noscapine (6f) binds tubulin with highest binding affinity (KD, 38 ± 4.0 µM), which is ~ 4.0 times higher than that of the parent compound, noscapine (KD, 144 ± 1.0 µM) and is also more potent than that of the first generation clinical candidate EM011, 9-bromonoscapine (KD, 54 ± 9.1 µM). All these compounds exhibited substantial cytotoxicity toward cancer cells, with IC50 values ranging from 6.7 µM to 72.9 µM; compound 6f showed prominent anti-cancer efficacy with IC50 values ranging from 6.7 µM to 26.9 µM in cancer cells of different tissues of origin. These compounds perturbed DNA synthesis, delayed the cell cycle progression at G2/M phase, and induced apoptotic cell death in cancer cells. Collectively, the study reported here identified potent, third generation noscapinoids as new anti-cancer agents. PMID:24205049

  12. A p53 growth arrest protects fibroblasts from anticancer agents.

    PubMed

    McCormack, E S; Bruskin, A M; Borzillo, G V

    1997-01-01

    Reversible inhibitors of the cell cycle such as the TGF-betas have been exploited to protect dividing cells from exposure to anticancer drugs and radiation. Here, rat embryo fibroblast (REF) lines expressing different p53 mutations were used to test whether the p53 growth arrest could also chemoprotect cells from high doses of anticancer drugs. Whereas the doubling times of the different REF lines at 37 degrees C were similar, cells bearing temperature-sensitive mutations (mouse 135V or human 143A) were growth arrested at 31 degrees C. Temperature-dependent p53 activity was associated with increased levels of MDM2 and p21/WAF1, and the induction of an integrated p53-responsive luciferase gene. The REF lines exhibited similar sensitivities to common anticancer drugs when grown at 37 degrees C. However, when exposed to the same agents following transient incubation at 31 degrees C, the p53-arrested cells exhibited a marked survival advantage as shown by colony-forming assays. Chemoprotection was not universal, in that colony formation was not enhanced significantly after treatment with cisplatin or 5-fluorouracil, two drugs which can cause cellular damage throughout the cell cycle. Like other negative growth regulators, an activated p53 checkpoint may mediate the survival of cells exposed to drugs that target DNA synthesis or mitosis. PMID:9351895

  13. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents.

    PubMed

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

    2015-12-14

    The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological "side" effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. PMID:26678337

  14. Anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma

    PubMed Central

    Kwak, Tae Won; Shin, Hee Jae; Jeong, Young-Il; Han, Myoung-Eun; Oh, Sae-Ock; Kim, Hyun-Jung; Kim, Do Hyung; Kang, Dae Hwan

    2015-01-01

    Background The aim of this study is to investigate the anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma. Methods The anticancer activity of streptochlorin was evaluated in vitro in various cholangiocarcinoma cell lines for apoptosis, proliferation, invasiveness, and expression of various protein levels. A liver metastasis model was prepared by splenic injection of HuCC-T1 cholangiocarcinoma cells using a BALB/c nude mouse model to study the systemic antimetastatic efficacy of streptochlorin 5 mg/kg at 8 weeks. The antitumor efficacy of subcutaneously injected streptochlorin was also assessed using a solid tumor xenograft model of SNU478 cells for 22 days in the BALB/c nude mouse. Results Streptochlorin inhibited growth and secretion of vascular endothelial growth factor by cholangiocarcinoma cells in a dose-dependent manner and induced apoptosis in vitro. In addition, streptochlorin effectively inhibited invasion and migration of cholangiocarcinoma cells. Secretion of vascular endothelial growth factor and activity of matrix metalloproteinase-9 in cholangiocarcinoma cells were also suppressed by treatment with streptochlorin. Streptochlorin effectively regulated metastasis of HuCC-T1 cells in a mouse model of liver metastasis. In a tumor xenograft study using SNU478 cells, streptochlorin significantly inhibited tumor growth without changes in body weight when compared with the control. Conclusion These results reveal that streptochlorin is a promising chemotherapeutic agent to the treatment of cholangiocarcinoma. PMID:25931814

  15. 2-Hydroxypropyl-?-Cyclodextrin Acts as a Novel Anticancer Agent

    PubMed Central

    Yokoo, Masako; Kubota, Yasushi; Motoyama, Keiichi; Higashi, Taishi; Taniyoshi, Masatoshi; Tokumaru, Hiroko; Nishiyama, Rena; Tabe, Yoko; Mochinaga, Sakiko; Sato, Akemi; Sueoka-Aragane, Naoko; Sueoka, Eisaburo; Arima, Hidetoshi; Irie, Tetsumi; Kimura, Shinya

    2015-01-01

    2-Hydroxypropyl-?-cyclodextrin (HP-?-CyD) is a cyclic oligosaccharide that is widely used as an enabling excipient in pharmaceutical formulations, but also as a cholesterol modifier. HP-?-CyD has recently been approved for the treatment of Niemann-Pick Type C disease, a lysosomal lipid storage disorder, and is used in clinical practice. Since cholesterol accumulation and/or dysregulated cholesterol metabolism has been described in various malignancies, including leukemia, we hypothesized that HP-?-CyD itself might have anticancer effects. This study provides evidence that HP-?-CyD inhibits leukemic cell proliferation at physiologically available doses. First, we identified the potency of HP-?-CyD in vitro against various leukemic cell lines derived from acute myeloid leukemia (AML), acute lymphoblastic leukemia and chronic myeloid leukemia (CML). HP-?-CyD treatment reduced intracellular cholesterol resulting in significant leukemic cell growth inhibition through G2/M cell-cycle arrest and apoptosis. Intraperitoneal injection of HP-?-CyD significantly improved survival in leukemia mouse models. Importantly, HP-?-CyD also showed anticancer effects against CML cells expressing a T315I BCR-ABL mutation (that confers resistance to most ABL tyrosine kinase inhibitors), and hypoxia-adapted CML cells that have characteristics of leukemic stem cells. In addition, colony forming ability of human primary AML and CML cells was inhibited by HP-?-CyD. Systemic administration of HP-?-CyD to mice had no significant adverse effects. These data suggest that HP-?-CyD is a promising anticancer agent regardless of disease or cellular characteristics. PMID:26535909

  16. Monofunctional and Higher-Valent Platinum Anticancer Agents

    PubMed Central

    Johnstone, Timothy C.; Wilson, Justin J.

    2013-01-01

    Platinum compounds represent one of the great success stories of metals in medicine. Following the serendipitous discovery of the anticancer activity of cisplatin by Rosenberg, a large number of cisplatin variants have been prepared and tested for their ability to kill cancer cells and inhibit tumor growth. These efforts continue today with increased realization that new strategies are needed to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents. One approach has been the use of so-called “non-traditional” platinum(II) and platinum(IV) compounds that violate the structure-activity relationships that governed platinum drug-development research for many years. Another is the use of specialized drug delivery strategies. Here we describe recent developments from our laboratory involving monofunctional platinum(II) complexes together with an historical account of the manner by which we came to investigate these compounds and their relationship to previously studied molecules. We also discuss work carried out using platinum(IV) prodrugs and the development of nanoconstructs designed to deliver them in vivo. PMID:23738524

  17. Comprehensive Review on Betulin as a Potent Anticancer Agent

    PubMed Central

    Kie?bus, Micha?; Stepulak, Andrzej

    2015-01-01

    Numerous plant-derived substances, and their derivatives, are effective antitumour and chemopreventive agents. Yet, there are also a plethora of tumour types that do not respond, or become resistant, to these natural substances. This requires the discovery of new active compounds. Betulin (BE) is a pentacyclic triterpene and secondary metabolite of plants abundantly found in the outer bark of the birch tree Betulaceae sp. BE displays a broad spectrum of biological and pharmacological properties, among which the anticancer and chemopreventive activity attract most of the attention. In this vein, BE and its natural and synthetic derivatives act specifically on cancer cells with low cytotoxicity towards normal cells. Although the antineoplastic mechanism of action of BE is not well understood yet, several interesting aspects of BE's interactions are coming to light. This review will summarize the anticancer and chemopreventive potential of BE in vitro and in vivo by carefully dissecting and comparing the doses and tumour lines used in previous studies, as well as focusing on mechanisms underlying its activity at cellular and molecular level, and discuss future prospects. PMID:25866796

  18. Dual extraction of essential oil and podophyllotoxin from creeping juniper (Juniperus horizontalis)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Juniperus horizontalis Moench (Family Cupressaceae), commonly called creeping juniper, is a widely distributed species in the United States and much of Canada. It is potentially a source for two important chemical products, the anticancer drug synthetic precursor, podophyllotoxin and essential oils....

  19. 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, ?-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

  20. Toward synthesis of third-generation spin-labeled podophyllotoxin derivatives using isocyanide multicomponent reactions

    PubMed Central

    Kou, Liang; Wang, Mei-Juan; Wang, Li-Ting; Zhao, Xiao-Bo; Nan, Xiang; Yang, Liu; Liu, Ying-Qian; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung

    2014-01-01

    Spin-labeled podophyllotoxins have elicited widespread interest due to their far superior antitumor activity compared to podophyllotoxin. To extend our prior studies in this research area, we synthesized a new generation of spin-labeled podophyllotoxin analogs via isocyanide multicomponent reactions and evaluated their cytotoxicity against four human cancer cell lines (A-549, DU-145, KB and KBvin). Most of the compounds exhibited potent cytotoxic activity against all four cell lines, notably against the drug resistant KBvin cancer cell line. Among the new analogs, compounds 12e (IC50: 0.60–0.75 µM) and 12h (IC50: 1.12–2.03 µM) showed superior potency to etoposide (IC50: 2.03 – >20 µM), a clinically available anticancer drug. With a concise efficient synthesis and potent cytotoxic profiles, compounds 12e and 12h merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates. PMID:24553146

  1. Toward synthesis of third-generation spin-labeled podophyllotoxin derivatives using isocyanide multicomponent reactions.

    PubMed

    Kou, Liang; Wang, Mei-Juan; Wang, Li-Ting; Zhao, Xiao-Bo; Nan, Xiang; Yang, Liu; Liu, Ying-Qian; Morris-Natschke, Susan L; Lee, Kuo-Hsiung

    2014-03-21

    Spin-labeled podophyllotoxins have elicited widespread interest due to their far superior antitumor activity compared to podophyllotoxin. To extend our prior studies in this research area, we synthesized a new generation of spin-labeled podophyllotoxin analogs via isocyanide multicomponent reactions and evaluated their cytotoxicity against four human cancer cell lines (A-549, DU-145, KB and KBvin). Most of the compounds exhibited potent cytotoxic activity against all four cell lines, notably against the drug resistant KBvin cancer cell line. Among the new analogs, compounds 12e (IC50: 0.60-0.75 ?M) and 12h (IC50: 1.12-2.03 ?M) showed superior potency to etoposide (IC50: 2.03 to >20 ?M), a clinically available anticancer drug. With a concise efficient synthesis and potent cytotoxic profiles, compounds 12e and 12h merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates. PMID:24553146

  2. Clinically relevant drug interactions between anticancer drugs and psychotropic agents.

    PubMed

    Yap, K Y-L; Tay, W L; Chui, W K; Chan, A

    2011-01-01

    Drug interactions are commonly seen in the treatment of cancer patients. Psychotropics are often indicated for these patients since they may also suffer from pre-existing psychological disorders or experience insomnia and anxiety associated with cancer therapy. Thus, the risk of anticancer drug (ACD)-psychotropic drug-drug interactions (DDIs) is high. Drug interactions were compiled from the British National Formulary (53rd edn), Lexi-Comp's Drug Information Handbook (15th edn), Micromedex (v5.1), Hansten & Horn's Drug Interactions (2000) and Drug Interaction Facts (2008 edn). Product information of the individual drugs, as well as documented literature on ACD-psychotropic interactions from PubMed and other databases was also incorporated. This paper identifies clinically important ACD-psychotropic DDIs that are frequently observed. Pharmacokinetic DDIs were observed for tyrosine kinase inhibitors, corticosteroids and antimicrotubule agents due to their inhibitory or inductive effects on cytochrome P450 isoenzymes. Pharmacodynamic DDIs were identified for thalidomide with central nervous system depressants, procarbazine with antidepressants, myelosuppressive ACDs with clozapine and anthracyclines with QT-prolonging psychotropics. Clinicians should be vigilant when psychotropics are prescribed concurrently with ACDs. Close monitoring of plasma drug levels should be carried out to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and psychotropic coverage. PMID:20030690

  3. Monofunctional and Higher-Valent Platinum Anticancer Agents

    E-print Network

    Wilson, Justin J.

    Platinum compounds represent one of the great success stories of metals in medicine. Following the serendipitous discovery of the anticancer activity of cisplatin by Rosenberg, a large number of cisplatin variants have ...

  4. Targeting Mitochondrial DNA with a Platinum-Based Anticancer Agent

    E-print Network

    Wisnovsky, Simon P.

    An analog of the anticancer drug cisplatin (mtPt) was delivered to mitochondria of human cells using a peptide specifically targeting this organelle. mtPt induces apoptosis without damaging nuclear DNA, indicating that ...

  5. Dual Extraction of Essential Oil and Podophyllotoxin from Creeping Juniper (Juniperus horizontalis)

    PubMed Central

    Cantrell, Charles L.; Zheljazkov, Valtcho D.; Carvalho, Camila R.; Astatkie, Tess; Jeliazkova, Ekaterina A.; Rosa, Luiz H.

    2014-01-01

    Juniperus horizontalis Moench (Family Cupressaceae), commonly called creeping juniper, is a widely distributed species in the United States and much of Canada. It is potentially a source for two important chemical products, the anticancer drug synthetic precursor, podophyllotoxin and essential oils. The objectives of this study were to ascertain the likelihood of utilizing J. horizontalis needles for the simultaneous production of both (?)-podophyllotoxin and essential oil components and to determine the optimum distillation time (DT) needed for the production of essential oil containing a specific ratio of constituents. Eleven different distillation times were tested in this study: 20, 40, 80, 160, 180, 240, 480, 600, 720, 840, and 960 min. Total essential oil content increased with increasing distillation time from a minimum of 0.023% at 20 min to a maximum of 1.098% at 960 min. The major constituents present in the oil were alpha-pinene, sabinene, and limonene. The percent concentration of sabinene in the essential oil varied from a high of 46.6% at 80 min to a low of 30.2% at 960 min, that of limonene changed very little as a result of distillation time and remained near 30% for all distillation times, whereas the concentration of alpha-pinene was 9.6% at 20 min DT and decreased to 4.2% at 960 min. Post distillation analysis of needles revealed elevated amounts of (?)-podophyllotoxin remaining in the tissue varied in the amount of podophyllotoxin present, from a low of 0.281% to a high of 0.364% as compared to undistilled needles which gave 0.217% podophyllotoxin. As a result of this study, specific essential oil components can now be targeted in J. horizontalis by varying the distillation time. Furthermore, needles can be successfully utilized as a source of both essential oil and podophyllotoxin, consecutively. PMID:25203255

  6. A review of ceramide analogs as potential anticancer agents

    PubMed Central

    Liu, Jiawang; Beckman, Barbara S.; Foroozesh, Maryam

    2014-01-01

    Summary Ceramide serves as a central mediator in sphingolipid metabolism and signaling pathways, regulating many fundamental cellular responses. It is referred to as a “tumor suppressor lipid”, since it powerfully potentiates signaling events which drive apoptosis, cell cycle arrest, and autophagic responses. In the typical cancer cell, ceramide levels and signaling are usually suppressed by over-expression of ceramide-metabolizing enzymes or down-regulation of ceramide-generating enzymes. However, chemotherapeutic drugs as well as radiotherapy increase intracellular ceramide levels while exogenously treating cancer cells with short-chain ceramides leads to anti-cancer effects. All evidence currently points to the fact that the up-regulation of ceramide level is a promising anti-cancer target. In this review, we exhibited a full scroll of anti-cancer ceramide analogs as down-stream receptor agonists and ceramide metabolizing enzyme inhibitors. PMID:23919551

  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. Synthesis and Evaluation of Flavanones as Anticancer Agents

    PubMed Central

    Murti, Y.; Mishra, P.

    2014-01-01

    A few flavanones were synthesised by cyclisation of corresponding 3-(heteroaryl)-1(2-hydroxyphenyl) prop-2-en-1-one with sodium acetate in alcohol–water and evaluated for activity. Synthesised compounds were assayed for their in vitro anticancer activity against three human cancer cell lines, mammary adenocarcinoma (MCF7), human colon adenocarcinoma (HT29) and human kidney adenocarcinoma (A498) using sulforhodamine B dye. Results indicated that most of the compounds exhibited significant in vitro anticancer potential. Among them, compound having furan ring showed most potent activity against all the tested cell lines. PMID:24843190

  9. Expression analysis of biosynthetic pathway genes vis-à-vis podophyllotoxin content in Podophyllum hexandrum Royle.

    PubMed

    Kumar, Pawan; Pal, Tarun; Sharma, Neha; Kumar, Varun; Sood, Hemant; Chauhan, Rajinder S

    2015-09-01

    Podophyllum hexandrum Royle is known for its vast medicinal properties, particularly anticancer. It contains higher amount of podophyllotoxin (4.3 %), compared to Podophyllum peltatum (0.025 %) and other plant species; as a result, it has been used worldwide in the preparation of various drugs including anticancer, antimalarial, antiviral, antioxidant, antifungal, and so on. Currently, Etoposide (VP-16-213), Vumon® (Teniposide; VM-26), Etopophos®, Pod-Ben- 25, Condofil, Verrusol, and Warticon are available in the market. Due to highly complex synthesis and low cell culture yields of podophyllotoxin (0.3 %), the supply of raw material cannot be met due to increasing industrial demands. The knowledge on podophyllotoxin biosynthetic pathway vis-à-vis expression status of genes is fragmentary. Quantitative expression analysis of 21 pathway genes has revealed 9 genes, namely SD, PD, PCH, CM, CMT, CAD, CCR, C4H, and ADH, that showed increase in transcript abundance up to 1.4 to 23.05 folds, respectively, vis-à-vis podophyllotoxin content in roots (1.37 %) and rhizomes (3.05 %) of P. hexandrum. In silico analysis of putative cis-regulatory elements in promoter regions of overexpressed genes showed the presence of common Skn-1 motif and MBS elements in CMT, CAD, CCR, C4H, and ADH genes, thereby, suggesting their common regulation. The outcome of the study has resulted in the identification of suitable candidate genes which might be contributing to podophyllotoxin biosynthesis that can act as potential targets for any genetic intervention strategies aimed at its enhanced production. PMID:25586110

  10. Microtubule-stabilizing agents: a growing class of important anticancer drugs.

    PubMed

    Altmann, K H

    2001-08-01

    Microtubule-stabilizing agents continue to play an important role in anticancer drug discovery and development. New agents were again discovered in the past year, including small synthetic molecules. At least three new taxanes and two compounds of the epothilone class of natural products underwent clinical trials in 2000. Unexpected new findings about synergistic effects between different microtubule-stabilizing agents in vitro raise new prospects for combination chemotherapy. PMID:11470606

  11. Potential Role of Garcinol as an Anticancer Agent

    PubMed Central

    Saadat, Nadia; Gupta, Smiti V.

    2012-01-01

    Garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Although the fruit has been consumed traditionally over centuries, its biological activities, specifically its anticancer potential is a result of recent scientific investigations. The anticarcinogenic properties of garcinol appear to be moderated via its antioxidative, anti-inflammatory, antiangiogenic, and proapoptotic activities. In addition, garcinol displays effective epigenetic influence by inhibiting histone acetyltransferases (HAT 300) and by possible posttranscriptional modulation by mi RNA profiles involved in carcinogenesis. In vitro as well as some in vivo studies have shown the potential of this compound against several cancers types including breast, colon, pancreatic, and leukemia. Although this is a promising molecule in terms of its anticancer properties, investigations in relevant animal models, and subsequent human trials are warranted in order to fully appreciate and confirm its chemopreventative and/or therapeutic potential. PMID:22745638

  12. A novel bifunctional mitochondria-targeted anticancer agent with high selectivity for cancer cells

    PubMed Central

    He, Huan; Li, Dong-Wei; Yang, Li-Yun; Fu, Li; Zhu, Xun-Jin; Wong, Wai-Kwok; Jiang, Feng-Lei; Liu, Yi

    2015-01-01

    Mitochondria have recently emerged as novel targets for cancer therapy due to its important roles in fundamental cellular function. Discovery of new chemotherapeutic agents that allow for simultaneous treatment and visualization of cancer is urgent. Herein, we demonstrate a novel bifunctional mitochondria-targeted anticancer agent (FPB), exhibiting both imaging capability and anticancer activity. It can selectively accumulate in mitochondria and induce cell apoptosis. Notably, it results in much higher toxicity toward cancer cells owing to much higher uptake by cancer cells. These features make it highly attractive in cancer imaging and treatment. PMID:26337336

  13. Cysteine-modifying agents: a possible approach for effective anticancer and antiviral drugs.

    PubMed Central

    Casini, Angela; Scozzafava, Andrea; Supuran, Claudiu T

    2002-01-01

    Modification of cysteine residues in proteins, due to a) the participation of the thiol moiety of this amino acid in oxido-reduction reactions, b) its ability to strongly coordinate transition metal ions, or c) its nucleophilic nature and facile reaction with electrophiles, may be critically important for the design of novel types of pharmacological agents. Application of such procedures recently led to the design of novel antivirals, mainly based on the reaction of zinc finger proteins with disulfides and related derivatives. This approach was particularly successful for developing novel antiviral agents for human immunodeficiency virus and human papilloma virus. Several new anticancer therapeutic approaches, mainly targeting tubulin, have also been reported. Thus, this unique amino acid offers very interesting possibilities for developing particularly useful pharmacological agents, which generally possess a completely different mechanism of action compared with classic agents in clinical use, thus avoiding major problems such as multidrug resistance (for antiviral and anticancer agents) or high toxicity. PMID:12426135

  14. Natural products of plant origin as anticancer agents.

    PubMed

    Ram, V J; Kumari, S

    2001-10-01

    Natural products have been used as effective remedies for the treatment of various ailments. Numerous plant products in the form of decoction, tincture, tablets and capsules have been clinically used for the treatment of different kinds of cancer. This review covers some of the important plants with clinically proven anticancer activity, including Catharanthus roseus, Podophyllum peltatum, Taxus brevifolia, Camptothecin acuminata, Cephalotaxus harringtonia, Viscum album, Onchrosia elliptica, Annona bullata, Asmina triloba and Rhizoma zedoariae. Synthetic analogues in some cases have also been prepared to improve the efficacy and decrease the side effects of parent compounds. The modes of action of clinically used drugs are also delineated. PMID:12806432

  15. Chrysin-benzothiazole conjugates as antioxidant and anticancer agents.

    PubMed

    Mistry, Bhupendra M; Patel, Rahul V; Keum, Young-Soo; Kim, Doo Hwan

    2015-12-01

    7-(4-Bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one, obtained from chrysin with 1,4-dibromobutane, was combined with a wide range of 6-substituted 2-aminobenzthiazoles, which had been prepared from the corresponding anilines with potassium thiocyanate. Free radical scavenging efficacies of newer analogues were measured using DPPH and ABTS assays, in addition to the assessment of their anticancer activity against cervical cancer cell lines (HeLa and CaSki) and ovarian cancer cell line (SK-OV-3) implementing the SRB assay. Cytotoxicity of titled compounds was checked using Madin-Darby canine kidney (MDCK) non-cancer cell line. Overall, 6a-r indicated remarkable antioxidant power as DPPH and ABTS(+) scavengers; particularly the presence of halogen(s) (6g, 6h, 6j-6l) was favourable with IC50 values comparable to the control ascorbic acid. Unsubstituted benzothiazole ring favored the activity of resultant compounds (6a and 6r) against HeLa cell line, whereas presence of chlorine (6g) or a di-fluoro group (6k) was a key to exert strong action against CaSki. Moreover, a mono-fluoro (6j) and a ketonic functionality (6o) were beneficial to display anticipated anticancer effects against ovarian cancer cell line SK-OV-3. The structural assignments of the new products were done on the basis of IR, (1)H NMR, (13)C NMR spectroscopy and elemental analysis. PMID:26514745

  16. Urokinase receptor and resistance to targeted anticancer agents

    PubMed Central

    Gonias, Steven L.; Hu, Jingjing

    2015-01-01

    The urokinase receptor (uPAR) is a GPI-anchored membrane protein, which regulates protease activity at the cell surface and, in collaboration with a system of co-receptors, triggers cell-signaling and regulates gene expression within the cell. In normal tissues, uPAR gene expression is limited; however, in cancer, uPAR is frequently over-expressed and the gene may be amplified. Hypoxia, which often develops in tumors, further increases uPAR expression by cancer cells. uPAR-initiated cell-signaling promotes cancer cell migration, invasion, metastasis, epithelial-mesenchymal transition, stem cell-like properties, survival, and release from states of dormancy. Newly emerging data suggest that the pro-survival cell-signaling activity of uPAR may allow cancer cells to “escape” from the cytotoxic effects of targeted anticancer drugs. Herein, we review the molecular properties of uPAR that are responsible for its activity in cancer cells and its ability to counteract the activity of anticancer drugs. PMID:26283964

  17. Recent advancement in discovery and development of natural product combretastatin-inspired anticancer agents.

    PubMed

    Patil, Pravin O; Patil, Ashwini G; Rane, Rajesh A; Patil, Pravin C; Deshmukh, Prashant K; Bari, Sanjay B; Patil, Dilip A; Naphade, Shital S

    2015-01-01

    The natural stilbenoids combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent antitubulin agents demonstrating antimitotic activity as well as tumor vascular disruption property. Due to structural simplicity and potent cytotoxicity of CA4 and CA1, they are considered as promising leads for the development of potent anticancer agents. In fact, scientific fraternity is motivated to synthesize several derivatives of CA4 and CA1 as novel therapeutic agents. In the literature, several studies have been carried out to evaluate the medicinal chemistry, pharmacology and structure-activity relationships (SAR) of a variety of modified combretastatin derivatives. The present report aimed at comprehensively revising the recent advancements (2006-2014) in the medicinal chemistry and SAR of diversified combretastatin analogues. The published data concerning new combretastatin A-4 analogues as antimitotic anticancer agents are presented and SAR is reviewed and discussed. PMID:26007283

  18. 1. (a) Why are DNA-targeted drugs largely used as anticancer agents and not as, say, antibacterial or antifungal agents?

    E-print Network

    Gates, Kent. S.

    CHEM 4170 Homework 4 1. (a) Why are DNA-targeted drugs largely used as anticancer agents and not as, say, antibacterial or antifungal agents? (b) Provide an explanation for how anticancer drugs can-damaging drugs mentioned in Question 1). (b) However, some medicinal chemists believe that these compounds

  19. Endophyte fungal isolates from Podophyllum peltatum produce podophyllotoxin.

    PubMed

    Eyberger, Amy L; Dondapati, Rajeswari; Porter, John R

    2006-08-01

    The lignan podophyllotoxin (1) is highly valued as the precursor to clinically useful anticancer drugs. Substantial drug development of this compound class continues, including potential new use for inflammatory disease. We have isolated two endophyte fungi, both strains of Phialocephala fortinii, from rhizomes of the plant Podophyllum peltatum. The fungi were identified through DNA sequencing and morphology. Both strains of fungi are slow-growing and produce 1 at low but measurable amounts in broth culture. The compound was confirmed through matching HPLC retention times, absorption spectra, and MS data to authentic 1. The yield of 1 has ranged from 0.5 to 189 microg/L in 4 weeks of culture. These fungi have implications for the sustained production of 1 independent of wild populations of the source plants. PMID:16933860

  20. Tubulin-interactive natural products as anticancer agents.

    PubMed

    Kingston, David G I

    2009-03-27

    This review provides an overview of the discovery, structures, and biological activities of anticancer natural products that act by inhibiting or promoting the assembly of tubulin to microtubules. The emphasis is on providing recent information on those compounds in clinical use or in advanced clinical trials. The vinca alkaloids, the combretastatins, NPI-2358, the halichondrin B analogue eribulin, dolastatin 10, noscapine, hemiasterlin, and rhizoxin are discussed as tubulin polymerization inhibitors, while the taxanes and the epothilones are the major classes of tubulin polymerization promoters presented, with brief treatments of discodermolide, eleutherobin, and laulimalide. The challenges and future directions of tubulin-interactive natural products-based drug discovery programs are also discussed briefly. PMID:19125622

  1. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents.

    PubMed

    Yadav, N; Kumar, S; Marlowe, T; Chaudhary, A K; Kumar, R; Wang, J; O'Malley, J; Boland, P M; Jayanthi, S; Kumar, T K S; Yadava, N; Chandra, D

    2015-01-01

    Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy. PMID:26539916

  2. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

    PubMed Central

    Yadav, N; Kumar, S; Marlowe, T; Chaudhary, A K; Kumar, R; Wang, J; O'Malley, J; Boland, P M; Jayanthi, S; Kumar, T K S; Yadava, N; Chandra, D

    2015-01-01

    Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy. PMID:26539916

  3. The Promise of Integrins as Effective Targets for Anticancer Agents

    PubMed Central

    2002-01-01

    This review will briefly describe integrin function, address why integrins are attractive targets for chemotherapeutic drug design, and discuss some ongoing studies aimed at inhibiting integrin activity. Integrins are cell surface heterodimeric receptors. They modulate many cellular processes including: growth, death (apoptosis), adhesion, migration, and invasion by activating several signaling pathways. Many potential chemotherapeutic agents target integrins directly (eg, polypeptides, monoclonal antibodies, adenovirus vectors). These agents may be clinically useful in controlling the metastatic spread of cancer. PMID:12488576

  4. Synthesis of pro-apoptotic indapamide derivatives as anticancer agents.

    PubMed

    Y?lmaz, Özgür; Özba? Turan, Suna; Akbu?a, Jülide; Tiber, P?nar Mega; Orun, Oya; Supuran, Claudiu T; Küçükgüzel, ? Güniz

    2015-12-01

    4-Chloro-3-({[(substitutedamino)carbonothioyl]amino}sulfonyl)-N-(2-methyl-2,3-dihydro-1H-indole-1-yl)benzamide (1-20) and 4-chloro-3-({[3-(substituted)-4-oxo-1,3-thiazolidine-2-ylidene]amino}sulfonyl)-N-(2-methyl-2,3-dihydro-1H-indole-1-yl)benzamide derivatives (21-31) were synthesized from 4-chloro-N-(2-methyl-2,3-dihydroindol-1-yl)-3-sulfamoylbenzamide (indapamide). 4-Chloro-3-({[(4-chlorophenyl) amino) carbonothioyl]amino}sulfonyl)-N-(2-methyl-2,3-dihydro-1H-indole-1-yl)benzamide 12 demonstrated the highest proapoptotic activity among all synthesized compounds on melanoma cell lines MDA-MB-435 with 3.7% growth inhibition at the concentration of 10?µM. Compound 12 (SGK 266) was evaluated in vitro using the MTT colorimetric method against melanoma cancer cell line MDA-MB435 growth inhibition for different doses and exhibited anticancer activity with IC50 values of 85-95?µM against melanoma cancer cell line MDA-MB435. In addition, this compound was investigated as inhibitors of four physiologically relevant human carbonic anhydrase isoforms, hCA I, II, IX and XII. The compund inhibited these enzymes with IC50 values ranging between 0.72 and 1.60?µM. PMID:25683085

  5. Can Some Marine-Derived Fungal Metabolites Become Actual Anticancer Agents?

    PubMed Central

    Gomes, Nelson G. M.; Lefranc, Florence; Kijjoa, Anake; Kiss, Robert

    2015-01-01

    Marine fungi are known to produce structurally unique secondary metabolites, and more than 1000 marine fungal-derived metabolites have already been reported. Despite the absence of marine fungal-derived metabolites in the current clinical pipeline, dozens of them have been classified as potential chemotherapy candidates because of their anticancer activity. Over the last decade, several comprehensive reviews have covered the potential anticancer activity of marine fungal-derived metabolites. However, these reviews consider the term “cytotoxicity” to be synonymous with “anticancer agent”, which is not actually true. Indeed, a cytotoxic compound is by definition a poisonous compound. To become a potential anticancer agent, a cytotoxic compound must at least display (i) selectivity between normal and cancer cells (ii) activity against multidrug-resistant (MDR) cancer cells; and (iii) a preferentially non-apoptotic cell death mechanism, as it is now well known that a high proportion of cancer cells that resist chemotherapy are in fact apoptosis-resistant cancer cells against which pro-apoptotic drugs have more than limited efficacy. The present review thus focuses on the cytotoxic marine fungal-derived metabolites whose ability to kill cancer cells has been reported in the literature. Particular attention is paid to the compounds that kill cancer cells through non-apoptotic cell death mechanisms. PMID:26090846

  6. Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents

    PubMed Central

    Zou, Lidi; Chen, Shenghui; Zhang, Chao; Zhang, Yulin; Chen, Meiwan; Wan, Jian-Bo; Su, Huanxing; Wang, Yitao; He, Chengwei

    2015-01-01

    Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 ?M) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 ?M) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer. PMID:26421434

  7. Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

    PubMed Central

    Vickers, Andrew J.; Kuo, Joyce; Cassileth, Barrie R.

    2006-01-01

    Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials. PMID:16382123

  8. Combination of 4-anilinoquinazoline, arylurea and tertiary amine moiety to discover novel anticancer agents.

    PubMed

    Zuo, Sai-Jie; Zhang, Sai; Mao, Shuai; Xie, Xiao-Xiao; Xiao, Xue; Xin, Min-Hnag; Xuan, Wei; He, Yuan-Yuan; Cao, Yong-Xiao; Zhang, San-Qi

    2016-01-15

    In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors. PMID:26706113

  9. Evaluation of Degradation Properties of Polyglycolide and Its Potential as Delivery Vehicle for Anticancer Agents

    SciTech Connect

    Noorsal, K.; Ghani, S. M.; Yunos, D. M.; Mohamed, M. S. W.; Yahya, A. F.

    2010-03-11

    Biodegradable polymers offer a unique combination of properties that can be tailored to suit nearly any controlled drug delivery application. The most common biodegradable polymers used for biomedical applications are semicrystalline polyesters and polyethers which possess good mechanical properties and have been used in many controlled release applications. Drug release from these polymers may be controlled by several mechanisms and these include diffusion of drug through a matrix, dissolution of polymer matrix and degradation of the polymer. This study aims to investigate the degradation and drug release properties of polyglycolide (1.03 dL/g), in which, cis platin, an anticancer agent was used as the model drug. The degradation behaviour of the chosen polymer is thought to largely govern the release of the anticancer agent in vitro.

  10. [Establishment and characterization of human ovarian fibrosarcoma cell line and its sensitivity to anticancer agents].

    PubMed

    Kiyozuka, Y; Nishimura, H; Iwanaga, S; Yakushiji, M; Ito, K; Nakano, S; Tamori, N; Adachi, S; Noda, T; Imai, S

    1992-04-01

    We succeeded in establishing a cell line (KEN-3) for subculture from a fibrosarcoma which originated in the ovary in a girl aged 17 years. Its characteristics and sensitivity to anticancer agents are reported in this paper. 1. Characteristics of established cell line. Lined cells consist of multinucleated giant cells mixed among many spindle-shaped cells. They grow in small colonies and have none of the pavement-like arrangement characteristic of epithelial tumor cells. The number of chromosomes ranged from 45 to 128 (mode: pseudo-triploidy region, 65). The doubling time, cellular density and plating efficiency were 76.9 hours, 5.4 x 10(5)/cm2 and 30.2%, respectively. Concerning tumor markers, CEA and sialyl SSEA-1 were only produced in small quantities. Subculture was possible subcutaneously in the nude mouse with no capacity for the production of ascites. 2. Susceptibility to anticancer agents and GP170 expression. The in vitro susceptibility to about 12 types of anticancer agents was investigated with the MTT assay. IC50/PPC was shown to be less than 1 for Adriamycin only. The sensitivity to CDDP (IC50/PPC: 4.8) was low, and no sensitivity was observed at all to DTIC, which is used frequently for mesenchymal tumors. GP170 (mdr-1 products) was positive in established cells in immunohistochemical stain. PMID:1351514

  11. Bacterial biosynthesis and maturation of the didemnin anticancer agents

    PubMed Central

    Xu, Ying; Kersten, Roland D.; Nam, Sang-Jip; Lu, Liang; Al-Suwailem, Abdulaziz M.; Zheng, Huajun; Fenical, William; Dorrestein, Pieter C.

    2012-01-01

    The antineoplastic agent didemnin B from the Caribbean tunicate Trididemnum solidum was the first marine drug to be clinically tested in humans. Because of its limited supply and its complex cyclic depsipeptide structure, considerable challenges were encountered during didemnin B's development that continue to limit aplidine (dehydrodidemnin B), which is currently being evaluated in numerous clinical trials. Herein we show that the didemnins are bacterial products produced by the marine ?-proteobacteria Tistrella mobilis and Tistrella bauzanensis via a unique post-assembly line maturation process. Complete genome sequence analysis of the 6,513,401 bp T. mobilis strain KA081020-065 with its five circular replicons revealed the putative didemnin biosynthetic gene cluster (did) on the 1,126,962 bp megaplasmid pTM3. The did locus encodes a 13-module hybrid nonribosomal peptide synthetase-polyketide synthase enzyme complex organized in a co-linear arrangement for the synthesis of the fatty acylglutamine ester derivatives didemnins X and Y rather than didemnin B as first anticipated. Imaging mass spectrometry of T. mobilis bacterial colonies captured the time-dependent extracellular conversion of the didemnin X and Y precursors to didemnin B in support of an unusual post-synthetase activation mechanism. Significantly, the discovery of the didemnin biosynthetic gene cluster may provide a long-term solution to the supply problem that presently hinders this group of marine natural products and pave the way for the genetic engineering of new didemnin congeners. PMID:22458477

  12. Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine.

    PubMed

    Guo, Lili; Shestov, Alexander A; Worth, Andrew J; Nath, Kavindra; Nelson, David S; Leeper, Dennis B; Glickson, Jerry D; Blair, Ian A

    2016-01-01

    The antitumor agent lonidamine (LND; 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid) is known to interfere with energy-yielding processes in cancer cells. However, the effect of LND on central energy metabolism has never been fully characterized. In this study, we report that a significant amount of succinate is accumulated in LND-treated cells. LND inhibits the formation of fumarate and malate and suppresses succinate-induced respiration of isolated mitochondria. Utilizing biochemical assays, we determined that LND inhibits the succinate-ubiquinone reductase activity of respiratory complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through complex II, which reduced the viability of the DB-1 melanoma cell line. The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived ?-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism. PMID:26521302

  13. Essential oils and their constituents as anticancer agents: a mechanistic view.

    PubMed

    Gautam, Nandini; Mantha, Anil K; Mittal, Sunil

    2014-01-01

    Exploring natural plant products as an option to find new chemical entities as anticancer agents is one of the fastest growing areas of research. Recently, in the last decade, essential oils (EOs) have been under study for their use in cancer therapy and the present review is an attempt to collect and document the available studies indicating EOs and their constituents as anticancer agents. This review enlists nearly 130 studies of EOs from various plant species and their constituents that have been studied so far for their anticancer potential and these studies have been classified as in vitro and in vivo studies for EOs and their constituents. This review also highlights in-depth various mechanisms of action of different EOs and their constituents reported in the treatment strategies for different types of cancer. The current review indicates that EOs and their constituents act by multiple pathways and mechanisms involving apoptosis, cell cycle arrest, antimetastatic and antiangiogenic, increased levels of reactive oxygen and nitrogen species (ROS/RNS), DNA repair modulation, and others to demonstrate their antiproliferative activity in the cancer cell. The effect of EOs and their constituents on tumour suppressor proteins (p53 and Akt), transcription factors (NF- ?B and AP-1), MAPK-pathway, and detoxification enzymes like SOD, catalase, glutathione peroxidase, and glutathione reductase has also been discussed. PMID:25003106

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

    PubMed Central

    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

    2015-01-01

    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. Essential Oils and Their Constituents as Anticancer Agents: A Mechanistic View

    PubMed Central

    Mantha, Anil K.

    2014-01-01

    Exploring natural plant products as an option to find new chemical entities as anticancer agents is one of the fastest growing areas of research. Recently, in the last decade, essential oils (EOs) have been under study for their use in cancer therapy and the present review is an attempt to collect and document the available studies indicating EOs and their constituents as anticancer agents. This review enlists nearly 130 studies of EOs from various plant species and their constituents that have been studied so far for their anticancer potential and these studies have been classified as in vitro and in vivo studies for EOs and their constituents. This review also highlights in-depth various mechanisms of action of different EOs and their constituents reported in the treatment strategies for different types of cancer. The current review indicates that EOs and their constituents act by multiple pathways and mechanisms involving apoptosis, cell cycle arrest, antimetastatic and antiangiogenic, increased levels of reactive oxygen and nitrogen species (ROS/RNS), DNA repair modulation, and others to demonstrate their antiproliferative activity in the cancer cell. The effect of EOs and their constituents on tumour suppressor proteins (p53 and Akt), transcription factors (NF-?B and AP-1), MAPK-pathway, and detoxification enzymes like SOD, catalase, glutathione peroxidase, and glutathione reductase has also been discussed. PMID:25003106

  16. New role for an established drug? Bisphosphonates as potential anticancer agents.

    PubMed

    Koul, H K; Koul, S; Meacham, R B

    2012-06-01

    As a result of their ability to effectively reduce the risk of skeletal-related events, bisphosphonates (BPs) were incorporated into clinical practice over a decade ago, leading to a new treatment paradigm for patients with skeletal involvement from advanced cancer. BPs are now a well-established treatment option in this setting. Our review of the literature found that in addition to maintaining bone health in patients with malignant bone lesions and patients at risk for cancer therapy-induced bone loss, emerging preclinical and clinical data suggest that BPs may also have anticancer activity. Later generation, nitrogen-containing BPs (N-BPs), such as zoledronic acid (ZOL), inhibit the mevalonate pathway, subsequently inhibiting a number of cellular functions in bone-resorbing osteoclasts. In addition, N-BPs inhibit cancer cell proliferation, viability, motility, invasion and angiogenesis; induce cancer cell apoptosis; and act in synergy with antineoplastic agents. N-BPs, especially ZOL, may be useful as anticancer agents. As evidence continues to emerge, another shift in cancer treatment paradigms, in which N-BPs are considered for their anticancer activity as well as palliative effects, may be approaching. PMID:21876554

  17. 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

  18. Biochemical characterization and molecular dynamic simulation of ?-sitosterol as a tubulin-binding anticancer agent.

    PubMed

    Mahaddalkar, Tejashree; Suri, Charu; Naik, Pradeep Kumar; Lopus, Manu

    2015-08-01

    ?eta-sitosterol (?-SITO), a phytosterol present in pomegranate, peanut, corn oil, almond, and avocado, has been recognized to offer health benefits and potential clinical uses. ?-SITO is orally bioavailable and, as a constituent of edible natural products, is considered to have no undesired side effects. It has also been considered as a potent anticancer agent. However, the molecular mechanism of action of ?-SITO as a tubulin-binding anticancer agent and its binding site on tubulin are poorly understood. Using a combination of biochemical analyses and molecular dynamic simulation, we investigated the molecular details of the binding interactions of ?-SITO with tubulin. A polymer mass assay comparing the effects of ?-SITO and of taxol and vinblastine on tubulin assembly showed that this phytosterol stabilized microtubule assembly in a manner similar to taxol. An 8-anilino-1-naphthalenesulfonic acid assay confirmed the direct interaction of ?-SITO with tubulin. Although ?-SITO did not show direct binding to the colchicine site on tubulin, it stabilized the colchicine binding. Interestingly, no sulfhydryl groups of tubulin were involved in the binding interaction of ?-SITO with tubulin. Based on the results from the biochemical assays, we computationally modeled the binding of ?-SITO with tubulin. Using molecular docking followed by molecular dynamic simulations, we found that ?-SITO binds tubulin at a novel site (which we call the 'SITO site') adjacent to the colchicine and noscapine sites. Our data suggest that ?-SITO is a potent anticancer compound that interferes with microtubule assembly dynamics by binding to a novel site on tubulin. PMID:25912799

  19. Synthesis and biological evaluation of novel 3,9-substituted ?-carboline derivatives as anticancer agents.

    PubMed

    Chen, Yi-Fong; Lin, Yi-Chien; Chen, Jeng-Pang; Chan, Hsu-Chin; Hsu, Mei-Hua; Lin, Hui-Yi; Kuo, Sheng-Chu; Huang, Li-Jiau

    2015-09-15

    In our previous studies on 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) analogs, we synthesised numerous substituted carbazole and ?-carboline derivatives, which exhibited anticancer activity. In this study, we designed and synthesised a series of 3,9-substituted ?-carbolines, by replacing the tricyclic rings of carbazole and ?-carboline derivatives with isosteric ?-carboline, and evaluated anticancer activity. We observed that 9-(2-methoxybenzyl)-?-carboline-3-carboxylic acid (11a) inhibited the growth of HL-60 cells by inducing apoptosis, with a half maximal inhibitory concentration of 4.0 ?M. Our findings indicate that ?-carboline derivatives can be used as lead compounds for developing novel antitumor agents. PMID:26235951

  20. Synthesis of xanthone derivatives based on ?-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, ?-mangostin is isolated from various parts of the mangosteen, Garcinia mangostana L. (Clusiaceae), a well-known tropical fruit. Novel xanthone derivatives based on ?-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. Synthesis and pharmacological evaluation of some new fluorine containing hydroxypyrazolines as potential anticancer and antioxidant agents.

    PubMed

    Dinesha; Viveka, Shivapura; Priya, Bolli Keerthi; Pai, K Sreedhara Ranganath; Naveen, Shivalingegowda; Lokanath, Neratur K; Nagaraja, Gundibasappa Karikannar

    2015-11-01

    Breast cancer is probably the most prevalent cancer in women. The development of resistance to therapeutic agents and lack of targeted therapy for breast cancer cells provide motivation to identify new compounds for the treatment. With this objective in mind, a new series of 3-fluoro-4-methoxyphenyl group based 1,3,5-trisubstituted aryl-5-hydroxypyrazoline analogues 4a-l was synthesized through multi-step reaction sequence. The structures of the newly synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR, LC-MS and elemental analysis. They were screened for their in vitro anticancer and in vitro antioxidant activities. Among the tested compounds 4h, 4c and particularly 4i displayed promising cytotoxic effect on breast cancer cell lines. The compounds were also found to possess antioxidant activity when tested against DPPH free radical. Overall, this work has contributed to the development of promising leads for anticancer and antioxidant activities. PMID:26433616

  2. Inner conflict in patients receiving oral anticancer agents: a qualitative study

    PubMed Central

    Komatsu, Hiroko; Takahashi, Tsunehiro

    2015-01-01

    Objectives To explore the experiences of patients receiving oral anticancer agents. Design A qualitative study using semistructured interviews with a grounded theory approach. Setting A university hospital in Japan. Participants 14 patients with gastric cancer who managed their cancer with oral anticancer agents. Results Patients with cancer experienced inner conflict between rational belief and emotional resistance to taking medication due to confrontation with cancer, doubt regarding efficacy and concerns over potential harm attached to use of the agent. Although they perceived themselves as being adherent to medication, they reported partial non-adherent behaviours. The patients reassessed their lives through the experience of inner conflict and, ultimately, they recognised their role in medication therapy. Conclusions Patients with cancer experienced inner conflict, in which considerable emotional resistance to taking their medication affected their occasional non-adherent behaviours. In patient-centred care, it is imperative that healthcare providers understand patients’ inner conflict and inconsistency between their subjective view and behaviour to support patient adherence. PMID:25872938

  3. Xanthones from mangosteen extracts as natural chemopreventive agents: potential anticancer drugs.

    PubMed

    Shan, T; Ma, Q; Guo, K; Liu, J; Li, W; Wang, F; Wu, E

    2011-11-01

    Despite decades of research, the treatment and management of malignant tumors still remain a formidable challenge for public health. New strategies for cancer treatment are being developed, and one of the most promising treatment strategies involves the application of chemopreventive agents. The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds. Xanthones, from the pericarp, whole fruit, heartwood, and leaf of mangosteen (Garcinia mangostana Linn., GML), are known to possess a wide spectrum of pharmacologic properties, including antioxidant, anti- tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities. The potential chemopreventive and chemotherapeutic activities of xanthones have been demonstrated in different stages of carcinogenesis (initiation, promotion, and progression) and are known to control cell division and growth, apoptosis, inflammation, and metastasis. Multiple lines of evidence from numerous in vitro and in vivo studies have confirmed that xanthones inhibit proliferation of a wide range of human tumor cell types by modulating various targets and signaling transduction pathways. Here we provide a concise and comprehensive review of preclinical data and assess the observed anticancer effects of xanthones, supporting its remarkable potential as an anticancer agent. PMID:21902651

  4. Xanthones from Mangosteen Extracts as Natural Chemopreventive Agents: Potential Anticancer Drugs

    PubMed Central

    Shan, T.; Ma, Q.; Guo, K.; Liu, J.; Li, W.; Wang, F.; Wu, E.

    2011-01-01

    Despite decades of research, the treatment and management of malignant tumors still remain a formidable challenge for public health. New strategies for cancer treatment are being developed, and one of the most promising treatment strategies involves the application of chemopreventive agents. The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds. Xanthones, from the pericarp, whole fruit, heartwood, and leaf of mangosteen (Garcinia mangostana Linn., GML), are known to possess a wide spectrum of pharmacologic properties, including anti-oxidant, anti-tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities. The potential chemopreventive and chemotherapeutic activities of xanthones have been demonstrated in different stages of carcinogenesis (initiation, promotion, and progression) and are known to control cell division and growth, apoptosis, inflammation, and metastasis. Multiple lines of evidence from numerous in vitro and in vivo studies have confirmed that xanthones inhibit proliferation of a wide range of human tumor cell types by modulating various targets and signaling transduction pathways. Here we provide a concise and comprehensive review of preclinical data and assess the observed anticancer effects of xanthones, supporting its remarkable potential as an anticancer agent. PMID:21902651

  5. PST-Gold nanoparticle as an effective anticancer agent with immunomodulatory properties.

    PubMed

    Joseph, Manu M; Aravind, S R; Varghese, Sheeja; Mini, S; Sreelekha, T T

    2013-04-01

    Polysaccharide PST001, which is isolated from the seed kernels of Tamarindus indica (Ti), is an antitumor and immunomodulatory compound. Gold nanoparticles have been used for various applications in cancer. In the present report, a novel strategy for the synthesis and stabilization of gold nanoparticles using anticancer polysaccharide PST001 was employed and the nanoparticles' antitumor activity was evaluated. PST-Gold nanoparticles were prepared such that PST001 acted both as a reducing agent and as a capping agent. PST-Gold nanoparticles showed high stability, no obvious aggregation for months and a wide range of pH tolerance. PST-Gold nanoparticles not only retained the antitumor effect of PST001 but also showed an enhanced effect even at a low concentration. It was also found that the nanoparticles exerted their antitumor effects through the induction of apoptosis. In vivo assays on BALB/c mice revealed that PST-Gold nanoparticles exhibited immunomodulatory effects. Evaluation of biochemical, hematological and histopathological features of mice revealed that PST-Gold nanoparticles could be administered safely without toxicity. Using the polysaccharide PST001 for the reduction and stabilization of gold nanoparticles does not introduce any environmental toxicity or biological hazards, and these particles are more effective than the parent polysaccharide. Further studies should be employed to exploit these particles as anticancer agents with imaging properties. PMID:23298585

  6. Rosemary (Rosmarinus officinalis L.) Extract as a Potential Complementary Agent in Anticancer Therapy.

    PubMed

    González-Vallinas, Margarita; Reglero, Guillermo; Ramírez de Molina, Ana

    2015-01-01

    Cancer remains an important cause of mortality nowadays and, therefore, new therapeutic approaches are still needed. Rosemary (Rosmarinus officinalis L.) has been reported to possess antitumor activities both in vitro and in animal studies. Some of these activities were attributed to its major components, such as carnosic acid, carnosol, ursolic acid, and rosmarinic acid. Initially, the antitumor effects of rosemary were attributed to its antioxidant activity. However, in recent years, a lack of correlation between antioxidant and antitumor effects exerted by rosemary was reported, and different molecular mechanisms were related to its tumor inhibitory properties. Moreover, supported by the U.S. Food and Drug Administration and the European Food and Safety Authority, specific compositions of rosemary extract were demonstrated to be safe for human health and used as antioxidant additive in foods, suggesting the potential easy application of this agent as a complementary approach in cancer therapy. In this review, we aim to summarize the reported anticancer effects of rosemary, the demonstrated molecular mechanisms related to these effects and the interactions between rosemary and currently used anticancer agents. The possibility of using rosemary extract as a complementary agent in cancer therapy in comparison with its isolated components is discussed. PMID:26452641

  7. Structure-Activity Relationships of Orotidine-5?-Monophosphate Decarboxylase Inhibitors as Anticancer Agents

    SciTech Connect

    Bello, A.; Konforte, D; Poduch, E; Furlonger, C; Wei, L; Liu, Y; Lewis, M; Pai, E; Paige, C; Kotra, L

    2009-01-01

    A series of 6-substituted and 5-fluoro-6-substituted uridine derivatives were synthesized and evaluated for their potential as anticancer agents. The designed molecules were synthesized from either fully protected uridine or the corresponding 5-fluorouridine derivatives. The mononucleotide derivatives were used for enzyme inhibition investigations against ODCase. Anticancer activities of all the synthesized derivatives were evaluated using the nucleoside forms of the inhibitors. 5-Fluoro-UMP was a very weak inhibitor of ODCase. 6-Azido-5-fluoro and 5-fluoro-6-iodo derivatives are covalent inhibitors of ODCase, and the active site Lys145 residue covalently binds to the ligand after the elimination of the 6-substitution. Among the synthesized nucleoside derivatives, 6-azido-5-fluoro, 6-amino-5-fluoro, and 6-carbaldehyde-5-fluoro derivatives showed potent anticancer activities in cell-based assays against various leukemia cell lines. On the basis of the overall profile, 6-azido-5-fluoro and 6-amino-5-fluoro uridine derivatives exhibited potential for further investigations.

  8. 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 and colorectal cancers. PMID:26288313

  9. 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 breast and colorectal cancers. PMID:26288313

  10. Potential use of folate-appended methyl-?-cyclodextrin as an anticancer agent.

    PubMed

    Onodera, Risako; Motoyama, Keiichi; Okamatsu, Ayaka; Higashi, Taishi; Arima, Hidetoshi

    2013-01-01

    To obtain a tumor cell-selectivity of methyl-?-cyclodextrin (M-?-CyD), we newly synthesized folate-appended M-?-CyD (FA-M-?-CyD), and evaluated the potential of FA-M-?-CyD as a novel anticancer agent in vitro and in vivo. Potent antitumor activity and cellular association of FA-M-?-CyD were higher than those of M-?-CyD in KB cells, folate receptor (FR)-positive cells. FA-M-?-CyD drastically inhibited the tumor growth after intratumoral or intravenous injection to FR-positive Colon-26 cells-bearing mice. The antitumor activity of FA-M-?-CyD was comparable and superior to that of doxorubicin after both intratumoral and intravenous administrations, respectively, at the same dose, in the tumor-bearing mice. All of the tumor-bearing mice after an intravenous injection of FA-M-?-CyD survived for at least more than 140 days. Importantly, an intravenous administration of FA-M-?-CyD to tumor-bearing mice did not show any significant change in blood chemistry values. These results strongly suggest that FA-M-?-CyD has the potential as a novel anticancer agent. PMID:23346361

  11. Combination of Hedgehog inhibitors and standard anticancer agents synergistically prevent osteosarcoma growth.

    PubMed

    Saitoh, Yoshinobu; Setoguchi, Takao; Nagata, Masahito; Tsuru, Arisa; Nakamura, Shunsuke; Nagano, Satoshi; Ishidou, Yasuhiro; Nagao-Kitamoto, Hiroko; Yokouchi, Masahiro; Maeda, Shingo; Tanimoto, Akihide; Furukawa, Tatsuhiko; Komiya, Setsuro

    2016-01-01

    High-dose chemotherapy and surgical intervention have improved long-term prognosis for non-metastatic osteosarcoma to 50-80%. However, metastatic osteosarcoma exhibits resistance to standard chemotherapy. We and others have investigated the function of Hedgehog pathway in osteosarcoma. To apply our previous findings in clinical settings, we examined the effects of Hedgehog inhibitors including arsenic trioxide (ATO) and vismodegib combined with standard anticancer agents. We performed WST-1 assays using ATO, cisplatin (CDDP), ifosfamide (IFO), doxorubicin (DOX), and vismodegib. Combination-index (CI) was used to examine synergism using CalcuSyn software. Xenograft models were used to examine the synergism in vivo. WST-1 assays showed that 143B and Saos2 cell proliferation was inhibited by ATO combined with CDDP, IFO, DOX, and vismodegib. Combination of ATO and CDDP, IFO, DOX or vismodegib was synergistic when the two compounds were used on proliferating 143B and Saos2 human osteosarcoma cells. An osteosarcoma xenograft model showed that treatment with ATO and CDDP, IFO, or vismodegib significantly prevented osteosarcoma growth in vivo compared with vehicle treatment. Our findings indicate that combination of Hedgehog pathway inhibitors and standard FDA-approved anticancer agents with established safety for human use may be an attractive therapeutic method for treating osteosarcoma. PMID:26548578

  12. Mechanism of Action of Phenethylisothiocyanate and Other Reactive Oxygen Species-Inducing Anticancer Agents

    PubMed Central

    Jutooru, Indira; Guthrie, Aaron S.; Chadalapaka, Gayathri; Pathi, Satya; Kim, KyoungHyun; Burghardt, Robert; Jin, Un-Ho

    2014-01-01

    Reactive oxygen species (ROS)-inducing anticancer agents such as phenethylisothiocyanate (PEITC) activate stress pathways for killing cancer cells. Here we demonstrate that PEITC-induced ROS decreased expression of microRNA 27a (miR-27a)/miR-20a:miR-17-5p and induced miR-regulated ZBTB10/ZBTB4 and ZBTB34 transcriptional repressors, which, in turn, downregulate specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells. Decreased expression of miR-27a/miR-20a:miR-17-5p by PEITC-induced ROS is a key step in triggering the miR-ZBTB Sp cascade leading to downregulation of Sp TFs, and this is due to ROS-dependent epigenetic effects associated with genome-wide shifts in repressor complexes, resulting in decreased expression of Myc and the Myc-regulated miRs. Knockdown of Sp1 alone by RNA interference also induced apoptosis and decreased pancreatic cancer cell growth and invasion, indicating that downregulation of Sp transcription factors is an important common mechanism of action for PEITC and other ROS-inducing anticancer agents. PMID:24732804

  13. Immuno-chemotherapeutic platinum(IV) prodrugs of cisplatin as multimodal anticancer agents.

    PubMed

    Wong, Daniel Yuan Qiang; Yeo, Charmian Hui Fang; Ang, Wee Han

    2014-06-23

    There is growing consensus that the clinical therapeutic efficacy of some chemotherapeutic agents depends on their off-target immune-modulating effects. Pt anticancer drugs have previously been identified to be potent immunomodulators of both the innate and the adaptive immune system. Nevertheless, there has been little development in the rational design of Pt-based chemotherapeutic agents to exploit their immune-activating capabilities. The FPR1/2 formyl peptide receptors are highly expressed in immune cells, as well as in many metastatic cancers. Herein, we report a rationally designed multimodal Pt(IV) prodrug containing a FPR1/2-targeting peptide that combines chemotherapy with immunotherapy to achieve therapeutic synergy and demonstrate the feasibility of this approach. PMID:24844571

  14. Dual Extraction of Essential Oil and Podophyllotoxin from Juniperus virginiana

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The leaves (needles) of Eastern red cedar (Juniperus virginiana L.) contain two important natural products: essential oil and podophyllotoxin. The hypothesis of this study was that it may be possible to extract both essential oil and podophyllotoxin from the leaves of the tree, by using a dual extra...

  15. 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

  16. 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 ?-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 ?-anomer caused a drastic accumulation of ceramide and glucosylceramide and reduction of lactosylceramide and GM3 ganglioside at concentrations above a threshold of 20 ?M. In order to understand how ceramide levels increase in response to ?-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 ?-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

  17. Engineering of Bacteria for the Visualization of Targeted Delivery of a Cytolytic Anticancer Agent

    PubMed Central

    Jiang, Sheng-Nan; Park, Seung-Hwan; Lee, Hee Jung; Zheng, Jin Hai; Kim, Hyung-Seok; Bom, Hee-Seung; Hong, Yeongjin; Szardenings, Michael; Shin, Myung Geun; Kim, Sun-Chang; Ntziachristos, Vasilis; Choy, Hyon E; Min, Jung-Joon

    2013-01-01

    A number of recent reports have demonstrated that attenuated Salmonella typhimurium are capable of targeting both primary and metastatic tumors. The use of bacteria as a vehicle for the delivery of anticancer drugs requires a mechanism that precisely regulates and visualizes gene expression to ensure the appropriate timing and location of drug production. To integrate these functions into bacteria, we used a repressor-regulated tetracycline efflux system, in which the expression of a therapeutic gene and an imaging reporter gene were controlled by divergent promoters (tetAP and tetRP) in response to extracellular tetracycline. Attenuated S. typhimurium was transformed with the expression plasmids encoding cytolysin A, a therapeutic gene, and renilla luciferase variant 8, an imaging reporter gene, and administered intravenously to tumor-bearing mice. The engineered Salmonella successfully localized to tumor tissue and gene expression was dependent on the concentration of inducer, indicating the feasibility of peripheral control of bacterial gene expression. The bioluminescence signal permitted the localization of gene expression from the bacteria. The engineered bacteria significantly suppressed both primary and metastatic tumors and prolonged survival in mice. Therefore, engineered bacteria that carry a therapeutic and an imaging reporter gene for targeted anticancer therapy can be designed as a theranostic agent. PMID:23922014

  18. Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001

    PubMed Central

    Ning, Shoucheng; Sekar, Thillai Veerapazham; Scicinski, Jan; Oronsky, Bryan; Peehl, Donna M.; Knox, Susan J.; Paulmurugan, Ramasamy

    2015-01-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulatory transcription factor that plays an important role in the antioxidant response pathway against anticancer drug-induced cytotoxic effects. RRx-001 is a new anticancer agent that generates reactive oxygen and nitrogen species, and leads to epigenetic alterations in cancer cells. Here we report the RRx-001 mediated nuclear translocation of Nrf2 and the activation of expression of its downstream enzymes HO-1 and NQO1 in tumor cells. Inhibition of intrinsic Nrf2 expression by Nrf2-specific siRNA increased cell sensitivity to RRx-001. Molecular imaging of tumor cells co-expressing pARE-Firefly luciferase and pCMV-Renilla luciferase-mRFP in vitro and in vivo in mice revealed that RRx-001 significantly increased ARE-FLUC signal in cells in a dose- and time-dependent manner, suggesting that RRx-001 is an effective activator of the Nrf2-ARE signaling pathway. The pre-treatment level of ARE-FLUC signal in cells, reflecting basal activity of Nrf2, negatively correlated with the tumor response to RRx-001. The results support the concept that RRx-001 activates Nrf2-ARE antioxidant signaling pathways in tumor cells. Hence measurement of Nrf2-mediated activation of downstream target genes through ARE signaling may constitute a useful molecular biomarker for the early prediction of response to RRx-001 treatment, and thereby guide therapeutic decision-making. PMID:26280276

  19. Design, synthesis and biological evaluation of arylcinnamide hybrid derivatives as novel anticancer agents

    PubMed Central

    Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Chayah, Mariem; Camacho, M. Encarnacion; Prencipe, Filippo; Hamel, Ernest; Consolaro, Francesca; Basso, Giuseppe; Viola, Giampietro

    2014-01-01

    The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. A series of novel antiproliferative agents designed by a pharmacophore hybridization approach, combining the arylcinnamide skeleton and an ?-bromoacryloyl moiety, was synthesized and evaluated for its antiproliferative activity against a panel of seven human cancer cell lines. In addition, the new derivatives were also active on multidrug-resistant cell lines over-expressing P-glycoprotein. The biological effects of various substituents on the N-phenyl ring of the benzamide portion were also described. In order to study the possible mechanism of action, we observed that 4p slightly increased the Reactive Oxygen Species (ROS) production in HeLa cells, but, more importantly, a remarkable decrease of intracellular reduced glutathione content was detected in treated cells compared with controls. These results were confirmed by the observation that only thiol-containing antioxidants were able to significantly protect the cells from induced cell death. Altogether our results indicate that the new derivatives are endowed with good anticancer activity in vitro, and their properties may result in the development of new cancer therapeutic strategies. PMID:24858544

  20. Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001.

    PubMed

    Ning, Shoucheng; Sekar, Thillai Veerapazham; Scicinski, Jan; Oronsky, Bryan; Peehl, Donna M; Knox, Susan J; Paulmurugan, Ramasamy

    2015-08-28

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulatory transcription factor that plays an important role in the antioxidant response pathway against anticancer drug-induced cytotoxic effects. RRx-001 is a new anticancer agent that generates reactive oxygen and nitrogen species, and leads to epigenetic alterations in cancer cells. Here we report the RRx-001 mediated nuclear translocation of Nrf2 and the activation of expression of its downstream enzymes HO-1 and NQO1 in tumor cells. Inhibition of intrinsic Nrf2 expression by Nrf2-specific siRNA increased cell sensitivity to RRx-001. Molecular imaging of tumor cells co-expressing pARE-Firefly luciferase and pCMV-Renilla luciferase-mRFP in vitro and in vivo in mice revealed that RRx-001 significantly increased ARE-FLUC signal in cells in a dose- and time-dependent manner, suggesting that RRx-001 is an effective activator of the Nrf2-ARE signaling pathway. The pre-treatment level of ARE-FLUC signal in cells, reflecting basal activity of Nrf2, negatively correlated with the tumor response to RRx-001. The results support the concept that RRx-001 activates Nrf2-ARE antioxidant signaling pathways in tumor cells. Hence measurement of Nrf2-mediated activation of downstream target genes through ARE signaling may constitute a useful molecular biomarker for the early prediction of response to RRx-001 treatment, and thereby guide therapeutic decision-making. PMID:26280276

  1. Design, Synthesis, and In Vitro Evaluation of Novel 3, 7-Disubstituted Coumarin Derivatives as Potent Anticancer Agents.

    PubMed

    Wang, Yubin; Liu, Haitao; Lu, Peng; Mao, Rui; Xue, Xiaojian; Fan, Chen; She, Jinxiong

    2015-10-01

    Twenty-seven 3, 7-disubstituted coumarin derivatives were designed, synthesized, and evaluated in vitro as anticancer agents. Most of the compounds showed moderate-to-potent antiproliferative activity against K562 cells. Compounds 7b and 7d were chosen to evaluate the concentration of 50% growth inhibition (GI50 ) against SN12C, OVCAR, BxPC-3, KATO-III, T24, SNU-1, WiDr, HeLa, K562, and AGS cell lines. The most potent compound 7d was selected for further cell cycle arrest assay in the AGS cell line. The in vitro data indicated that methylation of benzimidazole moiety at the 3-position of coumarin exhibited significant enhancement of anticancer activity. This study should provide important information for further modification and optimization of coumarin derivatives as anticancer agents. PMID:25626768

  2. Novel capsaicin analogues as potential anticancer agents: synthesis, biological evaluation, and in silico approach.

    PubMed

    Damião, Mariana C F C B; Pasqualoto, Kerly F M; Ferreira, Adilson K; Teixeira, Sarah F; Azevedo, Ricardo A; Barbuto, José A M; Palace-Berl, Fanny; Franchi-Junior, Gilberto C; Nowill, Alexandre E; Tavares, Maurício T; Parise-Filho, Roberto

    2014-12-01

    A novel class of benzo[d][1,3]dioxol-5-ylmethyl alkyl/aryl amide and ester analogues of capsaicin were designed, synthesized, and evaluated for their cytotoxic activity against human and murine cancer cell lines (B16F10, SK-MEL-28, NCI-H1299, NCI-H460, SK-BR-3, and MDA-MB-231) and human lung fibroblasts (MRC-5). Three compounds (5f, 6c, and 6e) selectively inhibited the growth of aggressive cancer cells in the micromolar (µM) range. Furthermore, an exploratory data analysis pointed at the topological and electronic molecular properties as responsible for the discrimination process regarding the set of investigated compounds. The findings suggest that the applied designing strategy, besides providing more potent analogues, indicates the aryl amides and esters as well as the alkyl esters as interesting scaffolds to design and develop novel anticancer agents. PMID:25283529

  3. Investigation of Degradation Properties of Poly(lactide-co-glycolide) Matrix for Anticancer Agent Delivery

    SciTech Connect

    Ghani, S. M.; Mohamed, M. S. W.; Yahya, A. F.; Noorsal, K.

    2010-03-11

    Poly(lactide-co-glycolide)(PLA{sub 50}GA{sub 50}) is a biodegradable and biocompatible polymer. It offers tremendous potential as a basis for drug delivery, either as drug delivery system alone or in conjugate with a medical device. The PLA{sub 50}GA{sub 50} is the material of choice for relatively shorter-duration applications, while the homopolymer PLA (poly-L-lactide) and PGA (polyglycolide) are preferred for longer term delivery of drugs. This paper discusses the degradation properties of poly(lactide-co-glycolide)(PLA{sub 50}GA{sub 50}) at inherent viscosity of 0.89 dL/g as preliminary studies for anticancer agent delivery.

  4. Novel anticancer agent, SQAP, binds to focal adhesion kinase and modulates its activity

    PubMed Central

    Izaguirre-Carbonell, Jesus; Kawakubo, Hirofumi; Murata, Hiroshi; Tanabe, Atsushi; Takeuchi, Toshifumi; Kusayanagi, Tomoe; Tsukuda, Senko; Hirakawa, Takeshi; Iwabata, Kazuki; Kanai, Yoshihiro; Ohta, Keisuke; Miura, Masahiko; Sakaguchi, Kengo; Matsunaga, Sachihiro; Sahara, Hiroeki; Kamisuki, Shinji; Sugawara, Fumio

    2015-01-01

    SQAP is a novel and promising anticancer agent that was obtained by structural modifications from a natural compound. SQAP inhibits angiogenesis in vivo resulting in increased hypoxia and reduced tumor volume. In this study, the mechanism by which SQAP modifies the tumor microenvironment was revealed through the application of a T7 phage display screening. This approach identified five SQAP-binding proteins including sterol carrier protein 2, multifunctional enzyme type 2, proteasomal ubiquitin receptor, UV excision repair protein and focal adhesion kinase (FAK). All the interactions were confirmed by surface plasmon resonance analysis. Since FAK plays an important role in cell turnover and angiogenesis, the influence of SQAP on FAK was the principal goal of this study. SQAP decreased FAK phosphorylation and cell migration in human umbilical vein endothelial cells and A549 cancer cells. These findings suggest that inhibition of FAK phosphorylation works as the mechanism for the anti-angiogenesis activity of SQAP. PMID:26456697

  5. Novel anticancer agent, SQAP, binds to focal adhesion kinase and modulates its activity.

    PubMed

    Izaguirre-Carbonell, Jesus; Kawakubo, Hirofumi; Murata, Hiroshi; Tanabe, Atsushi; Takeuchi, Toshifumi; Kusayanagi, Tomoe; Tsukuda, Senko; Hirakawa, Takeshi; Iwabata, Kazuki; Kanai, Yoshihiro; Ohta, Keisuke; Miura, Masahiko; Sakaguchi, Kengo; Matsunaga, Sachihiro; Sahara, Hiroeki; Kamisuki, Shinji; Sugawara, Fumio

    2015-01-01

    SQAP is a novel and promising anticancer agent that was obtained by structural modifications from a natural compound. SQAP inhibits angiogenesis in vivo resulting in increased hypoxia and reduced tumor volume. In this study, the mechanism by which SQAP modifies the tumor microenvironment was revealed through the application of a T7 phage display screening. This approach identified five SQAP-binding proteins including sterol carrier protein 2, multifunctional enzyme type 2, proteasomal ubiquitin receptor, UV excision repair protein and focal adhesion kinase (FAK). All the interactions were confirmed by surface plasmon resonance analysis. Since FAK plays an important role in cell turnover and angiogenesis, the influence of SQAP on FAK was the principal goal of this study. SQAP decreased FAK phosphorylation and cell migration in human umbilical vein endothelial cells and A549 cancer cells. These findings suggest that inhibition of FAK phosphorylation works as the mechanism for the anti-angiogenesis activity of SQAP. PMID:26456697

  6. Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications.

    PubMed

    Bar-Sela, G; Epelbaum, R; Schaffer, M

    2010-01-01

    Curcumin, commonly called diferuloyl methane, is a hydrophobic polyphenol derived from rhizome (turmeric) of the herb Curcuma longa. Extensive research over the last half century has revealed important functions of curcumin. In vitro and in vivo research has shown various activities, such as anti-inflammatory, cytokines release, antioxidant, immunomodulatory, enhancing of the apoptotic process, and anti-angiogenic properties. Curcumin has also been shown to be a mediator of chemo-resistance and radio-resistance. The anti-cancer effect has been seen in a few clinical trials, mainly as a native chemoprevention agent in colon and pancreatic cancer, cervical neoplasia and Barrets metaplasia. Some clinical studies with healthy volunteers revealed a low bioavailability of curcumin, casting doubt on the use of curcumin only as food additive. Our clinical experience with curcumin, along with the anti-metabolite gemcitabine in the treatment of patients with advanced pancreatic carcinoma, produced an objective response in less than 10% of patients, with a minor effect on survival. However, the safety of this combination was proved. Curcumin's potent anti-proliferative activity interacting with several intracellular signal transduction pathways may potentiate the anti-tumor effect of gemcitabine. The preclinical data lead to various, but still scarce, clinical studies (some on-going) that demonstrated the possible efficacy of this treatment as a chemopreventive or chemotherapeutic agent. This review will focus on the clinical evidence, including our experience with curcumin as a chemopreventive and therapeutic agent and the in vitro background results. PMID:20214562

  7. Synthesis of Some Benzimidazole Derivatives Bearing 1,3,4-Oxadiazole Moiety as Anticancer Agents

    PubMed Central

    MAZZIO, ELIZABETH; GANGAPURUM, MADHAVEI; MATEEVA, NELLY; REDDA, K. K.

    2015-01-01

    In an effort to establish new benzimidazole related structural leads with improved anticancer activity, several new benzimidazole derivatives (5a–i) with 1,3,4-oxadiazole scaffold incorporated were synthesized and studied for their anticancer activity. The anticancer screening against MDA-MB-231 breast cancer cell lines showed that compound (5c) exhibited moderate cytotoxicity. PMID:26451350

  8. Multiple-pool cell lifespan model of hematologic effects of anticancer agents.

    PubMed

    Krzyzanski, Wojciech; Jusko, William J

    2002-08-01

    The leukopenic effects of anticancer agents are described using a semi-physiologic multiple-pool cell lifespan model. The time course of myelosuppression in relation to the drug concentration vs. time profile was characterized using a three pool indirect model. The proliferation and maturation stages of myeloid cells in the bone marrow and cell removal from the circulation were quantitated with a cell life-span concept. Drug effects were assumed to take place in the bone marrow based on irreversible linear or capacity-limited cytotoxicity. Mathematical derivations and computer simulations (Adapt II) were used to examine the properties of the model. Data from the literature were also analyzed. Cell response profiles after therapy typically exhibit a lag period, reduction to a nadir, and return to baseline. The predicted values of the time periods of granulopoiesis were 10-14 days for proliferation, and 1-6 days for maturation of progenitor cells in the bone marrow. The proposed irreversible mechanism of cell killing by anticancer drugs explains previously observed relationships between leukocyte nadir counts and exposure to the drug and/or duration of drug concentrations above some threshold level. The model was applied to literature data for paclitaxel and etoposide effects on leukocyte counts. The predicted value of KC50 for paclitaxel ranged from 0.004 to 0.2 microgram/mL and for etoposide 2 micrograms/mL. The present model accounts for drug-induced leukopenia using a physiologic cell production and loss model and irreversible cytotoxicity in a precursor pool. PMID:12518707

  9. Ruthenium(II) polypyridyl complexes as mitochondria-targeted two-photon photodynamic anticancer agents.

    PubMed

    Liu, Jiangping; Chen, Yu; Li, Guanying; Zhang, Pingyu; Jin, Chengzhi; Zeng, Leli; Ji, Liangnian; Chao, Hui

    2015-07-01

    Clinical acceptance of photodynamic therapy is currently hindered by poor depth efficacy and inefficient activation of the cell death machinery in cancer cells during treatment. To address these issues, photoactivation using two-photon absorption (TPA) is currently being examined. Mitochondria-targeted therapy represents a promising approach to target tumors selectively and may overcome the resistance in current anticancer therapies. Herein, four ruthenium(II) polypyridyl complexes (RuL1-RuL4) have been designed and developed to act as mitochondria-targeted two-photon photodynamic anticancer agents. These complexes exhibit very high singlet oxygen quantum yields in methanol (0.74-0.81), significant TPA cross sections (124-198 GM), remarkable mitochondrial accumulation, and deep penetration depth. Thus, RuL1-RuL4 were utilized as one-photon and two-photon absorbing photosensitizers in both monolayer cells and 3D multicellular spheroids (MCSs). These Ru(II) complexes were almost nontoxic towards cells and 3D MCSs in the dark and generate sufficient singlet oxygen under one- and two-photon irradiation to trigger cell death. Remarkably, RuL4 exhibited an IC50 value as low as 9.6 ?M in one-photon PDT (?irr = 450 nm, 12 J cm(-2)) and 1.9 ?M in two-photon PDT (?irr = 830 nm, 800 J cm(-2)) of 3D MCSs; moreover, RuL4 is an order of magnitude more toxic than cisplatin in the latter test system. The combination of mitochondria-targeting and two-photon activation provides a valuable paradigm to develop ruthenium(II) complexes for PDT applications. PMID:25934287

  10. Design, synthesis, and biological evaluation of callophycin A and analogues as potential chemopreventive and anticancer agents.

    PubMed

    Shen, Li; Park, Eun-Jung; Kondratyuk, Tamara P; Guendisch, Daniela; Marler, Laura; Pezzuto, John M; Wright, Anthony D; Sun, Dianqing

    2011-11-01

    Callophycin A was originally isolated from the red algae Callophycus oppositifolius and shown to mediate anticancer and cytotoxic effects. In our collaborative effort to identify potential chemopreventive and anticancer agents with enhanced potency and selectivity, we employed a tetrahydro-?-carboline-based template inspired by callophycin A for production of a chemical library. Utilizing a parallel synthetic approach, 50 various functionalized tetrahydro-?-carboline derivatives were prepared and assessed for activities related to cancer chemoprevention and cancer treatment: induction of quinone reductase 1 (QR1) and inhibition of aromatase, nitric oxide (NO) production, tumor necrosis factor (TNF)-?-induced NF?B activity, and MCF7 breast cancer cell proliferation. Biological results showed that the n-pentyl urea S-isomer 6a was the strongest inducer of QR1 with an induction ratio (IR) value of 4.9 at 50 ?M [the concentration to double the activity (CD)=3.8 ?M] and its corresponding R-isomer 6f had an IR value of 4.3 (CD=0.2 ?M). The isobutyl carbamate derivative 3d with R stereochemistry demonstrated the most potent inhibitory activity of NF?B, with the half maximal inhibitory concentration (IC(50)) value of 4.8 ?M, and also showed over 60% inhibition at 50 ?M of NO production (IC(50)=2.8 ?M). The R-isomer urea derivative 6j, having an appended adamantyl group, exhibited the most potent MCF7 cell proliferation inhibitory activity (IC(50)=14.7 ?M). The S-isomer 12a of callophycin A showed the most potent activity in aromatase inhibition (IC(50)=10.5 ?M). PMID:21978950

  11. A novel valproic acid prodrug as an anticancer agent that enhances doxorubicin anticancer activity and protects normal cells against its toxicity in vitro and in vivo.

    PubMed

    Tarasenko, Nataly; Cutts, Suzanne M; Phillips, Don R; Berkovitch-Luria, Gili; Bardugo-Nissim, Elinor; Weitman, Michal; Nudelman, Abraham; Rephaeli, Ada

    2014-03-15

    The poor survival of patients with malignant gliomas, underscores the need to develop effective treatment modalities for this devastating disease. Epigenetic agents used in combination with chemotherapy provide a promising approach to evoke synergistic cytotoxicity in glioblastomas. Previously we have described the cytotoxic synergy between a butyric acid prodrug and radiation in glioblastoma cell lines and the potentiation of radiation efficacy in glioma xenografts. Herein, we describe and compare the activities of AN446 (valproyl ester-valpramide of acyclovir) a novel histone deacetylase inhibitor (HDACI) to the previously described AN7 a HDACI prodrug of butyric acid. In various cancer cell lines, AN446 was a ~2-5-fold more potent anticancer agent HDACI than AN7. While AN446 augmented the anticancer efficacy of doxorubicin (Dox) it also reduced the Dox toxicity in non-cancerous cells. The interaction between AN446 and Dox in U251 and in 4T1 cell lines was synergistic in inducing cytotoxicity. We examined the concomitant physical and molecular changes in the tumor and heart of glioblastoma xenografts treated with AN446, AN7, Dox and the combination of the prodrugs with Dox. A weekly dose of 4 mg/kg Dox, caused toxicity in mice whereas AN446 (25mg/kg) or AN7 (50mg/kg) administered thrice weekly, did not. When Dox was administered with AN446 or AN7, the prodrugs ameliorated the decline in body weight, prolonged the time to failure and increased anticancer efficacy. Thus, the combination of Dox with AN446 or AN7 could add safety and efficacy to future treatment protocols for treating glioblastoma and other cancers. PMID:24463168

  12. A Novel Isoquinoline Derivative Anticancer Agent and Its Targeted Delivery to Tumor Cells Using Transferrin-Conjugated Liposomes

    PubMed Central

    Yang, Xuewei; Yang, Shuang; Chai, Hongyu; Yang, Zhaogang; Lee, Robert J.; Liao, Weiwei; Teng, Lesheng

    2015-01-01

    We have screened 11 isoquinoline derivatives and ?-methylene-?-butyrolactones using the 3-(4,5-dimethylthi-azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay in HeLa and HEK-293T cells. Compound 2 was identified as potential anticancer agent. To further improve its therapeutic potential, this agent was incorporated into transferrin (Tf)-conjugated liposomes (LPs) for targeted delivery to tumor cells. We have demonstrated Tf-LP-Compound 2 have superior antitumor activity compared to non-targeted controls and the free drug. These data show Tf-LP-Compound 2 to be a promising agent that warrants further evaluation. PMID:26309138

  13. The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.

    PubMed Central

    Kivistö, K T; Kroemer, H K; Eichelbaum, M

    1995-01-01

    1. Little information is available about the pharmacokinetic interactions of anticancer drugs in man. However, clinically significant drug interactions do occur in cancer chemotherapy, and it is likely that important interactions have not been recognized. 2. Specific cytochrome P450 (CYP) enzymes have been recently shown to be involved in the metabolism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer drugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide could be activated in tumour tissues containing this enzyme. 3. As examples of recently found, clinically significant interactions, cyclosporin considerably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhibitors inhibit P-glycoprotein mediated drug elimination. 4. Appropriate caution should be exercised when combining P-glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy. PMID:8703657

  14. Synthesis and evaluation of a series of benzothiophene acrylonitrile analogs as anticancer agents.

    PubMed

    Penthala, Narsimha Reddy; Sonar, Vijayakumar N; Horn, Jamie; Leggas, Markos; Yadlapalli, Jai Shankar K B; Crooks, Peter A

    2013-07-01

    A new library of small molecules with structural features resembling combretastatin analogs was synthesized and evaluated for anticancer activity against a panel of 60 human cancer cell lines. Three novel acrylonitrile analogs (5, 6 and 13) caused a significant reduction in cell growth in almost all the cell lines examined, with GI50 values generally in the range 10-100 nM. Based on the structural characteristics of similar drugs, we hypothesized that the cytotoxic activity was likely due to interaction with tubulin. Furthermore, these compounds appeared to overcome cell-associated P-glycoprotein (P-gp)-mediated resistance, since they were equipotent in inhibiting OVCAR8 and NCI/ADR-Res cell growth. Given that antitubulin drugs are among the most effective agents for the treatment of advanced prostate cancer we sought to validate the results from the 60 cell panel by studying the representative analog 6 utilizing prostate cancer cell lines, as well as exploring the molecular mechanism of the cytotoxic action of this analog. PMID:23956835

  15. Rescuing chemotaxis of the anticancer agent Salmonella enterica serovar Typhimurium VNP20009.

    PubMed

    Broadway, Katherine M; Denson, Elizabeth A P; Jensen, Roderick V; Scharf, Birgit E

    2015-10-10

    The role of chemotaxis and motility in Salmonella enterica serovar Typhimurium tumor colonization remains unclear. We determined through swim plate assays that the well-established anticancer agent S. Typhimurium VNP20009 is deficient in chemotaxis, and that this phenotype is suppressible. Through genome sequencing, we revealed that VNP20009 and four selected suppressor mutants had a single nucleotide polymorphism (SNP) in cheY causing a mutation in the conserved proline residue at position 110. CheY is the response regulator that interacts with the flagellar motor-switch complex and modulates rotational bias. The four suppressor mutants additionally carried non-synonymous SNPs in fliM encoding a flagellar switch protein. The CheY-P110S mutation in VNP20009 likely rendered the protein unable to interact with FliM, a phenotype that could be suppressed by mutations in FliM. We replaced the mutated cheY in VNP20009 with the wild-type copy and chemotaxis was partially restored. The swim ring of the rescued strain, VNP20009 cheY(+), was 46% the size of the parental strain 14028 swim ring. When tested in capillary assays, VNP20009 cheY(+) was 69% efficient in chemotaxis towards the attractant aspartate as compared to 14028. Potential reasons for the lack of complete restoration and implications for bacterial tumor colonization will be discussed. PMID:26200833

  16. Parthenium hysterophorus: A Probable Source of Anticancer, Antioxidant and Anti-HIV Agents

    PubMed Central

    Kumar, Shashank; Chashoo, Gousia; Saxena, Ajit K.; Pandey, Abhay K.

    2013-01-01

    The present work reports the anticancer, antioxidant, lipo-protective, and anti-HIV activities of phytoconstituents present in P. hysterophorus leaf. Dried leaf samples were sequentially extracted with nonpolar and polar solvents. Ethanol fraction showed noticeable cytotoxic activity (81–85%) in SRB assay against MCF-7 and THP-1 cancer cell lines at 100??g/ml concentration, while lower activity was observed with DU-145 cell line. The same extract exhibited 17–98% growth inhibition of HL-60 cancer cell lines in MTT assay, showing concentration dependent response. Ethanol extract caused 12% reduction in mitochondrial membrane potential and 10% increment in sub G1 population of HL-60 cell lines. Several leaf fractions, namely, ethyl acetate, ethanol, and aqueous fractions exhibited considerable reducing capability at higher concentrations. Most of the extracts demonstrated appreciable (>75%) metal ion chelating and hydroxyl radical scavenging activities at 200?µg/ml. All the extracts except aqueous fraction accounted for about 70–80% inhibition of lipid peroxidation in rat liver homogenate indicating protective response against membrane damage. About 40% inhibition of reverse transcriptase (RT) activity was observed in hexane fraction in anti-HIV assay at 6.0?µg/ml concentration. The study showed that phytochemicals present in P. hysterophorus leaf have considerable potential as cytotoxic and antioxidant agents with low to moderate anti-HIV activity. PMID:24350290

  17. Inkjet printing of transdermal microneedles for the delivery of anticancer agents.

    PubMed

    Uddin, Md Jasim; Scoutaris, Nicolaos; Klepetsanis, Pavlos; Chowdhry, Babur; Prausnitz, Mark R; Douroumis, Dennis

    2015-10-30

    A novel inkjet printing technology is introduced as a process to coat metal microneedle arrays with three anticancer agents 5-fluororacil, curcumin and cisplatin for transdermal delivery. The hydrophilic graft copolymer Soluplus(®) was used as a drug carrier and the coating formulations consisted of drug-polymer solutions at various ratios. A piezoelectric dispenser jetted microdroplets on the microneedle surface to develop uniform, accurate and reproducible coating layers without any material losses. Inkjet printing was found to depend on the nozzle size, the applied voltage (mV) and the duration of the pulse (?s). The drug release rates were determined in vitro using Franz type diffusion cells with dermatomed porcine skin. The drug release rates depended on the drug-polymer ratio, the drug lipophilicity and the skin thickness. All drugs presented increased release profiles (750?m skin thickness), which were retarded for 900?m skin thickness. Soluplus assisted the drug release especially for the water insoluble curcumin and cisplatin due to its solubilizing capacity. Inkjet printing has been shown to be an effective technology for coating of metal microneedles which can then be used for further transdermal drug delivery applications. PMID:25617676

  18. Treatment Strategies that Enhance the Efficacy and Selectivity of Mitochondria-Targeted Anticancer Agents

    PubMed Central

    Modica-Napolitano, Josephine S.; Weissig, Volkmar

    2015-01-01

    Nearly a century has passed since Otto Warburg first observed high rates of aerobic glycolysis in a variety of tumor cell types and suggested that this phenomenon might be due to an impaired mitochondrial respiratory capacity in these cells. Subsequently, much has been written about the role of mitochondria in the initiation and/or progression of various forms of cancer, and the possibility of exploiting differences in mitochondrial structure and function between normal and malignant cells as targets for cancer chemotherapy. A number of mitochondria-targeted compounds have shown efficacy in selective cancer cell killing in pre-clinical and early clinical testing, including those that induce mitochondria permeability transition and apoptosis, metabolic inhibitors, and ROS regulators. To date, however, none has exhibited the standards for high selectivity and efficacy and low toxicity necessary to progress beyond phase III clinical trials and be used as a viable, single modality treatment option for human cancers. This review explores alternative treatment strategies that have been shown to enhance the efficacy and selectivity of mitochondria-targeted anticancer agents in vitro and in vivo, and may yet fulfill the clinical promise of exploiting the mitochondrion as a target for cancer chemotherapy. PMID:26230693

  19. Microencapsulation of lectin anti-cancer agent and controlled release by alginate beads, biosafety approach.

    PubMed

    El-Aassar, M R; Hafez, Elsayed E; El-Deeb, Nehal M; Fouda, Moustafa M G

    2014-08-01

    Hepatocellular carcinoma (HCC) is considered as one of the most aggressive cancer worldwide. In Egypt, the prevalence of HCC is increasing during last years. Recently, drug-loaded microparticles were used to improve the efficiency of various medical treatments. This study is designed to evaluate the anticancer potentialities of lectins against HCC while hinting to its safety usage. The aim is also extended to encapsulate lectins in alginate microbeads for oral drug delivery purposes. The extracted lectins showed anti-proliferative effect against HCC with a percentage of 60.76% by using its nontoxic dose with an up-regulation of P53 gene expression. Concerning the handling of lectin alginate microbeads for oral drug delivery, the prepared lectin alginate beads were ?100?m in diameter. The efficiency of the microcapsules was checked by scanning electron microscopy, the SEM showed the change on the alginate beads surface revealing the successful lectin encapsulation. The release of lectins from the microbeads depended on a variety of factors as the microbeads forming carriers and the amount-encapsulated lectins. The Pisum sativum extracted lectins may be considered as a promising agent in controlling HCC and this solid dosage form could be suitable for oral administration complemented with/or without the standard HCC drugs. PMID:24857870

  20. Preformulation studies of a novel camptothecin anticancer agent, CKD-602: physicochemical characterization and hydrolytic equilibrium kinetics.

    PubMed

    Kim, Jae-Hyun; Lee, Seok-Kyu; Lim, Jong-Lae; Shin, Hee-Jong; Hong, Chung Il

    2002-06-01

    (20S)-7-(2-isopropylamino)ethylcamptothecin.HCl (CKD-602), a new camptothecin (CPT) anticancer agent, is a pale yellowish crystalline compound. DSC thermogram exhibited a melt endotherm near 270 degrees C, and CKD-602 was found to be slightly hygroscopic. The solubility of CKD-602 in deionized water was 8.22 mg/ml, and two pK(a) values were measured to be 2.32 and 9.15, respectively. A pH-dependent partition coefficient behavior in octanol-buffer was observed. CKD-602 in solid state was stable over the range of temperature and humidity, but decomposed slightly by light. The hydrolysis of CKD-602 occurred reversibly and rapidly in aqueous buffer solutions. The conversion rate constants (k(f): from the lactone to the carboxylate and k(r): from the carboxylate to the lactone) and the final equilibrium ratio (K(eq)) between two species were dependent on the pH of aqueous solutions. PMID:12052706

  1. Synthesis and evaluation of a series of benzothiophene acrylonitrile analogs as anticancer agents

    PubMed Central

    Penthala, Narsimha Reddy; Sonar, Vijayakumar, N.; Horn, Jamie; Leggas, Markos; Yadlapalli, Jai Shankar K. B.; Crooks, Peter A.

    2013-01-01

    A new library of small molecules with structural features resembling combretastatin analogs was synthesized and evaluated for anticancer activity against a panel of 60 human cancer cell lines. Three novel acrylonitrile analogs (5, 6 and 13) caused a significant reduction in cell growth in almost all the cell lines examined, with GI50 values generally in the range 10–100 nM. Based on the structural characteristics of similar drugs, we hypothesized that the cytotoxic activity was likely due to interaction with tubulin. Furthermore, these compounds appeared to overcome cell-associated P-glycoprotein (P-gp)-mediated resistance, since they were equipotent in inhibiting OVCAR8 and NCI/ADR-Res cell growth. Given that antitubulin drugs are among the most effective agents for the treatment of advanced prostate cancer we sought to validate the results from the 60 cell panel by studying the representative analog 6 utilizing prostate cancer cell lines, as well as exploring the molecular mechanism of the cytotoxic action of this analog. PMID:23956835

  2. Genome-wide Association and Pharmacological Profiling of 29 Anticancer Agents Using Lymphoblastoid Cell Lines

    PubMed Central

    Brown, Chad C.; Havener, Tammy M.; Medina, Marisa W.; Jack, John R.; Krauss, Ronald M.; McLeod, Howard L.; Motsinger-Reif, Alison A.

    2014-01-01

    Aims Association mapping with lymphoblastoid cell lines (LCLs) is a promising approach in pharmacogenomics research, and in the current study we utilize this model to perform association mapping for 29 chemotherapy drugs. Materials and Methods Currently, we use LCLs to perform genome-wide association mapping of the cytotoxic response of 520 European Americans to 29 different anticancer drugs, the largest LCL study to date. A novel association approach using a multivariate analysis of covariance design was employed with the software program MAGWAS, testing for differences in the dose-response profiles between genotypes without making assumptions about the response curve or the biological mode of association. Additionally, by classifying 25 of the 29 drugs into 8 families according to structural and mechanistic relationships, MAGWAS was used to test for associations that were shared across each drug family. Finally, a unique algorithm using multivariate responses and multiple linear regressions across pairs of response curves was used for unsupervised clustering of drugs. Results Among the single drug studies, suggestive associations were obtained for 18 loci, 12 within/near genes. Three of these, MED12L, CHN2 and MGMT, have been previously implicated in cancer pharmacogenomics. The drug family associations resulted in 4 additional suggestive loci (3 contained within/near genes). One of these genes, HDAC4, associated with the DNA alkylating agents, shows possible clinical interactions with temozolomide. For the drug clustering analysis, 18 of 25 drugs clustered into the appropriate family. Conclusions This study demonstrates the utility of LCLs for identifying genes having clinical importance in drug response, for assigning unclassified agents to specific drug families, and proposes new candidate genes for follow-up in a large number of chemotherapy drugs. PMID:24444404

  3. [Visualization and analysis of adverse reactions of molecularly targeted anticancer agents using the self-organizing map (SOM)].

    PubMed

    Hamamoto, Tomoyuki; Serizawa, Ayaka; Ohtsuki, Kaori; Kawakami, Junko; Sato, Kenichi

    2014-01-01

    Molecularly targeted anticancer agents cause a variety of adverse reactions compared with conventional anticancer agents because of their unique mechanisms of action. Sources of drug information such as package inserts (PIs) provide primarily document-based and numerical information. Therefore it is not easy to obtain a complete picture of drugs with similar effects, or to understand differences among drugs. In this study we used the self-organizing map (SOM) technique to visualize the adverse reactions indicated on PIs of 23 molecularly targeted anticancer agents as of March 2013. In both the presence/absence version and the frequency version, SOM was divided into domains according to mechanism of action, antibody drug or low-molecular weight drug, and molecular target. The component planes of the 753 adverse reaction items in the frequency version enabled us to grasp all available information and differences among the drugs. In some component planes in the presence/absence version, an adverse reaction that had not been reported for a drug but had already been reported for its proximally positioned drug(s) as of March 2013, was found to be reported thereafter by the Drug Safety Update (DSU) or the Adverse Event Report Search System "CzeekV," which is based on FDA Adverse Event Reporting System (FAERS). Our results suggest that visualization of the adverse reactions of molecularly targeted anticancer agents by the SOM technique is useful not only to acquire all available information and differences among drugs, but also to predict the appearance of adverse reactions. PMID:25274218

  4. Rational design of biaryl pharmacophore inserted noscapine derivatives as potent tubulin binding anticancer agents.

    PubMed

    Santoshi, Seneha; Manchukonda, Naresh Kumar; Suri, Charu; Sharma, Manya; Sridhar, Balasubramanian; Joseph, Silja; Lopus, Manu; Kantevari, Srinivas; Baitharu, Iswar; Naik, Pradeep Kumar

    2015-03-01

    We have strategically designed a series of noscapine derivatives by inserting biaryl pharmacophore (a major structural constituent of many of the microtubule-targeting natural anticancer compounds) onto the scaffold structure of noscapine. Molecular interaction of these derivatives with ?,?-tubulin heterodimer was investigated by molecular docking, molecular dynamics simulation, and binding free energy calculation. The predictive binding affinity indicates that the newly designed noscapinoids bind to tubulin with a greater affinity. The predictive binding free energy (?G(bind, pred)) of these derivatives (ranging from -5.568 to -5.970 kcal/mol) based on linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model showed improved binding affinity with tubulin compared to the lead compound, natural ?-noscapine (-5.505 kcal/mol). Guided by the computational findings, these new biaryl type ?-noscapine congeners were synthesized from 9-bromo-?-noscapine using optimized Suzuki reaction conditions for further experimental evaluation. The derivatives showed improved inhibition of the proliferation of human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human lung adenocarcinoma cells (A549), compared to natural noscapine. The cell cycle analysis in MCF-7 further revealed that these compounds alter the cell cycle profile and cause mitotic arrest at G2/M phase more strongly than noscapine. Tubulin binding assay revealed higher binding affinity to tubulin, as suggested by dissociation constant (Kd) of 126 ± 5.0 µM for 5a, 107 ± 5.0 µM for 5c, 70 ± 4.0 µM for 5d, and 68 ± 6.0 µM for 5e compared to noscapine (Kd of 152 ± 1.0 µM). In fact, the experimentally determined value of ?G(bind, expt) (calculated from the Kd value) are consistent with the predicted value of ?G(bind, pred) calculated based on LIE-SGB. Based on these results, one of the derivative 5e of this series was used for further toxicological evaluation. Treatment of mice with a daily dose of 300 mg/kg and a single dose of 600 mg/kg indicates that the compound does not induce detectable pathological abnormalities in normal tissues. Also there were no significant differences in hematological parameters between the treated and untreated groups. Hence, the newly designed noscapinoid, 5e is an orally bioavailable, safe and effective anticancer agent with a potential for the treatment of cancer and might be a candidate for clinical evaluation. PMID:25481458

  5. Immune mechanisms regulating pharmacokinetics and pharmacodynamics of PEGylated liposomal anticancer agents

    NASA Astrophysics Data System (ADS)

    Song, Gina

    Nanotechnology has made significant advances in drug delivery system for the treatment of cancer. Among various nanoparticle (NP) platforms, liposomes have been most widely used as a NP drug carrier for cancer therapy. High variation in pharmacokinetics (PK) and pharmacodynamics (PD) of liposome-based therapeutics has been reported. However, the interaction of liposome-based therapeutics with the immune system, specifically the mononuclear phagocyte system (MPS), and underlying molecular mechanisms for variable responses to liposomal drugs remain poorly understood. The objective of this dissertation was to elucidate immune mechanisms for the variable responses to PEGylated liposomal doxorubicin (PLD; DoxilRTM), a clinically relevant NP, in animal models and in patients. In vitro, in vivo and clinical systems were investigated to evaluate the effects of chemokines (CCL2 and CCL5), heterogeneity of the tumor microenvironment, and genetic variations on PK and PD of PLD. Results showed that there was a significantly positive linear relationship between PLD exposure (AUC) and total amount of CCL2 and CCL5, most prevalent chemokines in plasma, in patients with recurrent ovarian cancer. Consistent with these findings, preclinical studies using mice bearing SKOV3 orthotopic ovarian cancer xenografts demonstrated that PLD induced the production and secretion of chemokines into plasma. In addition, in vitro studies using human monocytic THP-1 cells demonstrated that PLD altered monocyte migration towards CCL2 and CCL5. The PK and efficacy studies of PLD in murine models of breast cancer showed that heterogeneous tumor microenvironment was associated with significantly different tumor delivery and efficacy of PLD, but not small molecule doxorubicin between two breast tumor models. A candidate genetic locus that was associated with clearance of PLD in 23 inbred mouse strains contains a gene that encodes for engulfment adapter PTB domain containing 1 (Gulp1). By using integrated approaches, we were able to identify the immunological mechanisms at the molecular, tissue, and clinical levels that may contribute to inter-individual variability in PK and PD of PLD. This dissertation research has a potential to make an impact on development of future NP-based anticancer therapeutics as well as on clinical use of PLD (DoxilRTM) and other PEGylated liposomal anticancer agents.

  6. Novel linear and step-gradient counter-current chromatography for bio-guided isolation and purification of cytotoxic podophyllotoxins from Dysosma versipellis (Hance).

    PubMed

    Yang, Zhi; Liu, Xiaoman; Wang, Kuiwu; Cao, Xiaoji; Wu, Shihua

    2013-03-01

    Dysosma versipellis (Hance) is a famous traditional Chinese medicine for the treatment of snakebite, weakness, condyloma accuminata, lymphadenopathy, and tumors for thousands of years. In this work, four podophyllotoxin-like lignans including 4'-demethylpodophyllotoxin (1), ?-peltatin (2), podophyllotoxin (3), ?-peltatin (4) as major cytotoxic principles of D. versipellis were successfully isolated and purified by several novel linear and step gradient counter-current chromatography methods using the systems of hexane/ethyl acetate/methanol/water (4:6:3:7 and 4:6:4:6, v/v/v/v). Compared with isocratic elution, linear and step-gradient elution can provide better resolution and save more time for the separation of photophyllotoxin and its congeners. Their cytotoxicities were further evaluated and their structures were validated by high-resolution electrospray TOF MS and nuclear magnetic resonance spectra. All components showed potent anticancer activity against human hepatoma cells HepG2. PMID:23418155

  7. Novel hexahydrocannabinol analogs as potential anti-cancer agents inhibit cell proliferation and tumor angiogenesis.

    PubMed

    Thapa, Dinesh; Lee, Jong Suk; Heo, Se-Woong; Lee, Yong Rok; Kang, Keon Wook; Kwak, Mi-Kyoung; Choi, Han Gon; Kim, Jung-Ae

    2011-01-10

    Both natural and synthetic cannabinoids have been shown to suppress the growth of tumor cells in culture and in animal models by affecting key signaling pathways including angiogenesis, a pivotal step in tumor growth, invasion, and metastasis. In our search for cannabinoid-like anticancer agents devoid of psychoactive side effects, we synthesized and evaluated the anti-angiogenic effects of a novel series of hexahydrocannabinol analogs. Among these, two analogs LYR-7 [(9S)-3,6,6,9-tetramethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol] and LYR-8 [(1-((9S)-1-hydroxy-6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-yl)ethanone)] were selected based on their anti-angiogenic activity and lack of binding affinity for cannabinoid receptors. Both LYR-7 and LYR-8 inhibited VEGF-induced proliferation, migration, and capillary-like tube formation of HUVECs in a concentration-dependent manner. The inhibitory effect of the compounds on cell proliferation was more selective in endothelial cells than in breast cancer cells (MCF-7 and tamoxifen-resistant MCF-7). We also noted effective inhibition of VEGF-induced new blood vessel formation by the compounds in the in vivo chick chorioallantoic membrane (CAM) assay. Furthermore, both LYR analogs potently inhibited VEGF production and NF-?B transcriptional activity in cancer cells. Additionally, LYR-7 or LYR-8 strongly inhibited breast cancer cell-induced angiogenesis and tumor growth. Together, these results suggest that novel synthetic hexahydrocannabinol analogs, LYR-7 and LYR-8, inhibit tumor growth by targeting VEGF-mediated angiogenesis signaling in endothelial cells and suppressing VEGF production and cancer cell growth. PMID:20950604

  8. Protective effects and mechanisms of curcumin on podophyllotoxin toxicity in vitro and in vivo

    SciTech Connect

    Li, Juan; Dai, Cai-Xia; Sun, Hua; Jin, Lu; State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203 ; Guo, Chong-Yi; Cao, Wei; Wu, Jie; Tian, Hai-Yan; Luo, Cheng; Ye, Wen-Cai; Jiang, Ren-Wang

    2012-12-01

    Podophyllotoxin (POD) is a naturally occurring lignan with pronounced antineoplastic and antiviral properties. POD binds to tubulin and prevents the formation of mitotic spindle. Although cases of overdose or accidental ingestion are quite often, no specific therapy is currently available to treat the POD intoxication. In the current investigation, the protective effects and mechanisms of curcumin (CUR) on podophyllotoxin toxicity were evaluated in vitro and in vivo. The results showed that CUR could protect POD-induced cytotoxicity by recovering the G2/M arrest and decrease the changes of membrane potential and microtubule structure in Vero cells. A significant decrease of mortality rates was observed in Swiss mice treated by intragastrical administration of POD + CUR as compared with POD alone. The POD + CUR group also exhibited decreases in plasma transaminases, alkaline phosphatase, lactate dehydrogenase, plasma urea, creatinine and malondialdehyde level but elevated superoxide dismutase and glutathione levels as compared to the POD group. Histological examination of the liver and kidney demonstrated less morphological changes in the treatment of POD + CUR as compared with POD alone. The mechanism of the protective effects might be due to the competitive binding of CUR with POD in the same colchicines binding site as revealed by the tubulin polymerization assay and the molecular docking analysis, and the antioxidant activity against the oxidative stress induced by POD. In summary, both in vitro and in vivo data indicated the promising role of CUR as a protective agent against the POD poisoning. Highlights: ? A potential antidote to treat the podophyllotoxin (POD) intoxication is found. ? Curcumin showed promising effects against POD poisoning in vitro and in vivo. ? The mechanisms lie in the antioxidant activity and competitive binding with tubulin.

  9. Anti-Cancer Agents that Inhibit Cell Motility, Angiogenesis, and Metastasis

    Cancer.gov

    The National Cancer Institute's Urologic Oncology Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize anti-cancer drugs.

  10. The prince and the pauper. A tale of anticancer targeted agents

    PubMed Central

    Dueñas-González, Alfonso; García-López, Patricia; Herrera, Luis Alonso; Medina-Franco, Jose Luis; González-Fierro, Aurora; Candelaria, Myrna

    2008-01-01

    Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater. PMID:18947424

  11. Phosphorescent iridium(III)-bis-N-heterocyclic carbene complexes as mitochondria-targeted theranostic and photodynamic anticancer agents.

    PubMed

    Li, Yi; Tan, Cai-Ping; Zhang, Wei; He, Liang; Ji, Liang-Nian; Mao, Zong-Wan

    2015-01-01

    Mitochondria-targeted compounds represent a promising approach to target tumors selectively and overcome resistance to current anticancer therapies. In this work, three cyclometalated iridium(III) complexes (1-3) containing bis-N-heterocyclic carbene (NHC) ligands have been explored as theranostic and photodynamic agents targeting mitochondria. These complexes display rich photophysical properties, which greatly facilitates the study of their intracellular fate. All three complexes are more cytotoxic than cisplatin against the cancer cells screened. 1-3 can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, and they can carry out theranostic functions by simultaneously inducing and monitoring the morphological changes in mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by initiating a cascade of events related to mitochondrial dysfunction. Additionally, they display up to 3 orders of magnitude higher cytotoxicity upon irradiation at 365 nm, which is so far the highest photocytotoxic responses reported for iridium complexes. PMID:25477176

  12. Strigolactone analogs act as new anti-cancer agents in inhibition of breast cancer in xenograft model.

    PubMed

    Mayzlish-Gati, Einav; Laufer, Dana; Grivas, Christopher F; Shaknof, Julia; Sananes, Amiram; Bier, Ariel; Ben-Harosh, Shani; Belausov, Eduard; Johnson, Michael D; Artuso, Emma; Levi, Oshrat; Genin, Ola; Prandi, Cristina; Khalaila, Isam; Pines, Mark; Yarden, Ronit I; Kapulnik, Yoram; Koltai, Hinanit

    2015-10-30

    Strigolactones (SLs) are a novel class of plant hormones. Previously, we found that analogs of SLs induce growth arrest and apoptosis in breast cancer cell lines. These compounds also inhibited the growth of breast cancer stem cell enriched-mammospheres with increased potency. Furthermore, strigolactone analogs inhibited growth and survival of colon, lung, prostate, melanoma, osteosarcoma and leukemia cancer cell lines. To further examine the anti-cancer activity of SLs in vivo, we have examined their effects on growth and viability of MDA-MB-231 tumor xenografts model either alone or in combination with paclitaxel. We show that strigolactone act as new anti-cancer agents in inhibition of breast cancer in xenograft model. In addition we show that SLs affect the integrity of the microtubule network and therefore may inhibit the migratory phenotype of the highly invasive breast cancer cell lines that were examined. PMID:26192476

  13. Are platinum agents, paclitaxel and irinotecan effective for clear cell carcinoma of the ovary? DNA damage detected with ?H2AX induced by anticancer agents

    PubMed Central

    2012-01-01

    Objectives Differences in the incidences and types of DNA damage induced by antitumor agents for clear cell carcinoma (CCC) were determined in 2 ovarian CCC cell lines using ?H2AX. Material and methods The antitumor activity of anticancer agents, CDDP, CBDCA, PTX and SN-38, was examined using ovarian clear cell carcinoma cultured cell lines (OVISE and RMG-I). After culture, each cell line was treated with each anticancer agent, the cells were collected, fixed, and then reacted with the anti-?H2AX antibody. ?H2AX and nuclear DNA were then simultaneously detected by flow cytometry using FITC and propidium iodide, respectively, to determine ?H2AX in each cell cycle phase. Results After administration of CDDP, DNA damage was frequent in S-phase cells, while cell-cycle arrest occurred in the G1 and G2/M phases and ?H2AX did not increase in CDDP-resistant cells. Sensitivities to CDDP and CBDCA differed between the two cell lines. The antitumor effect of PTX is induced by G2/M arrest, and combination treatment with CBDCA, inducing DNA damage in G2/M-phase cells, might be effective. Conclusions This is the first study in Japan to evaluate the antitumor activity of anticancer agents by focusing on the relationship between the cell cycle and DNA damage using ?H2AX as an indicator. The immunocytochemical method used in this study detects ?H2AX, which indicates DNA damage even at very low concentrations and with high sensitivity. Therefore, a promising method of easily and rapidly identifying agents potentially effective against CCC. PMID:22691365

  14. Metabolic disposition of the anti-cancer agent [14C]laromustine in male rats

    PubMed Central

    Nassar, Ala F.; Wisnewski, Adam; King, Ivan

    2015-01-01

    Laromustine (VNP40101M, also known as Cloretazine) is a novel sulfonylhydrazine alkylating (anticancer) agent. This article describes the use of quantitative whole-body autoradiography (QWBA) and mass balance to study the tissue distribution, the excretion mass balance and pharmacokinetics after intravenous administration of [14C]VNP40101M to rats. A single 10 mg/kg IV bolus dose of [14C]VNP40101M was given to rats. The recovery of radioactivity from the Group 1 animals over a 7-day period was an average of 92.1% of the administered dose, which was accounted for in the excreta and carcass. Most of the radioactivity was eliminated within 48 h via urine (48%), with less excreted in feces (5%) and expired air accounted for (11%). The plasma half-life of [14C]laromustine was approximately 62 min and the peak plasma concentration (Cmax) averaged 8.3 ?g/mL The QWBA study indicated that the drug-derived radioactivity was widely distributed to tissues through 7 days post-dose after a single 10 mg/kg IV bolus dose of [14C]VNP40101M to male pigmented Long–Evans rats. The maximum concentrations were observed at 0.5 or 1 h post-dose for majority tissues (28 of 42). The highest concentrations of radioactivity were found in the small intestine contents at 0.5 h (112.137 ?g equiv/g), urinary bladder contents at 3 h (89.636 ?g equiv/g) and probably reflect excretion of drug and metabolites. The highest concentrations in specific organs were found in the renal cortex at 1 h (28.582 ?g equiv/g), small intestine at 3 h (16.946 ?g equiv/g), Harderian gland at 3 h (12.332 ?g equiv/g) and pancreas at 3 h (12.635 ?g equiv/g). Concentrations in the cerebrum (1.978 ?g equiv/g), cerebellum (2.109 ?g equiv/g), medulla (1.797 ?g equiv/g) and spinal cord (1.510 ?g equiv/g) were maximal at 0.5 h post-dose and persisted for 7 days. The predicted total body and target organ exposures for humans given a single 100?Ci IV dose of [14C]VNP40101M were well within the medical guidelines for maximum radioactivity exposures in human subjects. PMID:25798740

  15. Organometallic Palladium Complexes with a Water-Soluble Iminophosphorane Ligand as Potential Anticancer Agents

    PubMed Central

    Carreira, Monica; Calvo-Sanjuán, Rubén; Sanaú, Mercedes; Marzo, Isabel; Contel, María

    2012-01-01

    The synthesis and characterization of a new water-soluble iminophosphorane ligand TPA=N-C(O)-2BrC6H4 (C,N-IM; TPA = 1,3,5-triaza-7-phosphaadamantane) 1 is reported. Oxidative addition of 1 to Pd2(dba)3 affords the orthopalladated dimer [Pd(?-Br){C6H4(C(O)N=TPA-kC,N)-2}]2 (2) as a mixture of cis and trans isomers (1:1 molar ratio) where the iminophosphorane moeity behaves as a C,N-pincer ligand. By addition of different neutral or monoanionic ligands to 2, the bridging bromide can be cleaved and a variety of hydrophilic or water-soluble mononuclear organometallic palladium(II) complexes of the type [Pd{C6H4(C(O)N=TPA-kC,N)-2}(L-L)] (L-L = acac (3); S2CNMe2 (4); 4,7-Diphenyl-1,10-phenanthrolinedisulfonic acid disodium salt C12H6N2(C6H4SO3Na)2 (5)); [Pd{C6H4(C(O)N=TPA-kC,N)-2}(L)Br] (L = P(mC6H4SO3Na)3 (6); P(3-Pyridyl)3 (7)) and, [Pd(C6H4(C(O)N=TPA)-2}(TPA)2Br] (8) are obtained as single isomers. All new complexes were tested as potential anticancer agents and their cytotoxicity properties were evaluated in vitro against human Jurkat-T acute lymphoblastic leukemia cells, normal T-lymphocytes (PBMC) and DU-145 human prostate cancer cells. Compounds [Pd(?-Br){C6H4(C(O)N=TPA-kC,N)-2}]2 (2) and [Pd{C6H4(C(O)N=TPA-kC,N)-2}(acac)] 3 (which has been crystallographically characterized) display the higher cytotoxicity against the above mentioned cancer cell lines while being less toxic to normal T-lymphocytes (peripheral blood mononuclear cells: PBMC). In addition, 3 is very toxic to cisplatin resistant Jurkat shBak indicating a cell death pathway that may be different to that of cisplatin. The interaction of 2 and 3 with plasmid (pBR322) DNA is much weaker than that of cisplatin pointing to an alternative biomolecular target for these cytotoxic compounds. All the compounds show an interaction with human serum albumin (HSA) faster than that of cisplatin. PMID:23066172

  16. 1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation.

    PubMed

    Abou-Seri, Sahar M; Eldehna, Wagdy M; Ali, Mamdouh M; Abou El Ella, Dalal A

    2016-01-01

    In our endeavor towards the development of effective VEGFR-2 inhibitors, three novel series of phthalazine derivatives based on 1-piperazinyl-4-arylphthalazine scaffold were synthesized. All the newly prepared phthalazines 16a-k, 18a-e and 21a-g were evaluated in vitro for their inhibitory activity against VEGFR-2. In particular, compounds 16k and 21d potently inhibited VEGFR-2 at sub-micromolar IC50 values 0.35 ± 0.03 and 0.40 ± 0.04 ?M, respectively. Moreover, seventeen selected compounds 16c-e, 16g, 16h, 16j, 16k, 18c-e and 21a-g were evaluated for their in vitro anticancer activity according to US-NCI protocol, where compounds 16k and 21d proved to be the most potent anticancer agents. While, compound 16k exhibited potent broad spectrum anticancer activity with full panel GI50 (MG-MID) value of 3.62 ?M, compound 21d showed high selectivity toward leukemia and prostate cancer subpanels [subpanel GI50 (MG-MID) 3.51 and 5.15 ?M, respectively]. Molecular docking of compounds16k and 21d into VEGFR-2 active site was performed to explore their potential binding mode. PMID:26590508

  17. Enantioselective synthesis of pladienolide B and truncated analogues as new anticancer agents.

    PubMed

    Kumar, Vemula Praveen; Chandrasekhar, Srivari

    2013-07-19

    An enantioselective synthesis of natural anticancer macrolide pladienolide B is described. The synthetic highlights include Sharpless asymmetric epoxidation, ring closing metathesis (RCM), Ireland-Claisen rearrangement, Shi epoxidation, and Pd-catalyzed Stille coupling as key steps. The synthetic route also allowed the synthesis of the truncated analogues (41a-d) of pladienolide B. PMID:23822896

  18. Bioprospecting for podophyllotoxin in the Big Horn Mountains, Wyoming

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to evaluate variations in podophyllotoxin concentrations in Juniperus species found in the Big Horn Mountains in Wyoming. It was found that Juniperus species in the Big Horn Mountains included three species; J. communis L. (common juniper), J. horizontalis Moench. (c...

  19. 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

  20. Enhancement of Selectivity of an Organometallic Anticancer Agent by Redox Modulation

    PubMed Central

    2015-01-01

    Combination with redox modulators can potentiate the anticancer activity and maximize the selectivity of organometallic complexes with redox-based mechanisms of action. We show that nontoxic doses of l-buthionine sulfoximine increase the selectivity of organo-Os complex FY26 for human ovarian cancer cells versus normal lung fibroblasts to 63-fold. This increase is not due to changes in the mechanism of action of FY26 but to the decreased response of cancer cells to oxidative stress. PMID:26397305

  1. Dual pH-sensitive oxidative stress generating micellar nanoparticles as a novel anticancer therapeutic agent.

    PubMed

    Park, Sanga; Kwon, Byeongsu; Yang, Wonseok; Han, Eunji; Yoo, Wooyoung; Kwon, Byoung-Mog; Lee, Dongwon

    2014-12-28

    Cancer cells are under oxidative stress due to a large production of reactive oxygen species (ROS), which involve in cell proliferation and cancer promotion and progression. On the other hand, ROS promotes cell death, depending on the rate of ROS production and the activity of antioxidant systems. Recently, "oxidation therapy" has arisen as a promising anticancer strategy, which can be achieved by inducing the generation of cytotoxic level of ROS or inhibiting the antioxidant systems in tumor cells. Here, we report oxidative stress amplifying nanoplatforms as novel anticancer therapeutics, which are able not only to suppress antioxidant but also to generate ROS simultaneously in acidic tumor microenvironments. The oxidative stress amplifying nanoplatforms are composed of dual pH-sensitive PBCAE copolymer, polymeric prodrug of BCA (benzoyloxycinnamaldehyde) and heme oxygenase-1 (HO-1) inhibiting zinc protoporphyrin (ZnPP). PBCAE was designed to incorporate ROS-generating BCA in its backbone via acid-cleavable acetal linkages and self-assemble to form micelles that encapsulate ZnPP. In vitro proof-of-concept studies revealed that ZnPP encapsulated in PBCAE micelles suppressed HO-1 to make cancer cells more vulnerable to BCA-induced ROS, leading to enhanced apoptotic cell death. In addition, ZnPP-loaded PBCAE micelles significantly suppressed the tumor growth in human cancer xenograft mouse models. We believe that oxidative stress amplifying micellar nanoparticles have a great potential as novel redox anticancer therapeutics. PMID:25278257

  2. Structure-Activity Relationship for Fe(III)-Salen-Like Complexes as Potent Anticancer Agents

    PubMed Central

    Ghanbari, Zahra; Housaindokht, Mohammad R.; Izadyar, Mohammad; Bozorgmehr, Mohammad R.; Eshtiagh-Hosseini, Hossein; Bahrami, Ahmad R.; Matin, Maryam M.; Khoshkholgh, Maliheh Javan

    2014-01-01

    Quantitative structure activity relationship (QSAR) for the anticancer activity of Fe(III)-salen and salen-like complexes was studied. The methods of density function theory (B3LYP/LANL2DZ) were used to optimize the structures. A pool of descriptors was calculated: 1497 theoretical descriptors and quantum-chemical parameters, shielding NMR, and electronic descriptors. The study of structure and activity relationship was performed with multiple linear regression (MLR) and artificial neural network (ANN). In nonlinear method, the adaptive neuro-fuzzy inference system (ANFIS) was applied in order to choose the most effective descriptors. The ANN-ANFIS model with high statistical significance (R2train = 0.99, RMSE = 0.138, and Q2LOO = 0.82) has better capability to predict the anticancer activity of the new compounds series of this family. Based on this study, anticancer activity of this compound is mainly dependent on the geometrical parameters, position, and the nature of the substituent of salen ligand. PMID:24955417

  3. Characterization of human adenovirus serotypes 5, 6, 11, and 35 as anticancer agents

    SciTech Connect

    Shashkova, Elena V.; May, Shannon M.; Barry, Michael A.

    2009-11-25

    Human adenovirus type 5 (Ad5) has been the most popular platform for the development of oncolytic Ads. Alternative Ad serotypes with low seroprevalence might allow for improved anticancer efficacy in Ad5-immune patients. We studied the safety and efficacy of rare serotypes Ad6, Ad11 and Ad35. In vitro cytotoxicity of the Ads correlated with expression of CAR and CD46 in most but not all cell lines. Among CAR-binding viruses, Ad5 was often more active than Ad6, among CD46-binding viruses Ad35 was generally more cytotoxic than Ad11 in cell culture studies. Ad5, Ad6, and Ad11 demonstrated similar anticancer activity in vivo, whereas Ad35 was not efficacious. Hepatotoxicity developed only in Ad5-injected mice. Predosing with Ad11 and Ad35 did not increase infection of hepatocytes with Ad5-based vector demonstrating different interaction of these Ads with Kupffer cells. Data obtained in this study suggest developing Ad6 and Ad11 as alternative Ads for anticancer treatment.

  4. Anticancer/antiviral agent Akt inhibitor-IV massively accumulates in mitochondria and potently disrupts cellular bioenergetics.

    PubMed

    Meinig, J Matthew; Peterson, Blake R

    2015-02-20

    Inhibitors of the PI3-kinase/Akt (protein kinase B) pathway are under investigation as anticancer and antiviral agents. Akt inhibitor-IV (ChemBridge 5233705, CAS 681281-88-9, AKTIV), a small molecule reported to inhibit this pathway, exhibits potent anticancer and broad-spectrum antiviral activity. However, depending on concentration, this cationic benzimidazole derivative exhibits paradoxical positive or negative effects on the phosphorylation of Akt that are not well understood. To elucidate its mechanism of action, we investigated its spectroscopic properties. This compound proved to be sufficiently fluorescent (excitation ?max = 388 nm, emission ?max = 460 nm) to enable examination of its uptake and distribution in living mammalian cells. Despite a low quantum yield of 0.0016, imaging of HeLa cells treated with AKTIV (1 ?M, 5 min) by confocal laser scanning microscopy, with excitation at 405 nm, revealed extensive accumulation in mitochondria. Treatment of Jurkat lymphocytes with 1 ?M AKTIV for 15 min caused accumulation to over 250 ?M in these organelles, whereas treatment with 5 ?M AKTIV yielded concentrations of over 1 mM in mitochondria, as analyzed by flow cytometry. This massive loading resulted in swelling of these organelles, followed by their apparent disintegration. These effects were associated with profound disruption of cellular bioenergetics including mitochondrial depolarization, diminished mitochondrial respiration, and release of reactive oxygen species. Because mitochondria play key roles in both cancer proliferation and viral replication, we conclude that the anticancer and antiviral activities of AKTIV predominantly result from its direct and immediate effects on the structure and function of mitochondria. PMID:25415586

  5. Design, synthesis, biological evaluation and molecular docking studies of novel benzofuran-pyrazole derivatives as anticancer agents.

    PubMed

    Abd El-Karim, Somaia S; Anwar, Manal M; Mohamed, Neama A; Nasr, Tamer; Elseginy, Samia A

    2015-12-01

    This study deals with design and synthesis of novel benzofuran-pyrazole hybrids as anticancer agents. Eight compounds were chosen by National Cancer Institute (NCI), USA to evaluate their in vitro antiproliferative activity at 10(-5)M in full NCI 60 cell panel. The preliminary screening of the tested compounds showed promising broad-spectrum anticancer activity. Compound 4c was further assayed for five dose molar ranges in full NCI 60 cell panel and exhibited remarkable growth inhibitory activity pattern against Leukemia CCRF-CEM, MOLT-4, Lung Cancer HOP-92, Colon Cancer HCC-2998, CNS Cancer SNB-75, Melanoma SK-MEL-2, Ovarian Cancer IGROV1, Renal Cancer 786-0, RXF 393, Breast Cancer HS 578T and T-47D (GI50: 1.00-2.71?M). Moreover, enzyme assays were carried out to investigate the possible antiproliferative mechanism of action of compound 4c. The results revealed that compound 4c has good c-Src inhibitory activity at 10?M. In addition, molecular docking studies showed that 4c could bind to the ATP Src pocket sites. Fulfilling the Lipinskiís rule of five in addition to its ADME profile and the biological results, all strongly suggest that 4c is a promising Src kinase inhibitor. PMID:26368040

  6. Design and synthesis of novel hydroxyanthraquinone nitrogen mustard derivatives as potential anticancer agents via a bioisostere approach.

    PubMed

    Zhao, Li-Ming; Ma, Feng-Yan; Jin, Hai-Shan; Zheng, Shilong; Zhong, Qiu; Wang, Guangdi

    2015-09-18

    A series of hydroxyanthraquinones having an alkylating N-mustard pharmacophore at 1'-position were synthesized via a bioisostere approach to evaluate their cytotoxicity against four tumor cell lines (MDA-MB-231, HeLa, MCF-7 and A549). These compounds displayed significant in vitro cytotoxicity against MDA-MB-231 and MCF-7 cells, reflecting the excellent selectivity for the human breast cancer. Among them, compound 5k was the most cytotoxic with IC50 value of 0.263 nM and is more potent than DXR (IC50 = 0.294 nM) in inhibiting the growth of MCF-7 cells. The excellent cytotoxicity and good selectivity of compound 5k suggest that it could be a promising lead for further design and development of anticancer agents, especially for breast cancer. PMID:26291039

  7. Synthesis, structure-activity relationship and biological evaluation of novel nitrogen mustard sophoridinic acid derivatives as potential anticancer agents.

    PubMed

    Li, Dong-Dong; Dai, Lin-Lin; Zhang, Na; Tao, Zun-Wei

    2015-10-01

    A series of novel nitrogen mustard sophoridinic acid derivatives were designed, synthesized and evaluated for their cytotoxicity. Of the newly synthesized compounds, compound 6 exhibited a potent effect against hepatocellular carcinoma in vitro and in vivo. SAR analysis indicated that introduction of a nitrogen mustard group to the structure of sophoridinic acid significantly enhance the antitumor activity. Moreover, molecular docking study exhibited benzyl group introduced to the nitrogen atom at the 12-position and aryl nitrogen mustard group at the 4'-carboxyl region for compound 6 were beneficial for the higher anticancer activity. This work provides useful information for further structural modifications of these compounds and for the synthesis of new, potent antitumor agents. PMID:26299348

  8. New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer

    PubMed Central

    La Regina, Giuseppe; Bai, Ruoli; Coluccia, Antonio; Famiglini, Valeria; Pelliccia, Sveva; Passacantilli, Sara; Mazzoccoli, Carmela; Ruggieri, Vitalba; Sisinni, Lorenza; Bolognesi, Alessio; Rensen, Whilelmina Maria; Miele, Andrea; Nalli, Marianna; Alfonsi, Romina; Di Marcotullio, Lucia; Gulino, Alberto; Brancale, Andrea; Novellino, Ettore; Dondio, Giulio; Vultaggio, Stefania; Varasi, Mario; Mercurio, Ciro; Hamel, Ernest; Lavia, Patrizia; Silvestri, Romano

    2014-01-01

    We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway. PMID:25025991

  9. Synthesis and cytotoxicity evaluation of novel pyrido[3,4-d]pyrimidine derivatives as potential anticancer agents

    PubMed Central

    Wei, Linyi

    2014-01-01

    A new series of 4-substituted 2-amino pyrido[3,4-d]pyrimidine derivatives has been designed and synthesized as potential anticancer agents. These compounds were prepared from a common intermediate, 4-chloro-8-methoxy pyrido[3,4-d]pyrimidin-2-amine, followed by palladium catalyzed cross-coupling reactions or nucleophilic aromatic substitutions at the C-4 position. Evaluation of the representative analogs using the US National Cancer Institute’s 60 human cancer cell line (NCI 60) panel identified some of these compounds as exhibiting highly selective activities against breast cancer and renal cancer cell lines. A structure–activity relationship (SAR) study was explored to facilitate further development of this new class of compounds. PMID:25429348

  10. Synthesis of novel 1,2,4-oxadiazoles and analogues as potential anticancer agents.

    PubMed

    Kumar, Dalip; Patel, Gautam; Chavers, Angela K; Chang, Kuei-Hua; Shah, Kavita

    2011-07-01

    A library of 3,5-disubstituted-1,2,4-oxadiazoles 7-9 and their bioisosters, 1,3,4-oxadiazole 14 and 1,3,4-thiadiazole 16, were synthesized and evaluated in vitro for their anticancer potential against a panel of six human cancer cell lines. The key step in the synthesis of oxadiazoles 7-9 involve coupling of amidoxime 6 with an appropriate carboxylic acid followed by thermal cyclization. The bioisosteres, 1,3,4-oxadiazole 14 and 1,3,4-thiadiazole 16 were prepared from the reaction of a common precursor diacylhydrazine 13 with thionyl chloride and Lawesson's reagent, respectively. The anticancer studies on the synthesized compounds revealed that presence of a cyclopentyloxy or n-butyloxy on the C-3 aryl ring and piperdin-4-yl or trichloromethyl at the C-5 position of 1,2,4-oxadiazole is essential for good activity. In particular, 1,2,4-oxadiazole 7i and analogue 1,3,4-thiadiazole 16 exhibited significant activity against DU145 (IC(50): 9.3 ?M) and MDA-MB-231 (IC(50): 9.2 ?M) cell lines, respectively. PMID:21481985

  11. 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-1? 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

  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 PDGFR? pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-? (platelet-derived growth factor receptor-?) (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 PDGFR? pathway, and could be considered as an additional therapy for pediatric brain tumor patients. PMID:26248280

  13. 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 PDGFR? pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-? (platelet-derived growth factor receptor-?) (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 PDGFR? pathway, and could be considered as an additional therapy for pediatric brain tumor patients. PMID:26248280

  14. High yield of podophyllotoxin from leaves of Podophyllum peltatum by in situ conversion of podophyllotoxin 4- O-beta-D-glucopyranoside.

    PubMed

    Canel, C; Dayan, F E; Ganzera, M; Khan, I A; Rimando, A; Burandt, C L; Moraes, R M

    2001-02-01

    Rehydration of powdered tissues of Podophyllum peltatum L. prior to extraction with an organic solvent allows endogenous beta-glucosidases to hydrolyze lignan 4-O-beta-D-glucosides in situ and increase the yield of podophyllotoxin. Aqueous extraction of rhizomes and leaves of P. peltatum yielded 4- to 10-fold greater quantities of podophyllotoxin than the traditional ethanolic extraction. Most significantly, leaves were shown to contain over 52 mg of podophyllotoxin per g of dry weight (5.2%), exceeding levels previously reported from any source. These results point to the use of leaves harvested from cultivated P. peltatum as an attractive alternative to the destructive collection of natural populations. PMID:11270736

  15. Next Generation Sequencing in Predicting Gene Function in Podophyllotoxin Biosynthesis*

    PubMed Central

    Marques, Joaquim V.; Kim, Kye-Won; Lee, Choonseok; Costa, Michael A.; May, Gregory D.; Crow, John A.; Davin, Laurence B.; Lewis, Norman G.

    2013-01-01

    Podophyllum species are sources of (?)-podophyllotoxin, an aryltetralin lignan used for semi-synthesis of various powerful and extensively employed cancer-treating drugs. Its biosynthetic pathway, however, remains largely unknown, with the last unequivocally demonstrated intermediate being (?)-matairesinol. Herein, massively parallel sequencing of Podophyllum hexandrum and Podophyllum peltatum transcriptomes and subsequent bioinformatics analyses of the corresponding assemblies were carried out. Validation of the assembly process was first achieved through confirmation of assembled sequences with those of various genes previously established as involved in podophyllotoxin biosynthesis as well as other candidate biosynthetic pathway genes. This contribution describes characterization of two of the latter, namely the cytochrome P450s, CYP719A23 from P. hexandrum and CYP719A24 from P. peltatum. Both enzymes were capable of converting (?)-matairesinol into (?)-pluviatolide by catalyzing methylenedioxy bridge formation and did not act on other possible substrates tested. Interestingly, the enzymes described herein were highly similar to methylenedioxy bridge-forming enzymes from alkaloid biosynthesis, whereas candidates more similar to lignan biosynthetic enzymes were catalytically inactive with the substrates employed. This overall strategy has thus enabled facile further identification of enzymes putatively involved in (?)-podophyllotoxin biosynthesis and underscores the deductive power of next generation sequencing and bioinformatics to probe and deduce medicinal plant biosynthetic pathways. PMID:23161544

  16. Next generation sequencing in predicting gene function in podophyllotoxin biosynthesis.

    PubMed

    Marques, Joaquim V; Kim, Kye-Won; Lee, Choonseok; Costa, Michael A; May, Gregory D; Crow, John A; Davin, Laurence B; Lewis, Norman G

    2013-01-01

    Podophyllum species are sources of (-)-podophyllotoxin, an aryltetralin lignan used for semi-synthesis of various powerful and extensively employed cancer-treating drugs. Its biosynthetic pathway, however, remains largely unknown, with the last unequivocally demonstrated intermediate being (-)-matairesinol. Herein, massively parallel sequencing of Podophyllum hexandrum and Podophyllum peltatum transcriptomes and subsequent bioinformatics analyses of the corresponding assemblies were carried out. Validation of the assembly process was first achieved through confirmation of assembled sequences with those of various genes previously established as involved in podophyllotoxin biosynthesis as well as other candidate biosynthetic pathway genes. This contribution describes characterization of two of the latter, namely the cytochrome P450s, CYP719A23 from P. hexandrum and CYP719A24 from P. peltatum. Both enzymes were capable of converting (-)-matairesinol into (-)-pluviatolide by catalyzing methylenedioxy bridge formation and did not act on other possible substrates tested. Interestingly, the enzymes described herein were highly similar to methylenedioxy bridge-forming enzymes from alkaloid biosynthesis, whereas candidates more similar to lignan biosynthetic enzymes were catalytically inactive with the substrates employed. This overall strategy has thus enabled facile further identification of enzymes putatively involved in (-)-podophyllotoxin biosynthesis and underscores the deductive power of next generation sequencing and bioinformatics to probe and deduce medicinal plant biosynthetic pathways. PMID:23161544

  17. Synthesis and characterization of 2-substituted benzimidazoles and their evaluation as anticancer agent

    NASA Astrophysics Data System (ADS)

    Azam, Mohammad; Khan, Azmat Ali; Al-Resayes, Saud I.; Islam, Mohammad Shahidul; Saxena, Ajit Kumar; Dwivedi, Sourabh; Musarrat, Javed; Trzesowska-Kruszynska, Agata; Kruszynski, Rafal

    2015-05-01

    In this work, we report a series of benzimidazole derivatives synthesized from benzene-1,2-diamine and aryl-aldehydes at room temperature. The synthesized compounds have been characterized on the basis of elemental analysis and various spectroscopic studies viz., IR, 1H- and 13C-NMR, ESI-MS as well by X-ray single X-ray crystallographic study. Interaction of these compounds with CT-DNA has been examined with fluorescence experiments and showed significant binding ability. All the synthesized compounds have been screened for their antitumor activities against various human cancer cell lines viz., Human breast adenocarcinoma cell line (MCF-7), Human leukemia cell line (THP-1), Human prostate cancer cell lines (PC-3) and adenocarcinomic human alveolar basal epithelial cell lines (A-549). Interestingly, all the compounds showed significant anticancer activity.

  18. The effects of nanoparticle drug loading on the pharmacokinetics of anticancer agents

    PubMed Central

    Petschauer, Jennifer S.; Madden, Andrew J.; Kirschbrown, Whitney P.; Song, Gina; Zamboni, William C.

    2015-01-01

    Major advances in carrier-mediated agents, which include nanoparticles, nanosomes and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages, such as greater solubility, duration of exposure and delivery to the site of action over their small-molecule counterparts, there is substantial variability in systemic clearance and distribution, tumor delivery and pharmacologic effects (efficacy and toxicity) of these agents. This review provides an overview of factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents in preclinical models and patients. PMID:25707978

  19. Mechanistic investigation of anticancer agents that damage DNA and interact with the estrogen receptor

    E-print Network

    Gopal, Sreeja

    2009-01-01

    One of the primary goals of cancer chemotherapy is the design of antitumor agents that achieve selective targeting of tumor cells while minimizing toxicity to normal tissues. We have synthesized a series of DNA damaging ...

  20. Anticancer and carcinogenic properties of curcumin: considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent.

    PubMed

    López-Lázaro, Miguel

    2008-06-01

    A growing body of research suggests that curcumin, the major active constituent of the dietary spice turmeric, has potential for the prevention and therapy of cancer. Preclinical data have shown that curcumin can both inhibit the formation of tumors in animal models of carcinogenesis and act on a variety of molecular targets involved in cancer development. In vitro studies have demonstrated that curcumin is an efficient inducer of apoptosis and some degree of selectivity for cancer cells has been observed. Clinical trials have revealed that curcumin is well tolerated and may produce antitumor effects in people with precancerous lesions or who are at a high risk for developing cancer. This seems to indicate that curcumin is a pharmacologically safe agent that may be used in cancer chemoprevention and therapy. Both in vitro and in vivo studies have shown, however, that curcumin may produce toxic and carcinogenic effects under specific conditions. Curcumin may also alter the effectiveness of radiotherapy and chemotherapy. This review article analyzes the in vitro and in vivo cancer-related activities of curcumin and discusses that they are linked to its known antioxidant and pro-oxidant properties. Several considerations that may help develop curcumin as an anticancer agent are also discussed. PMID:18496811

  1. The search for novel anticancer agents: a differentiation-based assay and analysis of a folklore product.

    PubMed

    Dinnen, R D; Ebisuzaki, K

    1997-01-01

    One alternative approach to the current use of cytotoxic anticancer drugs involves the use of differentiation-inducing agents. However, a wider application of this strategy would require the development of assays to search for new differentiation-inducing agents. In this report we describe an in vitro assay using the murine erythroleukemia (clone 3-1) cells. Tests for the efficacy of this assay for the analysis of antineoplastic activity in natural products led to studies on pau d'arco, a South American folklore product used in the treatment of cancer. Purification of the activity in aqueous extracts by solvent partition and thin layer chromatography (TLC) indicated the presence of two activities, one of which was identified as lapachol. The activity in the pau d'arco extracts and of lapachol was inhibited by vitamin K1. As a vitamin K antagonist, lapachol might target such vitamin K-dependent reactions as the activation of a ligand for the Axl receptor tyrosine kinase. PMID:9137445

  2. Identification of endoplasmic reticulum stress-inducing agents by antagonizing autophagy: a new potential strategy for identification of anti-cancer therapeutics in B-cell malignancies

    PubMed Central

    Mahoney, Emilia; Maddocks, Kami; Flynn, Joseph; Jones, Jeffrey; Cole, Sara L.; Zhang, Xiaoli; Byrd, John C.; Johnson, Amy J.

    2013-01-01

    The endoplasmic reticulum (ER) plays a vital function in multiple cellular processes. There is a growing interest in developing therapeutic agents that can target the ER in cancer cells, inducing a stress response that leads to cell death. However, ER stress-inducing agents can also induce autophagy, a survival strategy of cancer cells. Therefore, by inhibiting autophagy we can increase the efficacy of the ER stress-inducing agents. Nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor with anti-cancer properties, can induce ER stress. Nelfinavir’s effects on chronic lymphocytic leukemia (CLL) are yet to be elucidated. Herein we demonstrate that nelfinavir induces ER morphological changes and stress response, along with an autophagic protective strategy. Our data reveal that chloroquine, an autophagy inhibitor, significantly increases nelfinavir cytotoxicity. These results identify a novel strategy potentially effective in CLL treatment, by repositioning two well-known drugs as a combinatorial therapy with anti-cancer properties. PMID:23469959

  3. Progress Toward the Development of Noscapine and Derivatives as Anticancer Agents.

    PubMed

    DeBono, Aaron; Capuano, Ben; Scammells, Peter J

    2015-08-13

    Many nitrogen-moiety containing alkaloids derived from plant origins are bioactive and play a significant role in human health and emerging medicine. Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, has been used as a cough suppressant since the mid 1950s, illustrating a good safety profile. Noscapine has since been discovered to arrest cells at mitosis, albeit with moderately weak activity. Immunofluorescence staining of microtubules after 24 h of noscapine exposure at 20 ?M elucidated chromosomal abnormalities and the inability of chromosomes to complete congression to the equatorial plane for proper mitotic separation ( Proc. Natl. Acad. Sci. U. S. A. 1998 , 95 , 1601 - 1606 ). A number of noscapine analogues possessing various modifications have been described within the literature and have shown significantly improved antiprolific profiles for a large variety of cancer cell lines. Several semisynthetic antimitotic alkaloids are emerging as possible candidates as novel anticancer therapies. This perspective discusses the advancing understanding of noscapine and related analogues in the fight against malignant disease. PMID:25811651

  4. Polygonum cuspidatum extracts as bioactive antioxidaion, anti-tyrosinase, immune stimulation and anticancer agents.

    PubMed

    Lee, Chih-Chen; Chen, Yen-Ting; Chiu, Chien-Chih; Liao, Wei-Ting; Liu, Yung-Chuan; David Wang, Hui-Min

    2015-04-01

    In our study, it was applied for the technology of supercritical fluid carbon dioxide extraction to achieve biological constitutes from a Taiwan native plant, Polygonum cuspidatum. We developed bioactive effects of P. cuspidatum extracts via multiple examinations that established bio-purposes at a range of dosage ranges. The research of P. cuspidatum extracts indicated that they possessed anti-oxidative properties on radical-scavenging abilities, reducing activities and metal chelating powers in dose-dependant manners. The extracts also had minor in vitro mushroom tyrosinase suppression and decreased cellular tyrosinase activities and melanin production in B16-F10 cells. Immunologically, P. cuspidatum extracts enhanced the release of tumor necrosis factor ? (TNF-?) induced by THP-1 macrophage cell line. In addition, the cell proliferation showed anti-proliferation in dose-dependent manner on human skin melanoma cells, A375 and A375.S2, of the extracts suggesting biological constitutes employed the anti-cancer possessions. This is the first statement presenting bioactivities on P. cuspidatum extracts including anti-oxidation, immune stimulation, anti-tyrosinase and anti-melanoma as far as we know. PMID:25311751

  5. Potential Anticancer Heterometallic Fe-Au and Fe-Pd Agents: Initial Mechanistic Insights

    PubMed Central

    Lease, Nicholas; Vasilevski, Vadim; Carreira, Monica; de Almeida, Andreia; Sanaú, Mercedes; Hirva, Pipsa; Casini, Angela; Contel, Maria

    2013-01-01

    A series of gold(III) and palladium(II) heterometallic complexes with new iminophosphorane ligands derived from ferrocenyl-phosphanes [{Cp-P(Ph2)=N-Ph}2Fe] (1), [{Cp-P(Ph2)=N-CH2-2-NC5H4}2Fe] (2) and [{Cp-P(Ph2)=N-CH2-2-NC5H4}Fe(Cp)] (3) have been synthesized and structurally characterized. Ligands 2 and 3 afford stable coordination complexes [AuCl2(3)]ClO4, [{AuCl2}2(2)](ClO4)2, [PdCl2(3)] and [{PdCl2}2(2)]. The complexes have been evaluated for their antripoliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), in human breast cancer cells (MCF7) and in a non-tumorigenic human embryonic kidney cell line (HEK-293T). The highly cytotoxic trimetallic derivatives M2Fe (M = Au, Pd) are more cytotoxic to cancer cells than their corresponding monometallic fragments. Moreover, these complexes were significantly more cytotoxic than cisplatin in the resistant A2780R and the MCF7 cell lines. Studies of the interactions of the trimetallic compounds with DNA and the zinc-finger protein PARP-1 indicate that they exert anticancer effects in vitro based on different mechanisms of actions with respect to cisplatin. PMID:23786413

  6. The disulfide compound ?-lipoic acid and its derivatives: A novel class of anticancer agents targeting mitochondria.

    PubMed

    Dörsam, Bastian; Fahrer, Jörg

    2016-02-01

    The endogenous disulfide ?-lipoic acid (LA) is an essential mitochondrial co-factor. In addition, LA and its reduced counterpart dihydro lipoic acid form a potent redox couple with antioxidative functions, for which it is used as dietary supplement and therapeutic. Recently, it has gained attention due to its cytotoxic effects in cancer cells, which is the key aspect of this review. We initially recapitulate the dietary occurrence, gastrointestinal absorption and pharmacokinetics of LA, illustrating its diverse antioxidative mechanisms. We then focus on its mode of action in cancer cells, in which it triggers primarily the mitochondrial pathway of apoptosis, whereas non-transformed primary cells are hardly affected. Furthermore, LA impairs oncogenic signaling and displays anti-metastatic potential. Novel LA derivatives such as CPI-613, which target mitochondrial energy metabolism, are described and recent pre-clinical studies are presented, which demonstrate that LA and its derivatives exert antitumor activity in vivo. Finally, we highlight clinical studies currently performed with the LA analog CPI-613. In summary, LA and its derivatives are promising candidates to complement the arsenal of established anticancer drugs due to their mitochondria-targeted mode of action and non-genotoxic properties. PMID:26604131

  7. Immune cell-based screening assay for response to anticancer agents: applications in pharmacogenomics

    PubMed Central

    Frick, Amber; Fedoriw, Yuri; Richards, Kristy; Damania, Blossom; Parks, Bethany; Suzuki, Oscar; Benton, Cristina S; Chan, Emmanuel; Thomas, Russell S; Wiltshire, Tim

    2015-01-01

    Background Interpatient variability in immune and chemotherapeutic cytotoxic responses is likely due to complex genetic differences and is difficult to ascertain in humans. Through the use of a panel of genetically diverse mouse inbred strains, we developed a drug screening platform aimed at examining interstrain differences in viability on normal, noncancerous immune cells following chemotherapeutic cytotoxic insult. Drug effects were investigated by comparing selective chemotherapeutic agents, such as BEZ-235 and selumetinib, against conventional cytotoxic agents targeting multiple pathways, including doxorubicin and idarubicin. Methods Splenocytes were isolated from 36 isogenic strains of mice using standard procedures. Of note, the splenocytes were not stimulated to avoid attributing responses to pathways involved with cellular stimulation rather than toxicity. Cells were incubated with compounds on a nine-point logarithmic dosing scale ranging from 15 nM to 100 ?M (37°C, 5% CO2). At 4 hours posttreatment, cells were labeled with antibodies and physiological indicator dyes and fixed with 4% paraformaldehyde. Cellular phenotypes (eg, viability) were collected and analyzed using flow cytometry. Dose-response curves with response normalized to the zero dose as a function of log concentration were generated using GraphPad Prism 6. Results Phenotypes were quantified using flow cytometry, yielding interstrain variation for measured endpoints in different immune cells. The flow cytometry assays produced over 16,000 data points that were used to generate dose-response curves. The more targeted agents, BEZ-235 and selumetinib, were less toxic to immune cells than the anthracycline agents. The calculated heritability for the viability of immune cells was higher with anthracyclines than the novel agents, making them better suited for downstream genetic analysis. Conclusion Using this approach, we identify cell lines of variable sensitivity to chemotherapeutic agents and aim to identify robust, replicable endpoints of cellular response to drugs that provide the starting point for identifying candidate genes and cellular toxicity pathways for future validation in human studies. PMID:25897258

  8. Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads

    PubMed Central

    2014-01-01

    Covering: through January 2014 Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of ??-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provides an overview of current developments of zampanolide and its related but less potent analogue dactylolide, covering their natural sources and isolation, structure and conformation, cytotoxic potential, structure–activity studies, mechanism of action, and syntheses. PMID:24945566

  9. Anti-cancer agents based on 6-trifluoromethoxybenzimidazole derivatives and method of making

    DOEpatents

    Gakh, Andrei A; Vovk, Mykhaylo V; Mel'nychenko, Nina V; Sukach, Volodymyr A

    2012-10-23

    The present disclosure relates to novel compounds having the structural Formulas (1a,1b), stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or pharmaceutically acceptable salt and/or solvate thereof as chemotherapy agents for treating of cancer, particularly androgen-independent prostate cancer. The disclosure also relates to methods for preparing said compounds, and to pharmaceutical compositions comprising said compounds.

  10. Multi-platinum anti-cancer agents. Substitution-inert compounds for tumor selectivity and new targets.

    PubMed

    Farrell, N P

    2015-12-21

    This tutorial review summarizes chemical, biophysical and cellular biological properties of formally substitution-inert "non-covalent" polynuclear platinum complexes (PPCs). We demonstrate how modulation of the pharmacological factors affecting platinum compound cytotoxicity such as cellular accumulation, reactivity toward extracellular and intracellular sulfur-ligand nucleophiles and consequences of DNA binding is achieved to afford a profile of biological activity distinct from that of covalently-binding agents. The DNA binding of substitution-inert complexes is achieved by molecular recognition through minor groove spanning and backbone tracking of the phosphate clamp. In this situation, the square-planar tetra-am(m)ine Pt(ii) coordination units hydrogen bond to phosphate oxygen OP atoms to form bidentate N-O-N motifs. The modular nature of the polynuclear compounds results in high-affinity binding to DNA and very efficient nuclear condensation. These combined effects distinguish the phosphate clamp as a third mode of ligand-DNA binding, discrete from intercalation and minor-groove binding. The cellular consequences mirror those of the biophysical studies and a significant portion of nuclear DNA is compacted, a unique effect different from mitosis, senescence or apoptosis. Substitution-inert PPCs display cytotoxicity similar to cisplatin in a wide range of cell lines, and sensitivity is indifferent to p53 status. Cellular accumulation is mediated through binding to heparan sulfate proteoglycans (HSPG) allowing for possibilities of tumor selectivity as well as disruption of HSPG function, opening new targets for platinum antitumor agents. The combined properties show that covalently-binding chemotypes are not the unique arbiters of cytotoxicity and antitumor activity and meaningful antitumor profiles can be achieved even in the absence of Pt-DNA bond formation. These dual properties make the substitution-inert compounds a unique class of inherently dual-action anti-cancer agents. PMID:25951946

  11. Fluorine-Containing Taxoid Anticancer Agents and Their Tumor-Targeted Drug Delivery

    PubMed Central

    Seitz, Joshua; Vineberg, Jacob G.; Zuniga, Edison S.; Ojima, Iwao

    2013-01-01

    A long-standing problem of conventional chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Consequently, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, including tumor-targeting drug delivery systems. In general, such a drug delivery system consists of a tumor recognition moiety and a cytotoxic “warhead” connected through a “smart” linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a “Trojan Horse” approach can be used for mass delivery of cytotoxic “warheads” to maximize the efficacy. Exploitation of the special properties of fluorine has proven successful in the development of new and effective biochemical tools as well as therapeutic agents. Fluorinated congeners can also serve as excellent probes for the investigation of biochemical mechanisms. 19F-NMR can provide unique and powerful tools for mechanistic investigations in chemical biology. This account presents our recent progress, in perspective, on the molecular approaches to the design and development of novel tumor-targeted drug delivery systems for new generation chemotherapy by exploiting the unique nature of fluorine. PMID:23935213

  12. Synthesis, molecular modeling, and biological evaluation of novel chiral thiosemicarbazone derivatives as potent anticancer agents.

    PubMed

    Ta?demir, Demet; Karaküçük-?yido?an, Ay?egül; Ula?li, Mustafa; Ta?kin-Tok, Tu?ba; Oruç-Emre, Em?ne Elç?n; Bayram, Hasan

    2015-02-01

    A series of new chiral thiosemicarbazones derived from homochiral amines in both enantiomeric forms were synthesized and evaluated for their in vitro antiproliferative activity against A549 (human alveolar adenocarcinoma), MCF-7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), and HGC-27 (human stomach carcinoma) cell lines. Some of compounds showed inhibitory activities on the growth of cancer cell lines. Especially, compound exhibited the most potent activity (IC50 4.6??M) against HGC-27 as compared with the reference compound, sindaxel (IC50 10.3??M), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents. PMID:25399965

  13. Anti-cancer agents based on 6-trifluoromethoxybenzimidazole derivatives and method of making

    DOEpatents

    Gakh, Andrei A.; Vovk, Mykhaylo V.; Mel'nychenko, Nina V.; Sukach, Volodymyr A.

    2012-08-14

    The present disclosure relates to novel compounds having the structural Formulas (1a,1b), stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or pharmaceutically acceptable salt and/or solvate thereof as chemotherapy agents for treating of cancer, particularly androgen-independent prostate cancer. The disclosure also relates to methods for preparing said compounds, and to pharmaceutical compositions comprising said compounds. embedded image

  14. Anticancer Agents: Does a Phosphonium Behave Like a Gold(I) Phosphine Complex? Let a "Smart" Probe Answer!

    PubMed

    Ali, Moussa; Dondaine, Lucile; Adolle, Anais; Sampaio, Carla; Chotard, Florian; Richard, Philippe; Denat, Franck; Bettaieb, Ali; Le Gendre, Pierre; Laurens, Véronique; Goze, Christine; Paul, Catherine; Bodio, Ewen

    2015-06-11

    Gold phosphine complexes, such as auranofin, have been recognized for decades as antirheumatic agents. Clinical trials are now underway to validate their use in anticancer or anti-HIV treatments. However, their mechanisms of action remain unclear. A challenging question is whether the gold phosphine complex is a prodrug that is administered in an inactive precursor form or rather that the gold atom remains attached to the phosphine ligand during treatment. In this study, we present two novel gold complexes, which we compared to auranofin and to their phosphonium analogue. The chosen ligand is a phosphine-based smart probe, whose strong fluorescence depends on the presence of the gold atom. The in vitro biological action of the gold complexes and the phosphonium derivative were investigated, and a preliminary in vivo study in healthy zebrafish larvae allowed us to evaluate gold complex biodistribution and toxicity. The different analyses carried out showed that these gold complexes were stable and behaved differently from phosphonium and auranofin, both in vitro and in vivo. Two-photon microscopy experiments demonstrated that the cellular targets of these gold complexes are not the same as those of the phosphonium analogue. Moreover, despite similar IC50 values in some cancer cell lines, gold complexes displayed a low toxicity in vivo, in contrast to the phosphonium salt. They are therefore suitable for future in vivo investigations. PMID:25973667

  15. Discovery of Akt kinase inhibitors through structure-based virtual screening and their evaluation as potential anticancer agents.

    PubMed

    Chuang, Chih-Hung; Cheng, Ta-Chun; Leu, Yu-Ling; Chuang, Kuo-Hsiang; Tzou, Shey-Cherng; Chen, Chien-Shu

    2015-01-01

    Akt acts as a pivotal regulator in the PI3K/Akt signaling pathway and represents a potential drug target for cancer therapy. To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal structure of human Akt kinase. From the virtual screening, 48 compounds were selected and subjected to the Akt kinase inhibition assay. Twenty-six of the test compounds showed more potent inhibitory effects on Akt kinase than the reference compound, H-89. These 26 compounds were further evaluated for their cytotoxicity against HCT-116 human colon cancer cells and HEK-293 normal human embryonic kidney cells. Twelve compounds were found to display more potent or comparable cytotoxic activity compared to compound H-89 against HCT-116 colon cancer cells. The best results were obtained with Compounds a46 and a48 having IC50 values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC50 for HEK-293/IC50 for HCT-116) of 12.5 and 16.1, respectively. Through structure-based virtual screening and biological evaluations, we have successfully identified several new Akt inhibitors that displayed cytotoxic activity against HCT-116 human colon cancer cells. Especially, Compounds a46 and a48 may serve as useful lead compounds for further development of new anticancer agents. PMID:25648320

  16. Direct Delivery of a Cytotoxic Anticancer Agent into the Metastatic Lymph Node Using Nano/Microbubbles and Ultrasound

    PubMed Central

    Sato, Takuma; Mori, Shiro; Sakamoto, Maya; Arai, Yoichi; Kodama, Tetsuya

    2015-01-01

    Direct injection of an anticancer agent into a metastatic lymph node (LN) has not been used as a standard treatment because evidence concerning the efficacy of local administration of a drug into a metastatic LN has not been established. Here we show that the combination of intralymphatic drug delivery with nano/microbubbles (NMBs) and ultrasound has the potential to improve the chemotherapeutic effect. We delivered cis-diamminedichloroplatinum (II) (CDDP) into breast carcinoma cells in vitro and found that apoptotic processes were involved in the antitumor action. Next, we investigated the antitumor effect of intralymphatic chemotherapy with NMBs and ultrasound in an experimental model of LN metastasis using MXH10/Mo-lpr/lpr mice exhibiting lymphadenopathy. The combination of intralymphatic chemotherapy with NMBs and ultrasound has the potential to improve the delivery of CDDP into target LNs without damage to the surrounding normal tissues. The present study indicates that intralymphatic drug delivery with NMBs and ultrasound will potentially be of great benefit in the clinical setting. PMID:25897663

  17. Identification of potential transmembrane protease serine 4 inhibitors as anti-cancer agents by integrated computational approach.

    PubMed

    Ilamathi, M; Hemanth, R; Nishanth, S; Sivaramakrishnan, V

    2016-01-21

    Transmembrane protease serine 4 is a well known cell surface protease facilitating the extracellular matrix degradation and epithelial mesenchymal transition in hepatocellular carcinoma. Henceforth targeting transmembrane protease serine 4 is strongly believed to provide therapeutic intervention against hepatocellular carcinoma. Owing to lack of crystal structure for human transmembrane protease serine 4, we predicted its three dimensional structure for the first time in this study. Experimentally proven inhibitor-Tyroserleutide (TSL) against hepatocellular carcinoma via transmembrane protease serine 4 was used as a benchmark to identify structurally similar candidates from PubChem database to create the TSL library. Virtual screening of TSL library against modeled transmembrane protease serine 4 revealed the top four potential inhibitors. Further binding free energy (?Gbind) analysis of the potential inhibitors revealed the best potential lead compound against transmembrane protease serine 4. Drug likeliness nature of the top four potential hits were additionally analyzed in comparison to TSL to confirm on the best potential lead compound with the highest % of human oral absorption. Consequently, e-pharmacophore mapping of the best potential lead compound yielded a six point feature. It was observed to contain four hydrogen bond donor sites (D), one positively ionizable site (P) and one aromatic ring (R). Such e-pharmacophore insight obtained from structural determinants by integrated computational analysis could serve as a framework for further advancement of drug discovery process of new anti-cancer agents with less toxicity and high specificity targeting transmembrane protease serine 4 and hepatocellular carcinoma. PMID:26590327

  18. HS-133, a novel fluorescent phosphatidylinositol 3-kinase inhibitor as a potential imaging and anticancer agent for targeted therapy

    PubMed Central

    Lee, Hyunseung; Son, Mi Kwon; Yun, Sun-Mi; Ahn, Sung-Hoon; Lee, Kyeong-Ryoon; Lee, Soyoung; Kim, Donghee; Hong, Sungwoo; Hong, Soon-Sun

    2014-01-01

    As PI3K/Akt signaling is frequently deregulated in a wide variety of human tumors, PI3K inhibitors are an emerging class of drugs for cancer treatment. The monitoring of the drug behavior and distribution in the biological system can play an important role for targeted therapy and provide information regarding the response or resistance to available therapies. In this study, therefore, we have developed a family of xanthine derivatives, serving as a dual function exhibiting fluorescence, as well as inhibiting PI3K. Among them, HS-133 showed anti-proliferative effects and was monitored for its subcellular localization by a fluorescence microscopy. HS-133 suppressed the PI3K/Akt pathway and induced cell cycle arrest at the G0/G1 phase. The induction of apoptosis by HS-133 was confirmed by the increases of the cleaved PARP, caspase-3, and caspase-8. Furthermore, HS-133 decreased the protein expression of HIF-1? and VEGF, as well inhibited the tube formation and migration of the human umbilical vein endothelial cells. In vivo imaging also showed that tumors were visualized fluorescent with HS-133, and its oral administration significantly inhibited the growth of tumor in SkBr3 mouse xenograft models. Thus, we suggest that HS-133 may be used as a fluorescent anticancer agent against human breast cancer. PMID:25338206

  19. Evaluation of cytotoxic potential of latex of Calotropis procera and podophyllotoxin in Allium cepa root model.

    PubMed

    Sehgal, R; Roy, S; Kumar, V L

    2006-04-01

    In the present study we have utilized the Allium cepa root tip meristem model to evaluate the cytotoxic and anti-mitotic activities of latex of Calotropis procera (DL) and podophyllotoxin. Standard cytotoxic drug cyclophosphamide and non-cytotoxic drugs cyprohcptadine and aspirin served as controls. Like cyclophosphamide, both DL and podophyllotoxin significantly inhibited the growth of roots and mitotic activity in a dose-dependent manner. However, podophyllotoxin was more potent in this regard and produced root decay. Cyproheptadine and aspirin, on the other hand, showed a marginal effect on the root growth and mitotic activity at much higher concentrations. PMID:16845823

  20. Activation of the anti-cancer agent upamostat by the mARC enzyme system.

    PubMed

    Froriep, Danilo; Clement, Bernd; Bittner, Florian; Mendel, Ralf R; Reichmann, Debora; Schmalix, Wolfgang; Havemeyer, Antje

    2013-09-01

    Upamostat (Mesupron®) is a new small molecule serine protease inhibitor. The drug candidate was developed to inhibit the urokinase-type plasminogen activator (uPA) system, which plays a major role in tumor invasion and metastasis. Upamostat is currently in clinical development as an anti-metastatic and non-cytotoxic agent against pancreatic and breast cancer. Upamostat is the orally available amidoxime- (i.e. hydroxyamidine-) prodrug of the pharmacologically active form, WX-UK1. In this study, the reductive enzymatic activation of upamostat to its corresponding amidine WX-UK1 was analyzed. The recently discovered molybdenum enzyme "mitochondrial Amidoxime Reducing Component" (mARC) catalyses together with its electron transport proteins cytochrome b? and NADH cytochrome b? reductase the reduction of N-hydroxylated prodrugs. In vitro biotransformation assays with porcine subcellular fractions and the reconstituted human enzymes demonstrate an mARC-dependent N-reduction of upamostat. PMID:23379481

  1. The Quest for a Simple Bioactive Analog of Paclitaxel as a Potential Anticancer Agent

    PubMed Central

    2015-01-01

    Conspectus Paclitaxel (PTX), introduced into the clinic in 1991, has revealed itself as an effective antimicrotubule drug for treatment of a range of otherwise intractable cancers. Along with docetaxel (DTX) and in combination with other agents such as cisplatin, it has proven to be a first-line therapy. Unfortunately, PTX and DTX carry severe liabilities such as debilitating side effects, rapid onset of resistance, and rather complex molecular structures offering substantial challenges to ease of synthetic manipulation. Consequently, the past 15 years has witnessed many efforts to synthesize and test highly modified analogs based on intuitive structural similarity relationships with the PTX molecular skeleton, as well as efforts to mimic the conformational profile of the ligand observed in the macromolecular tubulin–PTX complex. Highly successful improvements in potency, up to 50-fold increases in IC50, have been achieved by constructing bridges between distal centers in PTX that imitate the conformer of the electron crystallographic binding pose. Much less successful have been numerous attempts to truncate PTX by replacing the baccatin core with simpler moieties to achieve PTX-like potencies and applying a wide range of flexible synthesis-based chemistries. Reported efforts, characterized by a fascinating array of baccatin substitutes, have failed to surpass the bioactivities of PTX in both microtubule disassembly assays and cytotoxicity measurements against a range of cell types. Most of the structures retain the main elements of the PTX C13 side chain, while seeking a smaller rigid bicycle as a baccatin replacement adorned with substituents to mimic the C2 benzoyl moiety and the oxetane ring. We surmise that past studies have been handicapped by solubility and membrane permeability issues, but primarily by the existence of an expansive taxane binding pocket and the discrepancy in molecular size between PTX and the pruned analogs. A number of these molecules offer molecular volumes 50–60% that of PTX, fewer contacts with the tubulin protein, severe mismatches with the PTX pharmacophore, lessened capacity to dispel binding site waters contributing to ?Gbind, and unanticipated binding poses. The latter is a critical drawback if molecular designs of simpler PTX structures are based on a perceived or known PTX binding conformation. We conclude that design and synthesis of a highly cytotoxic tubulin-assembly agent based on the paclitaxel pharmacophore remains an unsolved challenge, but one that can be overcome by focus on the architecture of the taxane binding site independent of the effective, but not unique, hand-in-glove match represented by the PTX–tubulin complex. PMID:25052294

  2. Psoralea glandulosa as a Potential Source of Anticancer Agents for Melanoma Treatment

    PubMed Central

    Madrid, Alejandro; Cardile, Venera; González, César; Montenegro, Ivan; Villena, Joan; Caggia, Silvia; Graziano, Adriana; Russo, Alessandra

    2015-01-01

    With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on melanoma cancer, the present study was undertaken to investigate the biological activity of the resinous exudate of aerial parts from Psoralea glandulosa, and its active components (bakuchiol (1), 3-hydroxy-bakuchiol (2) and 12-hydroxy-iso-bakuchiol (3)) against melanoma cells (A2058). In addition, the effect in cancer cells of bakuchiol acetate (4), a semi-synthetic derivative of bakuchiol, was examined. The results obtained show that the resinous exudate inhibited the growth of cancer cells with IC50 value of 10.5 ?g/mL after 48 h of treatment, while, for pure compounds, the most active was the semi-synthetic compound 4. Our data also demonstrate that resin is able to induce apoptotic cell death, which could be related to an overall action of the meroterpenes present. In addition, our data seem to indicate that the apoptosis correlated to the tested products appears, at least in part, to be associated with an increase of reactive oxygen species (ROS) production. In summary, our study provides the first evidence that P. glandulosa may be considered a source of useful molecules in the development of analogues with more potent efficacy against melanoma cells. PMID:25860949

  3. Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents.

    PubMed

    Chen, Jia-Nian; Wang, Xian-Fu; Li, Ting; Wu, De-Wen; Fu, Xiao-Bo; Zhang, Guang-Ji; Shen, Xing-Can; Wang, Heng-Shan

    2016-01-01

    Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7g, 7m, 7o, 8e, 8g, and 8m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8g exhibited the strongest activity. In particular, compound 8g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure-activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8g may be a potent antitumor agent, representing a promising lead for further optimization. PMID:26560049

  4. Characterisation of Mesothelioma-Initiating Cells and Their Susceptibility to Anti-Cancer Agents

    PubMed Central

    Pasdar, Elham Alizadeh; Smits, Michael; Stapelberg, Michael; Bajzikova, Martina; Stantic, Marina; Goodwin, Jacob; Yan, Bing; Stursa, Jan; Kovarova, Jaromira; Sachaphibulkij, Karishma; Bezawork-Geleta, Ayenachew; Sobol, Margaryta; Filimonenko, Anatoly; Tomasetti, Marco; Zobalova, Renata; Hozak, Pavel; Dong, Lan-Feng; Neuzil, Jiri

    2015-01-01

    Malignant mesothelioma (MM) is an aggressive type of tumour causing high mortality. One reason for this paradigm may be the existence of a subpopulation of tumour-initiating cells (TICs) that endow MM with drug resistance and recurrence. The objective of this study was to identify and characterise a TIC subpopulation in MM cells, using spheroid cultures, mesospheres, as a model of MM TICs. Mesospheres, typified by the stemness markers CD24, ABCG2 and OCT4, initiated tumours in immunodeficient mice more efficiently than adherent cells. CD24 knock-down cells lost the sphere-forming capacity and featured lower tumorigenicity. Upon serial transplantation, mesospheres were gradually more efficiently tumrigenic with increased level of stem cell markers. We also show that mesospheres feature mitochondrial and metabolic properties similar to those of normal and cancer stem cells. Finally, we show that mesothelioma-initiating cells are highly susceptible to mitochondrially targeted vitamin E succinate. This study documents that mesospheres can be used as a plausible model of mesothelioma-initiating cells and that they can be utilised in the search for efficient agents against MM. PMID:25932953

  5. NF-?B-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT

    PubMed Central

    Nakshatri, H; Appaiah, H N; Anjanappa, M; Gilley, D; Tanaka, H; Badve, S; Crooks, P A; Mathews, W; Sweeney, C; Bhat-Nakshatri, P

    2015-01-01

    The transcription factor nuclear factor-kappaB (NF-?B) is constitutively active in several cancers and is a target of therapeutic development. We recently developed dimethylaminoparthenolide (DMAPT), a clinical grade water-soluble analog of parthenolide, as a potent inhibitor of NF-?B and demonstrated in vitro and in vivo anti-tumor activities in multiple cancers. In this study, we show DMAPT is an epigenetic modulator functioning in an NF-?B-dependent and -independent manner. DMAPT-mediated NF-?B inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of NF-?B or inhibitor-of-kappaB alpha super-repressor overexpression. DMAPT treatment and p65 ablation increased the levels of H3K36 trimethylases NSD1 (KMT3B) and SETD2 (KMT3A), suggesting that NF-?B directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive NF-?B activity. Overexpression of a constitutively active p65 subunit of NF-?B reduced NSD1 and H3K36me3 levels. NSD1 is essential for DMAPT-induced expression of pro-apoptotic BIM, indicating a functional link between epigenetic modification and gene expression. Interestingly, we observed enhanced H4K20 trimethylation and induction of H4K20 trimethylase KMT5C in DMAPT-treated cells independent of NF-?B inhibition. These results add KMT5C to the list NF-?B-independent epigenetic targets of parthenolide, which include previously described histone deacetylase 1 (HDAC-1) and DNA methyltransferase 1. As NSD1 and SETD2 are known tumor suppressors and loss of H4K20 trimethylation is an early event in cancer progression, which contributes to genomic instability, we propose DMAPT as a potent pharmacologic agent that can reverse NF-?B-dependent and -independent cancer-specific epigenetic abnormalities. PMID:25611383

  6. Level of Serum Enzymes and Electrocardiogram in Healthy Rabbits after Injection of ICD-85 as an Anticancer Agent

    PubMed Central

    Zare Mirakabadi, Abbas; Sarzaeem, Ali

    2015-01-01

    Background: Our previous in vivo studies confirmed that ICD-85, as an anticancer agent, was able to prevent further growth of breast tumors and expand the life expectancy of mice with breast cancer. Methods: Blood collection was carried out before, 1, 3, and 6 hours after ICD-85 injection. Sera were used to determinate the cardio and hepatic enzymes levels, including ALT, AST, LDH, CPK, and Ck-MB. Coagulation factors such as PT and PTT were also assayed. ECGs of all rabbits were recorded during the experiment. Results: ECG results showed that the injection of 50 and 100 µg/kg ICD-85 into healthy rabbits has no significant effect on heart function while the injection of 150 to 200 µg/kg ICD-85 caused ECG wave changes and mild bradycardia without toxic effects on heart. After ICD-85 injection (concentrations below 100 µg/kg), no significant increase was observed in liver and cardiac enzymes (ALT, AST, LDH, CPK, and CK-MB). However, the concentration of 150 µg/kg and above caused a rise in the enzymes. Comparison of the PT and PTT before and after ICD-85 injection showed no significant clotting time at any concentrations below 200 µg/kg. Conclusion: Based on the results obtained in the present study as well as our previous reports, ICD-85 at concentrations below 100 µg/kg seems to have no significant effect on the serum enzymes as indicators of hepatotoxicity and cardiotoxicity in healthy rabbits. However, to confirm this conclusion, more detailed surveys on heart and liver is needed to be carried out. PMID:26239313

  7. Flushing Out Carcinoid Syndrome: Beneficial Effect of the Anticancer Epigenetic Agent RRx-001 in a Patient with a Treatment-Refractory Neuroendocrine Tumor

    PubMed Central

    Carter, Corey A.; Degesys, Aiste; Oronsky, Bryan; Scicinski, Jan; Caroen, Scott Z.; Oronsky, Arnold L.; Reid, Tony; Cabrales, Pedro; Roswarski, Joe

    2015-01-01

    Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms defined by the presence of cells with secretory granules and the potential to produce and release high levels of vasoactive peptides into the circulation, leading to severe flushing and diarrhea, which may adversely affect quality of life. This report presents the case of a 64-year-old man with chronic refractory diarrhea due to pulmonary NET treated with the experimental anticancer agent RRx-001 in a phase II trial called TRIPLE THREAT with subsequent resolution of his diarrhea. PMID:26600780

  8. Anti-cancer agents based on 4-(hetero)Ary1-1,2,5-oxadiazol-3-yl Amino derivatives and a method of making

    DOEpatents

    Gakh, Andrei A.; Krasavin, Mikhail; Karapetian, Ruben; Rufanov, Konstantin A.; Konstantinov, Igor; Godovykh, Elena; Soldatkina, Olga; Sosnov, Andrey V.

    2013-01-29

    The present disclosure relates to novel compounds that can be used as anti-cancer agents in the prostate cancer therapy. ##STR00001## In particular, the invention relates N-substituted derivatives of 4-(hetero)aryl-1,2,5-oxadiazol-3-yl amines having the structural Formula (I) and (II), stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or pharmaceutically acceptable salt and/or solvate thereof. Meaning of R1 and R2 in the Formula (I) and (II) are defined in claim 1. The invention also relates to methods for preparing said compounds, and to pharmaceutical compositions comprising said compounds.

  9. Structure-based lead optimization and biological evaluation of BAX direct activators as novel potential anticancer agents.

    PubMed

    Stornaiuolo, Mariano; La Regina, Giuseppe; Passacantilli, Sara; Grassia, Gianluca; Coluccia, Antonio; La Pietra, Valeria; Giustiniano, Mariateresa; Cassese, Hilde; Di Maro, Salvatore; Brancaccio, Diego; Taliani, Sabrina; Ialenti, Armando; Silvestri, Romano; Martini, Claudia; Novellino, Ettore; Marinelli, Luciana

    2015-03-12

    The first direct activator of BAX, a pro-apoptotic member of the BCL-2 family, has been recently identified. Herein, a structure-based lead optimization turned out into a small series of analogues, where 8 is the most potent compound published so far. 8 was used as pharmacological tool to ascertain, for the first time, the anticancer potential of BAX direct activators and the obtained results would suggest that BAX direct activators are potential future anticancer drugs rather than venoms. PMID:25668341

  10. Design, Synthesis and Biological Evaluation of (E)-N-Aryl-2-arylethene-sulfonamide Analogues as Potent and Orally Bioavailable Microtubule-targeted Anticancer Agents

    PubMed Central

    Ramana Reddy, M. V.; Mallireddigari, Muralidhar R.; Pallela, Venkat R.; Cosenza, Stephen C.; Billa, Vinay K.; Akula, Balaiah; Venkata Subbaiah, D. R. C.; Bharathi, E. Vijaya; Padgaonkar, Amol; Lv, Hua; Gallo, James M.; Reddy, E. Premkumar

    2013-01-01

    A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-Amino-4-methoxyphenyl)-2-(2?,4?,6?-trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used anti-mitotic agents. Mechanistic studies indicate that 6t and some other analogs disrupted microtubule formation, formation of mitotic spindles and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin indicating its binding site on tubulin. PMID:23750455

  11. Design, synthesis and biological evaluation of novel bromophenol derivatives incorporating indolin-2-one moiety as potential anticancer agents.

    PubMed

    Wang, Li-Jun; Wang, Shuai-Yu; Jiang, Bo; Wu, Ning; Li, Xiang-Qian; Wang, Bao-Cheng; Luo, Jiao; Yang, Meng; Jin, Shui-Hua; Shi, Da-Yong

    2015-02-01

    A series of bromophenol derivatives containing indolin-2-one moiety were designed and evaluated that for their anticancer activities against A549, Bel7402, HepG2, HeLa and HCT116 cancer cell lines using MTT assay in vitro. Among them, seven compounds (4g-4i, 5h, 6d, 7a, 7b) showed potent activity against the tested five human cancer cell lines. Wound-healing assay demonstrated that compound 4g can be used as a potent compound for inactivating invasion and metastasis by inhibiting the migration of cancer cells. The structure-activity relationships (SARs) of bromophenol derivatives had been discussed, which were useful for exploring and developing bromophenol derivatives as novel anticancer drugs. PMID:25648512

  12. Synthetic strategies for the design of platinum anticancer drug candidates

    E-print Network

    Wilson, Justin Jeff

    2013-01-01

    Chapter 1. The Synthetic Chemistry of Platinum Anticancer Agents Since the inception of cisplatin as a clinically approved anticancer agent, a large number of platinum compounds have been synthesized with the aim of finding ...

  13. Biotin-Containing Reduced Graphene Oxide-Based Nanosystem as a Multieffect Anticancer Agent: Combining Hyperthermia with Targeted Chemotherapy.

    PubMed

    Mauro, Nicolò; Scialabba, Cinzia; Cavallaro, Gennara; Licciardi, Mariano; Giammona, Gaetano

    2015-09-14

    Among the relevant properties of graphene derivatives, their ability of acting as an energy-converting device so as to produce heat (i.e., thermoablation and hyperthermia) was more recently taken into account for the treatment of solid tumors. In this pioneering study, for the first time, the in vitro RGO-induced hyperthermia was assessed and combined with the stimuli-sensitive anticancer effect of a biotinylated inulin-doxorubicin conjugate (CJ-PEGBT), hence, getting to a nanosystem endowed with synergic anticancer effects and high specificity. CJ-PEGBT was synthesized by linking pentynoic acid and citraconic acid to inulin. The citraconylamide pendants, used as pH reversible spacer, were exploited to further conjugate doxorubicin, whereas the alkyne moiety was orthogonally functionalized with an azido PEG-biotin derivative by copper(II) catalyzed 1,3-dipolar cycloaddition. DSC measures, AFM, and UV spectrophotometry were employed to systematically investigate adsorption of CJ-PEGBT onto RGO and its physicochemical stability in aqueous media, demonstrating that a stable ?-staked nanosystem can be obtained. In vitro tests using cancer breast cells (MCF-7) showed the ability of the RGO/CJ-PEGBT of efficiently killing cancer cells both via a selective laser beam thermoablation and hyperthermia-triggered chemotherapy. If compared with the nonbiotinylated nanosystem, including virgin RGO and the free conjugate, RGO/CJ-PEGBT is endowed with a smart combination of properties which warrant potential as an anticancer nanomedicine. PMID:26204419

  14. Methyl Jasmonate Induces Enhanced Podophyllotoxin Production in Cell Cultures of Thracian Flax (Linum thracicum ssp. thracicum).

    PubMed

    Sasheva, Pavlina; Ionkova, Iliana; Stoilova, Nadezhda

    2015-07-01

    The Linum thracicum ssp. thracicum cell lines developed in this study are a feasible source for the sustainable production of podophyllotoxin, a lignan with an aryltetralin skeleton that is used for the manufacture of the chemotherapeutic drugs etopophos and teniposide. We used mass spectrometry to confirm the presence of the aryltetralin lignan in the thracian flax cell cultures. Next, we explored how changes in the culture medium influenced the podophyllotoxin content. Out of six developed cell lines, four were selected for further experiments and challenged with elicitors. The selected cell lines clustered into two groups: developed in full strength medium (Li) vs developed in half strength medium (HS). While podophyllotoxin production in the Li cell lines was boosted by 80% upon administration of the elicitor methyl jasmonate, the HS lines produced high amounts of the target metabolite triggered by reduced concentration of nutrients and were only slightly influenced by the elicitor. PMID:26411016

  15. Podophyllum peltatum possesses a beta-glucosidase with high substrate specificity for the aryltetralin lignan podophyllotoxin.

    PubMed

    Dayan, Franck E; Kuhajek, Jeanne M; Canel, Camilo; Watson, Susan B; Moraes, Rita M

    2003-03-21

    A beta-glucosidase with high specificity for podophyllotoxin-4-O-beta-D-glucopyranoside was purified from the leaves of Podophyllum peltatum. The 65-kDa polypeptide had optimum activity at pH 5.0 and was essentially inactive at pH 6.5 or above. Maximum catalytic activity of this glucosidase was obtained at 45 degrees C, but the enzyme was not heat stable. This beta-glucosidase displayed higher substrate specificity for podophyllotoxin-4-O-beta-D-glucopyranoside than for the other lignans tested, and for the (1-->3) linkage of laminaribiose than for other glucosidic linkages. PMID:12637023

  16. Cheminformatics models based on machine learning approaches for design of USP1/UAF1 abrogators as anticancer agents.

    PubMed

    Wahi, Divya; Jamal, Salma; Goyal, Sukriti; Singh, Aditi; Jain, Ritu; Rana, Preeti; Grover, Abhinav

    2015-06-01

    Cancer cells have upregulated DNA repair mechanisms, enabling them survive DNA damage induced during repeated rapid cell divisions and targeted chemotherapeutic treatments. Cancer cell proliferation and survival targeting via inhibition of DNA repair pathways is currently a very promiscuous anti-tumor approach. The deubiquitinating enzyme, USP1 is known to promote DNA repair via complexing with UAF1. The USP1/UAF1 complex is responsible for regulating DNA break repair pathways such as trans-lesion synthesis pathway, Fanconi anemia pathway and homologous recombination. Thus, USP1/UAF1 inhibition poses as an efficient anti-cancer strategy. The recently made available high throughput screen data for anti USP1/UAF1 activity prompted us to compute bioactivity predictive models that could help in screening for potential USP1/UAF1 inhibitors having anti-cancer properties. The current study utilizes publicly available high throughput screen data set of chemical compounds evaluated for their potential USP1/UAF1 inhibitory effect. A machine learning approach was devised for generation of computational models that could predict for potential anti USP1/UAF1 biological activity of novel anticancer compounds. Additional efficacy of active compounds was screened by applying SMARTS filter to eliminate molecules with non-drug like features. The structural fragment analysis was further performed to explore structural properties of the molecules. We demonstrated that modern machine learning approaches could be efficiently employed in building predictive computational models and their predictive performance is statistically accurate. The structure fragment analysis revealed the structures that could play an important role in identification of USP1/UAF1 inhibitors. PMID:25972987

  17. Anti-cancer agents based on N-acyl-2, 3-dihydro-1H-pyrrolo[2,3-b] quinoline derivatives and a method of making

    DOEpatents

    Gakh, Andrei; Krasavin, Mikhail; Karapetian, Ruben; Rufanov, Konstantin A; Konstantinov, Igor; Godovykh, Elena; Soldatkina, Olga; Sosnov, Andrey V

    2013-04-16

    The present disclosure relates to novel compounds that can be used as anti-cancer agents in the prostate cancer therapy. In particular, the invention relates to N-acyl derivatives of 2,3-dihydro-1H-pyrrolo[2,3-b]quinolines having the structural Formula (I), ##STR00001## stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or pharmaceutically acceptable salt and/or solvate thereof. The meaning of R1 is independently selected from H; C1-C6 Alkyl, cyclo-Alkyl or iso-Alkyl substituents; R2 is selected from C1-C6 Alkyl, cyclo-Alkyl or iso-Alkyl; substituted or non-substituted, fused or non-fused to substituted or non-substituted aromatic ring, aryl or heteroaryl groups. The invention also relates to methods for preparing said compounds, and to pharmaceutical compositions comprising said compounds.

  18. Synthesis and biological evaluation of novel N-phenyl ureidobenzenesulfonate derivatives as potential anticancer agents. Part 2. Modulation of the ring B.

    PubMed

    Gagné-Boulet, Mathieu; Moussa, Hanane; Lacroix, Jacques; Côté, Marie-France; Masson, Jean-Yves; Fortin, Sébastien

    2015-10-20

    DNA double strand-breaks (DSBs) are the most deleterious lesions that can affect the genome of living beings and are lethal if not quickly and properly repaired. Recently, we discovered a new family of anticancer agents designated as N-phenyl ureidobenzenesulfonates (PUB-SOs) that are blocking the cells cycle progression in S-phase and inducing DNA DSBs. Previously, we have studied the effect of several modifications on the molecular scaffold of PUB-SOs on their cytocidal properties. However, the effect of the nature and the position of substituents on the aromatic ring B is still poorly studied. In this study, we report the preparation and the biological evaluation of 45 new PUB-SO derivatives substituted by alkyl, alkoxy, halogen and nitro groups at different positions on the aromatic ring B. All PUB-SOs were active in the submicromolar to low micromolar range (0.24-20 ?M). The cell cycle progression analysis showed that PUB-SOs substituted at position 2 by alkyl, halogen or nitro groups or substituted at position 4 by a hydroxyl group arrest the cell cycle progression in S-phase. Interestingly, all others PUB-SOs substituted at positions 3 and 4 arrested the cell cycle in G2/M-phase. PUB-SOs arresting the cell cycle progression in S-phase also induced the phosphorylation of H2AX (?H2AX) which is indicating the generation of DNA DSBs. We evidenced that few modifications on the ring B of PUB-SOs scaffold lead to cytocidal derivatives arresting the cell cycle in S-phase and inducing ?H2AX and DSBs. In addition, this study shows that these new anticancer agents are promising and could be used as alternative to circumvent some of the biopharmaceutical complications that might be encountered during the development of PUB-SOs. PMID:26408815

  19. Podophyllotoxin-loaded solid lipid nanoparticles for epidermal targeting.

    PubMed

    Chen, Huabing; Chang, Xueling; Du, Danrong; Liu, Wei; Liu, Jie; Weng, Ting; Yang, Yajiang; Xu, Huibi; Yang, Xiangliang

    2006-01-10

    The purpose of this study was to evaluate solid lipid nanoparticles as the topical carrier for epidermal targeting of podophyllotoxin (POD). The high pressure homogenization was employed to prepare drug-loaded solid lipid nanoparticles. The POD-loaded SLN stabilized by 0.5% poloxamer 188 and 1.5% soybean lecithin (P-SLN) and 2% polysorbate 80 (T-SLN) was characterized by photon correlation spectroscopy (PCS). P-SLN showed an average diameter of 73.4 nm and a zeta potential of -48.36 mV. The imaging of AFM indicated that the P-SLN had a spherical shape. DSC and X-ray diffraction analysis showed that POD was dispersed in SLN in an amorphous state. The in vitro permeation study showed that P-SLN increased the accumulative amount of POD in porcine skin 3.48 times over 0.15% tincture. But T-SLN with a diameter of 123.1 nm and a zeta potential of -17.4 mV did not show a high accumulative amount of POD when compared with P-SLN, though both P-SLN and T-SLN could avoid the systemic uptake of POD. Because of the fluorescence property of POD, fluorescence microscopy imaging was employed to visualize the penetration of POD into skin from SLN. The penetration of POD from P-SLN seemed to follow two pathways along the stratum corneum and hair follicle route. The imaging revealed that P-SLN had a strong localization of POD within epidermis. The penetration of P-SLN with low particle size into stratum corneum along the skin surface 'furrow' and the consequent controlled release of POD might lead to the epidermal targeting. P-SLN provides a good epidermal targeting effect and may be a promising carrier for topical delivery of POD. PMID:16325954

  20. PODOPHYLLUM PELTATUM POSSESSES A BETA-GLUCOSIDASE WITH HIGH SUBSTRATE SPECIFICITY FOR THE ARYLTETRALIN LIGNAN PODOPHYLLOTOXIN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A beta-glucosidase with high specificity for podophyllotoxin-4-O-b-d-glucopyranoside was purified from the leaves of Podophyllum peltatum. The 65 kD polypeptide had optimum activity at pH 5.0 and was essentially inactive at physiological pH (6.5 or above). The maximum catalytic activity of this glu...

  1. Synthesis and biological evaluation of spiro[cyclopropane-1,3'-indolin]-2'-ones as potential anticancer agents.

    PubMed

    Reddy, Chada Narsimha; Nayak, V Lakshma; Mani, Geeta Sai; Kapure, Jeevak Sopanrao; Adiyala, Praveen Reddy; Maurya, Ram Awatar; Kamal, Ahmed

    2015-10-15

    Libraries of spiro[cyclopropane-1,3'-indolin]-2'-ones were synthesized and evaluated for their biological activity against five different human cancer cell lines HT-29 (colon cancer), DU-145 (prostate cancer), Hela (cervical cancer), A-549 (Lung cancer), and MCF-7 (breast cancer). Many compounds of the series exhibited promising anticancer activity (IC50<20?M) against the studied cell lines. Based on the screening results, a structure activity relationship (SAR) of the pharmacophore was proposed. Among the series compound 6b and 6u showed significant activity against human prostate cancer cell line, DU-145. Flow cytometric analysis showed that these two compounds arrested the cell cycle in the G0/G1 phase leading to caspase-3 dependent apoptotic cell death. Further, measurement of mitochondrial membrane potential and Annexin V-FITC assay also suggested that 6b and 6u induced cell death by apoptosis. PMID:26330077

  2. Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists.

    PubMed

    Benbrook, Doris M; Kamelle, Scott A; Guruswamy, Suresh B; Lightfoot, Stan A; Rutledge, Teresa L; Gould, Natalie S; Hannafon, Bethany N; Dunn, S Terence; Berlin, K Darrell

    2005-10-01

    The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute's human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists. PMID:16133793

  3. 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 could be implicated in the well-documented anti-cancer property of GA/structure related compounds.

  4. Chemical genetics analysis of an aniline mustard anticancer agent reveals complex I of the electron transport chain as a target

    E-print Network

    Fedeles, Bogdan I.

    The antitumor agent 11? (CAS 865070-37-7), consisting of a DNA-damaging aniline mustard linked to an androgen receptor (AR) ligand, is known to form covalent DNA adducts and to induce apoptosis potently in AR-positive ...

  5. Redesigning the DNA-Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

    PubMed Central

    Pickard, Amanda J.; Liu, Fang; Bartenstein, Thomas F.; Haines, Laura G.; Levine, Keith E.; Kucera, Gregory L.; Bierbach, Ulrich

    2014-01-01

    Platinum–acridine hybrid agents show low-nanomolar potency in chemoresistant non-small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7-Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent (P1–B1) that maintained submicromolar activity in several of the DNA-repair proficient and p53-mutant cancer models, while showing improved tolerability in mice by 32-fold compared to the parent platinum–acridine (P1–A1). The distribution and DNA/RNA adduct levels produced by the acridine- and benz[c]acridine-based analogues in NCI-H460 cells (confocal microscopy, ICP-MS), and their ability to bind G-quadruplex forming DNA sequences (CD spectroscopy, HR-ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target-selective hybrid agent than P1–A1. PMID:25302716

  6. Marine-Sourced Anti-Cancer and Cancer Pain Control Agents in Clinical and Late Preclinical Development †

    PubMed Central

    Newman, David J.; Cragg, Gordon M.

    2014-01-01

    The marine habitat has produced a significant number of very potent marine-derived agents that have the potential to inhibit the growth of human tumor cells in vitro and, in a number of cases, in both in vivo murine models and in humans. Although many agents have entered clinical trials in cancer, to date, only Cytarabine, Yondelis® (ET743), Eribulin (a synthetic derivative based on the structure of halichondrin B), and the dolastatin 10 derivative, monomethylauristatin E (MMAE or vedotin) as a warhead, have been approved for use in humans (Adcetris®). In this review, we show the compounds derived from marine sources that are currently in clinical trials against cancer. We have included brief discussions of the approved agents, where they are in trials to extend their initial approved activity (a common practice once an agent is approved), and have also included an extensive discussion of the use of auristatin derivatives as warheads, plus an area that has rarely been covered, the use of marine-derived agents to ameliorate the pain from cancers in humans, and to act as an adjuvant in immunological therapies. PMID:24424355

  7. Marine-sourced anti-cancer and cancer pain control agents in clinical and late preclinical development.

    PubMed

    Newman, David J; Cragg, Gordon M

    2014-01-01

    The marine habitat has produced a significant number of very potent marine-derived agents that have the potential to inhibit the growth of human tumor cells in vitro and, in a number of cases, in both in vivo murine models and in humans. Although many agents have entered clinical trials in cancer, to date, only Cytarabine, Yondelis® (ET743), Eribulin (a synthetic derivative based on the structure of halichondrin B), and the dolastatin 10 derivative, monomethylauristatin E (MMAE or vedotin) as a warhead, have been approved for use in humans (Adcetris®). In this review, we show the compounds derived from marine sources that are currently in clinical trials against cancer. We have included brief discussions of the approved agents, where they are in trials to extend their initial approved activity (a common practice once an agent is approved), and have also included an extensive discussion of the use of auristatin derivatives as warheads, plus an area that has rarely been covered, the use of marine-derived agents to ameliorate the pain from cancers in humans, and to act as an adjuvant in immunological therapies. PMID:24424355

  8. Continuous intravenous infusion in athymic (nude) rats: an animal model for evaluating the efficacy of anti-cancer agents.

    PubMed

    van Wijk, H; Dick, A; Greenough, R J; Oshodi, R O; Robb, D

    2000-01-01

    The athymic (nude) rat (rnu/rnu) has been used for a number of years in research into various human tumours involving xenotransplantation. We now report the validation of a continuous intravenous infusion method in nude rats using a tail cuff tether, which enables the study of the efficacy of novel anti-cancer materials in this mutant strain, using intravenous infusion and with no restriction of the animals or of the tumour implantation sites by jackets. Ten animals each had a cannula surgically implanted into the vena cava via the femoral vein and exteriorized via a tail cuff. Animals were housed singly in conventional cages following surgery. Following a recovery period of 5 days all animals were continuously infused with physiological saline at an infusion rate of 0.5 ml/h for a further 37 days. Body weights and food consumption were recorded weekly. Blood samples were taken approximately 14 days post-surgery and analysed for haematology and clinical chemistry parameters. All animals were successfully cannulated, and no unexpected adverse clinical signs were noted during the recovery period and the 37 days of infusion. The results demonstrate that it is possible to surgically cannulate the femoral vein of athymic (nude) rats and infuse them in conventional cages for a period of up to 37 days with minimal adverse effects. The minimal restraint required provides benefits both to the animal and to the conduct of studies such as assessment of tumour growth in the absence of a jacket. Recent work has demonstrated that the same techniques can be successfully applied to the nude mouse. PMID:10759368

  9. Synthesis, antiproliferative and apoptotic activities of N-(6(4)-indazolyl)-benzenesulfonamide derivatives as potential anticancer agents.

    PubMed

    Abbassi, Najat; Chicha, Hakima; Rakib, El Mostapha; Hannioui, Abdellah; Alaoui, Mdaghri; Hajjaji, Abdelouahed; Geffken, Detlef; Aiello, Cinzia; Gangemi, Rosaria; Rosano, Camillo; Viale, Maurizio

    2012-11-01

    Recently, it has been reported that compounds bearing a sulfonamide moiety possess many types of biological activities, including anticancer activity. The present work reports the synthesis and antiproliferative evaluation of some N-(6(4)-indazolyl)benzenesulfonamides and 7-ethoxy-N-(6(4)-indazolyl)benzenesulfonamides. All compounds were evaluated for their in vitro antiproliferative activity against three tumor cell lines: A2780 (human ovarian carcinoma) A549 (human lung adenocarcinoma) and P388 (murine leukemia). The results indicated that sulfonamides 2c, 3c, 6d, 8, 13, 3b and 16 were endowed with a pharmacologically interesting antiproliferative activity with compounds 2c and 3c showing the lower IC(50) (from 0.50 ± 0.09 to 1.83 ± 0.52 ?M and from 0.58 ± 0.17 to 5.83 ± 1.83 ?M, respectively). Moreover, these indazoles were able to trigger apoptosis through the upregulation of the typical apoptosis markers p53 and bax. As regard to the hypothetic targets of these compounds, a preliminary docking analysis showed that all compounds seemed to interact with ?-tubulin, in particular compound 3b that showed the lower Ki. The cytofluorimetric analysis of the cell cycle phases indicates that all compounds, when administered at their IC(75), caused a block in the G2/M phase of the cell cycle with the generation of subpopulations of cells with a number of chromosome >4n. When the IC(50)s were applied we observed a prevalent block in the G0/G1 phase except for compounds 16 and 8 where a partial G2/M block was present with a concomitant decrease of cells in the G0/G1 and S phases of the cell cycle. Altogether these results suggest a possible, but not exclusive, interaction with microtubules. PMID:23072738

  10. Newly Synthesized Water Soluble Cholinium-Purpurin Photosensitizers and Their Stabilized Gold Nanoparticles as Promising Anticancer Agents

    PubMed Central

    Demberelnyamba, Dorjnamjin; Ariunaa, Mama; Shim, Young Key

    2008-01-01

    For possible future use in Photodynamic Therapy (PDT) and/or Photothermal Therapy (PTT) of cancer and screening of cancer cells a new type of ionic liquid photosensitizer –Cholinium-Purpurin-18 (Chol-Pu-18) – was synthesized and small gold (Au) nanoparticles, stabilized by this photosensitizer were prepared without adding any particular reducing agents and CTAB. UV-Vis spectroscopy and Transmission Electron Microscopy (TEM) were used for characterization of the nanoparticles and FAB-MS and NMR of the ionic liquid choline hydroxide, purpurin carboxylate and their ionic liquid type of photosensitizer were obtained. PMID:19325790

  11. Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model: a case study with the anticancer agent SNX-2112

    PubMed Central

    Dong, Dong; Wang, Xiao; Wang, Huailing; Zhang, Xingwang; Wang, Yifei; Wu, Baojian

    2015-01-01

    Introduction SNX-2112 is a promising anticancer agent but has poor solubility in both water and oil. In the study reported here, we aimed to develop a nanocrystal formulation for SNX-2112 and to determine the pharmacokinetic behaviors of the prepared nanocrystals. Methods Nanocrystals of SNX-2112 were prepared using the wet-media milling technique and characterized by particle size, differential scanning calorimetry, drug release, etc. Physiologically based pharmacokinetic (PBPK) modeling was undertaken to evaluate the drug’s disposition in rats following administration of drug cosolvent or nanocrystals. Results The optimized SNX-2112 nanocrystals (with poloxamer 188 as the stabilizer) were 203 nm in size with a zeta potential of ?11.6 mV. In addition, the nanocrystals showed a comparable release profile to the control (drug cosolvent). Further, the rat PBPK model incorporating the parameters of particulate uptake (into the liver and spleen) and of in vivo drug release was well fitted to the experimental data following administration of the drug nanocrystals. The results reveal that the nanocrystals rapidly released drug molecules in vivo, accounting for their cosolvent-like pharmacokinetic behaviors. Due to particulate uptake, drug accumulation in the liver and spleen was significant at the initial time points (within 1 hour). Conclusion The nanocrystals should be a good choice for the systemic delivery of the poorly soluble drug SNX-2112. Also, our study contributes to an improved understanding of the in vivo fate of nanocrystals. PMID:25848269

  12. N-4-iodophenyl-N'-2-chloroethylurea, a novel potential anticancer agent with colon-specific accumulation: radioiodination and comparative in vivo biodistribution profiles.

    PubMed

    Mounetou, Emmanuelle; Miot-Noirault, Elisabeth; Gaudreault, René C; Madelmont, J Claude

    2010-04-01

    In a search for more selective anticancer drugs, we have designed nitrogen mustard and nitrosourea conjugates leading to a series of N-4-aryl-N'-2-chloroethylureas (CEUs). The iodinated derivative N-4-iodophenyl-N'-2-chloroethylurea (4-ICEU) has demonstrated significant antineoplastic and antiangiogenic potency in preclinical evaluations. In this study, 4-ICEU was radiolabelled with [(125)I]iodide in order to carry out a comparative study of its in vivo behavior profile. 4-[(125)I]-ICEU was synthesized by direct electrophilic radioiodination with 80% radiochemical yield and 97% radiopurity. Three different routes of administration (intraperitoneal (ip), intravenous (iv) and intratumoral (it)) were tested in mice bearing subcutaneously implanted CT-26 murine colon carcinoma. The results clearly established that 4-ICEU was more stable to biotransformation than previously studied CEUs congeners. It was readily bioavailable and reached the CT-26 colorectal tumor regardless of the route of administration. Additionally, the colon mucosa was an important target tissue where 4-ICEU accumulated and remained largely untransformed. In conclusion, these results justify further investigations for developing 4-ICEU as a new chemotherapeutic agent for colorectal cancer. PMID:19205625

  13. Biological evaluation of new potential anticancer agent for tumour imaging and radiotherapy by two methods: 99mTc-radiolabelling and EPR spectroscopy

    PubMed Central

    Karamalakova, Yanka; Chuttani, Krishna; Sharma, Rakesh; Zheleva, Antoaneta; Gadjeva, Veselina; Mishra, Anil

    2014-01-01

    Recently, a new class of in vitro and ex vivo radiotracers/radioprotectors, the nitroxyl-labelled agent 1-ethyl-1-nitroso–3-[4-(2,2,6,6–tetramethylpiperidine-1-oxyl)]-urea (SLENU), has been discovered. Our previous investigations demonstrated that SLENU is a low-molecular-weight stable free radical which is freely membrane permeable, easily crosses the blood brain barrier and exhibited in/ex vivo the lowest general toxicity and higher anticancer activity against some experimental tumour models. Further investigation was aimed to develop a 99mTc-labelled SLENU (97%) as a chelator and evaluate its labelling efficiency and potential use as a tumour seeking agent and for early diagnosis. Tissue biodistribution of 99mTc-SLENU was determined in normal mice at 1, 2 and 24 h (n = 4/time interval, route of administration i.v.). The distribution data were compared using male albino non-inbred mice and electron paramagnetic resonance investigation. The imaging characteristics of 99mTc-SLENU conjugate examined in BALB/c mice grafted with Ehrlich Ascitis tumour in the thigh of hind leg demonstrated major accumulation of the radiotracer in the organs and tumour. Planar images and auto-radiograms confirmed that the tumours could be visualized clearly with 99mTc-SLENU. Blood kinetic study of radio-conjugate showed a bi-exponential pattern, as well as quick reduced duration in the blood circulation. This study establishes nitroxyls as a general class of new spin-labelled diagnostic markers that reduce the negative lateral effects of radiotherapy and drug damages, and are appropriate for tumour-localization. PMID:26019604

  14. Synthesis, in vitro, and in vivo evaluation of novel functionalized quaternary ammonium curcuminoids as potential anti-cancer agents.

    PubMed

    Solano, Lucas N; Nelson, Grady L; Ronayne, Conor T; Lueth, Erica A; Foxley, Melissa A; Jonnalagadda, Sravan K; Gurrapu, Shirisha; Mereddy, Venkatram R

    2015-12-15

    Novel functionalized quaternary ammonium curcuminoids have been synthesized from piperazinyl curcuminoids and Baylis-Hillman reaction derived allyl bromides. These molecules are found to be highly water soluble with increased cytotoxicity compared to native curcumin against three cancer cell lines MIAPaCa-2, MDA-MB-231, and 4T1. Preliminary in vivo toxicity evaluation of a representative curcuminoid 5a in healthy mice indicates that this molecule is well tolerated based on normal body weight gains compared to control group. Furthermore, the efficacy of 5a has been tested in a pancreatic cancer xenograft model of MIAPaCa-2 and has been found to exhibit good tumor growth inhibition as a single agent and also in combination with clinical pancreatic cancer drug gemcitabine. PMID:26561365

  15. Can the chemotherapeutic agents perform anticancer activity though miRNA expression regulation? Proposing a new hypothesis.

    PubMed

    Chakraborty, Chiranjib; Doss, C George Priya; Sarin, Renu; Hsu, Minna J; Agoramoorthy, Govindasamy

    2015-11-01

    In the recent advancement of cancer therapy, mortality of the immortal cancer cells begins to decline, and it shows great promise for the chemotherapy regimen supported by targeted therapy. In this post-genomic era boosted by the discovery of microRNA (miRNA), it has been understood that miRNA regulates gene expression at the post-transcriptional level. On the other hand, some studies have also indicated that miRNA expression level has changed during the treatment of chemotherapy. Data based on various previous studies, we propose that the chemotherapeutic agents modulate miRNA expression that might perform anticancerous activities through cellular changes such as DNA repair, cell cycle arrest, or apoptosis. PMID:25698235

  16. Application of ultrasound as pretreatment for extraction of podophyllotoxin from rhizomes of Podophyllum peltatum.

    PubMed

    Zhao, Shuna; Baik, Oon Doo

    2012-01-01

    The effect of high-power ultrasound pretreatment on the extraction of podophyllotoxin from Podophyllum peltatum was investigated. Direct sonication by an ultrasound probe horn was applied at 24 kHz and a number of factors were investigated: particle size (0.18-0.6 mm), type of solvent (0-100% aqueous ethanol), ultrasonic treatment time (2-40 min), and power of ultrasound (0-100% power intensity, maximum power: 78 W). The optimal condition of ultrasound was achieved with 0.425-0.6 mm particle size, 10 min sonication time, 35 W ultrasound power, and water as the medium. There was no obvious degradation of podophyllotoxin with ultrasound under the applied conditions, and an improvement in extractability was observed. The SEM microscopic structure change of treated samples disclosed the effect of ultrasound on the tissue cells. The increased pore volume and surface area after ultrasonic treatment also confirmed the positive effect of ultrasound pretreatment on the extraction yield of podophyllotoxin from the plant cells. PMID:21664168

  17. New Oxidovanadium Complexes Incorporating Thiosemicarbazones and 1, 10-Phenanthroline Derivatives as DNA Cleavage, Potential Anticancer Agents, and Hydroxyl Radical Scavenger.

    PubMed

    Ying, Peng; Zeng, Pengfei; Lu, Jiazheng; Chen, Hongyuan; Liao, Xiangwen; Yang, Ning

    2015-10-01

    Four novel oxidovanadium(IV) complexes, [VO(hntdtsc)(PHIP)] (1) (hntdtsc = 2-hydroxy-1-naphthaldehyde thiosemicarbazone, PHIP= 2-phenyl-imidazo[4,5-f]1,10-phenanthroline), [VO(hntdtsc)(DPPZ)](2)(DPPZ= dipyrido[3,2-a:2',3'-c]phenazine), [VO(satsc)(PHIP)](3) (satsc=salicylaldehyde thiosemicarbazone), and [VO(satsc)(DPPZ)](4), have been prepared and characterized. The chemical nuclease activities and photocleavage reactions of the complexes were tested. All four complexes can efficiently cleave pBR322 DNA, and complex 1 has the best cleaving ability. The antitumor properties of these complexes were examined with three different tumor cell lines using MTT assay. Their antitumor mechanism has been analyzed using cell cycle analysis, fluorescence microscopy of apoptosis, and Annexin V-FITC/PI assay. The results showed that the growth of human neuroblastoma (SH-SY5Y, SK-N-SH) and human breast adenocarcinoma (MCF-7) cells were inhibited significantly with very low IC50 values. Complex 1 was found to be the most potent antitumor agent among the four complexes. It can cause G0/G1 phase arrest of the cell cycle and exhibited significant induced apoptosis in SK-N-SH cells and displayed typical morphological apoptotic characteristics. In addition, they all displayed reasonable abilities to scavenge hydroxyl radical, and complex 1 was the best inhibitor. PMID:25659415

  18. Using immunoadjuvant agent glycated chitosan to enhance anti-cancer stem like cell immunity induced by HIFU

    NASA Astrophysics Data System (ADS)

    Chen, Y.-L.; Chen, W.-R.; Liu, R.-S.; Yang, F.-Y.; Wang, C.-Y.; Lee, Y.-J.

    2013-02-01

    Thermal therapy is based on the observation that tumor cells are sensitive to increased temperature, which is important for tumor control. In this study, the high intensity focused ultrasound (HIFU) system was used to simulate thermal therapy on breast cancer control in the small animal model. Additionally, the immunoadjuvant agent, so called glycated chitosan (GC), was used to enhance the immunological effects on tumor control. The bioluminescent imaging showed that tumor metastasis was apparently suppressed by a combined treatment using HIFU and GC, but not in HIFU or GC alone. Using immunohistochemical (IHC) staining, lung metastasis of 4T1-3R tumor cells further agree the observations obtained from non-invasive in vivo imaging. We also found that plasma collected from mice treated with combined HIFU and GC could significantly suppress the viability of cultured 4T1 cells compared to untreated or single treated group. In summary, these results suggest that the HIFU therapy combined with GC can enhance the tumor immunogenicity and tumor control.

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

    PubMed

    Yang, Min Hye; Kim, Jinwoong; Khan, Ikhlas A; Walker, Larry A; Khan, Shabana I

    2014-04-01

    Natural products are rich sources of gene modulators that may be useful in prevention and treatment of cancer. Recently, nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) has been focused as a target of action against diverse cancers like colorectal, pancreatic, prostate, and breast. A variety of natural agents have been reported to play a pivotal role in regulation of NAG-1 through multiple transcriptional mechanisms. The aim of this paper is to review the NAG-1 modulators derived from natural products including plants, marine organisms, and microorganisms. Plant extracts belonging to the families of Fabaceae (Astragalus membranaceus), Ranunculaceae (Coptis chinensis), Menispermaceae (Coscinium fenestratum), Umbelliferae (Pleurospermum kamtschaticum), Lamiaceae (Marubium vulgare), and Rosaceae (Prunus serotina) increased the protein expression of NAG-1 in human colon cancer or hepatocarcinoma cells. Phytochemicals in the class of flavonoids (apigenin, quercetin, isoliquiritigenin, and 2'-hydroxyflavanone), isoflavonoids (formononetin and genistein), catechins (epigallocatechin gallate and epicatechin gallate), stilbenoids (resveratrol and pinosylvin), phenolics (6-gingerol), phloroglucinols (rottlerin and aspidin PB), terpenoids (18 ?-glycyrrhetinic acid, platycodin D, pseudolaric acid B, and xanthorrhizol), alkaloids (berberine, capsaicin, and indole-3-carbinol), lignans (isochaihulactone), anthraquinones (damnacanthal), and allyl sulfides (diallyl disulfide) elicited NAG-1 overexpression in various cancer cells. Pectenotoxin-2 from marine organisms and prodigiosin and anisomycin from microorganisms were also reported as NAG-1 modulators. Several transcription factors including EGR-1, p53, ATF-3, Sp1 and PPAR? were involved in natural products-induced NAG-1 transcriptional signaling pathway. PMID:24530873

  20. Synthesis and antimicrobial activity of guanylhydrazones. Synthesis of 2-(2-methylthio-2-aminovinyl)-1-methylpyridinium iodides and 2-(2-methylthio-2-aminovinyl)-1-methylquinolinium iodides as potential radioprotective and anticancer agents

    SciTech Connect

    Almassian, B.

    1985-01-01

    The finding of appreciable antileukemic activity in a series of 2-(2-methylthio-2-amino)vinyl-1-methylquinolinium iodides (Foye et al., 1980, 1983) suggested that greater basicity, as compared with the corresponding dithioacetic acids, was contributing to the increase in activity. The addition of a greater degree of basicity in the design of anticancer possibilities in this series was considered worth investigation, particularly in view of the activity of a series of bis(quanylhydrazones) synthesized at Lederle Laboratories. Accordingly, a series of guanylhydrazones of 4-pyridine-,2-pyridine- and 4-quinolinecarboxyaldehydes was synthesized for anticancer as well as antibacterial screening. Also, substitution of additional basic functions in the 2-(2-methylthio-2-amino) vinyl-1-methylquinolinium and pyridinium iodide series has been made. Appreciable antimicrobial activities have been found with both 2-pyridine and 4-quinolinealdehyde guanylhydrazones, as well as with 2-(2-methylthio-2-amino)vinyl-1-methyl-pyridinium iodides. The overall approach to the synthesis of potential anticancer agents in this project is thus to observe the effect of increasing basicity of these compounds on DNA binding and anticancer activity.

  1. Carboxymethylcellulose-tetrahydrocurcumin conjugates for colon-specific delivery of a novel anti-cancer agent, 4-amino tetrahydrocurcumin.

    PubMed

    Plyduang, Thipapun; Lomlim, Luelak; Yuenyongsawad, Supreeya; Wiwattanapatapee, Ruedeekorn

    2014-10-01

    Several curcumin derivatives are now becoming increasingly of interest because of their bioactive attributes, especially their action as antioxidants and anti-carcinogenic activities. Tetrahydrocurcumin (THC), an active metabolite of curcumin, was selected to be a proper starting material for the work presented here as it is stable in physiological pH and has the typical pharmacological properties of curcumin. We have now reported that novel synthesized water-soluble polymeric macromolecule prodrugs can specifically deliver the drug to the colon. To study the drug loading and drug release, THC was conjugated with a hydrophilic polymer, carboxymethylcellulose (CMC) with the degree of substitution (DS) values of 0.7 and 1.2. THC was also attached to two different spacers including p-aminobenzoic acid (PABA) and p-aminohippuric acid (PAH) via an azo bond that was cleaved by the azoreductase activities of colonic bacteria. The novel active molecule, 4-amino-THC, was readily released from the conjugates in the colon (>62% within 24h) with only very small amounts released in the upper GI tract (<12% over 12h). The polymer conjugates showed chemical stability at various pH values along the gastrointestinal tract and increased water solubility of up to 5mg/mL. 4-Amino-THC demonstrated cytotoxic ability against the human colon adenocarcinoma cell lines (HT-29) with an IC50 of 28.67 ± 1.01 ?g/mL, and even greater selectivity (? 4 folds) to inhibit HT-29 cells than to normal human colon epithelial cell lines while curcumin was a non-selective agent against both cell lines. Our study has demonstrated that the use of THC-CMC conjugates may be a promising colon-specific drug delivery system with its sustained release in the colon to be an effective treatment for colonic cancer. PMID:24859389

  2. Human ovarian cancer multicellular spheroids: a model for testing antiproliferation activity of Devil's club (Oplopanax horridus) and anticancer agents.

    PubMed

    Tai, Joseph; Cheung, Susan S C; Hasman, David

    2014-06-01

    This study was conducted to employ an ovarian cancer Ovcar 10 three-dimensional model to assess the antiproliferation activity of the medicinal plant Devil's club, Oplopanax horridus, and its active compound, alone and in combination, with chemotherapeutic agents compared to Ovcar 10 two-dimensional cells grown as monolayer cells. Ovcar 10 three-dimensional spheroids were prepared with a rotary cell culture system. Cell counting kit-8 assessed the antiproliferation activity. Apoptosis-related gene expression in three-dimensional spheroids and two- dimensional cells was analyzed with an apoptosis antibody array. Flow cytometry was used to analyze the cell cycle. Ovcar 10 cells formed compact three-dimensional spheroids after 5 days of culture in a rotary culture system. Ovcar 10 three-dimensional spheroids were significantly more resistant to killing by Devil's club extract, its active compound alone, gemcitabine, and paclitaxel, but not cisplatin compared to two-dimensional cells, with IC50 levels closer to that observed in vivo. Devil's club extract and its active compound alone significantly enhanced the antiproliferation activity of cisplatin and gemcitabine at some concentrations, but did not affect the activity of paclitaxel. A number of apoptosis-related genes were differentially expressed in three-dimensional spheroids, two-dimensional cells, and cells treated with Devil's club extract compared to untreated controls. In three-dimensional spheroids, the proportion of cells in the G2/M phase was slightly increased and the S phase was slightly decreased compared to two-dimensional cells. Ovcar 10 cells in three-dimensional spheroids altered the expression of multiple apoptosis-related genes, which may have contributed to the increased resistance of the cells to some drugs. PMID:24922275

  3. Design, synthesis and biological evaluation of di-substituted noscapine analogs as potent and microtubule-targeted anticancer agents.

    PubMed

    Mishra, Ram C; Gundala, Sushma R; Karna, Prasanthi; Lopus, Manu; Gupta, Kamlesh K; Nagaraju, Mulpuri; Hamelberg, Donald; Tandon, Vibha; Panda, Dulal; Reid, Michelle D; Aneja, Ritu

    2015-01-01

    Noscapine is an opium-derived kinder-gentler microtubule-modulating drug, currently in Phase I/II clinical trials for cancer chemotherapy. Here, we report the synthesis of four more potent di-substituted brominated derivatives of noscapine, 9-Br-7-OH-NOS (2), 9-Br-7-OCONHEt-NOS (3), 9-Br-7-OCONHBn-NOS (4), and 9-Br-7-OAc-NOS (5) and their chemotherapeutic efficacy on PC-3 and MDA-MB-231 cells. The four derivatives were observed to have higher tubulin binding activity than noscapine and significantly affect tubulin polymerization. The equilibrium dissociation constant (KD) for the interaction between tubulin and 2, 3, 4, 5 was found to be, 55±6?M, 44±6?M, 26±3?M, and 21±1?M respectively, which is comparable to parent analog. The effects of these di-substituted noscapine analogs on cell cycle parameters indicate that the cells enter a quiescent phase without undergoing further cell division. The varying biological activity of these analogs and bulk of substituent at position-7 of the benzofuranone ring system of the parent molecule was rationalized utilizing predictive in silico molecular modeling. Furthermore, the immunoblot analysis of protein lysates from cells treated with 4 and 5, revealed the induction of apoptosis and down-regulation of survivin levels. This result was further supported by the enhanced activity of caspase-3/7 enzymes in treated samples compared to the controls. Hence, these compounds showed a great potential for studying microtubule-mediated processes and as chemotherapeutic agents for the management of human cancers. PMID:25891106

  4. Chemical genetics analysis of an aniline mustard anticancer agent reveals complex I of the electron transport chain as a target.

    PubMed

    Fedeles, Bogdan I; Zhu, Angela Y; Young, Kellie S; Hillier, Shawn M; Proffitt, Kyle D; Essigmann, John M; Croy, Robert G

    2011-09-30

    The antitumor agent 11? (CAS 865070-37-7), consisting of a DNA-damaging aniline mustard linked to an androgen receptor (AR) ligand, is known to form covalent DNA adducts and to induce apoptosis potently in AR-positive prostate cancer cells in vitro; it also strongly prevents growth of LNCaP xenografts in mice. The present study describes the unexpectedly strong activity of 11? against the AR-negative HeLa cells, both in cell culture and tumor xenografts, and uncovers a new mechanism of action that likely explains this activity. Cellular fractionation experiments indicated that mitochondria are the major intracellular sink for 11?; flow cytometry studies showed that 11? exposure rapidly induced oxidative stress, mitochondria being an important source of reactive oxygen species (ROS). Additionally, 11? inhibited oxygen consumption both in intact HeLa cells and in isolated mitochondria. Specifically, 11? blocked uncoupled oxygen consumption when mitochondria were incubated with complex I substrates, but it had no effect on oxygen consumption driven by substrates acting downstream of complex I in the mitochondrial electron transport chain. Moreover, 11? enhanced ROS generation in isolated mitochondria, suggesting that complex I inhibition is responsible for ROS production. At the cellular level, the presence of antioxidants (N-acetylcysteine or vitamin E) significantly reduced the toxicity of 11?, implicating ROS production as an important contributor to cytotoxicity. Collectively, our findings establish complex I inhibition and ROS generation as a new mechanism of action for 11?, which supplements conventional DNA adduct formation to promote cancer cell death. PMID:21832047

  5. Development of a chimeric recombinant disintegrin as a cost-effective anticancer agent with promising translational potential

    PubMed Central

    Minea, Radu; Helchowski, Corey; Rubino, Barbara; Brodmann, Kyle; Swenson, Stephen; Markland, Francis

    2011-01-01

    Vicrostatin (VCN) is a chimeric recombinant disintegrin generated in Origami B (DE3) E. coli as a genetic fusion between the C-terminal tail of a viperid disintegrin echistatin and crotalid disintegrin contortrostatin (CN). The therapeutic modulation of multiple integrin pathways via soluble disintegrins was previously shown by us and others to elicit potent anti-angiogenic and anti-metastatic effects in several animal cancer models. Despite these favorable attributes, these polypeptides are notoriously difficult to produce recombinantly in significant quantity due to their structure which requires the correct pairing of multiple disulfide bonds for biological activity. In this report, we show that VCN can be reliably produced in large amounts (yields in excess of 200mg of active purified disintegrin per liter of bacterial culture) in Origami B (DE3), an E. coli expression strain engineered to support the folding of disulfide-rich heterologous proteins directly in its oxidative cytoplasmic compartment. VCN retains the integrin binding specificity of both parental molecules it was derived from, but with a different binding affinity profile. While competing for the same integrin receptors that are preferentially upregulated in the tumor microenvironment, VCN exerts a potent inhibitory effect on endothelial cell (EC) migration and tube formation in a dose-dependent manner, by forcing these cells to undergo significant actin cytoskeleton reorganization when exposed to this agent in vitro. Moreover, VCN has a direct effect on breast cancer cells inhibiting their in vitro motility. In an effort to address our main goal of developing a clinically relevant delivery method for recombinant disintegrins, VCN was efficiently packaged in liposomes (LVCN) and evaluated in vivo in an animal breast cancer model. Our data demonstrate that LVCN is well tolerated, its intravenous administration inducing a significant delay in tumor growth and an increase in animal survival, results that can be partially explained by potent tumor apoptotic effects. PMID:21354198

  6. Artemisinin-Derived Dimer Phosphate Esters as Potent Anti-Cytomegalovirus (Anti-CMV) and Anti-Cancer Agents: A Structure-Activity Study

    PubMed Central

    Mott, Bryan T.; He, Ran; Chen, Xiaochun; Fox, Jennifer M.; Civin, Curt I.; Arav-Boger, Ravit; Posner, Gary H.

    2013-01-01

    We recently reported the anti-cancer and anti-cytomegalovirus (CMV) activity of artemisinin-derived trioxane diphenylphosphate dimer 838. To probe the relationship between chemical structure and anti-CMV and anti-cancer activities, we now report synthesis and evaluation of a series of eight new dimer phosphate ester analogs of 838. This series of novel molecules was screened against human foreskin fibroblasts (HFFs) infected with CMV and against the human Jurkat T cell acute lymphoblastic leukemia cell line. This SAR study confirms the very high anti-CMV and anti-cancer potencies of dimer diphenyl phosphate ester 838 without its being toxic to normal cells. PMID:23673218

  7. Anticancer properties of lamellarins.

    PubMed

    Bailly, Christian

    2015-03-01

    In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids. PMID:25706633

  8. Anticancer Properties of Lamellarins

    PubMed Central

    Bailly, Christian

    2015-01-01

    In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids. PMID:25706633

  9. Pharmacokinetics and Pharmacodynamics of Phase II Drug Metabolizing/Antioxidant Enzymes Gene Response by Anti-cancer Agent Sulforaphane in Rat Lymphocytes

    PubMed Central

    Wang, Hu; Khor, Tin Oo; Yang, Qian; Huang, Ying; Wu, Tien-yuan; Saw, Constance Lay-Lay; Lin, Wen; Androulakis, Ioannis P.; Kong, Ah-Ng Tony

    2012-01-01

    PURPOSE This study assesses the pharmacokinetics (PK) and pharmacodynamics (PD) of Nrf2-mediated increased expression of Phase II drug metabolizing enzyme (DME) and antioxidant enzymes which represents an important component of cancer chemoprevention in rat lymphocytes following intravenous (i.v.) administration of an anti-cancer phytochemical sulforaphane (SFN) METHODS SFN was administered intravenously to four groups of male Sprague-Dawley JVC rats each group comprising four animals. Blood samples were drawn at selected time points. Plasma were obtained from half of the blood samples and analyzed using a validated LC-MS/MS method. Lymphocytes were collected from the remaining blood samples using Ficoll-Paque™ Plus centrifuge medium. Lymphocyte RNAs were extracted, converted to cDNA, and quantitative real-time PCR analyses were performed and fold changes were calculated against those at time zero for the relative expression of Nrf2-target genes of phase II DME/antioxidant enzymes. PK-PD modeling was conducted based on Jusko’s indirect response model (IDR) using GastroPlus™ and Bootstrap Method. RESULTS SFN plasma concentration declined biexponentially and the pharmacokinetic parameters were generated. Rat lymphocyte mRNA expression levels showed no change for GSTM1, SOD, NF-?B, UGT1A1, or UGT1A6. Moderate increases (2-5 folds) over the time zero were seen for HO-1, Nrf2, and NQO1, and significant increase (> 5 folds) for GSTT1, GPx1, and Maf. PK-PD analyses using GastroPlus™ and Bootstrap method provided reasonable fitting for the PK and PD profiles and parameter estimates. CONCLUSION Our present study shows that SFN could induce Nrf2-mediated phase II DME/antioxidant mRNA expression for NQO1, GSTT1, Nrf2, GPx, Maf, and HO-1 in rat lymphocytes after i.v. administration, suggesting that Nrf2-mediated mRNA expression in lymphocytes may serve as surrogate biomarkers. The PK-PD IDR model simultaneously linking the plasma concentrations of SFN and the PD response of lymphocyte mRNA expression is valuable for quantitating Nrf2 mediated effects of SFN. This study may provide a conceptual framework for future clinical PK-PD studies of dietary cancer chemopreventive agents in human. PMID:22931102

  10. CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

    PubMed Central

    Paw?owska, Monika; Augustin, Ewa; Mazerska, Zofia

    2014-01-01

    Aim: To examine whether CYP3A4 overexpression influences the metabolism of anticancer agent imidazoacridinone C-1311 in CHO cells and the responses of the cells to C-1311. Methods: Wild type CHO cells (CHO-WT), CHO cells overexpressing cytochrome P450 reductase (CPR) [CHO-HR] and CHO cells coexpressing CPR and CYP3A4 (CHO-HR-3A4) were used. Metabolic transformation of C-1311 and CYP3A4 activity were measured using RP-HPLC. Flow cytometry analyses were used to examine cell cycle, caspase-3 activity and cell apoptosis. The expression of pH 6.0-dependent ?-galactosidase (SA-?-gal) was studied to evaluate accelerated senescence. ROS generation was analyzed with CM-H2 DCFDA staining. Results: CYP3A4 overexpression did not change the metabolism of C-1311 in CHO cells: the levels of all metabolites of C-1311 increased with the exposure time to a similar extent, and the differences in the peak level of the main metabolite M3 were statistically insignificant among the three CHO cell lines. In CHO-HR-3A4 cells, C-1311 effectively inhibited CYP3A4 activity without affecting CYP3A4 protein level. In the presence of C-1311, CHO-WT cells underwent rather stable G2/M arrest, while the two types of transfected cells only transiently accumulated at this phase. C-1311-induced apoptosis and necrosis in the two types of transfected cells occurred with a significantly faster speed and to a greater extent than in CHO-WT cells. Additionally, C-1311 induced ROS generation in the two types of transfected cells, but not in CHO-WT cells. Moreover, CHO-HR-3A4 cells that did not die underwent accelerated senescence. Conclusion: CYP3A4 overexpression in CHO cells enhances apoptosis induced by C-1311, whereas the metabolism of C-1311 is minimal and does not depend on CYP3A4 expression. PMID:24292379

  11. Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10.

    PubMed

    Allen, Joshua E; Prabhu, Varun V; Talekar, Mala; van den Heuvel, A Pieter J; Lim, Bora; Dicker, David T; Fritz, Jennifer L; Beck, Adam; El-Deiry, Wafik S

    2015-04-15

    ONC201/TIC10 is a small-molecule inducer of the TRAIL gene under current investigation as a novel anticancer agent. In this study, we identify critical molecular determinants of ONC201 sensitivity offering potential utility as pharmacodynamic or predictive response markers. By screening a library of kinase siRNAs in combination with a subcytotoxic dose of ONC201, we identified several kinases that ablated tumor cell sensitivity, including the MAPK pathway-inducer KSR1. Unexpectedly, KSR1 silencing did not affect MAPK signaling in the presence or absence of ONC201, but instead reduced expression of the antiapoptotic proteins FLIP, Mcl-1, Bcl-2, cIAP1, cIAP2, and survivin. In parallel to this work, we also conducted a synergy screen in which ONC201 was combined with approved small-molecule anticancer drugs. In multiple cancer cell populations, ONC201 synergized with diverse drug classes, including the multikinase inhibitor sorafenib. Notably, combining ONC201 and sorafenib led to synergistic induction of TRAIL and its receptor DR5 along with a potent induction of cell death. In a mouse xenograft model of hepatocellular carcinoma, we demonstrated that ONC201 and sorafenib cooperatively and safely triggered tumor regressions. Overall, our results established a set of determinants for ONC201 sensitivity that may predict therapeutic response, particularly in settings of sorafenib cotreatment to enhance anticancer responses. PMID:25681273

  12. Hydrothiolation of benzyl mercaptan to arylacetylene: application to the synthesis of (E) and (Z)-isomers of ON 01910·Na (Rigosertib®), a phase III clinical stage anti-cancer agent.

    PubMed

    Pallela, Venkat R; Mallireddigari, Muralidhar R; Cosenza, Stephen C; Akula, Balaiah; Subbaiah, D R C Venkata; Reddy, E Premkumar; Reddy, M V Ramana

    2013-03-28

    A stereoselective and efficient method for free radical addition of benzyl thiol to aryl acetylene in the presence of Et3B-hexane has been developed for the synthesis of (Z) and (E)-styryl benzyl sulfides where base catalyzed hydrothiolations have failed. The scope of this reaction was successfully extended for the synthesis of (E)-ON 01910·Na, a phase III clinical stage anti-cancer agent and its inactive geometrical isomer (Z)-ON 01910·Na. It is interesting to note that all the E-isomers synthesized have shown better cytotoxicity profile on cancer cells compared to the Z-isomers. PMID:23386308

  13. Biological activities of ribosome-inactivating proteins and their possible applications as antimicrobial, anticancer, and anti-pest agents and in neuroscience research.

    PubMed

    Akkouh, Ouafae; Ng, Tzi Bun; Cheung, Randy Chi Fai; Wong, Jack Ho; Pan, Wenliang; Ng, Charlene Cheuk Wing; Sha, Ou; Shaw, Pang Chui; Chan, Wai Yee

    2015-12-01

    Ribosome-inactivating proteins (RIPs) are enzymes which depurinate ribosomal RNA (rRNA), thus impeding the process of translation resulting in inhibition of protein synthesis. They are produced by various organisms including plants, fungi and bacteria. RIPs from plants are linked to plant defense due to their antiviral, antifungal, antibacterial, and insecticidal activities in which they can be applied in agriculture to combat microbial pathogens and pests. Their anticancer, antiviral, embryotoxic, and abortifacient properties may find medicinal applications. Besides, conjugation of RIPs with antibodies or other carriers to form immunotoxins has been found useful to research in neuroscience and anticancer therapy. PMID:26394859

  14. Anticancer chemotherapy

    SciTech Connect

    Weller, R.E.

    1991-10-01

    This document examines chemotherapeutic agents for use in veterinary oncology. It lists some of the most common categories of chemotherapeutic drugs, such as alkylating agents and corticosteroids. For each category, the paper lists some example drugs, gives their mode of action, tumors usually susceptible to the drug, and common side effects. A brief discussion of mechanisms of drug resistance is also provided. (MHB)

  15. Dirigent-mediated podophyllotoxin biosynthesis in Linum flavum and Podophyllum peltatum.

    PubMed

    Xia, Z Q; Costa, M A; Proctor, J; Davin, L B; Lewis, N G

    2000-11-01

    Given the importance of the antitumor/antiviral lignans, podophyllotoxin and 5-methoxypodophyllotoxin, as biotechnological targets, their biosynthetic pathways were investigated in Podophyllum peltatum and Linum flavum. Entry into their pathways was established to occur via dirigent mediated coupling of E-coniferyl alcohol to afford (+)-pinoresinol; the encoding gene was cloned and the recombinant protein subsequently obtained. Radiolabeled substrate studies using partially purified enzyme preparations next revealed (+)-pinoresinol was enantiospecifically converted sequentially into (+)-lariciresinol and (-)-secoisolariciresinol via the action of an NADPH-dependent bifunctional pinoresinol/lariciresinol reductase. The resulting (-)-secoisolariciresinol was enantiospecifically dehydrogenated into (-)-matairesinol, as evidenced through the conversion of both radio- and stable isotopically labeled secoisolariciresinol into matairesinol, this being catalyzed by the NAD-dependent secoisolariciresinol dehydrogenase. (-)-Matairesinol was further hydroxylated to afford 7'-hydroxymatairesinol, this being efficiently metabolized into 5-methoxypodophyllotoxin. Thus much of the overall biosynthetic pathway to podophyllotoxin has been established, that is, from the dirigent mediated coupling of E-coniferyl alcohol to the subsequent conversions leading to 7'-hydroxymatairesinol. PMID:11130663

  16. Topical treatment of penile condylomata acuminata with podophyllin, podophyllotoxin and colchicine. A comparative study.

    PubMed

    von Krogh, G

    1978-01-01

    The effect of alcoholic solutions with 20% podophyllin from Podophyllum peltatum and Podophyllum emodi, 8% podophyllotoxin, and 8% colchicine, when applied to penile condylomata acuminata in 227 men, were statistically alike. Of the patients initially judged to be cured after 1-2 applications, 13% showed recurrence, thus bringing down the permanent cure frequency to only 43%. Local side effects were absent after only half the series of colchicine applications, whereas as much as about 3/4 of the treatment course with podophyllin and pure podophyllotoxin could be completed without provoking discomfort. Warts in the urinary meatus healed significantly less well than warts on the other genital mucous membranes. Eighty-nine per cent of patients who had previously been cured of concylomata became wart-free after 1-2 treatments, as opposed to only 40% of those who had never had this wart type previously. The use of the commercially available colchicine offers an opportunity to establish a standardized therapy; following application of an 8% solution, rinsing off should be performed after 6-8 hours. PMID:76398

  17. Could the FDA-approved anti-HIV PR inhibitors be promising anticancer agents? An answer from enhanced docking approach and molecular dynamics analyses

    PubMed Central

    Arodola, Olayide A; Soliman, Mahmoud ES

    2015-01-01

    Based on experimental data, the anticancer activity of nelfinavir (NFV), a US Food and Drug Administration (FDA)-approved HIV-1 protease inhibitor (PI), was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized that the anticancer activity of NFV is due to its inhibitory effect on heat shock protein 90 (Hsp90), a promising target for anticancer therapy. Such findings prompted us to investigate the potential anticancer activity of all other FDA-approved HIV-1 PIs against human Hsp90. To accomplish this, “loop docking” – an enhanced in-house developed molecular docking approach – followed by molecular dynamic simulations and postdynamic analyses were performed to elaborate on the binding mechanism and relative binding affinities of nine FDA-approved HIV-1 PIs against human Hsp90. Due to the lack of the X-ray crystal structure of human Hsp90, homology modeling was performed to create its 3D structure for subsequent simulations. Results showed that NFV has better binding affinity (?G =?9.2 kcal/mol) when compared with other PIs: this is in a reasonable accordance with the experimental data (IC50 3.1 ?M). Indinavir, saquinavir, and ritonavir have close binding affinity to NFV (?G =?9.0, ?8.6, and ?8.5 kcal/mol, respectively). Per-residue interaction energy decomposition analysis showed that hydrophobic interaction (most importantly with Val534 and Met602) played the most predominant role in drug binding. To further validate the docking outcome, 5 ns molecular dynamic simulations were performed in order to assess the stability of the docked complexes. To our knowledge, this is the first account of detailed computational investigations aimed to investigate the potential anticancer activity and the binding mechanism of the FDA-approved HIV PIs binding to human Hsp90. Information gained from this study should also provide a route map toward the design, optimization, and further experimental investigation of potential derivatives of PIs to treat HER2+ breast cancer. PMID:26622167

  18. Anticancer Advances of Matrine and Its Derivatives.

    PubMed

    Yong, Jianping; Wu, Xiaoyuan; Lu, Canzhong

    2015-01-01

    As the second leading cause of death in the world, the total number caused by cancer in 2008 is 1.4 million. The great cancer incidence worldwide increases the search for new, safer and efficient anticancer agents (especially to find the new structures and more active anticancer drugs from the natural products) aiming the prevention or the cure of such illness. For a century, matrine (an alkaloid isolated from sophorae flavescens Ait.) has been widely studied in the field of cancer. This review briefly describes the progress of matrine, its derivatives and their anticancer activity. PMID:25613788

  19. Frequency and timing of leaf removal affect growth and podophyllotoxin content of Podophyllum peltatum in full sun.

    PubMed

    Cushman, Kent E; Moraes, Rita M; Gerard, Patrick D; Bedir, Ebru; Silva, Bladimiro; Khan, Ikhlas A

    2006-07-01

    Podophyllotoxin is a pharmaceutical compound found in leaves and rhizomes of American mayapple (P. peltatum L.), a species being investigated as an alternative to that of the Indian mayapple (P. emodi). Leaves alone can serve as a renewable source of podophyllotoxin (and other lignans) leaving rhizomes undisturbed to produce leaf biomass in subsequent years. It is not known, however, how frequently or severely plants can be defoliated without adversely affecting future plant growth, lignan content, or podophyllotoxin yield (g.m(-2)). This study compared harvest strategies that were mild to severe in frequency and timing of leaf removal. A wild population in full sun was subjected to leaf removal treatments of varying frequency (every year, every 2nd or 3rd year) and timing (early or late). Control plots not previously harvested were included every year. Plots were 1.0 m2 and established during spring of 2001. Duration of the study was four years. P. peltatum plants did not tolerate the most severe harvest treatment: annual harvest frequency in combination with early harvest time. Early annual harvests reduced total leaf dry mass and total leaf area in a consistent and linear manner. In contrast, plants tolerated annual harvests when conducted late in the growing season and tolerated early harvests when conducted every 2nd or 3rd year. The number of sexual shoots was reduced to zero by early annual harvests. Podophyllotoxin content was 2.7 to 6.5 times greater in leaves harvested early compared to those harvested late, though content was significantly greater in only two out of four years. In conclusion, we can recommend leaf removal every year from well-established P. peltatum populations grown in full sun if harvests are conducted late in the growing season. This harvest strategy ensures maximum podophyllotoxin yield without jeopardizing future leaf biomass yield. Leaves harvested early appear to have greater podophyllotoxin content, but we discourage early harvest every year. Instead, our results indicate that leaves can be harvested early every other year without reducing long-term performance of P. peltatum populations. PMID:16791769

  20. Production of podophyllotoxin from roots and plantlets of Hyptis suaveolens cultivated in vitro

    PubMed Central

    Velóz, Rafael A.; Cardoso-Taketa, Alexandre; Villarreal, María Luisa

    2013-01-01

    Background: Hyptis suaveolens was an important source of food and medicines in pre-hispanic M?xico and is actually used popularly to treat respiratory and skin diseases, fever, pain, and cramps, between other ailments. In 2008 the presence of podophyllotoxin (PTOX) was reported in this plant. Objective: To establish in vitro cultures of H. suaveolens able to produce PTOX. Materials and Methods: Explants of H. suaveolens were cultivated in Murashige and Skoog (MS) medium supplemented with different concentrations of the phytohormones 6-benzylaminopurine (6-BAP), 2,4-dichlorophenoxyacetic acid (2,4-D), 1-naphthaleneacetic acid (NAA) and kinetin (Kin), in order to induce the production of podophyllotoxin. Root cultures without hormones were also established and the quantification of PTOX was performed by HPLC analysis. Results: The presence of growth regulators during in vitro cultivation of H. suaveolens, provoked morphological variations in explants, and induced the accumulation of different levels of PTOX. Roots grown without phytohormones accumulated PTOX at 0.013% dry weight (DW), while in three of the callus cultures cell lines growing together with roots, PTOX accumulated at concentrations of 0.003, 0.005 and 0.006% DW when NAA was combined with either Kin or BAP. In wild plant material PTOX was present in trace amounts in the aerial parts, while in the roots it was found at 0.005% DW. Conclusion: This study demonstrated that although it is possible to obtain PTOX in a variety of in vitro cultures of H. suaveolens, in vitro roots grown without the addition of growth regulators were better producers of PTOX. PMID:23798883

  1. 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

  2. 6-Methoxy Podophyllotoxin Induces Apoptosis via Inhibition of TUBB3 and TOPIIA Gene Expressions in 5637 and K562 Cancer Cell Lines

    PubMed Central

    Sadeghi, Iman; Behmanesh, Mehrdad; Ahmadian Chashmi, Najmeh; Sharifi, Mohsen; Soltani, Bahram Mohammad

    2015-01-01

    Objective Podophyllotoxin (PTOX), a natural compound in numerous plants, contains remarkable biological properties that include anti-tumor, anti-viral such as anti-human im- munodeficiency virus (HIV) activities. In order to avoid its adverse effects, various com- pounds have been derived from PTOX. 6-methoxy PTOX (MPTOX) is one of the natural PTOX derivatives with an extra methoxy group. MPTOX is mostly isolated from the Linum species. This study has sought to determine the biological effects of MPTOX on cancer cell lines, 5637 and K562. Materials and Methods In this experimental study, we treated the 5637 and K562 cancer cell lines with MPTOX in a doseand time-dependent manner. Apoptosis was examined by flow cytometry and viability rate was analyzed by the MTT assay. Expressions of the tubulin (TUBB3) and topoisomerase II (TOPIIA) genes were determined by real-time poly- merase chain reaction (PCR). Results Treatment with MPTOX led to significant induction of apoptosis in cancer cells compared to control cells. Gene expression analysis showed reduced levels of TUBB3 and TOPIIA mRNA following MPTOX treatment. Conclusion MPTOX inhibited TUBB3 and TOPIIA gene expression and subsequently induced cell death through apoptosis. These results suggested that MPTOX could be considered a potential anti-tumor agent. PMID:26464822

  3. A library of 1,2,3-triazole-substituted oleanolic acid derivatives as anticancer agents: design, synthesis, and biological evaluation.

    PubMed

    Wei, Gaofei; Luan, Weijing; Wang, Shuai; Cui, Shanshan; Li, Fengran; Liu, Yongxiang; Liu, Yang; Cheng, Maosheng

    2015-02-01

    A series of novel oleanolic acid coupled 1,2,3-triazole derivatives have been designed and synthesized by employing a Cu(I) catalyzed Huisgen 1,3-dipolar cycloaddition reaction. The anti-proliferative evaluation indicated that some compounds exhibited excellent anti-cancer activity against the examined cancer cell lines. Among all derivatives, compound 3t possesses the best inhibitory activity against HT1080 cells. A series of pharmacology experiments show that compound 3t significantly induced HT1080 cell apoptosis. Therefore, this compound can serve as a promising lead candidate for further study. PMID:25476168

  4. Trial Watch: Anticancer radioimmunotherapy.

    PubMed

    Vacchelli, Erika; Vitale, Ilio; Tartour, Eric; Eggermont, Alexander; Sautès-Fridman, Catherine; Galon, Jérôme; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2013-09-01

    Radiotherapy has extensively been employed as a curative or palliative intervention against cancer throughout the last century, with a varying degree of success. For a long time, the antineoplastic activity of X- and ?-rays was entirely ascribed to their capacity of damaging macromolecules, in particular DNA, and hence triggering the (apoptotic) demise of malignant cells. However, accumulating evidence indicates that (at least part of) the clinical potential of radiotherapy stems from cancer cell-extrinsic mechanisms, including the normalization of tumor vasculature as well as short- and long-range bystander effects. Local bystander effects involve either the direct transmission of lethal signals between cells connected by gap junctions or the production of diffusible cytotoxic mediators, including reactive oxygen species, nitric oxide and cytokines. Conversely, long-range bystander effects, also known as out-of-field or abscopal effects, presumably reflect the elicitation of tumor-specific adaptive immune responses. Ionizing rays have indeed been shown to promote the immunogenic demise of malignant cells, a process that relies on the spatiotemporally defined emanation of specific damage-associated molecular patterns (DAMPs). Thus, irradiation reportedly improves the clinical efficacy of other treatment modalities such as surgery (both in neo-adjuvant and adjuvant settings) or chemotherapy. Moreover, at least under some circumstances, radiotherapy may potentiate anticancer immune responses as elicited by various immunotherapeutic agents, including (but presumably not limited to) immunomodulatory monoclonal antibodies, cancer-specific vaccines, dendritic cell-based interventions and Toll-like receptor agonists. Here, we review the rationale of using radiotherapy, alone or combined with immunomodulatory agents, as a means to elicit or boost anticancer immune responses, and present recent clinical trials investigating the therapeutic potential of this approach in cancer patients. PMID:24319634

  5. Efficacy of a Non-Hypercalcemic Vitamin-D2 Derived Anti-Cancer Agent (MT19c) and Inhibition of Fatty Acid Synthesis in an Ovarian Cancer Xenograft Model

    PubMed Central

    Moore, Richard G.; Lange, Thilo S.; Robinson, Katina; Kim, Kyu K.; Uzun, Alper; Horan, Timothy C.; Kawar, Nada; Yano, Naohiro; Chu, Sharon R.; Mao, Quanfu; Brard, Laurent; DePaepe, Monique E.; Padbury, James F.; Arnold, Leggy A.; Brodsky, Alexander; Shen, Tun-Li; Singh, Rakesh K.

    2012-01-01

    Background Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models. Methodology/Principal Finding Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3) xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c–VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR) antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN) activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K) activity independently of PPAR-gamma protein. Significance Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis. PMID:22509304

  6. Design and synthesis of novel 5,6-disubstituted pyridine-2,3-dione-3-thiosemicarbazone derivatives as potential anticancer agents.

    PubMed

    Xie, Wenlin; Xie, Shimin; Zhou, Ying; Tang, Xufu; Liu, Jian; Yang, Wenqian; Qiu, Minghua

    2014-06-23

    A series of 5,6-disubstituted pyridine-2,3-dione-3-thiosemicarbazone derivatives(2a-2n) and 5,6-disubstituted pyridine-2,3-dione S-benzyl-3-thiosemicarbazones(3a-3g) were synthesized starting from 2,3-dihydroxypyridine via oxidation-Michael additions, condensations and nucleophilic substitutions. The structures of the compounds were established by IR, (1)H NMR, (13)C NMR, and HRMS. All newly synthesized compounds were screened for their anticancer activity against Breast cancer (MCF-7), Colon cancer (HCT-116) and hepatocellular cancer (BEL7402) cell lines. Bioassay results indicated that most of the prepared compounds exhibited cytotoxicity against various cancer cells in vitro. Some of the compounds exhibited promising antiproliferative activity, which were comparable to the positive control (5-fluorouracil). The structure-activity relationship was discussed. PMID:24819956

  7. Distribution of withaferin A, an anticancer potential agent, in different parts of two varieties of Withania somnifera (L.) Dunal. grown in Sri Lanka.

    PubMed

    Siriwardane, A S; Dharmadasa, R M; Samarasinghe, Kosala

    2013-02-01

    Withania somnifera (L.) Dunal. (Family: Solanaceae) is a therapeutically important medicinal plant in traditional and Ayurveda systems of medicine in Sri Lanka. Witheferin A, is a potential anticancer compound found in W. somnifera. In the present study, attempts have been made to compare witheferin A content, in different parts of (root, stem, bark, leaf) two varieties of (LC1 and FR1) W. somnifera grown in same soil and climatic conditions. Ground sample (1g) of leaves, bark, stem and roots of two W. somnifera varieties were extracted with CHCl3 three times. Thin Layer Chromatographic analysis (TLC) of withaferin A in both plant extracts were performed on pre-coated Silica gel 60 GF254 plates in hexane: ethyl acetate: methanol (2: 14: 1) mobile phase. Densitometer scanning was performed at lambda(max) = 215 nm. HPLC of W. somnifera extracts was performed using Kromasil C18 reverse phase column. Both varieties of W. somnifera differed in withaferin A. After visualizing TLC plates with vanillin-sulphuric acid leaf and bark extracts of both varieties showed high intensity purple colour spots (R(f) 0.14) than in stem and roots. The highest amount of withaferin A (3812 ppm) was observed in leaves of variety LC1 while the lowest amount was observed in roots of variety FR1 (5 ppm). According to the results it could be concluded that content of Witheferin A was vary leaf > bark > stem > roots in both varieties. Therefore, there is a high potential of incorporation of leaves and bark of W. somnifera for the preparation of Ayurveda drug leading to anticancer activity instead of roots. PMID:24171276

  8. A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis*

    PubMed Central

    Wang, Jigang; Tan, Xing Fei; Nguyen, Van Sang; Yang, Peng; Zhou, Jing; Gao, Mingming; Li, Zhengjun; Lim, Teck Kwang; He, Yingke; Ong, Chye Sun; Lay, Yifei; Zhang, Jianbin; Zhu, Guili; Lai, Siew-Li; Ghosh, Dipanjana; Mok, Yu Keung; Shen, Han-Ming; Lin, Qingsong

    2014-01-01

    Drug target identification is a critical step toward understanding the mechanism of action of a drug, which can help one improve the drug's current therapeutic regime and expand the drug's therapeutic potential. However, current in vitro affinity-chromatography-based and in vivo activity-based protein profiling approaches generally face difficulties in discriminating specific drug targets from nonspecific ones. Here we describe a novel approach combining isobaric tags for relative and absolute quantitation with clickable activity-based protein profiling to specifically and comprehensively identify the protein targets of andrographolide (Andro), a natural product with known anti-inflammation and anti-cancer effects, in live cancer cells. We identified a spectrum of specific targets of Andro, which furthered our understanding of the mechanism of action of the drug. Our findings, validated through cell migration and invasion assays, showed that Andro has a potential novel application as a tumor metastasis inhibitor. Moreover, we have unveiled the target binding mechanism of Andro with a combination of drug analog synthesis, protein engineering, and mass-spectrometry-based approaches and determined the drug-binding sites of two protein targets, NF-?B and actin. PMID:24445406

  9. Synthesis and characterization of mixed-ligand diimine-piperonal thiosemicarbazone complexes of ruthenium(II): Biophysical investigations and biological evaluation as anticancer and antibacterial agents

    NASA Astrophysics Data System (ADS)

    Beckford, Floyd A.; Thessing, Jeffrey; Shaloski, Michael, Jr.; Canisius Mbarushimana, P.; Brock, Alyssa; Didion, Jacob; Woods, Jason; Gonzalez-Sarrías, Antonio; Seeram, Navindra P.

    2011-04-01

    We have used a novel microwave-assisted method developed in our laboratories to synthesize a series of ruthenium-thiosemicarbazone complexes. The new thiosemicarbazone ligands are derived from benzo[ d][1,3]dioxole-5-carbaldehyde (piperonal) and the complexes are formulated as [(diimine) 2Ru(TSC)](PF 6) 2 (where the TSC is the bidentate thiosemicarbazone ligand). The diimine in the complexes is either 2,2'-bipyridine or 1,10-phenanthroline. The complexes have been characterized by spectroscopic means (NMR, IR and UV-Vis) as well as by elemental analysis. We have studied the biophysical characteristics of the complexes by investigating their anti-oxidant ability as well as their ability to disrupt the function of the human topoisomerase II enzyme. The complexes are moderately strong binders of DNA with binding constants of 10 4 M -1. They are also strong binders of human serum albumin having binding constants on the order of 10 4 M -1. The complexes show good in vitro anticancer activity against human colon cancer cells, Caco-2 and HCT-116 and indeed show some cytotoxic selectivity for cancer cells. The IC 50 values range from 7 to 159 ?M (after 72 h drug incubation). They also have antibacterial activity against Gram-positive strains of pathogenic bacteria with IC 50 values as low as 10 ?M; little activity was seen against Gram-negative strains. It has been established that all the compounds are catalytic inhibitors of human topoisomerase II.

  10. Synthesis and discovery of 18?-GAMG as anticancer agent in vitro and in vivo via down expression of protein p65

    PubMed Central

    Tang, Wen-jian; Yang, Yong-an; Xu, He; Shi, Jing-bo; Liu, Xin-hua

    2014-01-01

    Glycyrrhizic acid (GA) is a natural product with favorable antitumor activity. But, glycyrrhetinic acid monoglucuronide (GAMG) showed stronger antitumor activity than GA. It is of our interest to generate and identify novel compounds with regulation telomerase for cancer therapy. So, in this study, 18?-GAMG was synthesized via biotransformation. In vitro studies showed that it displayed potent anticancer activity and high selectivity on tumor liver cell SMMC-7721 versus human normal liver cell L-02. The further results in vivo confirmed that it could significantly improve pathological changes of N,N-diethylnitrosamine (DEN)-induced rat hepatic tumor. Western blot and immunofluorescence results indicated that the expression of p65-telomerase reverse transcriptase (TERT) was clearly down-regulated treated with it. Taken together, this study for the first time identified an active compound with high selectivity on tumor liver cell in mice. Furthermore, the title compound could inhibit the expression of protein p65 and TERT. These data support further studies to assess the rational design of more efficient p65 modulators in the future. PMID:25407586

  11. Fucoidan Extract Enhances the Anti-Cancer Activity of Chemotherapeutic Agents in MDA-MB-231 and MCF-7 Breast Cancer Cells

    PubMed Central

    Zhang, Zhongyuan; Teruya, Kiichiro; Yoshida, Toshihiro; Eto, Hiroshi; Shirahata, Sanetaka

    2013-01-01

    Fucoidan, a fucose-rich polysaccharide isolated from brown alga, is currently under investigation as a new anti-cancer compound. In the present study, fucoidan extract (FE) from Cladosiphon navae-caledoniae Kylin was prepared by enzymatic digestion. We investigated whether a combination of FE with cisplatin, tamoxifen or paclitaxel had the potential to improve the therapeutic efficacy of cancer treatment. These co-treatments significantly induced cell growth inhibition, apoptosis, as well as cell cycle modifications in MDA-MB-231 and MCF-7 cells. FE enhanced apoptosis in cancer cells that responded to treatment with three chemotherapeutic drugs with downregulation of the anti-apoptotic proteins Bcl-xL and Mcl-1. The combination treatments led to an obvious decrease in the phosphorylation of ERK and Akt in MDA-MB-231 cells, but increased the phosphorylation of ERK in MCF-7 cells. In addition, we observed that combination treatments enhanced intracellular ROS levels and reduced glutathione (GSH) levels in breast cancer cells, suggesting that induction of oxidative stress was an important event in the cell death induced by the combination treatments. PMID:23303302

  12. Bio-synthesis of silver nanoparticles using Potentilla fulgens Wall. ex Hook. and its therapeutic evaluation as anticancer and antimicrobial agent.

    PubMed

    Mittal, Amit Kumar; Tripathy, Debabrata; Choudhary, Alka; Aili, Pavan Kumar; Chatterjee, Anupam; Singh, Inder Pal; Banerjee, Uttam Chand

    2015-08-01

    The present study aims to develop an easy and eco-friendly method for the synthesis of silver nanoparticles using extracts from the medicinal plant, Potentilla fulgens and evaluation of its anticancer and antimicrobial properties. The various parts of P. fulgens were screened and the root extract was found to have the highest potential for the synthesis of nanoparticles. The root extracts were able to quickly reduce Ag(+) to Ag(0) and stabilized the nanoparticles. The synthesis of nanoparticles was confirmed by UV-Visible spectrophotometry and further characterized using Zeta sizer, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscope (TEM) and X-ray diffraction (XRD). Electron microscopic study showed that the size of the nanoparticle was in the range of 10 to 15 nm and spherical in shape. The studies of phytochemical analysis of nanoparticles indicated that the adsorbed components on the surface of nanoparticles were mainly flavonoid in nature. Furthermore, nanoparticles were evaluated as cytotoxic against various cancer cell lines and 0.2 to 12 ?g/mL nanoparticles showed good toxicity. The IC50 value of nanoparticles was found to be 4.91 and 8.23 ?g/mL against MCF-7 and U-87 cell lines, respectively. Additionally, the apoptotic effect of synthesized nanoparticles on normal and cancer cells was studied using trypan blue assay and flow-cytometric analysis. The results indicate the synthesized nanoparticle ability to kill cancer cells compared to normal cells. The nanoparticles also exhibited comparable antimicrobial activity against both Gram-positive and Gram-negative bacteria. PMID:26042698

  13. Targeted NF1 cancer therapeutics with multiple modes of action: small molecule hormone-like agents resembling the natural anticancer metabolite, 2-methoxyoestradiol

    PubMed Central

    Shen, Yu-chi; Upadhyayula, Ravi; Cevallos, Stephanie; Messick, Ryan J; Hsia, Tammy; Leese, Mathew P; Jewett, Douglas M; Ferrer-Torres, Daysha; Roth, Therese M; Dohle, Wolfgang; Potter, Barry V L; Barald, Kate F

    2015-01-01

    Background: Both the number and size of tumours in NF1 patients increase in response to the rise in steroid hormones seen at puberty and during pregnancy. The size of tumours decreases after delivery, suggesting that hormone-targeting therapy might provide a viable new NF1 treatment approach. Our earlier studies demonstrated that human NF1 tumour cell lines either went through apoptosis or ceased growth in the presence of 2-methoxyoestradiol (2ME2), a naturally occurring anticancer metabolite of 17-? estradiol. Previous reports of treatment with sulfamoylated steroidal and non-steroidal derivatives of 2ME2 showed promising reductions in tumour burden in hormone-responsive cancers other than NF1. Here we present the first studies indicating that 2ME2 derivatives could also provide an avenue for treating NF1, for which few treatment options are available. Methods: STX3451, (2-(3-Bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), a non-steroidal sulphamate analogue of 2ME2, was tested in dose-dependent studies of malignant and benign NF1 human tumour cell lines and cell lines with variable controlled neurofibromin expression. The mechanisms of action of STX3451 were also analysed. Results: We found that STX3451-induced apoptosis in human malignant peripheral nerve sheath tumour (MPNST) cell lines, even in the presence of elevated oestrogen and progesterone. It inhibits both PI3 kinase and mTOR signalling pathways. It disrupts actin- and microtubule-based cytoskeletal structures in cell lines derived from human MPNSTs and in cells derived from benign plexiform neurofibromas. STX3451 selectively kills MPNST-derived cells, but also halts growth of other tumour-derived NF1 cell lines. Conclusion: STX3451 provides a new approach for inducing cell death and lowering tumour burden in NF1 and other hormone-responsive cancers with limited treatment options. PMID:26461061

  14. Drug delivery system for an anticancer agent, chlorogenate-Zn/Al-layered double hydroxide nanohybrid synthesised using direct co-precipitation and ion exchange methods

    NASA Astrophysics Data System (ADS)

    Barahuie, Farahnaz; Hussein, Mohd Zobir; Arulselvan, Palanisamy; Fakurazi, Sharida; Zainal, Zulkarnain

    2014-09-01

    A nano-structured drug-inorganic clay hybrid involving an active anticancer compound, which is chlorogenic acid (CA) intercalated into Zn/Al-layered double hydroxide, has been assembled via ion-exchange and co-precipitation methods to form a nanohybrid CZAE (a chlorogenic acid-Zn/Al nanohybrid synthesised using an ion-exchange method) and CZAC (a chlorogenic acid-Zn/Al nanohybrid synthesised using a direct method), respectively. The X-ray diffraction (XRD) results confirmed that the CA-LDH had a hybrid structure in which the anionic chlorogenate is arranged between the interlayers as a horizontal monolayer at 90 and 20° angles from the x axis for CZAE and CZAC, respectively. Both nanohybrids have the properties of mesoporous materials. The high loading percentage of chlorogenic acid (approximately 43.2% for CZAE and 45.3% for CZAC) with basal spacings of 11.7 and 12.6 Å for CZAE and CZAC, respectively, corroborates the successful intercalation of chlorogenic acid into the interlayer gallery of layered double hydroxides. Free chlorogenic acid and the synthesised nanocomposites (CZAE, CZAC) were assessed for their cytotoxicity against various cancer cells. The Fourier transform infrared data supported the formation of both nanohybrids, and a thermal analysis showed that the nanohybrids are more thermally stable than their counterparts. The chlorogenate shows a sustained release, and the release rate of chlorogenate from CZAE and CZAC nanohybrids at pH 7.4 is remarkably lower than that at pH 4.8 due to their different release mechanisms. The release rate of chlorogenate from both nanohybrids can be described as pseudo-second order. The present investigation revealed the potential of the nanohybrids to enhance the in vitro anti-tumour effect of chlorogenic acid in liver and lung cancer cells in vitro.

  15. Anticancer Effects of Sandalwood (Santalum album).

    PubMed

    Santha, Sreevidya; Dwivedi, Chandradhar

    2015-06-01

    Effective management of tumorigenesis requires development of better anticancer agents with greater efficacy and fewer side-effects. Natural products are important sources for the development of chemotherapeutic agents and almost 60% of anticancer drugs are of natural origin. ?-Santlol, a sesquiterpene isolated from Sandalwood, is known for a variety of therapeutic properties including anti-inflammatory, anti-oxidant, anti-viral and anti-bacterial activities. Cell line and animal studies reported chemopreventive effects of sandalwood oil and ?-santalol without causing toxic side-effects. Our laboratory identified its anticancer effects in chemically-induced skin carcinogenesis in CD-1 and SENCAR mice, ultraviolet-B-induced skin carcinogenesis in SKH-1 mice and in vitro models of melanoma, non-melanoma, breast and prostate cancer. Its ability to induce cell-cycle arrest and apoptosis in cancer cells is its most reported anticancer mechanism of action. The present review discusses studies that support the anticancer effect and the mode of action of sandalwood oil and ?-santalol in carcinogenesis. PMID:26026073

  16. Proteins differentially expressed in elicited cell suspension culture of Podophyllum hexandrum with enhanced podophyllotoxin content

    PubMed Central

    2012-01-01

    Background Podophyllotoxin (PTOX), the precursor for semi-synthesis of cancer therapeutics like etoposide, teniposide and etophos, is primarily obtained from an endangered medicinal herb, Podophyllum hexandrum Royle. PTOX, a lignan is biosynthetically derived from the phenylpropanoid pathway. The aim of this study is to investigate changes in the P. hexandrum cell proteome potentially related to PTOX accumulation in response to methyl jasmonate (MeJA) elicitation. High-resolution two-dimensional gel electrophoresis (2-DE) followed by colloidal Coomassie staining and mass spectrometric analysis was used to detect statistically significant changes in cell’s proteome. Result The HPLC analysis showed approximately 7–8 fold change in accumulation of PTOX, in the 12day old cell suspension culture (i.e. after 9days of elicitation) elicited with 100??M MeJA as compared to the control. Using 2-DE a total of 233 spots was detected, out of which 105 spots were identified by MALDI TOF-TOF MS/MS. Data were subjected to functional annotation from a biological point of view through KEGG. The phenylpropanoid and monolignol pathway enzymes were identified, amongst these, chalcone synthase, polyphenol oxidase, caffeoyl CoA 3-O-methyltransferase, S-adenosyl-L-methionine-dependent methyltransferases, caffeic acid-O-methyl transferase etc. are noted as important. The relation of other differentially accumulated proteins with varied effects caused by elicitors on P. hexandrum cells namely stress and defense related protein, transcription and DNA replication and signaling are also discussed. Conclusions Elicitor-induced PTOX accumulation in P. hexandrum cell cultures provides a responsive model system to profile modulations in proteins related to phenylpropanoid/monolignol biosynthesis and other defense responses. Present findings form a baseline for future investigation on a non-sequenced medicinal herb P. hexandrum at molecular level. PMID:22621772

  17. Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis.

    PubMed

    Arneaud, Sonja L B; Porter, John R

    2015-12-01

    Podophyllotoxin (PPT) is a plant natural product that serves as a precursor for the synthesis of many well-known chemotherapeutic drugs. The limited availability and high demand for the source plants of PPT have led to the exploration of alternative sources for this compound. In this study, we utilized the endophytic fungus Phialocephala podophylli (strain PPE7) that we isolated from the rhizomes of Podophyllum peltatum and is known to produce detectable amounts of PPT in broth culture. To date, the complete PPT biosynthetic pathway has yet to be determined in any species. Since fungi are well known for clustering genes that belong to secondary metabolite pathways, use of a fungal system for investigation of the PPT biosynthesis genes may ultimately lead to elucidation of the entire pathway. In this study, we investigated the secoisolariciresinol dehydrogenase (SD) gene that facilitates the dehydrogenation of secoisolariciresinol to form matairesinol, a mid-pathway intermediate product in PPT biosynthesis. We utilized PCR amplification to acquire the complete SD gene sequence in PPE7 and opted to synthesize the P. peltatum SD sequence for expression. Through western blotting, we confirmed the expression of the recombinant SD (PpSD) and verified protein functionality with a bioconversion assay followed by HPLC and LC-MS analyses. Here, we report the identification of the SD gene in PPE7; this is the first report of the SD gene in an endophytic fungus. Additionally, we established the groundwork for the future expression of the complete PPT biosynthetic pathway in the heterologous host Pichia pastoris. PMID:26289300

  18. An Improved High Yield Total Synthesis and Cytotoxicity Study of the Marine Alkaloid Neoamphimedine: An ATP-Competitive Inhibitor of Topoisomerase II? and Potent Anticancer Agent

    PubMed Central

    Li, Linfeng; Abraham, Adedoyin D.; Zhou, Qiong; Ali, Hadi; O’Brien, Jeremy V.; Hamill, Brayden D.; Arcaroli, John J.; Messersmith, Wells A.; LaBarbera, Daniel V.

    2014-01-01

    Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase II?. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (?6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC50 values) in all, with significant potency against colorectal cancer (lowest IC50 = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis. PMID:25244109

  19. Dendrimer-encapsulated naphthalocyanine as a single agent-based theranostic nanoplatform for near-infrared fluorescence imaging and combinatorial anticancer phototherapy

    NASA Astrophysics Data System (ADS)

    Taratula, Olena; Schumann, Canan; Duong, Tony; Taylor, Karmin L.; Taratula, Oleh

    2015-02-01

    Multifunctional theranostic platforms capable of concurrent near-infrared (NIR) fluorescence imaging and phototherapies are strongly desired for cancer diagnosis and treatment. However, the integration of separate imaging and therapeutic components into nanocarriers results in complex theranostic systems with limited translational potential. A single agent-based theranostic nanoplatform, therefore, was developed for concurrent NIR fluorescence imaging and combinatorial phototherapy with dual photodynamic (PDT) and photothermal (PTT) therapeutic mechanisms. The transformation of a substituted silicon naphthalocyanine (SiNc) into a biocompatible nanoplatform (SiNc-NP) was achieved by SiNc encapsulation into the hydrophobic interior of a generation 5 polypropylenimine dendrimer following surface modification with polyethylene glycol. Encapsulation provides aqueous solubility to SiNc and preserves its NIR fluorescence, PDT and PTT properties. Moreover, an impressive photostability in the dendrimer-encapsulated SiNc has been detected. Under NIR irradiation (785 nm, 1.3 W cm-2), SiNc-NP manifested robust heat generation capability (?T = 40 °C) and efficiently produced reactive oxygen species essential for PTT and PDT, respectively, without releasing SiNc from the nanopaltform. By varying the laser power density from 0.3 W cm-2 to 1.3 W cm-2 the therapeutic mechanism of SiNc-NP could be switched from PDT to combinatorial PDT-PTT treatment. In vitro and in vivo studies confirmed that phototherapy mediated by SiNc can efficiently destroy chemotherapy resistant ovarian cancer cells. Remarkably, solid tumors treated with a single dose of SiNc-NP combined with NIR irradiation were completely eradicated without cancer recurrence. Finally, the efficiency of SiNc-NP as an NIR imaging agent was confirmed by recording the strong fluorescence signal in the tumor, which was not photobleached during the phototherapeutic procedure.Multifunctional theranostic platforms capable of concurrent near-infrared (NIR) fluorescence imaging and phototherapies are strongly desired for cancer diagnosis and treatment. However, the integration of separate imaging and therapeutic components into nanocarriers results in complex theranostic systems with limited translational potential. A single agent-based theranostic nanoplatform, therefore, was developed for concurrent NIR fluorescence imaging and combinatorial phototherapy with dual photodynamic (PDT) and photothermal (PTT) therapeutic mechanisms. The transformation of a substituted silicon naphthalocyanine (SiNc) into a biocompatible nanoplatform (SiNc-NP) was achieved by SiNc encapsulation into the hydrophobic interior of a generation 5 polypropylenimine dendrimer following surface modification with polyethylene glycol. Encapsulation provides aqueous solubility to SiNc and preserves its NIR fluorescence, PDT and PTT properties. Moreover, an impressive photostability in the dendrimer-encapsulated SiNc has been detected. Under NIR irradiation (785 nm, 1.3 W cm-2), SiNc-NP manifested robust heat generation capability (?T = 40 °C) and efficiently produced reactive oxygen species essential for PTT and PDT, respectively, without releasing SiNc from the nanopaltform. By varying the laser power density from 0.3 W cm-2 to 1.3 W cm-2 the therapeutic mechanism of SiNc-NP could be switched from PDT to combinatorial PDT-PTT treatment. In vitro and in vivo studies confirmed that phototherapy mediated by SiNc can efficiently destroy chemotherapy resistant ovarian cancer cells. Remarkably, solid tumors treated with a single dose of SiNc-NP combined with NIR irradiation were completely eradicated without cancer recurrence. Finally, the efficiency of SiNc-NP as an NIR imaging agent was confirmed by recording the strong fluorescence signal in the tumor, which was not photobleached during the phototherapeutic procedure. Electronic supplementary information (ESI) available: Fig. S1-S5: Size distribution of SiNc-NP measured by dynamic light scattering (Fig. S1); absorption spectra of free SiNc 2 in THF before and after ir

  20. Developing Exposure/Response Models for Anticancer Drug Treatment: Special Considerations

    PubMed Central

    Mould, DR; Walz, A-C; Lave, T; Gibbs, JP; Frame, B

    2015-01-01

    Anticancer agents often have a narrow therapeutic index (TI), requiring precise dosing to ensure sufficient exposure for clinical activity while minimizing toxicity. These agents frequently have complex pharmacology, and combination therapy may cause schedule-specific effects and interactions. We review anticancer drug development, showing how integration of modeling and simulation throughout development can inform anticancer dose selection, potentially improving the late-phase success rate. This article has a companion article in Clinical Pharmacology & Therapeutics with practical examples. PMID:26225225

  1. CancerHSP: anticancer herbs database of systems pharmacology.

    PubMed

    Tao, Weiyang; Li, Bohui; Gao, Shuo; Bai, Yaofei; Shar, Piar Ali; Zhang, Wenjuan; Guo, Zihu; Sun, Ke; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Mu, Jiexin; Pei, Tianli; Wang, Yuan; Li, Yan; Wang, Yonghua

    2015-01-01

    The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php. PMID:26074488

  2. CancerHSP: anticancer herbs database of systems pharmacology

    PubMed Central

    Tao, Weiyang; Li, Bohui; Gao, Shuo; Bai, Yaofei; Shar, Piar Ali; Zhang, Wenjuan; Guo, Zihu; Sun, Ke; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Mu, Jiexin; Pei, Tianli; Wang, Yuan; Li, Yan; Wang, Yonghua

    2015-01-01

    The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php. PMID:26074488

  3. CancerHSP: anticancer herbs database of systems pharmacology

    NASA Astrophysics Data System (ADS)

    Tao, Weiyang; Li, Bohui; Gao, Shuo; Bai, Yaofei; Shar, Piar Ali; Zhang, Wenjuan; Guo, Zihu; Sun, Ke; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Mu, Jiexin; Pei, Tianli; Wang, Yuan; Li, Yan; Wang, Yonghua

    2015-06-01

    The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php.

  4. Intracellular Distribution-based Anticancer Drug Targeting: Exploiting a Lysosomal Acidification Defect Associated with Cancer Cells

    E-print Network

    Ndolo, Rosemary A.; Jacobs, Damon T.; Forrest, Laird; Krise, Jeffrey P.

    2010-09-09

    The therapeutic usefulness of anticancer agents relies on their ability to exert maximal toxicity to cancer cells and minimal toxicity to normal cells. The difference between these two parameters defines the therapeutic index of the agent...

  5. A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/Jak2/Stat3 pathway.

    PubMed

    Zhao, Hong; Guo, Yuming; Li, Shu; Han, Ruiqin; Ying, Jianming; Zhu, Hai; Wang, Yuanyuan; Yin, Li; Han, Yuqing; Sun, Lingzhi; Wang, Zhaoyi; Lin, Qingcong; Bi, Xinyu; Jiao, Yuchen; Jia, Hongying; Zhao, Jianjun; Huang, Zhen; Li, Zhiyu; Zhou, Jianguo; Song, Wei; Meng, Kun; Cai, Jianqiang

    2015-10-13

    Tumor-initiating cell (TIC) is a subpopulation of cells in tumors that are responsible for tumor initiation and progression. Recent studies indicate that hepatocellular carcinoma-initiating cells (HCICs) confer the high malignancy, recurrence and multi-drug resistance in hepatocellular carcinoma (HCC). In this study, we found that Icaritin, a prenylflavonoid derivative from Epimedium Genus, inhibited malignant growth of HCICs. Icaritin decreased the proportion of EpCAM-positive (a HCICs marker) cells, suppressed tumorsphere formation in vitro and tumor formation in vivo. We also found that Icaritin reduced expression of Interleukin-6 Receptors (IL-6Rs), attenuated both constitutive and IL-6-induced phosphorylation of Janus-activated kinases 2 (Jak2) and Signal transducer and activator of transcription 3 (Stat3), and inhibited Stat3 downstream genes, such as Bmi-1 and Oct4. The inhibitory activity of Icaritin in HCICs was augmented by siRNA-mediated silencing of Stat3 but attenuated by constitutive activation of Stat3.Taken together, our results indicate that Icaritin is able to inhibit malignant growth of HCICs and suggest that Icaritin may be developed into a novel therapeutic agent for effective treatment of HCC. PMID:26376676

  6. Discovery of new human epidermal growth factor receptor-2 (HER2) inhibitors for potential use as anticancer agents via ligand-based pharmacophore modeling.

    PubMed

    Zalloum, Hiba; Tayyem, Rabab; Irmaileh, Basha'er Abu-; Bustanji, Yasser; Zihlif, Malek; Mohammad, Mohammad; Rjai, Talal Abu; Mubarak, Mohammad S

    2015-09-01

    To discover potential antitumor agents directed toward human epidermal growth factor receptor-2HER2/ErbB2 overexpression in cancer, we have explored the pharmacophoric space of 115 HER2/ErbB2 inhibitors. This identified 240 pharmacophores which were subsequently clustered into 20 groups and cluster centers were used as 3D-pharmacophoric descriptors in QSAR analysis with 2D-physicochemical descriptors to select the optimal combination. We were obliged to use ligand efficiency as the response variable because the logarithmic transformation of bioactivities failed to access self-consistent QSAR models. Two binding pharmacophore models emerged in the optimal QSAR equation, suggesting the existence of distinct binding modes accessible to ligands within the HER2/ErbB2 binding pocket. The QSAR equation and its associated pharmacophore models were employed to screen the National Cancer Institute (NCI) and Drug Bank databases to search for new, promising, and structurally diverse HER2 inhibitory leads. Inhibitory activities were tested against HER2-overexpressing SKOV3 Ovarian cancer cell line and MCF-7 which express low levels of HER2. In silico mining identified 80 inhibitors out of which four HER2 selective compounds inhibited the growth of SKOV3 cells with IC50 values < 5?M and with virtually no effect in MCF-7 cells. These lead compounds are excellent candidates for further optimization. PMID:26188796

  7. 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

  8. 'Smartening' anticancer therapeutic nanosystems using biomolecules.

    PubMed

    Núñez-Lozano, Rebeca; Cano, Manuel; Pimentel, Belén; de la Cueva-Méndez, Guillermo

    2015-12-01

    To be effective, anticancer agents must induce cell killing in a selective manner, something that is proving difficult to achieve. Drug delivery systems could help to solve problems associated with the lack of selectivity of classical chemotherapeutic agents. However, to realize this, such systems must overcome multiple physiological barriers. For instance, they must evade surveillance by the immune system, attach selectively to target cells, and gain access to their interior. Furthermore, there they must escape endosomal entrapment, and release their cargoes in a controlled manner, without affecting their functionality. Here we review recent efforts aiming at using biomolecules to confer these abilities to bare nanoparticles, to transform them into smart anticancer therapeutic nanosystems. PMID:26277646

  9. Are isothiocyanates potential anti-cancer drugs?

    PubMed Central

    Wu, Xiang; Zhou, Qing-hua; Xu, Ke

    2009-01-01

    Isothiocyanates are naturally occurring small molecules that are formed from glucosinolate precursors of cruciferous vegetables. Many isothiocyanates, both natural and synthetic, display anticarcinogenic activity because they reduce activation of carcinogens and increase their detoxification. Recent studies show that they exhibit anti-tumor activity by affecting multiple pathways including apoptosis, MAPK signaling, oxidative stress, and cell cycle progression. This review summarizes the current knowledge on isothiocyanates and focuses on their role as potential anti-cancer agents. PMID:19417730

  10. Ferrocene Functionalized Endocrine Modulators as Anticancer Agents

    NASA Astrophysics Data System (ADS)

    Hillard, Elizabeth A.; Vessières, Anne; Jaouen, Gerard

    We present here some of our studies on the synthesis and behaviour of ferrocenyl selective endocrine receptor modulators against cancer cells, particularly breast and prostate cancers. The proliferative/anti-proliferative effects of compounds based on steroidal and non-steroidal endocrine modulators have been extensively explored in vitro. Structure-activity relationship studies of such molecules, particularly the hydroxyferrocifens and ferrocene phenols, have shown the effect of (1) the presence and the length of the N,N-dimethylamino side chain, (2) the presence and position of the phenol group, (3) the role of the ferrocenyl moiety, (4) that of conjugation, (5) phenyl functionalisation and (6) the placement of the phenyl group. Compounds possessing a ferrocene moiety linked to a p-phenol by a conjugated ?-system are among the most potent of the series, with IC50 values ranging from 0.090 to 0.6µM on hormone independent breast cancer cells. Based on the SAR data and electrochemical studies, we have proposed an original mechanism to explain the unusual behaviour of these bioorganometallic species and coin the term "kronatropic" to qualify this effect, involving ROS production and bio-oxidation. In addition, the importance of formulation is underlined. We also discuss the behaviour of ferrocenyl androgens and anti-androgens for possible use against prostate cancers. In sum, ferrocene has proven to be a fascinating substituent due to its vast potential for oncology.

  11. Co-culture of arbuscular mycorrhiza-like fungi (Piriformospora indica and Sebacina vermifera) with plant cells of Linum album for enhanced production of podophyllotoxins: a first report.

    PubMed

    Baldi, Ashish; Jain, Abhishek; Gupta, Nishant; Srivastava, A K; Bisaria, V S

    2008-09-01

    Cell suspension cultures of Linum album were developed from internode portions of in vitro germinated plant in Gamborg's B5 medium supplemented with 0.4 mg naphthalene acetic acid/l. The highest biomass was 8.5 g/l with podophyllotoxin and 6-methoxypodophyllotoxin at 29 and 1.9 mg/l, respectively after 12 d cultivation. Co-cultures of L. album cells with axenically cultivable arbuscular mycorrhiza-like fungi, Piriformospora indica and Sebacina vermifera, were established for the first time. These enhanced podophyllotoxin and 6-methoxypodophyllotoxin production by about four- and eight-fold, respectively, along with a 20% increase in biomass compared to the control cultures. PMID:18427926

  12. Podophyllin 0.5% or 2.0% v podophyllotoxin 0.5% for the self treatment of penile warts: a double blind randomised study.

    PubMed Central

    White, D J; Billingham, C; Chapman, S; Drake, S; Jayaweera, D; Jones, S; Opaneye, A; Temple, C

    1997-01-01

    OBJECTIVE: To compare the effectiveness and cost of self treatment of penile warts with a commercial preparation of podophyllotoxin 0.5% (PDX 0.5%) with podophyllin 0.5% and podophyllin 2.0% sourced from Podophyllum emodii. DESIGN: A prospective double blind randomised study. SUBJECTS: 315 patients with penile warts attending two departments of genitourinary medicine. MAIN OUTCOME MEASURES: Absence of warts, cessation of treatment due to severe side effects at 5 weeks. RESULTS: Of the 315 patients, 244 conformed to the protocol. Analysis was on an intention to treat basis. At 5 weeks no significant differences were found in the extent of healing of warts or in side effects for the three treatment groups. The costs of drug treatment (excluding staff time) are at least pounds 10.00 less for podophyllin than podophyllotoxin. A fourfold variation in the active constituents of the podophyllin preparations did not produce appreciably different clinical responses. In a subanalysis no evidence of deterioration in effectiveness of podophyllin over time was demonstrated. CONCLUSIONS: Penile warts in selected cases can be safely treated with 0.5-2.0% podophyllin self applied by the patient at a fraction of the cost of commercially available podophyllotoxin. The shelf life of the podophyllin extracts is at least 3 months. These findings may be especially relevant in countries where resources for health care are limited. PMID:9306898

  13. Applications of Nanoparticles for Anticancer Drug Delivery: A Review.

    PubMed

    Zhu, Yuanyuan; Liao, Lianming

    2015-07-01

    Biodegradable nanometer-sized particles have novel structural and physical properties that are attracting great interests from pharmaceuticals for the targeted delivery of anticancer drugs and imaging contrast agents. These smart nanoparticles are designed to ferry chemotherapeutic agents or therapeutic genes into malignant cells while sparing healthy cells. In this review, we describe currently clinically used chemotherapeutics in nanoparticle formulation and discuss the current status of nanoparticles developed as targeting delivery systems for anticancer drugs, with emphasis on formulations of micelles, liposome, polymeric nanoparticles, gold nanoparticle dendrimers, and bionanocapsules. PMID:26373036

  14. Type I interferons in anticancer immunity.

    PubMed

    Zitvogel, Laurence; Galluzzi, Lorenzo; Kepp, Oliver; Smyth, Mark J; Kroemer, Guido

    2015-07-01

    Type I interferons (IFNs) are known for their key role in antiviral immune responses. In this Review, we discuss accumulating evidence indicating that type I IFNs produced by malignant cells or tumour-infiltrating dendritic cells also control the autocrine or paracrine circuits that underlie cancer immunosurveillance. Many conventional chemotherapeutics, targeted anticancer agents, immunological adjuvants and oncolytic viruses are only fully efficient in the presence of intact type I IFN signalling. Moreover, the intratumoural expression levels of type I IFNs or of IFN-stimulated genes correlate with favourable disease outcome in several cohorts of patients with cancer. Finally, new anticancer immunotherapies are being developed that are based on recombinant type I IFNs, type I IFN-encoding vectors and type I IFN-expressing cells. PMID:26027717

  15. An ortho-carbonyl substituted hydroquinone derivative is an anticancer agent that acts by inhibiting mitochondrial bioenergetics and by inducing G?/M-phase arrest in mammary adenocarcinoma TA3.

    PubMed

    Urra, Félix A; Martínez-Cifuentes, Maximiliano; Pavani, Mario; Lapier, Michel; Jaña-Prado, Fabián; Parra, Eduardo; Maya, Juan Diego; Pessoa-Mahana, Hernán; Ferreira, Jorge; Araya-Maturana, Ramiro

    2013-03-15

    Tumor cells present a known metabolic reprogramming, which makes them more susceptible for a selective cellular death by modifying its mitochondrial bioenergetics. Anticancer action of the antioxidant 9,10-dihydroxy-4,4-dimethyl-5,8-dihydroanthracen-1(4H)-one (HQ) on mouse mammary adenocarcinoma TA3, and its multiresistant variant TA3-MTXR, were evaluated. HQ decreased the viability of both tumor cells, affecting slightly mammary epithelial cells. This hydroquinone blocked the electron flow through the NADH dehydrogenase (Complex I), leading to ADP-stimulated oxygen consumption inhibition, transmembrane potential dissipation and cellular ATP level decrease, without increasing ROS production. Duroquinol, an electron donor at CoQ level, reversed the decrease of cell viability induced by HQ. Additionally, HQ selectively induced G?/M-phase arrest. Taken together, our results suggest that the bioenergetic dysfunction provoked by HQ is implicated in its anticancer action. PMID:23333614

  16. Synthesis and characterization of Cu(II)-based anticancer chemotherapeutic agent targeting topoisomerase I?: in vitro DNA binding, pBR322 cleavage, molecular docking studies and cytotoxicity against human cancer cell lines.

    PubMed

    Tabassum, Sartaj; Zaki, Mehvash; Afzal, Mohd; Arjmand, Farukh

    2014-03-01

    New metal-based anticancer chemotherapeutic drug candidates [Cu(phen)L](NO?)? (1) and [Zn(phen)L](NO?)? (2) were synthesized from ligand L (derived from pharmacophore scaffold barbituric acid and pyrazole). In vitro DNA binding studies of the L, 1 and 2 were carried out by various biophysical techniques revealing electrostatic mode. Complex 1 cleaves pBR322 DNA via oxidative pathway and recognizes major groove of DNA double helix. The molecular docking study was carried out to ascertain the mode of action towards the molecular target DNA and enzymes. The complex 1 exhibited remarkably good anticancer activity on a panel of human cancer cell lines (GI?? values < 10 ?g/ml), and to elucidate the mechanism of cancer inhibition, Topo-I enzymatic activity was carried out. PMID:24508781

  17. Design and synthesis of 6,7-methylenedioxy-4-substituted phenylquinolin-2(1H)-one derivatives as novel anticancer agents that induce apoptosis with cell cycle arrest at G2/M phase

    PubMed Central

    Chen, Yi-Fong; Lin, Yi-Chien; Huang, Po-Kai; Chan, Hsu-Chin; Kuo, Sheng-Chu; Lee, Kuo-Hsiung; Huang, Li-Jiau

    2013-01-01

    Novel 6,7-methylenedioxy-4-substituted phenylquinolin-2-one derivatives 12a–n were designed and prepared through an intramolecular cyclization reaction and evaluated for in vitro anticancer activity. Among the synthesized compounds, 6,7-methylenedioxy-4-(2,4-dimethoxyphenyl)quinolin-2(1H)-one (12e) displayed potent cytotoxicity against several different tumor cell lines at a sub-micromolar level. Furthermore, results of fluorescence-activated cell sorting (FACS) analysis suggested that 12e induced cell cycle arrest in the G2/M phase accompanied by apoptosis in HL-60 and H460 cells. This action was confirmed by Hoechst staining and caspase-3 activation. Due to their easy synthesis and remarkable biological activities, 4-phenylquinolin-2(1H)-one analogs (4-PQs) are promising new anticancer leads based on the quinoline scaffold. Accordingly, compound 12e was identified as a new lead compound that merits further optimization and development as an anticancer candidate. PMID:23867385

  18. Studies on Anticancer Activities of Antimicrobial Peptides

    PubMed Central

    Hoskin, David W.; Ramamoorthy, Ayyalusamy

    2008-01-01

    In spite of great advances in cancer therapy, there is considerable current interest in developing anticancer agents with a new mode of action because of the development of resistance by cancer cells towards current anticancer drugs. A growing number of studies have shown that some of the cationic antimicrobial peptides (AMPs), which are toxic to bacteria but not to normal mammalian cells, exhibit a broad spectrum of cytotoxic activity against cancer cells. Such studies have considerably enhanced the significance of AMPs, both synthetic and from natural sources, which have been of importance both for an increased understanding of the immune system and for their potential as clinical antibiotics. The electrostatic attraction between the negatively charged components of bacterial and cancer cells and the positively charged AMPs is believed to play a major role in the strong binding and selective disruption of bacterial and cancer cell membranes, respectively. However, it is unclear why some host defense peptides are able to kill cancer cells when others do not. In addition, it is not clear whether the molecular mechanism(s) underlying the antibacterial and anticancer activities of AMPs are the same or different. In this article, we review various studies on different AMPs that exhibit cytotoxic activity against cancer cells. The suitability of cancer cell-targeting AMPs as cancer therapeutics is also discussed. PMID:18078805

  19. Novel anticancer therapeutics targeting telomerase.

    PubMed

    Ruden, Maria; Puri, Neelu

    2013-08-01

    Telomeres are protective caps at the ends of human chromosomes. Telomeres shorten with each successive cell division in normal human cells whereas, in tumors, they are continuously elongated by human telomerase reverse transcriptase (hTERT). Telomerase is overexpressed in 80-95% of cancers and is present in very low levels or is almost undetectable in normal cells. Because telomerase plays a pivotal role in cancer cell growth it may serve as an ideal target for anticancer therapeutics. Inhibition of telomerase may lead to a decrease of telomere length resulting in cell senescence and apoptosis in telomerase positive tumors. Several strategies of telomerase inhibition are reviewed, including small molecule inhibitors, antisense oligonucleotides, immunotherapies and gene therapies, targeting the hTERT or the ribonucleoprotein subunit hTER. G-quadruplex stabilizers, tankyrase and HSP90 inhibitors targeting telomere and telomerase assembly, and T-oligo approach are also covered. Based on this review, the most promising current telomerase targeting therapeutics are the antisense oligonucleotide inhibitor GRN163L and immunotherapies that use dendritic cells (GRVAC1), hTERT peptide (GV1001) or cryptic peptides (Vx-001). Most of these agents have entered phase I and II clinical trials in patients with various tumors, and have shown good response rates as evidenced by a reduction in tumor cell growth, increased overall disease survival, disease stabilization in advanced staged tumors and complete/partial responses. Most therapeutics have shown to be more effective when used in combination with standard therapies, resulting in concomitant telomere shortening and tumor mass shrinkage, as well as preventing tumor relapse and resistance to single agent therapy. PMID:22841437

  20. Melatonin anticancer effects: review.

    PubMed

    Di Bella, Giuseppe; Mascia, Fabrizio; Gualano, Luciano; Di Bella, Luigi

    2013-01-01

    Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main hormone produced by the pineal gland, not only regulates circadian rhythm, but also has antioxidant, anti-ageing and immunomodulatory properties. MLT plays an important role in blood composition, medullary dynamics, platelet genesis, vessel endothelia, and in platelet aggregation, leukocyte formula regulation and hemoglobin synthesis. Its significant atoxic, apoptotic, oncostatic, angiogenetic, differentiating and antiproliferative properties against all solid and liquid tumors have also been documented. Thanks, in fact, to its considerable functional versatility, MLT can exert both direct and indirect anticancer effects in factorial synergy with other differentiating, antiproliferative, immunomodulating and trophic molecules that form part of the anticancer treatment formulated by Luigi Di Bella (Di Bella Method, DBM: somatostatin, retinoids, ascorbic acid, vitamin D3, prolactin inhibitors, chondroitin-sulfate). The interaction between MLT and the DBM molecules counters the multiple processes that characterize the neoplastic phenotype (induction, promotion, progression and/or dissemination, tumoral mutation). All these particular characteristics suggest the use of MLT in oncological diseases. PMID:23348932

  1. Melatonin Anticancer Effects: Review

    PubMed Central

    Di Bella, Giuseppe; Mascia, Fabrizio; Gualano, Luciano; Di Bella, Luigi

    2013-01-01

    Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main hormone produced by the pineal gland, not only regulates circadian rhythm, but also has antioxidant, anti-ageing and immunomodulatory properties. MLT plays an important role in blood composition, medullary dynamics, platelet genesis, vessel endothelia, and in platelet aggregation, leukocyte formula regulation and hemoglobin synthesis. Its significant atoxic, apoptotic, oncostatic, angiogenetic, differentiating and antiproliferative properties against all solid and liquid tumors have also been documented. Thanks, in fact, to its considerable functional versatility, MLT can exert both direct and indirect anticancer effects in factorial synergy with other differentiating, antiproliferative, immunomodulating and trophic molecules that form part of the anticancer treatment formulated by Luigi Di Bella (Di Bella Method, DBM: somatostatin, retinoids, ascorbic acid, vitamin D3, prolactin inhibitors, chondroitin-sulfate). The interaction between MLT and the DBM molecules counters the multiple processes that characterize the neoplastic phenotype (induction, promotion, progression and/or dissemination, tumoral mutation). All these particular characteristics suggest the use of MLT in oncological diseases. PMID:23348932

  2. Anticancer substances of mushroom origin.

    PubMed

    Ivanova, T S; Krupodorova, T A; Barshteyn, V Y; Artamonova, A B; Shlyakhovenko, V A

    2014-06-01

    The present status of investigations about the anticancer activity which is inherent to medicinal mushrooms, as well as their biomedical potential and future prospects are discussed. Mushroom products and extracts possess promising immunomodulating and anticancer effects, so the main biologically active substances of mushrooms responsible for immunomodulation and direct cytoto-xicity toward cancer cell lines (including rarely mentioned groups of anticancer mushroom proteins), and the mechanisms of their antitumor action were analyzed. The existing to date clinical trials of mushroom substances are mentioned. Mushroom anticancer extracts, obtained by the different solvents, are outlined. Modern approaches of cancer treatment with implication of mushroom products, including DNA vaccinotherapy with mushroom immunomodulatory adjuvants, creation of prodrugs with mushroom lectins that can recognize glycoconjugates on the cancer cell surface, development of nanovectors etc. are discussed. The future prospects of mushroom anticancer substances application, including chemical modification of polysaccharides and terpenoids, gene engineering of proteins, and implementation of vaccines are reviewed. PMID:24980757

  3. Antitumor Agents 293. Non-toxic Dimethyl-4,4?-dimethoxy-5,6,5?,6?-dimethylenedioxybiphenyl-2,2?-dicarboxylate (DDB) Analogs Chemosensitize Multidrug Resistant Cancer Cells to Clinical Anticancer Drugs

    PubMed Central

    Hung, Hsin-Yi; Ohkoshi, Emika; Goto, Masuo; Bastow, Kenneth F.; Nakagawa-Goto, Kyoko; Lee, Kuo-Hsiung

    2012-01-01

    Novel dimethyl-4,4?-dimethoxy-5,6,5?,6?-dimethylenedioxybiphenyl-2,2?-dicarboxylate (DDB) analogs were designed and synthesized to improve their chemosensitizing action on KBvin (vincristine resistant nasopharyngeal carcinoma) cells, a multi-drug resistant cell line over-expressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic and bulky aliphatic side chains at the 2,2?-positions effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as paclitaxel (TAX), vincristine (VCR), and doxorubicin (DOX). DDB derivatives 16 and 23 showed 5–10 times more effective reversal ability than verapamil (VRP) for TAX and VCR. Analog 6 also exhibited five times greater chemosensitizing effect against DOX than VRP. Importantly, no cytotoxicity was observed by the active DDB analogs against both non-MDR and MDR cells, suggesting that DDB analogs serve as the novel lead compounds for the development of chemosensitizers to overcome MDR phenotype. The mechanism of action studies demonstrated that effective inhibition of P-glycoprotein by DDB analogs dramatically elevated cellular concentration of anticancer drugs. PMID:22612652

  4. Autophagy modulation as a target for anticancer drug discovery

    PubMed Central

    Li, Xin; Xu, Huai-long; Liu, Yong-xi; An, Na; Zhao, Si; Bao, Jin-ku

    2013-01-01

    Autophagy, an evolutionarily conserved catabolic process involving the engulfment and degradation of non-essential or abnormal cellular organelles and proteins, is crucial for homeostatic maintenance in living cells. This highly regulated, multi-step process has been implicated in diverse diseases including cancer. Autophagy can function as either a promoter or a suppressor of cancer, which makes it a promising and challenging therapeutic target. Herein, we overview the regulatory mechanisms and dual roles of autophagy in cancer. We also describe some of the representative agents that exert their anticancer effects by regulating autophagy. Additionally, some emerging strategies aimed at modulating autophagy are discussed as having the potential for future anticancer drug discovery. In summary, these findings will provide valuable information to better utilize autophagy in the future development of anticancer therapeutics that meet clinical requirements. PMID:23564085

  5. Synthesis and in vitro evaluation of N-alkyl-3-hydroxy-3-(2-imino-3-methyl-5-oxoimidazolidin-4-yl)indolin-2-one analogs as potential anticancer agents

    PubMed Central

    Penthala, Narsimha Reddy; Yerramreddy, Thirupathi Reddy; Madadi, Nikhil Reddy; Crooks, Peter A.

    2013-01-01

    A series of novel 3-hydroxy-3-(2-imino-3-methyl-5-oxoimidazolidin-4-yl)indolin-2-one analogs (3) have been synthesized under microwave irradiation and conventional heating methods. These analogs were evaluated for in vitro cytotoxicity against a panel of 57 human tumor cell lines. Compound 3o had GI50 values of 190 nM and 750 nM against A549/ATTC non-small cell lung cancer and LOX IMVI melanoma cell lines, respectively, and both 3n and 3o exhibited GI50 values ranging from 2–5 ?M against CCRF-CEM, HL-60(TB), K-562, MOLT-4, and RPMI-8226 leukemia cell lines. These results indicate that N-4-methoxybenzyl-3-hydroxy-(2-imino-3-methyl-5-oxo-4-yl)indolin-2-one analogs may be useful leads for anticancer drug development. PMID:20598531

  6. Anticancer, Anti-Inflammatory, and Analgesic Activities of Synthesized 2-(Substituted phenoxy) Acetamide Derivatives

    PubMed Central

    Pal, Dilipkumar; Hegde, Rahul Rama; Hashim, Syed Riaz

    2014-01-01

    The aphorism was to develop new chemical entities as potential anticancer, anti-inflammatory, and analgesic agents. The Leuckart synthetic pathway was utilized in development of novel series of 2-(substituted phenoxy)-N-(1-phenylethyl)acetamide derivatives. The compounds containing 1-phenylethylamine as basic moiety attached to substituted phenols were assessed for their anticancer activity against MCF-7 (breast cancer), SK-N-SH (neuroblastoma), anti-inflammatory activity, and analgesic activity. These investigations revealed that synthesized products 3a–j with halogens on the aromatic ring favors as the anticancer and anti-inflammatory activity. Among all, compound 3c N-(1-(4-chlorophenyl)ethyl)-2-(4-nitrophenoxy)acetamide exhibited anticancer, anti-inflammatory, and analgesic activities. In conclusion, 3c may have potential to be developed into a therapeutic agent. PMID:25197642

  7. Anticancer activity of koningic acid and semisynthetic derivatives.

    PubMed

    Rahier, Nicolas J; Molinier, Nicolas; Long, Christophe; Deshmukh, Sunil Kumar; Kate, Abhijeet S; Ranadive, Prafull; Verekar, Shilpa Amit; Jiotode, Mangesh; Lavhale, Rahul R; Tokdar, Pradipta; Balakrishnan, Arun; Meignan, Samuel; Robichon, Céline; Gomes, Bruno; Aussagues, Yannick; Samson, Arnaud; Sautel, François; Bailly, Christian

    2015-07-01

    A screening program aimed at discovering novel anticancer agents based on natural products led to the selection of koningic acid (KA), known as a potent inhibitor of glycolysis. A method was set up to produce this fungal sesquiterpene lactone in large quantities by fermentation, thus allowing (i) an extensive analysis of its anticancer potential in vitro and in vivo and (ii) the semi-synthesis of analogues to delineate structure-activity relationships. KA was characterized as a potent, but non-selective cytotoxic agent, active under both normoxic and hypoxic conditions and inactive in the A549 lung cancer xenograft model. According to our SAR, the acidic group could be replaced to keep bioactivity but an intact epoxide is essential. PMID:25937235

  8. In vivo anticancer activity of vanillin semicarbazone

    PubMed Central

    Ali, Shaikh M Mohsin; Azad, M Abul Kalam; Jesmin, Mele; Ahsan, Shamim; Rahman, M Mijanur; Khanam, Jahan Ara; Islam, M Nazrul; Shahriar, Sha M Shahan

    2012-01-01

    Objective To evaluate the anticancer activity of vanillin semicarbazone (VSC) against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. Methods The compound VSC at three doses (5, 7.5 and 10 mg/kg i.p.) was administered into the intraperitoneal cavity of the EAC inoculated mice to observe its efficiency by studying the cell growth inhibition, reduction of tumour weight, enhancement of survival time as well as the changes in depleted hematological parameters. All such parameters were also studied with a known standard drug bleomycin at the dose of 0.3 mg/kg (i.p.). Results Among the doses studied, 10 mg/kg (i.p.) was found to be quite comparable in potency to that of bleomycin at the dose of 0.3 mg/kg (i.p.). The host toxic effects of VSC was found to be negligible. Conclusions It can be concluded that VSC can therefore be considered as potent anticancer agent. PMID:23569946

  9. Repurposing of nitroxoline as a potential anticancer agent against human prostate cancer: a crucial role on AMPK/mTOR signaling pathway and the interplay with Chk2 activation.

    PubMed

    Chang, Wei-Ling; Hsu, Lih-Ching; Leu, Wohn-Jenn; Chen, Ching-Shih; Guh, Jih-Hwa

    2015-11-24

    Nitroxoline is an antibiotic by chelating Zn2+ and Fe2+ from biofilm matrix. In this study, nitroxoline induced G1 arrest of cell cycle and subsequent apoptosis in prostate cancer cells through ion chelating-independent pathway. It decreased protein levels of cyclin D1, Cdc25A and phosphorylated Rb, but activated AMP-activated protein kinase (AMPK), a cellular energy sensor and signal transducer, leading to inhibition of downstream mTOR-p70S6K signaling. Knockdown of AMPK? significantly rescued nitroxoline-induced inhibition of cyclin D1-Rb-Cdc25A axis indicating AMPK-dependent mechanism. However, cytoprotective autophagy was simultaneously evoked by nitroxoline. Comet assay and Western blot analysis demonstrated DNA damaging effect and activation of Chk2 other than Chk1 to nitroxoline action. Instead of serving as a DNA repair transducer, nitroxoline-mediated Chk2 activation was identified to function as a pro-apoptotic inducer. In conclusion, the data suggest that nitroxoline induces anticancer activity through AMPK-dependent inhibition of mTOR-p70S6K signaling pathway and cyclin D1-Rb-Cdc25A axis, leading to G1 arrest of cell cycle and apoptosis. AMPK-dependent activation of Chk2, at least partly, contributes to apoptosis. The data suggest the potential role of nitroxoline for therapeutic development against prostate cancers. PMID:26447757

  10. Targeting protein-protein interactions as an anticancer strategy

    Cancer.gov

    Extensive biological and clinical investigations have led to the identification of protein interaction hubs and nodes that are critical for the acquisition and maintenance of characteristics of cancer essential for cell transformation. Such cancer-enabling PPIs have become promising therapeutic targets. With technological advances in PPI modulator discovery and validation of PPI-targeting agents in clinical settings, targeting of PPI interfaces as an anticancer strategy has become a reality.

  11. 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

  12. Classification of current anticancer immunotherapies.

    PubMed

    Galluzzi, Lorenzo; Vacchelli, Erika; Bravo-San Pedro, José-Manuel; Buqué, Aitziber; Senovilla, Laura; Baracco, Elisa Elena; Bloy, Norma; Castoldi, Francesca; Abastado, Jean-Pierre; Agostinis, Patrizia; Apte, Ron N; Aranda, Fernando; Ayyoub, Maha; Beckhove, Philipp; Blay, Jean-Yves; Bracci, Laura; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; Celis, Estaban; Cerundolo, Vincenzo; Clayton, Aled; Colombo, Mario P; Coussens, Lisa; Dhodapkar, Madhav V; Eggermont, Alexander M; Fearon, Douglas T; Fridman, Wolf H; Fu?íková, Jitka; Gabrilovich, Dmitry I; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M; Klein, Eva; Knuth, Alexander; Lewis, Claire E; Liblau, Roland; Lotze, Michael T; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J; Mittendorf, Elizabeth A; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E; Pienta, Kenneth J; Porgador, Angel; Prendergast, George C; Rabinovich, Gabriel A; Restifo, Nicholas P; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J; Speiser, Daniel E; Spisek, Radek; Srivastava, Pramod K; Talmadge, James E; Tartour, Eric; Van Der Burg, Sjoerd H; Van Den Eynde, Benoît J; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S; Whiteside, Theresa L; Wolchok, Jedd D; Zitvogel, Laurence; Zou, Weiping; Kroemer, Guido

    2014-12-30

    During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches. PMID:25537519

  13. Classification of current anticancer immunotherapies

    PubMed Central

    Vacchelli, Erika; Pedro, José-Manuel Bravo-San; Buqué, Aitziber; Senovilla, Laura; Baracco, Elisa Elena; Bloy, Norma; Castoldi, Francesca; Abastado, Jean-Pierre; Agostinis, Patrizia; Apte, Ron N.; Aranda, Fernando; Ayyoub, Maha; Beckhove, Philipp; Blay, Jean-Yves; Bracci, Laura; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; Celis, Estaban; Cerundolo, Vincenzo; Clayton, Aled; Colombo, Mario P.; Coussens, Lisa; Dhodapkar, Madhav V.; Eggermont, Alexander M.; Fearon, Douglas T.; Fridman, Wolf H.; Fu?íková, Jitka; Gabrilovich, Dmitry I.; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M.; Klein, Eva; Knuth, Alexander; Lewis, Claire E.; Liblau, Roland; Lotze, Michael T.; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J.; Mittendorf, Elizabeth A.; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E.; Pienta, Kenneth J.; Porgador, Angel; Prendergast, George C.; Rabinovich, Gabriel A.; Restifo, Nicholas P.; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J.; Speiser, Daniel E.; Spisek, Radek; Srivastava, Pramod K.; Talmadge, James E.; Tartour, Eric; Van Der Burg, Sjoerd H.; Van Den Eynde, Benoît J.; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S.; Whiteside, Theresa L.; Wolchok, Jedd D.; Zitvogel, Laurence; Zou, Weiping

    2014-01-01

    During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches. PMID:25537519

  14. Polyphenols as mitochondria-targeted anticancer drugs.

    PubMed

    Gorlach, Sylwia; Fichna, Jakub; Lewandowska, Urszula

    2015-10-01

    Mitochondria are the respiratory and energetic centers of the cell where multiple intra- and extracellular signal transduction pathways converge leading to dysfunction of those organelles and, consequently, apoptotic or/and necrotic cell death. Mitochondria-targeted anticancer drugs are referred to as mitocans; they have recently been classified by Neuzil et al. (2013) according to their molecular mode of action into: hexokinase inhibitors; mimickers of the Bcl-2 homology-3 (BH3) domains; thiol redox inhibitors; deregulators of voltage-dependent anionic channel (VDAC)/adenine nucleotide translocase (ANT) complex; electron redox chain-targeting agents; lipophilic cations targeting the mitochondrial inner membrane; tricarboxylic acid cycle-targeting agents; and mitochondrial DNA-targeting agents. Polyphenols of plant origin and their synthetic or semisynthetic derivatives exhibit pleiotropic biological activities, including the above-mentioned modes of action characteristic of mitocans. Some of them have already been tested in clinical trials. Gossypol has served as a lead compound for developing more efficient BH3 mimetics such as ABT-737 and its orally available structural analog ABT-263 (Navitoclax). Furthermore, mitochondriotropic derivatives of phenolic compounds such as quercetin and resveratrol have been synthesized and reported to efficiently induce cancer cell death in vitro. PMID:26185003

  15. Synergistic Anti-Cancer Effect of Phenformin and Oxamate

    PubMed Central

    Miskimins, W. Keith; Ahn, Hyun Joo; Kim, Ji Yeon; Ryu, Sun; Jung, Yuh-Seog; Choi, Joon Young

    2014-01-01

    Phenformin (phenethylbiguanide; an anti-diabetic agent) plus oxamate [lactate dehydrogenase (LDH) inhibitor] was tested as a potential anti-cancer therapeutic combination. In in vitro studies, phenformin was more potent than metformin, another biguanide, recently recognized to have anti-cancer effects, in promoting cancer cell death in the range of 25 times to 15 million times in various cancer cell lines. The anti-cancer effect of phenformin was related to complex I inhibition in the mitochondria and subsequent overproduction of reactive oxygen species (ROS). Addition of oxamate inhibited LDH activity and lactate production by cells, which is a major side effect of biguanides, and induced more rapid cancer cell death by decreasing ATP production and accelerating ROS production. Phenformin plus oxamate was more effective than phenformin combined with LDH knockdown. In a syngeneic mouse model, phenformin with oxamate increased tumor apoptosis, reduced tumor size and 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography compared to control. We conclude that phenformin is more cytotoxic towards cancer cells than metformin. Furthermore, phenformin and oxamate have synergistic anti-cancer effects through simultaneous inhibition of complex I in the mitochondria and LDH in the cytosol, respectively. PMID:24465604

  16. In silico inspired design and synthesis of a novel tubulin-binding anti-cancer drug: folate conjugated noscapine (Targetin).

    PubMed

    Naik, Pradeep K; Lopus, Manu; Aneja, Ritu; Vangapandu, Surya N; Joshi, Harish C

    2012-02-01

    Our screen for tubulin-binding small molecules that do not depolymerize bulk cellular microtubules, but based upon structural features of well known microtubule-depolymerizing colchicine and podophyllotoxin, revealed tubulin binding anti-cancer property of noscapine (Ye et al. in Proc Natl Acad Sci USA 95:2280-2286, 1998). Guided by molecular modelling calculations and structure-activity relationships we conjugated at C9 of noscapine, a folate group-a ligand for cellular folate receptor alpha (FR?). FR? is over-expressed on some solid tumours such as ovarian epithelial cancers. Molecular docking experiments predicted that a folate conjugated noscapine (Targetin) accommodated well inside the binding cavity (docking score -11.295 kcal/mol) at the interface between ?- and ?-tubulin. The bulky folate moiety of Targetin is extended toward lumen of microtubules. The binding free energy (?G (bind)) computed based on molecular mechanics energy minimization was -221.01 kcal/mol that revealed favourable interaction of Targetin with the receptor. Chemical synthesis, tubulin-binding experiments, and anti-cancer activity in vitro corroborate fully well with the molecular modelling experiments. Targetin binds tubulin with a dissociation constant (K (d) value) of 149 ± 3.0 ?M and decreases the transition frequencies between growth and shortening phases of microtubule assembly dynamics at concentrations that do not alter the total polymer mass. Cancer cells in general were more sensitive to Targetin compared with the founding compound noscapine (IC(50) in the range of 15-40 ?M). Quite strikingly, ovarian cancer cells (SKOV3 and A2780), known to overexpress FR?, were much more sensitive to targetin (IC(50) in the range of 0.3-1.5 ?M). PMID:22170255

  17. Anticancer Drug-Incorporated Layered Double Hydroxide Nanohybrids and Their Enhanced Anticancer Therapeutic Efficacy in Combination Cancer Treatment

    PubMed Central

    Lee, Gyeong Jin; Kang, Joo-Hee

    2014-01-01

    Objective. Layered double hydroxide (LDH) nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles. Method. Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML), 5-FU/LDH (FL), and (MTX + 5-FU)/LDH (MFL) nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy. Conclusion. All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy. PMID:24860812

  18. Nanodelivery of Parthenolide Using Functionalized Nanographene Enhances its Anticancer Activity

    PubMed Central

    Karmakar, A.; Mustafa, T.; Kannarpady, G.; Bratton, S.M.; Radominska-Pandya, A.; Crooks, P.A.

    2014-01-01

    Advances in anticancer chemotherapy have been hindered by the lack of biocompatibility of new prospective drugs. One significant challenge concerns water insolubility, which compromises the bioavailability of the drugs leading to increased dosage and higher systemic toxicity. To overcome these problems, nanodelivery has been established as a promising approach for increasing the efficacy and lowering the required dosage of chemotherapeutics. The naturally derived compound, parthenolide (PTL), is known for its anti-inflammatory and anticancer activity, but its poor water solubility limits its clinical value. In the present study, we have used carboxyl-functionalized nanographene (fGn) delivery to overcome the extreme hydrophobicity of this drug. A water-soluble PTL analog, dimethylamino parthenolide (DMAPT), was also examined for comparison with the anticancer efficacy of our PTL-fGn complex. Delivery by fGn was found to increase the anticancer/apoptotic effects of PTL (but not DMAPT) when delivered to the human pancreatic cancer cell line, Panc-1. The IC50 value for PTL decreased from 39 µM to 9.5 µM when delivered as a mixture with fGn. The IC50 of DMAPT did not decrease when delivered as DMAPT-fGn and was significantly higher than that for PTL-fGn. There were significant increases in ROS formation and in mitochondrial membrane disruption in Panc-1 cells after PTL-fGn treatment as compared to PTL treatment, alone. Increases in toxicity were also seen with apoptosis detection assays using flow cytometry, ethidium bromide/acridine orange/DAPI staining, and TUNEL. Thus, fGn delivery was successfully used to overcome the poor water solubility of PTL, providing a strategy for improving the effectiveness of this anticancer agent. PMID:25574376

  19. Catalytic organometallic anticancer complexes

    PubMed Central

    Dougan, Sarah J.; Habtemariam, Abraha; McHale, Sarah E.; Parsons, Simon; Sadler, Peter J.

    2008-01-01

    Organometallic complexes offer chemistry that is not accessible to purely organic molecules and, hence, potentially new mechanisms of drug action. We show here that the presence of both an iodido ligand and a ?-donor/?-acceptor phenylazopyridine ligand confers remarkable inertness toward ligand substitution on the half-sandwich “piano-stool” ruthenium arene complexes [(?6-arene)Ru(azpy)I]+ (where arene = p-cymene or biphenyl, and azpy = N,N-dimethylphenyl- or hydroxyphenyl-azopyridine) in aqueous solution. Surprisingly, despite this inertness, these complexes are highly cytotoxic to human ovarian A2780 and human lung A549 cancer cells. Fluorescence-trapping experiments in A549 cells suggest that the cytotoxicity arises from an increase in reactive oxygen species. Redox activity of these azopyridine RuII complexes was confirmed by electrochemical measurements. The first one-electron reduction step (half-wave potential ?0.2 to ?0.4 V) is assignable to reduction of the azo group of the ligand. In contrast, the unbound azopyridine ligands are not readily reduced. Intriguingly the ruthenium complex acted as a catalyst in reactions with the tripeptide glutathione (?-l-Glu-l-Cys-Gly), a strong reducing agent present in cells at millimolar concentrations; millimolar amounts of glutathione were oxidized to glutathione disulfide in the presence of micromolar ruthenium concentrations. A redox cycle involving glutathione attack on the azo bond of coordinated azopyridine is proposed. Such ligand-based redox reactions provide new concepts for the design of catalytic drugs. PMID:18687892

  20. Drug Delivery Innovations for Enhancing the Anticancer Potential of Vitamin E Isoforms and Their Derivatives

    PubMed Central

    Neophytou, Christiana M.; Constantinou, Andreas I.

    2015-01-01

    Vitamin E isoforms have been extensively studied for their anticancer properties. Novel drug delivery systems (DDS) that include liposomes, nanoparticles, and micelles are actively being developed to improve Vitamin E delivery. Furthermore, several drug delivery systems that incorporate Vitamin E isoforms have been synthesized in order to increase the bioavailability of chemotherapeutic agents or to provide a synergistic effect. D-alpha-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) is a synthetic derivative of natural alpha-tocopherol which is gaining increasing interest in the development of drug delivery systems and has also shown promising anticancer effect as a single agent. This review provides a summary of the properties and anticancer effects of the most potent Vitamin E isoforms and an overview of the various formulations developed to improve their efficacy, with an emphasis on the use of TPGS in drug delivery approaches. PMID:26137487

  1. Evaluation of anticancer activity of celastrol liposomes in prostate cancer cells

    PubMed Central

    Wolfram, Joy; Suri, Krishna; Huang, Yi; Molinaro, Roberto; Borsoi, Carlotta; Scott, Bronwyn; Boom, Kathryn; Paolino, Donatella; Fresta, Massimo; Wang, Jianghua; Ferrari, Mauro

    2014-01-01

    Context Celastrol, a natural compound derived from the herb Tripterygium wilfordii, is known to have anticancer activity, but is not soluble in water. Objective Formation of celastrol liposomes, to avoid the use of toxic solubilizing agents. Materials and methods Two different formulations of pegylated celastrol liposomes were fabricated. Liposomal characteristics and serum stability were determined using dynamic light scattering. Drug entrapment efficacy and drug release were measured spectrophotometrically. Cellular internalization and anticancer activity was measured in prostate cancer cells. Results Liposomal celastrol displayed efficient serum stability, cellular internalization and anticancer activity, comparable to that of the free drug reconstituted in dimethyl sulfoxide. Discussion and conclusion Liposomal celastrol can decrease the viability of prostate cancer cells, while eliminating the need for toxic solubilizing agents. PMID:24654943

  2. Synthesis, antimicrobial, anticancer evaluation and QSAR studies of 3/4-bromo benzohydrazide derivatives.

    PubMed

    Kumar, Pradeep; Narasimhan, Balasubramanian; Ramasamy, Kalavathy; Mani, Vasudevan; Mishra, Rakesh Kumar; Majeed, Abu Bakar Abdul

    2015-01-01

    A series 3/4-bromo-N'-(substituted benzylidene/furan-2-ylmethylene/5-oxopentylidene/3- phenylallylidene)benzohydrazides (1-23) was synthesized and characterized by physicochemical and spectral means. The synthesized compounds were screened for their antimicrobial and anticancer potentials. Antimicrobial activity results indicated that compound 12 (pMICam = 1.67 ?M/ml) was the most potent antimicrobial agent. The synthesized benzohydrazides were also having good anticancer potential and compound 22 (IC50 = 1.20 ?M ?M) was found to be the most potent anticancer agent which was more potent than standard drugs, tetrandrine (IC50 = 1.53) and 5- fluorouracil (IC50 = 4.6 ?M). QSAR studies indicated that antimicrobial activity of synthesized compounds was best described by electronic parameter, total energy (Te) and topological parameters, valance zero order molecular connectivity index ((0)?(v)) and Wiener index (W). PMID:25860177

  3. Polygamain, a New Microtubule Depolymerizing Agent That Occupies a Unique Pharmacophore in the Colchicine Site

    PubMed Central

    Hartley, R. M.; Peng, J.; Fest, G. A.; Dakshanamurthy, S.; Frantz, D. E.; Brown, M. L.

    2012-01-01

    Bioassay-guided fractionation was used to isolate the lignan polygamain as the microtubule-active constituent in the crude extract of the Mountain torchwood, Amyris madrensis. Similar to the effects of the crude plant extract, polygamain caused dose-dependent loss of cellular microtubules and the formation of aberrant mitotic spindles that led to G2/M arrest. Polygamain has potent antiproliferative activities against a wide range of cancer cell lines, with an average IC50 of 52.7 nM. Clonogenic studies indicate that polygamain effectively inhibits PC-3 colony formation and has excellent cellular persistence after washout. In addition, polygamain is able to circumvent two clinically relevant mechanisms of drug resistance, the expression of P-glycoprotein and the ?III isotype of tubulin. Studies with purified tubulin show that polygamain inhibits the rate and extent of purified tubulin assembly and displaces colchicine, indicating a direct interaction of polygamain within the colchicine binding site on tubulin. Polygamain has structural similarities to podophyllotoxin, and molecular modeling simulations were conducted to identify the potential orientations of these compounds within the colchicine binding site. These studies suggest that the benzodioxole group of polygamain occupies space similar to the trimethoxyphenyl group of podophyllotoxin but with distinct interactions within the hydrophobic pocket. Our results identify polygamain as a new microtubule destabilizer that seems to occupy a unique pharmacophore within the colchicine site of tubulin. This new pharmacophore will be used to design new colchicine site compounds that might provide advantages over the current agents. PMID:22169850

  4. Synthesis and biological studies of the thiols-triggered anticancer prodrug for a more effective cancer therapy.

    PubMed

    Xu, Yuanzhen; Chen, Jianjun; Li, Ya; Peng, Shoujiao; Gu, Xueyan; Sun, Meng; Gao, Kun; Fang, Jianguo

    2015-03-01

    A novel anticancer prodrug compound 1, which was designed to be triggered by thiols and release the chemotherapeutic agent mechlorethamine, was successfully prepared and evaluated for the first time. The activation of compound 1 was determined by NMR analysis and denaturing alkaline agarose gel electrophoresis. A fluorescence image and comet assay indicated that the inducible reactivity of 1 could be accomplished in cell media. The anticancer activities are also discussed. PMID:25581090

  5. Genetic Interactions of STAT3 and Anticancer Drug Development

    PubMed Central

    Fang, Bingliang

    2014-01-01

    Signal transducer and activator of transcription 3 (STAT3) plays critical roles in tumorigenesis and malignant evolution and has been intensively studied as a therapeutic target for cancer. A number of STAT3 inhibitors have been evaluated for their antitumor activity in vitro and in vivo in experimental tumor models and several approved therapeutic agents have been reported to function as STAT3 inhibitors. Nevertheless, most STAT3 inhibitors have yet to be translated to clinical evaluation for cancer treatment, presumably because of pharmacokinetic, efficacy, and safety issues. In fact, a major cause of failure of anticancer drug development is lack of efficacy. Genetic interactions among various cancer-related pathways often provide redundant input from parallel and/or cooperative pathways that drives and maintains survival environments for cancer cells, leading to low efficacy of single-target agents. Exploiting genetic interactions of STAT3 with other cancer-related pathways may provide molecular insight into mechanisms of cancer resistance to pathway-targeted therapies and strategies for development of more effective anticancer agents and treatment regimens. This review focuses on functional regulation of STAT3 activity; possible interactions of the STAT3, RAS, epidermal growth factor receptor, and reduction-oxidation pathways; and molecular mechanisms that modulate therapeutic efficacies of STAT3 inhibitors. PMID:24662938

  6. Anticancer efficacy of unique pyridine-based tetraindoles.

    PubMed

    Fu, Chih-Wei; Hsieh, Yun-Jung; Chang, Tzu Ting; Chen, Chia-Ling; Yang, Cheng-Yu; Liao, Anne; Hsiao, Pei-Wen; Li, Wen-Shan

    2015-11-01

    Results of previous studies demonstrated that the tetraindole, SK228, which has a high lipid but low water solubility, displayed moderate anticancer efficacy in a xenograft model of breast cancer. This finding led to the proposal that new, pyridine based tetraindole (PBT) analogs of SK228, containing tetraindole moieties distributed about central protonated pyridine cores, would have enhanced bioavailabilities and anticancer efficacies. Among the PBTs prepared and subjected to biological studies, 3f (FCW81) was observed to display the highest antiproliferative activity against the two triple negative breast cancer (TNBCs) cell lines, MDA-MB-231 and BT549. In addition, its mode of action was shown to involve G2/M arrest of the cell cycle along with the promotion of increased levels of cyclin B1 and p-chk2 and a decreased level of p-cdc2. DNA damage and induction of apoptosis caused by FCW81 was found to be associated with a decrease in DNA repair. Significantly, FCW81 displays therapeutic efficacy in a xenograft model of human breast cancer by not only serving to inhibit markedly the growth of cancer cells but also to block effectively cancer cell metastasis. Collectively, the results of these studies have led to the identification of novel pyridine-tetraindole based anticancer agents with potential use in TNBC therapy. PMID:26457743

  7. Dihydromyricetin prevents cardiotoxicity and enhances anticancer activity induced by adriamycin

    PubMed Central

    Fu, Yingying; Wang, Jincheng; Dai, Jiabin; Shao, Jinjin; Yang, Xiaochun; Chang, Linlin; Weng, Qinjie; Yang, Bo; He, Qiaojun

    2015-01-01

    Adriamycin, a widely used anthracycline antibiotic in multiple chemotherapy regimens, has been challenged by the cardiotoxicity leading to fatal congestive heart failure in the worst condition. The present study demonstrated that Dihydromyricetin, a natural product extracted from ampelopsis grossedentat, exerted cardioprotective effect against the injury in Adriamycin-administrated ICR mice. Dihydromyricetin decreased ALT, LDH and CKMB levels in mice serum, causing a significant reduction in the toxic death triggered by Adriamycin. The protective effects were also indicated by the alleviation of abnormal electrocardiographic changes, the abrogation of proliferation arrest and apoptotic cell death in primary myocardial cells. Further study revealed that Dihydromyricetin-rescued loss of anti-apoptosis protein ARC provoked by Adriamycin was involved in the cardioprotection. Intriguingly, the anticancer activity of Adriamycin was not compromised upon the combination with Dihydromyricetin, as demonstrated by the enhanced anticancer effect achieved by Adriamycin plus Dihydromyricetin in human leukemia U937 cells and xenograft models, in a p53-dependent manner. These results collectively promised the potential value of Dihydromyricetin as a rational cardioprotective agent of Adriamycin, by protecting myocardial cells from apoptosis, while potentiating anticancer activities of Adriamycin, thus further increasing the therapeutic window of the latter one. PMID:25226612

  8. Antiangiogenic and anticancer molecules in cartilage.

    PubMed

    Patra, Debabrata; Sandell, Linda J

    2012-01-01

    Cartilage is one of the very few naturally occurring avascular tissues where lack of angiogenesis is the guiding principle for its structure and function. This has attracted investigators who have sought to understand the biochemical basis for its avascular nature, hypothesising that it could be used in designing therapies for treating cancer and related malignancies in humans through antiangiogenic applications. Cartilage encompasses primarily a specialised extracellular matrix synthesised by chondrocytes that is both complex and unique as a result of the myriad molecules of which it is composed. Of these components, a few such as thrombospondin-1, chondromodulin-1, the type XVIII-derived endostatin, SPARC (secreted protein acidic and rich in cysteine) and the type II collagen-derived N-terminal propeptide (PIIBNP) have demonstrated antiangiogenic or antitumour properties in vitro and in vivo preclinical trials that involve several complicated mechanisms that are not completely understood. Thrombospondin-1, endostatin and the shark-cartilage-derived Neovastat preparation have also been investigated in human clinical trials to treat several different kinds of cancers, where, despite the tremendous success seen in preclinical trials, these molecules are yet to show success as anticancer agents. This review summarises the current state-of-the-art antiangiogenic characterisation of these molecules, highlights their most promising aspects and evaluates the future of these molecules in antiangiogenic applications. PMID:22559283

  9. Anticancer activity of sea cucumber triterpene glycosides.

    PubMed

    Aminin, Dmitry L; Menchinskaya, Ekaterina S; Pisliagin, Evgeny A; Silchenko, Alexandra S; Avilov, Sergey A; Kalinin, Vladimir I

    2015-03-01

    Triterpene glycosides are characteristic secondary metabolites of sea cucumbers (Holothurioidea, Echinodermata). They have hemolytic, cytotoxic, antifungal, and other biological activities caused by membranotropic action. These natural products suppress the proliferation of various human tumor cell lines in vitro and, more importantly, intraperitoneal administration in rodents of solutions of some sea cucumber triterpene glycosides significantly reduces both tumor burden and metastasis. The anticancer molecular mechanisms include the induction of tumor cell apoptosis through the activation of intracellular caspase cell death pathways, arrest of the cell cycle at S or G2/M phases, influence on nuclear factors, NF-?B, and up-down regulation of certain cellular receptors and enzymes participating in cancerogenesis, such as EGFR (epidermal growth factor receptor), Akt (protein kinase B), ERK (extracellular signal-regulated kinases), FAK (focal adhesion kinase), MMP-9 (matrix metalloproteinase-9) and others. Administration of some glycosides leads to a reduction of cancer cell adhesion, suppression of cell migration and tube formation in those cells, suppression of angiogenesis, inhibition of cell proliferation, colony formation and tumor invasion. As a result, marked growth inhibition of tumors occurs in vitro and in vivo. Some holothurian triterpene glycosides have the potential to be used as P-gp mediated MDR reversal agents in combined therapy with standard cytostatics. PMID:25756523

  10. Anticancer Activity of Sea Cucumber Triterpene Glycosides

    PubMed Central

    Aminin, Dmitry L.; Menchinskaya, Ekaterina S.; Pisliagin, Evgeny A.; Silchenko, Alexandra S.; Avilov, Sergey A.; Kalinin, Vladimir I.

    2015-01-01

    Triterpene glycosides are characteristic secondary metabolites of sea cucumbers (Holothurioidea, Echinodermata). They have hemolytic, cytotoxic, antifungal, and other biological activities caused by membranotropic action. These natural products suppress the proliferation of various human tumor cell lines in vitro and, more importantly, intraperitoneal administration in rodents of solutions of some sea cucumber triterpene glycosides significantly reduces both tumor burden and metastasis. The anticancer molecular mechanisms include the induction of tumor cell apoptosis through the activation of intracellular caspase cell death pathways, arrest of the cell cycle at S or G2/M phases, influence on nuclear factors, NF-?B, and up-down regulation of certain cellular receptors and enzymes participating in cancerogenesis, such as EGFR (epidermal growth factor receptor), Akt (protein kinase B), ERK (extracellular signal-regulated kinases), FAK (focal adhesion kinase), MMP-9 (matrix metalloproteinase-9) and others. Administration of some glycosides leads to a reduction of cancer cell adhesion, suppression of cell migration and tube formation in those cells, suppression of angiogenesis, inhibition of cell proliferation, colony formation and tumor invasion. As a result, marked growth inhibition of tumors occurs in vitro and in vivo. Some holothurian triterpene glycosides have the potential to be used as P-gp mediated MDR reversal agents in combined therapy with standard cytostatics. PMID:25756523

  11. Synthesis and anticancer activity of epipolythiodiketopiperazine alkaloids

    E-print Network

    Hergenrother, Paul J.

    Synthesis and anticancer activity of epipolythiodiketopiperazine alkaloids Nicolas Boyer,a Karen C (ETP) alkaloids are a highly complex class of natural products with potent anticancer activity. Herein Epipolythiodiketopiperazine (ETP)1 alkaloids constitute a large (ca. 120 members) and diverse family of biologically active

  12. Anticancer Activity of Apaziquone in Oral Cancer Cells and Xenograft Model: Implications for Oral Cancer Therapy

    PubMed Central

    Srivastava, Gunjan; Somasundaram, Raj Thani; Walfish, Paul G.; Ralhan, Ranju

    2015-01-01

    Oral squamous cell carcinoma (OSCC) patients diagnosed in late stages have limited chemotherapeutic options underscoring the great need for development of new anticancer agents for more effective disease management. We aimed to investigate the anticancer potential of Apaziquone, [EOquin, USAN, E09, 3-hydroxy-5- aziridinyl-1-methyl-2(1H-indole-4,7-dione)–prop-?-en-?-ol], a pro-drug belonging to a class of anti-cancer agents called bioreductive alkylating agents, for OSCC. Apaziquone treatment inhibited cell proliferation and induced apoptosis in OSCC cells in vitro. Apaziquone treated OSCC cells showed increased activation of Caspase 9 and Caspase 3, and Poly (ADP ribose) polymerase (PARP) cleavage suggesting induction of apoptosis by apaziquone in oral cancer cells. Importantly, apaziquone treatment significantly reduced oral tumor xenograft volume in immunocompromised NOD/SCID/Crl mice without causing apparent toxicity to normal tissues. In conclusion, our in vitro and in vivo studies identified and demonstrated the pre-clinical efficacy of Apaziquone, as a potential novel anti-cancer therapeutic candidate for oral cancer management. PMID:26208303

  13. Phytochemicals as Anticancer and Chemopreventive Topoisomerase II Poisons

    PubMed Central

    Ketron, Adam C.

    2013-01-01

    Phytochemicals are a rich source of anticancer drugs and chemopreventive agents. Several of these chemicals appear to exert at least some of their effects through interactions with topoisomerase II, an essential enzyme that regulates DNA supercoiling and removes knots and tangles from the genome. Topoisomerase II-active phytochemicals function by stabilizing covalent protein-cleaved DNA complexes that are intermediates in the catalytic cycle of the enzyme. As a result, these compounds convert topoisomerase II to a cellular toxin that fragments the genome. Because of their mode of action, they are referred to as topoisomerase II poisons as opposed to catalytic inhibitors. The first sections of this article discuss DNA topology, the catalytic cycle of topoisomerase II, and the two mechanisms (interfacial vs. covalent) by which different classes of topoisomerase II poisons alter enzyme activity. Subsequent sections discuss the effects of several phytochemicals on the type II enzyme, including demethyl-epipodophyllotoxins (semisynthetic anticancer drugs) as well as flavones, flavonols, isoflavones, catechins, isothiocyanates, and curcumin (dietary chemopreventive agents). Finally, the leukemogenic potential of topoisomerase II-targeted phytochemicals is described. PMID:24678287

  14. Developments in the chemistry and nanodelivery of platinum anticancer agents

    E-print Network

    Johnstone, Timothy Charles

    2014-01-01

    Approximately half of all patients receiving cancer chemotherapy are treated with a platinum-containing drug. Despite this intense clinical use, only three platinum complexes, cisplatin, carboplatin, and oxaliplatin, are ...

  15. Sea Cucumbers Metabolites as Potent Anti-Cancer Agents

    PubMed Central

    Janakiram, Naveena B.; Mohammed, Altaf; Rao, Chinthalapally V.

    2015-01-01

    Sea cucumbers and their extracts have gained immense popularity and interest among researchers and nutritionists due to their nutritive value, potential health benefits, and use in the treatment of chronic inflammatory diseases. Many areas of the world use sea cucumbers in traditional foods and folk medicine. Though the actual components and their specific functions still remain to be investigated, most sea cucumber extracts are being studied for their anti-inflammatory functions, immunostimulatory properties, and for cancer prevention and treatment. There is large scope for the discovery of additional bioactive, valuable compounds from this natural source. Sea cucumber extracts contain unique components, such as modified triterpene glycosides, sulfated polysaccharides, glycosphingolipids, and esterified phospholipids. Frondanol A5, an isopropyl alcohol/water extract of the enzymatically hydrolyzed epithelia of the edible North Atlantic sea cucumber, Cucumaria frondosa, contains monosulfated triterpenoid glycoside Frondoside A, the disulfated glycoside Frondoside B, the trisulfated glycoside Frondoside C, 12-methyltetradecanoic acid, eicosapentaenoic acid, and fucosylated chondroitin sulfate. We have extensively studied the efficacy of this extract in preventing colon cancer in rodent models. In this review, we discuss the anti-inflammatory, immunostimulatory, and anti-tumor properties of sea cucumber extracts. PMID:25984989

  16. Hedgehog Signaling Inhibitors as Anti-Cancer Agents in Osteosarcoma

    PubMed Central

    Ram Kumar, Ram Mohan; Fuchs, Bruno

    2015-01-01

    Osteosarcoma is a rare type of cancer associated with a poor clinical outcome. Even though the pathologic characteristics of OS are well established, much remains to be understood, particularly at the molecular signaling level. The molecular mechanisms of osteosarcoma progression and metastases have not yet been fully elucidated and several evolutionary signaling pathways have been found to be linked with osteosarcoma pathogenesis, especially the hedgehog signaling (Hh) pathway. The present review will outline the importance and targeting the hedgehog signaling (Hh) pathway in osteosarcoma tumor biology. Available data also suggest that aberrant Hh signaling has pro-migratory effects and leads to the development of osteoblastic osteosarcoma. Activation of Hh signaling has been observed in osteosarcoma cell lines and also in primary human osteosarcoma specimens. Emerging data suggests that interference with Hh signal transduction by inhibitors may reduce osteosarcoma cell proliferation and tumor growth thereby preventing osteosarcomagenesis. From this perspective, we outline the current state of Hh pathway inhibitors in osteosarcoma. In summary, targeting Hh signaling by inhibitors promise to increase the efficacy of osteosarcoma treatment and improve patient outcome. PMID:25985215

  17. Molecular Mechanisms of Cannabinoids as Anti-cancer Agents 

    E-print Network

    Sreevalsan, Sandeep

    2013-05-31

    of Andreas Vesalius (1514-1564) and Theophrastus Paracelsus (1493-1541), undermined the long existent Galenic principles of humoral theory. The humoral theory was superseded by the lymph theory proposed by the French physician Ren? Descartes (1596...

  18. Sea Cucumbers Metabolites as Potent Anti-Cancer Agents.

    PubMed

    Janakiram, Naveena B; Mohammed, Altaf; Rao, Chinthalapally V

    2015-05-01

    Sea cucumbers and their extracts have gained immense popularity and interest among researchers and nutritionists due to their nutritive value, potential health benefits, and use in the treatment of chronic inflammatory diseases. Many areas of the world use sea cucumbers in traditional foods and folk medicine. Though the actual components and their specific functions still remain to be investigated, most sea cucumber extracts are being studied for their anti-inflammatory functions, immunostimulatory properties, and for cancer prevention and treatment. There is large scope for the discovery of additional bioactive, valuable compounds from this natural source. Sea cucumber extracts contain unique components, such as modified triterpene glycosides, sulfated polysaccharides, glycosphingolipids, and esterified phospholipids. Frondanol A5, an isopropyl alcohol/water extract of the enzymatically hydrolyzed epithelia of the edible North Atlantic sea cucumber, Cucumaria frondosa, contains monosulfated triterpenoid glycoside Frondoside A, the disulfated glycoside Frondoside B, the trisulfated glycoside Frondoside C, 12-methyltetradecanoic acid, eicosapentaenoic acid, and fucosylated chondroitin sulfate. We have extensively studied the efficacy of this extract in preventing colon cancer in rodent models. In this review, we discuss the anti-inflammatory, immunostimulatory, and anti-tumor properties of sea cucumber extracts. PMID:25984989

  19. Synthesis of Novel Oxime Sulfonate Derivatives of 2'(2',6')-(Di)chloropicropodophyllotoxins as Insecticidal Agents.

    PubMed

    Wang, Rong; Zhi, Xiaoyan; Li, Jie; Xu, Hui

    2015-08-01

    To discover novel natural-product-based pesticidal agents, we prepared a series of oxime sulfonate derivatives of 2'(2',6')-(Di)chloropicropodophyllotoxins by structural modification of podophyllotoxin. Their structures were well-characterized by proton nuclear magnetic resonance ((1)H NMR), high-resolution mass spectrometry (HRMS), optical rotation, and melting point. Moreover, the key steric structure of compound 5f was unambiguously determined by single-crystal X-ray diffraction. Additionally, their insecticidal activity was evaluated at 1 mg/mL against the pre-third-instar larvae of oriental armyworm (Mythimna separata Walker), a typical lepidopteran pest. Among all derivatives, compounds 4c, 5c, and 5d exhibited more promising insecticidal activity, with the final mortality rates greater than 60%, when compared to their precursor podophyllotoxin and the positive control, toosendanin. It demonstrated that introduction of the chlorine atom at the C-2' or C-2',6' position on the E ring of picropodophyllotoxin or oxime sulfonate derivatives of picropodophyllotoxin was important for the insecticidal activity and introduction of a halogen (e.g., fluorine, chlorine, or bromine) atom-substituted phenylsulfonyl group on the oxime fragment of 2'(2',6')-(di)chloropicropodophyllones could lead to more promising compounds. PMID:26166302

  20. Development of Platinum(iv) Complexes as Anticancer Prodrugs: the Story so Far

    NASA Astrophysics Data System (ADS)

    Wong, Daniel Yuan Qiang; Ang, Wee Han

    2012-06-01

    The serendipitous discovery of the antitumor properties of cisplatin by Barnett Rosenberg some forty years ago brought about a paradigm shift in the field of medicinal chemistry and challenged conventional thinking regarding the role of potentially toxic heavy metals in drugs. Platinum(II)-based anticancer drugs have since become some of the most effective and widely-used drugs in a clinician's arsenal and have saved countless lives. However, they are limited by high toxicity, severe side-effects and the incidence of drug resistance. In recent years, attention has shifted to stable platinum(IV) complexes as anticancer prodrugs. By exploiting the unique chemical and structural attributes of their scaffolds, these platinum(IV) prodrugs offer new strategies of targeting and killing cancer cells. This review summarizes the development of anticancer platinum(IV) prodrugs to date and some of the exciting strategies that utilise the platinum(IV) construct as targeted chemotherapeutic agents against cancer.

  1. Cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms.

    PubMed

    Chen, Jingjing; Luo, Zuandi; Zhao, Zhennan; Xie, Lina; Zheng, Wenjie; Chen, Tianfeng

    2015-12-01

    Elucidation of relationship among cellular uptake, localization and biological activities of metal complexes could make great breakthrough in the understanding of their action mechanisms and provide useful information for rational design of metal-based anticancer drugs. Iron(II) complexes have emerged as potential anticancer drug candidates with application potential in cancer imaging and therapy. Herein, a series of iron(II) polypyridyl complexes with different lipophilicity were rationally designed, synthesized and identified as potent anticancer agents. The relationship between the cellular localization and molecular action mechanisms of the complexes was also elucidated. The results showed that, the increase in planarity of the Fe(II) polypyridyl complexes enhanced their lipophilicity and cellular uptake, leading to improved anticancer efficacy. The hydrophilic Fe(II) complex entered cancer cells through transferring receptor (TfR)-mediated endocytosis, and translocated to cell nucleus, where they induced S phase cell cycle arrest through triggering DNA damage-mediated p53 pathway. Interestingly, the hydrophobic Fe(II) complexes displayed higher anticancer efficacy than the hydrophilic ones, but shared the same uptake pathway (TfR-mediated endocytosis) in cancer cells. They accumulated and localized in cell cytoplasm, and induced G0/G1 cells cycle arrest through regulation of AKT pathway and activation of downstream effector proteins. These results support that the cellular localization of Fe(II) complexes regulated by their lipophilicity could affect the anticancer efficacy and action mechanisms. Taken together, this study may enhance our understanding on the rational design of the next-generation anticancer metal complexes. PMID:26342440

  2. Computational studies of the electronic, conductivities, and spectroscopic properties of hydrolysed Ru(II) anticancer complexes.

    PubMed

    Adeniyi, Adebayo A; Ajibade, Peter A

    2013-11-01

    The mechanism of activation of metal-based anticancer agents was reported to be through hydrolysis. In this study, computational method was used to gain insight to the correlation between the chemistry of the hydrolysis and the anticancer activities of selected Ru(II)-based complexes. Interestingly, we observed that the mechanism of activation by hydrolysis and their consequential anticancer activities is associated with favourable thermodynamic changes, higher hyperpolarizability (?), lower band-gap and higher first-order net current. The Fermi contact (FC) and spin dipole (SD) are found to be the two most significant Ramsey terms that determine the spin-spin couplings (J(HZ)) of most of the existing bonds in the complexes. Many of the computed properties give insights into the change in the chemistry of the complexes due to hydrolysis. Besides strong correlations of the computed properties to the anticancer activities of the complexes, using the quantum theory of atoms in a molecule (QTAIM) to analyse the spectroscopic properties shows a stronger correlation between the spectroscopic properties of Ru atom to the reported anticancer activities than the sum over of the spectroscopic properties of all atoms in the complexes. PMID:23867645

  3. Synthesis and anticancer activity of epipolythiodiketopiperazine alkaloids

    E-print Network

    Boyer, Nicolas Cedric

    The epipolythiodiketopiperazine (ETP) alkaloids are a highly complex class of natural products with potent anticancer activity. Herein, we report the application of a flexible and scalable synthesis, allowing the construction ...

  4. Understanding and Improving Platinum Anticancer Drugs - Phenanthriplatin

    E-print Network

    Johnstone, Timothy

    Approximately half of all patients who receive anticancer chemotherapy are treated with a platinum drug. Despite the widespread use of these drugs, the only cure that can be claimed is that of testicular cancer following ...

  5. ANTI-CANCER NANOPARTICLE SYNTHESIS AND CHARACTERIZATION

    E-print Network

    ANTI-CANCER NANOPARTICLE SYNTHESIS AND CHARACTERIZATION Fan Mei1 , Da-Ren Chen2 and Yin-Nan Lee1 1, (-)-epigallocatechin-3-gallate (EGCG) from Green tea, Irresa and resveratrol have been shown to exhibit cancer

  6. Nanoscale coordination polymers for anticancer drug delivery

    NASA Astrophysics Data System (ADS)

    Phillips, Rachel Huxford

    This dissertation reports the synthesis and characterization of nanoscale coordination polymers (NCPs) for anticancer drug delivery. Nanoparticles have been explored in order to address the limitations of small molecule chemotherapeutics. NCPs have been investigated as drug delivery vehicles as they can exhibit the same beneficial properties as the bulk metal-organic frameworks as well as interesting characteristics that are unique to nanomaterials. Gd-MTX (MTX = methotrexate) NCPs with a MTX loading of 71.6 wt% were synthesized and stabilized by encapsulation within a lipid bilayer containing anisamide (AA), a small molecule that targets sigma receptors which are overexpressed in many cancer tissues. Functionalization with AA allows for targeted delivery and controlled release to cancer cells, as shown by enhanced efficacy against leukemia cells. The NCPs were doped with Ru(bpy)32+ (bpy = 2,2'-bipyridine), and this formulation was utilized as an optical imaging agent by confocal microscopy. NCPs containing the chemotherapeutic pemetrexed (PMX) were synthesized using different binding metals. Zr-based materials could not be stabilized by encapsulation with a lipid bilayer, and Gd-based materials showed that PMX had degraded during synthesis. However, Hf-based NCPs containing 19.7 wt% PMX were stabilized by a lipid coating and showed in vitro efficacy against non-small cell lung cancer (NSCLC) cell lines. Enhanced efficacy was observed for formulations containing AA. Additionally, NCP formulations containing the cisplatin prodrug disuccinatocisplatin were prepared; one of these formulations could be stabilized by encapsulation within a lipid layer. Coating with a lipid layer doped with AA rendered this formulation an active targeting agent. The resulting formulation proved more potent than free cisplatin in NSCLC cell lines. Improved NCP uptake was demonstrated by confocal microscopy and competitive binding assays. Finally, a Pt(IV) oxaliplatin prodrug was synthesized and incorporated in different NCPs using various binding metals. A moderate drug loading of 44.9 wt% was determined for Zr-based NCPs. This drug loading, along with a diameter less than 200 nm, make these particles promising candidates for further stabilization via lipid encapsulation.

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

    PubMed

    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

  8. 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

  9. Anticancer potential of Syzygium aromaticum L. in MCF-7 human breast cancer cell lines

    PubMed Central

    Kumar, Parvinnesh S.; Febriyanti, Raden M.; Sofyan, Ferry F.; Luftimas, Dimas E.; Abdulah, Rizky

    2014-01-01

    Background: The common treatment for cancer is unfavorable because it causes many detrimental side effects, and lately, there has been a growing resistance toward anticancer drugs, which worsens the future of cancer treatment. Therefore, the focus has now shifted toward natural products, such as spices and plants, among many others, to save the future of cancer treatment. Cloves (Syzygium aromaticum L.) are spices with the highest antioxidant content among natural products. Besides acting as an antioxidant, cloves also possess many other functions, such as anti-inflammatory, antibacterial, and antiseptic, which makes them an ideal natural source to be developed as an anticancer agent. Objective: This study aims to evaluate the cytotoxic activity of cloves toward MCF-7 human breast cancer cell lines. Materials and Methods: Different concentrations of water extract, ethanol extract, and essential oil of cloves were investigated for their anticancer potential in vitro through a brine shrimp lethality test (BSLT) and an MTT assay. Results: In both BSLT and MTT assays, the essential oil showed the highest cytotoxic effect, followed by ethanol and water extract. The LD50 concentration of essential oil in the 24 hours BSLT was 37 ?g/mL. Furthermore, the IC50 values in the 24 hours and 48 hours MTT assays of the essential oil were 36.43 ?g/mL and 17.6 ?g/mL, respectively. Conclusion: Cloves are natural products with excellent cytotoxicity toward MCF-7 cells; thus, they are promising sources for the development of anticancer agents. PMID:25276075

  10. Targeted anticancer therapy: overexpressed receptors and nanotechnology.

    PubMed

    Akhtar, Mohd Javed; Ahamed, Maqusood; Alhadlaq, Hisham A; Alrokayan, Salman A; Kumar, Sudhir

    2014-09-25

    Targeted delivery of anticancer drugs to cancer cells and tissues is a promising field due to its potential to spare unaffected cells and tissues, but it has been a major challenge to achieve success in these therapeutic approaches. Several innovative approaches to targeted drug delivery have been devised based on available knowledge in cancer biology and on technological advancements. To achieve the desired selectivity of drug delivery, nanotechnology has enabled researchers to design nanoparticles (NPs) to incorporate anticancer drugs and act as nanocarriers. Recently, many receptor molecules known to be overexpressed in cancer have been explored as docking sites for the targeting of anticancer drugs. In principle, anticancer drugs can be concentrated specifically in cancer cells and tissues by conjugating drug-containing nanocarriers with ligands against these receptors. Several mechanisms can be employed to induce triggered drug release in response to either endogenous trigger or exogenous trigger so that the anticancer drug is only released upon reaching and preferentially accumulating in the tumor tissue. This review focuses on overexpressed receptors exploited in targeting drugs to cancerous tissues and the tumor microenvironment. We briefly evaluate the structure and function of these receptor molecules, emphasizing the elegant mechanisms by which certain characteristics of cancer can be exploited in cancer treatment. After this discussion of receptors, we review their respective ligands and then the anticancer drugs delivered by nanotechnology in preclinical models of cancer. Ligand-functionalized nanocarriers have delivered significantly higher amounts of anticancer drugs in many in vitro and in vivo models of cancer compared to cancer models lacking such receptors or drug carrying nanocarriers devoid of ligand. This increased concentration of anticancer drug in the tumor site enabled by nanotechnology could have a major impact on the efficiency of cancer treatment while reducing systemic side effects. PMID:24836529

  11. Trial watch: Dendritic cell-based anticancer therapy

    PubMed Central

    Bloy, Norma; Pol, Jonathan; Aranda, Fernando; Eggermont, Alexander; Cremer, Isabelle; Fridman, Wolf Hervé; Fu?íková, Jitka; Galon, Jérôme; Tartour, Eric; Spisek, Radek; Dhodapkar, Madhav V.; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2014-01-01

    The use of patient-derived dendritic cells (DCs) as a means to elicit therapeutically relevant immune responses in cancer patients has been extensively investigated throughout the past decade. In this context, DCs are generally expanded, exposed to autologous tumor cell lysates or loaded with specific tumor-associated antigens (TAAs), and then reintroduced into patients, often in combination with one or more immunostimulatory agents. As an alternative, TAAs are targeted to DCs in vivo by means of monoclonal antibodies, carbohydrate moieties or viral vectors specific for DC receptors. All these approaches have been shown to (re)activate tumor-specific immune responses in mice, often mediating robust therapeutic effects. In 2010, the first DC-based preparation (sipuleucel-T, also known as Provenge®) has been approved by the US Food and Drug Administration (FDA) for use in humans. Reflecting the central position occupied by DCs in the regulation of immunological tolerance and adaptive immunity, the interest in harnessing them for the development of novel immunotherapeutic anticancer regimens remains high. Here, we summarize recent advances in the preclinical and clinical development of DC-based anticancer therapeutics. PMID:25941593

  12. Targeting protein-protein interactions as an anticancer strategy | Office of Cancer Genomics

    Cancer.gov

    Extensive biological and clinical investigations have led to the identification of protein interaction hubs and nodes that are critical for the acquisition and maintenance of characteristics of cancer essential for cell transformation. Such cancer-enabling PPIs have become promising therapeutic targets. With technological advances in PPI modulator discovery and validation of PPI-targeting agents in clinical settings, targeting of PPI interfaces as an anticancer strategy has become a reality.

  13. A smart magnetic nanoplatform for synergistic anticancer therapy: manoeuvring mussel-inspired functional magnetic nanoparticles for pH responsive anticancer drug delivery and hyperthermia.

    PubMed

    Sasikala, Arathyram Ramachandra Kurup; GhavamiNejad, Amin; Unnithan, Afeesh Rajan; Thomas, Reju George; Moon, Myeongju; Jeong, Yong Yeon; Park, Chan Hee; Kim, Cheol Sang

    2015-10-29

    We report the versatile design of a smart nanoplatform for thermo-chemotherapy treatment of cancer. For the first time in the literature, our design takes advantage of the outstanding properties of mussel-inspired multiple catecholic groups - presenting a unique copolymer poly(2-hydroxyethyl methacrylate-co-dopamine methacrylamide) p(HEMA-co-DMA) to surface functionalize the superparamagnetic iron oxide nanoparticles as well as to conjugate borate containing anticancer drug bortezomib (BTZ) in a pH-dependent manner for the synergistic anticancer treatment. The unique multiple anchoring groups can be used to substantially improve the affinity of the ligands to the surfaces of the nanoparticles to form ultrastable iron oxide nanoparticles with control over their hydrodynamic diameter and interfacial chemistry. Thus the BTZ-incorporated-bio-inspired-smart magnetic nanoplatform will act as a hyperthermic agent that delivers heat when an alternating magnetic field is applied while the BTZ-bound catechol moieties act as chemotherapeutic agents in a cancer environment by providing pH-dependent drug release for the synergistic thermo-chemotherapy application. The anticancer efficacy of these bio-inspired multifunctional smart magnetic nanoparticles was tested both in vitro and in vivo and found that these unique magnetic nanoplatforms can be established to endow for the next generation of nanomedicine for efficient and safe cancer therapy. PMID:26471016

  14. Curcumin: a promising agent targeting cancer stem cells.

    PubMed

    Zang, Shufei; Liu, Tao; Shi, Junping; Qiao, Liang

    2014-01-01

    Cancer stem cells are a subset of cells that are responsible for cancer initiation and relapse. They are generally resistant to the current anticancer agents. Successful anticancer therapy must consist of approaches that can target not only the differentiated cancer cells, but also cancer stem cells. Emerging evidence suggested that the dietary agent curcumin exerted its anti-cancer activities via targeting cancer stem cells of various origins such as those of colorectal cancer, pancreatic cancer, breast cancer, brain cancer, and head and neck cancer. In order to enhance the therapeutic potential of curcumin, this agent has been modified or used in combination with other agents in the experimental therapy for many cancers. In this mini-review, we discussed the effect of curcumin and its derivatives in eliminating cancer stem cells and the possible underlying mechanisms. PMID:24851881

  15. 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-?B 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-?B activation through p65 nuclear translocation via blocking I?B-? 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 GSK3?. 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

  16. Biological and therapeutic activities, and anticancer properties of curcumin

    PubMed Central

    PERRONE, DONATELLA; ARDITO, FATIMA; GIANNATEMPO, GIOVANNI; DIOGUARDI, MARIO; TROIANO, GIUSEPPE; LO RUSSO, LUCIO; DE LILLO, ALFREDO; LAINO, LUIGI; LO MUZIO, LORENZO

    2015-01-01

    Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Curcumin has been used extensively in Ayurvedic medicine, as it is nontoxic and exhibits a variety of therapeutic properties, including antioxidant, analgesic, anti-inflammatory and antiseptic activities. Recently, certain studies have indicated that curcumin may exert anticancer effects in a variety of biological pathways involved in mutagenesis, apoptosis, tumorigenesis, cell cycle regulation and metastasis. The present study reviewed previous studies in the literature, which support the therapeutic activity of curcumin in cancer. In addition, the present study elucidated a number of the challenges concerning the use of curcumin as an adjuvant chemotherapeutic agent. All the studies reviewed herein suggest that curcumin is able to exert anti-inflammatory, antiplatelet, antioxidative, hepatoprotective and antitumor activities, particularly against cancers of the liver, skin, pancreas, prostate, ovary, lung and head neck, as well as having a positive effect in the treatment of arthritis. PMID:26640527

  17. Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

    PubMed Central

    2013-01-01

    Abstract Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2?). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2? inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 00, 000–000. PMID:22900902

  18. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance.

    PubMed

    Zitvogel, Laurence; Galluzzi, Lorenzo; Smyth, Mark J; Kroemer, Guido

    2013-07-25

    Conventional chemotherapeutics and targeted antineoplastic agents have been developed based on the simplistic notion that cancer constitutes a cell-autonomous genetic or epigenetic disease. However, it is becoming clear that many of the available anticancer drugs that have collectively saved millions of life-years mediate therapeutic effects by eliciting de novo or reactivating pre-existing tumor-specific immune responses. Here, we discuss the capacity of both conventional and targeted anticancer therapies to enhance the immunogenic properties of malignant cells and to stimulate immune effector cells, either directly or by subverting the immunosuppressive circuitries that preclude antitumor immune responses in cancer patients. Accumulating evidence indicates that the therapeutic efficacy of several antineoplastic agents relies on their capacity to influence the tumor-host interaction, tipping the balance toward the activation of an immune response specific for malignant cells. We surmise that the development of successful anticancer therapies will be improved and accelerated by the immunological characterization of candidate agents. PMID:23890065

  19. Anticancer activity of Ficus religiosa engineered copper oxide nanoparticles.

    PubMed

    Sankar, Renu; Maheswari, Ramasamy; Karthik, Selvaraju; Shivashangari, Kanchi Subramanian; Ravikumar, Vilwanathan

    2014-11-01

    The design, synthesis, characterization and application of biologically synthesized nanomaterials have become a vital branch of nanotechnology. There is a budding need to develop a method for environmentally benign metal nanoparticle synthesis, that do not use toxic chemicals in the synthesis protocols to avoid adverse effects in medical applications. Here, it is a report on an eco-friendly process for rapid synthesis of copper oxide nanoparticles using Ficus religiosa leaf extract as reducing and protecting agent. The synthesized copper oxide nanoparticles were confirmed by UV-vis spectrophotometer, absorbance peaks at 285 nm. The copper oxide nanoparticles were analyzed with field emission-scanning electron microscope (FE-SEM), Fourier transform infrared (FT-IR) spectroscopy, dynamic light scattering (DLS) and X-ray diffraction (XRD) spectrum. The FE-SEM and DLS analyses exposed that copper oxide nanoparticles are spherical in shape with an average particle size of 577 nm. FT-IR spectral analysis elucidates the occurrence of biomolecules required for the reduction of copper oxide ions. Zeta potential studies showed that the surface charge of the formed nanoparticles was highly negative. The XRD pattern revealed that synthesized nanoparticles are crystalline in nature. Further, biological activities of the synthesized nanoparticles were confirmed based on its stable anti-cancer effects. The apoptotic effect of copper oxide nanoparticles is mediated by the generation of reactive oxygen species (ROS) involving the disruption of mitochondrial membrane potential (??m) in A549 cells. The observed characteristics and results obtained in our in vitro assays suggest that the copper nanoparticles might be a potential anticancer agent. PMID:25280701

  20. Anticancer Properties of Phyllanthus emblica (Indian Gooseberry).

    PubMed

    Zhao, Tiejun; Sun, Qiang; Marques, Maud; Witcher, Michael

    2015-01-01

    There is a wealth of information emanating from both in vitro and in vivo studies indicating fruit extract of the Phyllanthus emblica tree, commonly referred to as Indian Gooseberries, has potent anticancer properties. The bioactivity in this extract is thought to be principally mediated by polyphenols, especially tannins and flavonoids. It remains unclear how polyphenols from Phyllanthus emblica can incorporate both cancer-preventative and antitumor properties. The antioxidant function of Phyllanthus emblica can account for some of the anticancer activity, but clearly other mechanisms are equally important. Herein, we provide a brief overview of the evidence supporting anticancer activity of Indian Gooseberry extracts, suggest possible mechanisms for these actions, and provide future directions that might be taken to translate these findings clinically. PMID:26180601

  1. Anticancer Properties of Phyllanthus emblica (Indian Gooseberry)

    PubMed Central

    Zhao, Tiejun; Sun, Qiang; Marques, Maud; Witcher, Michael

    2015-01-01

    There is a wealth of information emanating from both in vitro and in vivo studies indicating fruit extract of the Phyllanthus emblica tree, commonly referred to as Indian Gooseberries, has potent anticancer properties. The bioactivity in this extract is thought to be principally mediated by polyphenols, especially tannins and flavonoids. It remains unclear how polyphenols from Phyllanthus emblica can incorporate both cancer-preventative and antitumor properties. The antioxidant function of Phyllanthus emblica can account for some of the anticancer activity, but clearly other mechanisms are equally important. Herein, we provide a brief overview of the evidence supporting anticancer activity of Indian Gooseberry extracts, suggest possible mechanisms for these actions, and provide future directions that might be taken to translate these findings clinically. PMID:26180601

  2. Studies with Myrtus communis L.: Anticancer properties.

    PubMed

    Ogur, Recai

    2014-01-01

    Myrtus communis (MC) L. is a well-known Mediterranean plant with important cultural significance in this region. In ancient times, MC was accepted as a symbol of immortality. Maybe due to this belief, it is used during cemetery visits in some regions. Although it is a well-known plant in cosmetics, and there is a lot of studies about its different medical properties, anticancer studies performed using its different extracts or oils are not so much, but increasing. We collected these anticancer property-related studies in this review. PMID:26401362

  3. Anticancer and Anti-Inflammatory Activities of a Standardized Dichloromethane Extract from Piper umbellatum L. Leaves

    PubMed Central

    Iwamoto, Leilane Hespporte; Vendramini-Costa, Débora Barbosa; Monteiro, Paula Araújo; Ruiz, Ana Lúcia Tasca Gois; Sousa, Ilza Maria de Oliveira; Foglio, Mary Ann; de Carvalho, João Ernesto; Rodrigues, Rodney Alexandre Ferreira

    2015-01-01

    Despite the advances in anticancer drug discovery field, the worldwide cancer incidence is remarkable, highlighting the need for new therapies focusing on both cancer cell and its microenvironment. The tumor microenvironment offers multiple targets for cancer therapy, including inflammation. Nowadays, almost 75% of the anticancer agents used in chemotherapy are derived from natural products, and plants are an important source of new promising therapies. Continuing our research on Piper umbellatum species, here we describe the anticancer (in vitro antiproliferative activity and in vivo Ehrlich solid tumor model) and anti-inflammatory (carrageenan-induced paw edema and peritonitis models) activities of a standardized dichloromethane extract (SDE) from P. umbellatum leaves, containing 23.9% of 4-nerolidylcatechol. SDE showed in vitro and in vivo antiproliferative activity, reducing Ehrlich solid tumor growth by 38.7 and 52.2% when doses of 200 and 400?mg/kg, respectively, were administered daily by oral route. Daily treatments did not produce signals of toxicity. SDE also reduced paw edema and leukocyte migration on carrageenan-induced inflammation models, suggesting that the anticancer activity of SDE from Piper umbellatum leaves could involve antiproliferative and anti-inflammatory effects. These findings highlight P. umbellatum as a source of compounds against cancer and inflammation. PMID:25713595

  4. Telomerase inhibitory effects of medicinal mushrooms and lichens, and their anticancer activity.

    PubMed

    Xu, Baojun; Li, Chantian; Sung, Changkeun

    2014-01-01

    Telomerase has been widely accepted as a cancer marker and a promising therapeutic target for novel anticancer drugs. The aim of this study was to investigate the in vitro telomerase inhibitory effects of mushrooms and their anticancer properties. The inhibitory effects of mushrooms and lichens against telomerase activity of HL-60 cells were systematically assessed using polymerase chain reaction based on assay of telomeric repeat amplification protocol. Telomerase inhibitory samples were further tested for antiproliferation effects against the gastric cell line SNU-1 using the MTT method. Ethyl acetate extract of Pleurotus ostreatus, ethyl acetate and water extracts of Lasiosphaera fenzlii, hexane extract of Strobilomyces floccopus, water extract of Sarcodon aspratus, and hexane, ethyl acetate, and water extracts from Umbilicaria esculenta showed strong positive telomerase inhibitory activity. Hexane extract of S. floccopus and water extracts from the edible lichen U. esculenta exhibited strong anticancer effects against SNU-1 cells through antiproliferation assay. The water extract of U. esculenta has a great potential to be developed into an anticancer agent that targets telomerase. PMID:24940901

  5. Comparison of Doxorubicin Anticancer Drug Loading on Different Metal Oxide Nanoparticles

    PubMed Central

    Javed, Khalid Rashid; Ahmad, Munir; Ali, Salamat; Butt, Muhammad Zakria; Nafees, Muhammad; Butt, Alvina Rafiq; Nadeem, Muhammad; Shahid, Abubakar

    2015-01-01

    Abstract Nanomaterials are being vigorously investigated for their use in anticancer drug delivery regimes or as biomarkers agents and are considered to be a candidate to provide a way to combat severe weaknesses of anticancer drug pharmacokinetics, such as their nonspecificity. Because of this weakness, a bigger proportion of the drug-loaded nanomaterials flow toward healthy tissues and result in undesirable side effects. It is very important to evaluate drug loading and release efficiency of various nanomaterials to find out true pharmacokinetics of these drugs. This observational study aims to evaluate various surface functionalized and naked nanomaterials for their drug loading capability and consequently strengthens the Reporting of Observational Studies in Epidemiology (STROBE). We analyzed naked and coated nanoparticles of transition metal oxides for their further loading with doxorubicin, a representative water-soluble anticancer drug. Various uncoated and polyethylene glycol-coated metal oxide nanoparticles were synthesized and loaded with anticancer drug using simple stirring of the nanoparticles in a saturated aqueous solution of the drug. Results showed that surface-coated nanoparticles have higher drug-loading capabilities; however, certain naked metal oxide nanoparticles, such as cobalt oxide nanoparticles, can load a sufficient amount of drug. PMID:25789952

  6. Identification of a novel compound (?-sesquiphellandrene) from turmeric (Curcuma longa) with anticancer potential: comparison with curcumin.

    PubMed

    Tyagi, Amit Kumar; Prasad, Sahdeo; Yuan, Wei; Li, Shiyou; Aggarwal, Bharat B

    2015-12-01

    Considering that as many as 80 % of the anticancer drugs have their roots in natural products derived from traditional medicine, we examined compounds other than curcumin from turmeric (Curcuma longa) that could exhibit anticancer potential. Present study describes the isolation and characterization of another turmeric-derived compound, ?-sesquiphellandrene (SQP) that exhibits anticancer potential comparable to that of curcumin. We isolated several compounds from turmeric, including SQP, ?-curcumene, ar-turmerone, ?-turmerone, ?-turmerone, and ?-turmerone, only SQP was found to have antiproliferative effects comparable to those of curcumin in human leukemia, multiple myeloma, and colorectal cancer cells. While lack of the NF-?B-p65 protein had no effect on the activity of SQP, lung cancer cells that expressed p53 were more susceptible to the cytotoxic effect of SQP than were cells that lacked p53 expression. SQP was also found to be highly effective in suppressing cancer cell colony formation and inducing apoptosis, as shown by assays of intracellular esterase activity, plasma membrane integrity, and cell-cycle phase. SQP was found to induce cytochrome c release and activate caspases that lead to poly ADP ribose polymerase cleavage. SQP exposure was associated with downregulation of cell survival proteins such cFLIP, Bcl-xL, Bcl-2, c-IAP1, and survivin. Furthermore, SQP was found to be synergistic with the chemotherapeutic agents velcade, thalidomide and capecitabine. Overall, our results indicate that SQP has anticancer potential comparable to that of curcumin. PMID:26521943

  7. Activation Mechanisms for Organometallic Anticancer Complexes

    NASA Astrophysics Data System (ADS)

    Pizarro, Ana M.; Habtemariam, Abraha; Sadler, Peter J.

    Organometallic complexes offer potential for design as anticancer drugs. They can act as inert scaffolds and specifically inhibit enzymes such as kinases, or as pro-drugs which undergo activation by various mechanisms. The activation of metallocenes, arene, alkyl or aryl complexes by hydrolysis, and metal- or ligand-based redox reactions is discussed.

  8. The spliceosome as target for anticancer treatment

    PubMed Central

    van Alphen, R J; Wiemer, E A C; Burger, H; Eskens, F A L M

    2008-01-01

    The spliceosome is a ribonucleoprotein complex involved in RNA splicing, that is, the removal of non-coding introns from precursor messenger RNA. (Alternative) Splicing events may play an essential role in tumourigenesis. The recent discovery that the spliceosome is a target for novel compounds with anticancer activity opens up new therapeutic avenues. PMID:19034274

  9. Folding Graft Copolymer with Pedant Drug Segment for Co-Delivery of Anticancer Drugs

    PubMed Central

    Tai, Wanyi; Mo, Ran; Lu, Yue; Jiang, Tianyue; Gu, Zhen

    2014-01-01

    A graft copolymer with pendant drug segment can fold into nanostructures in a protein folding-like manner. The graft copolymer is constructed by directly polymerizing ?-camptothecin-glutamate N-carboxyanhydride (Glu(CPT)-NCA) on multiple sites of poly(ethylene glycol) (PEG)-based main chain via the ring open polymerization (ROP). The “purely” conjugated anticancer agent camptothecin (CPT) is hydrophobic and serves as the principal driving force during the folding process. When exposed to water, the obtained copolymer, together with doxorubicin (Dox), another anticancer agent, can fold into monodispersed nanocarriers (with a diameter of around 50 nm) for dual-drug delivery. Equipped with a PEG shell, the nanocarriers displayed good stability and can be internalized by a variety of cancer cell lines via the lipid raft and clathrin-mediated endocytotic pathway without premature leakage, which showed a high synergetic activity of CPT and Dox toward various cancer cells. In vivo study validated that the nanocarriers exhibited strong accumulation in tumor sites and showed a prominent anticancer activity against the lung cancer xenograft mice model compared with free drugs. PMID:24875756

  10. Design, synthesis, and anticancer evaluation of long-chain alkoxylated mono-carbonyl analogues of curcumin.

    PubMed

    Weng, Qiaoyou; Fu, Lili; Chen, Gaozhi; Hui, Junguo; Song, Jingjing; Feng, Jianpeng; Shi, Dengjian; Cai, Yuepiao; Ji, Jiansong; Liang, Guang

    2015-10-20

    Curcumin is a nontoxic phenolic compound that modulates the activity of several cellular targets that have been linked with cancers and other chronic diseases. However, the efficacy of curcumin in the clinic has been limited by its poor bioavailability and rapid metabolism in vivo. We have previously reported the design and discovery of series of 5-carbon linker-containing mono-carbonyl analogues of curcumin (MACs) as anti-cancer agents. In continuation of our ongoing research, we designed and synthesized 37 novel long-chain alkoxylated MACs for anti-cancer evaluation here. The MTS assay was used to determine the cytotoxicity of compounds in gastrointestinal cancer cells. Compounds 5, 28, and 29 showed strongest inhibition against gastric cancer cell proliferation and were subjected to further analysis. The effects of 5, 28, and 29 on cell apoptosis were measured by flow cytometry. Expression levels of Bcl-2, cleaved poly ADP-ribose polymerase (PARP), and pro-caspase-3 were detected by western blotting. Compounds 5, 28, and 29 induced apoptosis in human gastric carcinoma cells, increased PARP cleavage, and decreased expression of Bcl-2 and pro-caspase-3 protein. We then showed that compound 28, which possessed the strongest activity among the test compounds in vitro, exhibited significant tumor inhibition in SGC7901-driven xenograft mouse model. Taken together, the novel compound 28 could be further explored as an effective anticancer agent for the treatment of human gastric cancer. PMID:26318057

  11. Anticancer and antioxidant properties of terpinolene in rat brain cells.

    PubMed

    Aydin, Elanur; Türkez, Hasan; Ta?demir, Sener

    2013-09-01

    Terpinolene (TPO) is a natural monoterpene present in essential oils of many aromatic plant species. Although various biological activities of TPO have been demonstrated, its neurotoxicity has never been explored. In this in vitro study we investigated TPO's antiproliferative and/or cytotoxic properties using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test, genotoxic damage potential using the single-cell gel electrophoresis (SCGE), and oxidative effects through total antioxidant capacity (TAC) and total oxidative stress (TOS) in cultured primary rat neurons and N2a neuroblastoma cells. Dose-dependent effects of TPO (at 10 mg L(-1), 25 mg L(-1), 50 mg L(-1), 100 mg L(-1), 200 mg L(-1), and 400 mg L(-1)) were tested in both cell types. Significant (P<0.05) decrease in cell proliferation were observed in cultured primary rat neurons starting with the dose of 100 mg L(-1) and in N2a neuroblastoma cells starting with 50 mg L(-1). TPO was not genotoxic in either cell type. In addition, TPO treatment at 10 mg L(-1), 25 mg L(-1), and 50 mg L(-1) increased TAC in primary rat neurons, but not in N2a cells. However, at concentrations above 50 mg L(-1) it increased TOS in both cell types. Our findings clearly demonstrate that TPO is a potent antiproliferative agent for brain tumour cells and may have potential as an anticancer agent, which needs to be further studied. PMID:24084350

  12. Role of glycosylation in the anticancer activity of antibacterial peptides against breast cancer cells.

    PubMed

    Han, Yang-Yang; Liu, Hong-Yan; Han, Dong-Ju; Zong, Xi-Cui; Zhang, Shuang-Quan; Chen, Yu-Qing

    2013-11-01

    Antibacterial peptides (ABPs) with cancer-selective toxicity have received much more attention as alternative chemotherapeutic agents in recent years. However, the basis of their anticancer activity remains unclear. The modification of cell surface glycosylation is a characteristic of cancer cells. The present study investigated the effect of glycosylation, in particular sialic acid, on the anticancer activity of ABPs. We showed that aurein 1.2, buforin IIb and BMAP-28m exhibited selective cytotoxicity toward MX-1 and MCF-7 breast cancer cells. The binding activity, cytotoxicity and apoptotic activity of ABPs were enhanced by the presence of O-, N-glycoproteins, gangliosides and sialic acid on the surface of breast cancer cells. Among N-, O-glycoproteins and ganglioside, O-glycoproteins almost had the strongest effect on the binding and cytotoxicity of the three peptides. Further, up-regulation of hST6Gal1 in CHO-K1 cells enhanced the susceptibility of cells to these peptides. Finally, the growth of MX-1 xenograft tumors in mice was significantly suppressed by buforin IIb treatment, which was associated with induction of apoptosis and inhibition of vascularization. These data demonstrate that the three peptides bind to breast cancer cells via an interaction with surface O-, N-glycoproteins and gangliosides. Sialic acids act as key glycan binding sites for cationic ABP binding to glycoproteins and gangliosides. Therefore, glycosylation in breast cancer cells plays an important role in the anticancer activity of ABPs, which may partly explain their cancer-selective toxicity. Anticancer ABPs with cancer-selective cytotoxicity will be promising candidates for anticancer therapy in the future. PMID:23962446

  13. 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

  14. In vitro anticancer activity of extracts of Mentha Spp. against human cancer cells.

    PubMed

    Sharma, Vikas; Hussain, Shabir; Gupta, Moni; Saxena, Ajit Kumar

    2014-10-01

    In vitro anticancer potential of methanolic and aqueous extracts of whole plants of Mentha arvensis, M. longifolia, M. spicata and M. viridis at concentration of 100 ?g/ml was evaluated against eight human cancer cell lines--A-549, COLO-205, HCT-116, MCF-7, NCI-H322, PC-3, THP-1 and U-87MG from six different origins (breast, colon, glioblastoma, lung, leukemia and prostate) using sulphorhodamine blue (SRB) assay. Methanolic extracts of above-mentioned Mentha Spp. displayed anti-proliferative effect in the range of 70-97% against four human cancer cell lines, namely COLO-205, MCF-7, NCI-H322 and THP-1; however, aqueous extracts were found to be active against HCT-116 and PC-3. The results indicate that Mentha Spp. contain certain constituents with cytotoxic properties which may find use in developing anticancer agents. PMID:25630112

  15. In Vitro and in Vivo Antitumoral Effects of Combinations of Polyphenols, or Polyphenols and Anticancer Drugs: Perspectives on Cancer Treatment

    PubMed Central

    Fantini, Massimo; Benvenuto, Monica; Masuelli, Laura; Frajese, Giovanni Vanni; Tresoldi, Ilaria; Modesti, Andrea; Bei, Roberto

    2015-01-01

    Carcinogenesis is a multistep process triggered by genetic alterations that activate different signal transduction pathways and cause the progressive transformation of a normal cell into a cancer cell. Polyphenols, compounds ubiquitously expressed in plants, have anti-inflammatory, antimicrobial, antiviral, anticancer, and immunomodulatory properties, all of which are beneficial to human health. Due to their ability to modulate the activity of multiple targets involved in carcinogenesis through direct interaction or modulation of gene expression, polyphenols can be employed to inhibit the growth of cancer cells. However, the main problem related to the use of polyphenols as anticancer agents is their poor bioavailability, which might hinder the in vivo effects of the single compound. In fact, polyphenols have a poor absorption and biodistribution, but also a fast metabolism and excretion in the human body. The poor bioavailability of a polyphenol will affect the effective dose delivered to cancer cells. One way to counteract this drawback could be combination treatment with different polyphenols or with polyphenols and other anti-cancer drugs, which can lead to more effective antitumor effects than treatment using only one of the compounds. This report reviews current knowledge on the anticancer effects of combinations of polyphenols or polyphenols and anticancer drugs, with a focus on their ability to modulate multiple signaling transduction pathways involved in cancer. PMID:25918934

  16. Quinonaphthothiazines, syntheses, structures and anticancer activities

    NASA Astrophysics Data System (ADS)

    Jele?, M.; Pluta, K.; Suwi?ska, K.; Morak-M?odawska, B.; Latocha, M.; Shkurenko, A.

    2015-11-01

    Two new types of pentacyclic azaphenothiazines being quinonaphthothiazines were obtaining from the reactions of dichlorodiquinolinyl disulfide with 1- and 2-naphthylamines. As the reactions could proceed in many ways, the proper structure elucidation was crucial. The structure determination was based on the 2D NMR spectra (NOESY, HSQC and HMBC) of the methyl derivatives. The final structure evidences came from X-ray analysis of the monocrystals. The new quinonaphthothiazines represent angularly fused pentacyclic ring systems which is folded along the N-S axis. The parent NH-compounds were transformed into the N-derivatives. Some quinonaphthothiazines exhibited promising anticancer activity against glioblastoma SNB-19, melanoma C-32 and human ductal breast epithelial tumor T47D cell lines. The anticancer activity dependent on the nature of the substituents and the ring fusion between the thiazine and naphthalene moieties. Two compounds were more active than the reference drug, cisplatin.

  17. Flavonoids: A versatile source of anticancer drugs

    PubMed Central

    Chahar, Maheep K.; Sharma, Neelu; Dobhal, Mahabeer P.; Joshi, Yogesh C.

    2011-01-01

    An exponential increase in the number of studies investigating how different components of the diet interact at the molecular and cellular level to determine the fate of a cell has been witnessed. In search for anticancer drugs compelling data from laboratories, epidemiologic investigations, and human clinical trials showed that flavonoids have important effects on cancer chemoprevention and chemotherapy. In many molecular mechanisms of action for prevention against cancer, flavonoids play a major role by interacting between different types of genes and enzymes. Many mechanisms of action have been identified, including carcinogen inactivation, antiproliferation, cell cycle arrest, induction of apoptosis, inhibition of angiogenesis, antioxidation, and reversal of multidrug resistance or a combination of these mechanisms. This review focuses on the anticancer activity of flavonoids as well as their molecular mechanisms, including the treatment of mammary and prostate cancer. This review also highlights some advanced derivatives of flavonoids, which play an important role against cancer. PMID:22096313

  18. Melittin: a lytic peptide with anticancer properties.

    PubMed

    Gajski, Goran; Garaj-Vrhovac, Vera

    2013-09-01

    Melittin (MEL) is a major peptide constituent of bee venom that has been proposed as one of the upcoming possibilities for anticancer therapy. Recent reports point to several mechanisms of MEL cytotoxicity in different types of cancer cells such as cell cycle alterations, effect on proliferation and/or growth inhibition, and induction of apoptotic and necrotic cell death trough several cancer cell death mechanisms, including the activation of caspases and matrix metalloproteinases. Although cytotoxic to a broad spectrum of tumour cells, the peptide is also toxic to normal cells. Therefore its therapeutic potential cannot be achieved without a proper delivery vehicle which could be overcome by MEL nanoparticles that possess the ability to safely deliver significant amount of MEL intravenously, and to target and kill tumours. This review paper summarizes the current knowledge and brings latest research findings on the anticancer potential of this lytic peptide with diverse functions. PMID:23892471

  19. Synthesis and Anticancer Activity of Epipolythiodiketopiperazine Alkaloids

    PubMed Central

    Boyer, Nicolas; Morrison, Karen C.; Kim, Justin; Hergenrother, Paul J.; Movassaghi, Mohammad

    2013-01-01

    The epipolythiodiketopiperazine (ETP) alkaloids are a highly complex class of natural products with potent anticancer activity. Herein, we report the application of a flexible and scalable synthesis, allowing the construction of dozens of ETP derivatives. The evaluation of these compounds against cancer cell lines in culture allows for the first expansive structure–activity relationship (SAR) to be defined for monomeric and dimeric ETP-containing natural products and their synthetic cognates. Many ETP derivatives demonstrate potent anticancer activity across a broad range of cancer cell lines, and kill cancer cellsviainduction of apoptosis. Several traits thatbode well for the translational potential of the ETP class of natural products includeconcise and efficient synthetic access, potent induction of apoptotic cell death, activity against a wide range of cancer types, and a broad tolerance for modifications at multiple sitesthat should facilitate small-molecule drug development, mechanistic studies, and evaluation in vivo. PMID:23914293

  20. Anticancer Drugs from Marine Flora: An Overview

    PubMed Central

    Sithranga Boopathy, N.; Kathiresan, K.

    2010-01-01

    Marine floras, such as bacteria, actinobacteria, cyanobacteria, fungi, microalgae, seaweeds, mangroves, and other halophytes are extremely important oceanic resources, constituting over 90% of the oceanic biomass. They are taxonomically diverse, largely productive, biologically active, and chemically unique offering a great scope for discovery of new anticancer drugs. The marine floras are rich in medicinally potent chemicals predominantly belonging to polyphenols and sulphated polysaccharides. The chemicals have displayed an array of pharmacological properties especially antioxidant, immunostimulatory, and antitumour activities. The phytochemicals possibly activate macrophages, induce apoptosis, and prevent oxidative damage of DNA, thereby controlling carcinogenesis. In spite of vast resources enriched with chemicals, the marine floras are largely unexplored for anticancer lead compounds. Hence, this paper reviews the works so far conducted on this aspect with a view to provide a baseline information for promoting the marine flora-based anticancer research in the present context of increasing cancer incidence, deprived of the cheaper, safer, and potent medicines to challenge the dreadful human disease. PMID:21461373

  1. Medicinal Plants: Their Use in Anticancer Treatment

    PubMed Central

    Greenwell, M.; Rahman, P.K.S.M.

    2015-01-01

    Globally cancer is a disease which severely effects the human population. There is a constant demand for new therapies to treat and prevent this life-threatening disease. Scientific and research interest is drawing its attention towards naturally-derived compounds as they are considered to have less toxic side effects compared to current treatments such as chemotherapy. The Plant Kingdom produces naturally occurring secondary metabolites which are being investigated for their anticancer activities leading to the development of new clinical drugs. With the success of these compounds that have been developed into staple drugs for cancer treatment new technologies are emerging to develop the area further. New technologies include nanoparticles for nano-medicines which aim to enhance anticancer activities of plant-derived drugs by controlling the release of the compound and investigating new methods for administration. This review discusses the demand for naturally-derived compounds from medicinal plants and their properties which make them targets for potential anticancer treatments. PMID:26594645

  2. In vitro anticancer activity of Anemopsis californica.

    PubMed

    Kaminski, Catherine N; Ferrey, Seth L; Lowrey, Timothy; Guerra, Leo; VAN Slambrouck, Severine; Steelant, Wim F A

    2010-07-01

    Three different extract conditions (aqueous, EtOH and EtOAc) of four different parts (bracts, leaves, roots and stems) of the plant Anemopsis californica (A. californica) were evaluated for their effect on the growth and migration of human colon cancer cells, HCT-8, and the breast cancer cell lines Hs 578T and MCF-7/AZ. Our aim was to identify potential anticancer activity in crude A. californica extracts, given that this plant is used by Native Americans to treat a variety of diseases, including cancer. Our results demonstrated that for each of the cell lines tested, the majority of ethyl acetate extracts of all the plant parts are more toxic than the aqueous and ethanol extracts. Furthermore, significant growth inhibitory activity against the three cell lines was found for the ethyl acetate extract of the roots, while the aqueous extract of the roots influenced the migratory capacity of the three cell lines. This study provides evidence for the anticancer properties of A. californica when extracted in water and ethyl acetate, and supports the importance for further purification of the crude extracts and isolation of potential new anticancer compounds through bio-guided fractionation. PMID:21941602

  3. A smart magnetic nanoplatform for synergistic anticancer therapy: manoeuvring mussel-inspired functional magnetic nanoparticles for pH responsive anticancer drug delivery and hyperthermia

    NASA Astrophysics Data System (ADS)

    Sasikala, Arathyram Ramachandra Kurup; Ghavaminejad, Amin; Unnithan, Afeesh Rajan; Thomas, Reju George; Moon, Myeongju; Jeong, Yong Yeon; Park, Chan Hee; Kim, Cheol Sang

    2015-10-01

    We report the versatile design of a smart nanoplatform for thermo-chemotherapy treatment of cancer. For the first time in the literature, our design takes advantage of the outstanding properties of mussel-inspired multiple catecholic groups - presenting a unique copolymer poly(2-hydroxyethyl methacrylate-co-dopamine methacrylamide) p(HEMA-co-DMA) to surface functionalize the superparamagnetic iron oxide nanoparticles as well as to conjugate borate containing anticancer drug bortezomib (BTZ) in a pH-dependent manner for the synergistic anticancer treatment. The unique multiple anchoring groups can be used to substantially improve the affinity of the ligands to the surfaces of the nanoparticles to form ultrastable iron oxide nanoparticles with control over their hydrodynamic diameter and interfacial chemistry. Thus the BTZ-incorporated-bio-inspired-smart magnetic nanoplatform will act as a hyperthermic agent that delivers heat when an alternating magnetic field is applied while the BTZ-bound catechol moieties act as chemotherapeutic agents in a cancer environment by providing pH-dependent drug release for the synergistic thermo-chemotherapy application. The anticancer efficacy of these bio-inspired multifunctional smart magnetic nanoparticles was tested both in vitro and in vivo and found that these unique magnetic nanoplatforms can be established to endow for the next generation of nanomedicine for efficient and safe cancer therapy.We report the versatile design of a smart nanoplatform for thermo-chemotherapy treatment of cancer. For the first time in the literature, our design takes advantage of the outstanding properties of mussel-inspired multiple catecholic groups - presenting a unique copolymer poly(2-hydroxyethyl methacrylate-co-dopamine methacrylamide) p(HEMA-co-DMA) to surface functionalize the superparamagnetic iron oxide nanoparticles as well as to conjugate borate containing anticancer drug bortezomib (BTZ) in a pH-dependent manner for the synergistic anticancer treatment. The unique multiple anchoring groups can be used to substantially improve the affinity of the ligands to the surfaces of the nanoparticles to form ultrastable iron oxide nanoparticles with control over their hydrodynamic diameter and interfacial chemistry. Thus the BTZ-incorporated-bio-inspired-smart magnetic nanoplatform will act as a hyperthermic agent that delivers heat when an alternating magnetic field is applied while the BTZ-bound catechol moieties act as chemotherapeutic agents in a cancer environment by providing pH-dependent drug release for the synergistic thermo-chemotherapy application. The anticancer efficacy of these bio-inspired multifunctional smart magnetic nanoparticles was tested both in vitro and in vivo and found that these unique magnetic nanoplatforms can be established to endow for the next generation of nanomedicine for efficient and safe cancer therapy. Electronic supplementary information (ESI) available: Characterization of p(HEMA-co-DMA) abbreviated as (HEDO), XRD spectra of Fe3O4 & HEDO-Fe3O4, DLS of Fe3O4 & HEDO-Fe3O4, UV-VIS photospectroscopy of HEDO, BTZ and HEDO-BTZ. See DOI: 10.1039/C5NR05844A

  4. Therapeutic Strategies to Enhance the Anticancer Efficacy of Histone Deacetylase Inhibitors

    PubMed Central

    Miller, Claudia P.; Singh, Melissa M.; Rivera-Del Valle, Nilsa; Manton, Christa A.; Chandra, Joya

    2011-01-01

    Histone acetylation is a posttranslational modification that plays a role in regulating gene expression. More recently, other nonhistone proteins have been identified to be acetylated which can regulate their function, stability, localization, or interaction with other molecules. Modulating acetylation with histone deacetylase inhibitors (HDACi) has been validated to have anticancer effects in preclinical and clinical cancer models. This has led to development and approval of the first HDACi, vorinostat, for the treatment of cutaneous T cell lymphoma. However, to date, targeting acetylation with HDACi as a monotherapy has shown modest activity against other cancers. To improve their efficacy, HDACi have been paired with other antitumor agents. Here, we discuss several combination therapies, highlighting various epigenetic drugs, ROS-generating agents, proteasome inhibitors, and DNA-damaging compounds that together may provide a therapeutic advantage over single-agent strategies. PMID:21765634

  5. Anticancer compounds from marine macroalgae and their application as medicinal foods.

    PubMed

    Kim, Se-Kwon; Thomas, Noel Vinay; Li, Xifeng

    2011-01-01

    Cancer is one of the most challenging medical conditions that need a proper therapeutic approach for its proper management with fewer side effects. Until now, many of the phytochemicals from terrestrial origin have been assessed for their anticancer ability and few of them are in clinical trials too. However, marine environment also has been a greatest resource that harbors taxonomically diverse and a variety of life forms and serves as store house for several biologically beneficial metabolites. Hitherto, many metabolites have been isolated from marine biomasses that have exhibited excellent biological activities, especially as anticancer agents. In particular, marine macroalgae which are considered as dietary constituents in Pacific Asian region have become chief resources for their unparalleled and unique metabolites like sulfated polysaccharides (SPs), phlorotannins, and their ability in reducing the risk of cancer and its related diseases. In this chapter, we have discussed the anticancer activities of marine algae-derived SPs, phlorotannins, and carotenoids and the possibilities of marine algae as potential medicinal foods in the management of cancer. PMID:22054949

  6. Anticancer effects of deproteinized asparagus polysaccharide on hepatocellular carcinoma in vitro and in vivo.

    PubMed

    Xiang, Jianfeng; Xiang, Yanjie; Lin, Shengming; Xin, Dongwei; Liu, Xiaoyu; Weng, Lingling; Chen, Tao; Zhang, Minguang

    2014-04-01

    Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in the world whose chemoprevention became increasingly important in HCC treatment. Although the anticancer effects of asparagus constituents have been investigated in several cancers, its effects on hepatocellular carcinoma have not been fully studied. In this study, we investigated the anticancer effects of the deproteinized asparagus polysaccharide on the hepatocellular carcinoma cells using the in vitro and in vivo experimental model. Our data showed that deproteinized asparagus polysaccharide might act as an effective inhibitor on cell growth in vitro and in vivo and exert potent selective cytotoxicity against human hepatocellular carcinoma Hep3B and HepG2 cells. Further study showed that it could potently induce cell apoptosis and G2/M cell cycle arrest in the more sensitive Hep3B and HepG2 cell lines. Moreover, deproteinized asparagus polysaccharide potentiated the effects of mitomycin both in vitro and in vivo. Mechanistic studies revealed that deproteinized asparagus polysaccharide might exert its activity through an apoptosis-associated pathway by modulating the expression of Bax, Bcl-2, and caspase-3. In conclusion, deproteinized asparagus polysaccharide exhibited significant anticancer activity against hepatocellular carcinoma cells and could sensitize the tumoricidal effects of mitomycin, indicating that it is a potential therapeutic agent (or chemosensitizer) for liver cancer therapy. PMID:24310501

  7. Anticancer metal complexes: synthesis and cytotoxicity evaluation by the MTT assay.

    PubMed

    Ganot, Nitzan; Meker, Sigalit; Reytman, Lilia; Tzubery, Avia; Tshuva, Edit Y

    2013-01-01

    Titanium (IV) and vanadium (V) complexes are highly potent anticancer agents. A challenge in their synthesis refers to their hydrolytic instability; therefore their preparation should be conducted under an inert atmosphere. Evaluation of the anticancer activity of these complexes can be achieved by the MTT assay. The MTT assay is a colorimetric viability assay based on enzymatic reduction of the MTT molecule to formazan when it is exposed to viable cells. The outcome of the reduction is a color change of the MTT molecule. Absorbance measurements relative to a control determine the percentage of remaining viable cancer cells following their treatment with varying concentrations of a tested compound, which is translated to the compound anticancer activity and its IC50 values. The MTT assay is widely common in cytotoxicity studies due to its accuracy, rapidity, and relative simplicity. Herein we present a detailed protocol for the synthesis of air sensitive metal based drugs and cell viability measurements, including preparation of the cell plates, incubation of the compounds with the cells, viability measurements using the MTT assay, and determination of IC50 values. PMID:24300943

  8. Anticancer Metal Complexes: Synthesis and Cytotoxicity Evaluation by the MTT Assay

    PubMed Central

    Tshuva, Edit Y.

    2013-01-01

    Titanium (IV) and vanadium (V) complexes are highly potent anticancer agents. A challenge in their synthesis refers to their hydrolytic instability; therefore their preparation should be conducted under an inert atmosphere. Evaluation of the anticancer activity of these complexes can be achieved by the MTT assay. The MTT assay is a colorimetric viability assay based on enzymatic reduction of the MTT molecule to formazan when it is exposed to viable cells. The outcome of the reduction is a color change of the MTT molecule. Absorbance measurements relative to a control determine the percentage of remaining viable cancer cells following their treatment with varying concentrations of a tested compound, which is translated to the compound anticancer activity and its IC50 values. The MTT assay is widely common in cytotoxicity studies due to its accuracy, rapidity, and relative simplicity. Herein we present a detailed protocol for the synthesis of air sensitive metal based drugs and cell viability measurements, including preparation of the cell plates, incubation of the compounds with the cells, viability measurements using the MTT assay, and determination of IC50 values. PMID:24300943

  9. Bis-demethoxy curcumin analog nanoparticles: synthesis, characterization, and anticancer activity in vitro.

    PubMed

    Francis, Arul Prakash; Murthy, Prakhya Balakishna; Devas, Thiyagarajan

    2014-07-01

    We have optimized a protocol for the preparation of bisdemethoxy curcumin analog nanoparticles (BDMCA-NP) by the solvent assisted process. The structural similarities between bulk and nano BDMCA were determined by Co-TLC, NMR and F-TIR. This shows that our synthesis protocol enhanced the dispersibility and reduce the size of BDMCA without altering the integrity of functional moieties and structure, which is crucial for anticancer and antioxidant activities. The morphology and size of BDMCA-NP as determined by SEM, HRTEM and DLS was found to be around 80 nm. BDMCA-NP treated breast cancer cell lines (MCF 7) showed cell death as characterized by MTT assay. Flow cytometric analysis of BDMCA-NP treated MCF 7 cell lines showed an increase of cell count in G2/M phase indicates the cell cycle arrest. Western blot analysis revealed the presence of caspase 3, caspase 9, cleaved fragments of PARP and Bax proteins in the BDMCA-NP treated MCF 7 cell lines, but not in untreated cell lines. To recap, we have prepared BDMCA-NP by solvent assisted process, which exerted anticancer activity against breast cancer cells, which may be due to (i) enhanced dispersibility and surface: volume ratio, (ii) apoptosis (iii) mitochondrial pathway induced cell death, (iv) G2/M phase cell cycle arrest and (v) disassembly of mitotic spindle of the cancer cells. Thus, nano BDMCA can be used as a potent anticancer agent. PMID:24757955

  10. Anticancer potential of selected Fallopia Adans species

    PubMed Central

    OLARU, OCTAVIAN TUDOREL; VENABLES, LUANNE; VAN DE VENTER, MARYNA; NITULESCU, GEORGE MIHAI; MARGINA, DENISA; SPANDIDOS, DEMETRIOS A.; TSATSAKIS, ARISTIDIS M.

    2015-01-01

    The aim of the present study was to determine the anticancer potential of three species belonging to the Fallopia genus (Polygonaceae): Fallopia convolvulus (F. convolvulus, Fallopia dumetorum (F. dumetorum) and Fallopia aubertii (F. aubertii). For this purpose, crude extracts were obtained and characterized for their phenolic and flavonoid total content and examined for their anticancer activity on three tumor cell lines: breast cancer (MCF7), colon carcinoma (Caco-2) and cervical cancer (HeLa) cells. The cytotoxic potential of the three species was assessed by MTT assay, cell cycle analysis and by the evaluation of mitochondrial membrane potential (MMP). The acute toxicity of the extracts was evaluated using one in vitro cell model (Vero cells, an African Green monkey kidney cell line) and two invertebrate in vivo models (Daphnia magna and Artemia salina). The highest total phenolic and flavonoid content was found in the F. aubertii flower extracts. The cytotoxic effects of the extracts from F. aubertii and F. convolvulus on all three cell lines were examined at concentrations ranging from 3 to 300 µg/ml. G2/M cell cycle arrest was induced by all the extracts, and a significant increase in the subG1 cell population was observed. The hydroethanolic extract from the flowers of F. aubertii induced cell apoptosis more rapidly than the other extracts. The MMP indicates the involvement of the mitochondria in the induction of apoptosis. A positive correlation between the total phenolic content of the extracts and the IC50 values against the HeLa cells was also noted. None of the extracts exhibited significantly toxic effects. Considering the antitumor potential of F. aubertii and F. convolvulus, these two species may represent a good source of plant extracts with anticancer properties. PMID:26622671

  11. Mitosis-targeted anti-cancer therapies: where they stand

    PubMed Central

    Chan, K-S; Koh, C-G; Li, H-Y

    2012-01-01

    The strategy of clinically targeting cancerous cells at their most vulnerable state during mitosis has instigated numerous studies into the mitotic cell death (MCD) pathway. As the hallmark of cancer revolves around cell-cycle deregulation, it is not surprising that antimitotic therapies are effective against the abnormal proliferation of transformed cells. Moreover, these antimitotic drugs are also highly selective and sensitive. Despite the robust rate of discovery and the development of mitosis-selective inhibitors, the unpredictable complexities of the human body's response to these drugs still herald the biggest challenge towards clinical success. Undoubtedly, the need to bridge the gap between promising preclinical trials and effective translational bedside treatment prompts further investigations towards mapping out the mechanistic pathways of MCD, understanding how these drugs work as medicine in the body and more comprehensive target validations. In this review, current antimitotic agents are summarized with particular emphasis on the evaluation of their clinical efficacy as well as their limitations. In addition, we discuss the basis behind the lack of activity of these inhibitors in human trials and the potential and future directions of mitotic anticancer strategies. PMID:23076219

  12. 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.

  13. Anticancer potential of curcumin: preclinical and clinical studies.

    PubMed

    Aggarwal, Bharat B; Kumar, Anushree; Bharti, Alok C

    2003-01-01

    Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF-kappa B, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies. PMID:12680238

  14. Gamma irradiation reduces the immunological toxicity of doxorubicin, anticancer drug

    NASA Astrophysics Data System (ADS)

    Kim, Jae-Hun; Sung, Nak-Yun; Raghavendran, H. Balaji; Yoon, Yohan; Song, Beom-Seok; Choi, Jong-il; Yoo, Young-Choon; Byun, Myung-Woo; Hwang, Young-Jeong; Lee, Ju-Woon

    2009-07-01

    Doxorubicin (DOX) is a widely used anticancer agent, but exhibits some immunological toxicity to patients during chemotherapy. The present study was conducted to evaluate the effect of gamma irradiation on the immunological response and the inhibition activity on in vivo tumor mass of DOX. The results showed that DOX irradiated at 10 and 20 kGy reduce the inhibition of mouse peritoneal macrophage proliferation and induce the release of cytokines (TNF-? and IL-6) when compared with non-irradiated DOX. The cytotoxicity against human breast (MCF-7), murine colon adenocarcinoma (Colon 26) and human monocytic (THP-1) tumor cell were not significantly different between non-irradiated and irradiated DOX ( P<0.05). In vivo study on the tumor mass inhibition, gamma-irradiated DOX showed a considerable inhibition of tumor mass and this effect was statistically non-significant as compared with non-irradiated DOX. In conclusion, gamma irradiation could be regarded as a potential method for reducing the immunological toxicity of DOX. Further researches is needed to reveal the formation and activity of radiolysis products by gamma irradiation.

  15. Optical Interferometric Response of Living Tissue to Cytoskeletal Anticancer Drugs

    NASA Astrophysics Data System (ADS)

    Nolte, David; Jeong, Kwan; Turek, John

    2007-03-01

    Living tissue illuminated by short-coherence light can be optically sectioned in three dimensions using coherent detection such as interferometry. We have developed full-field coherence-gated imaging of tissue using digital holography. Two-dimensional image sections from a fixed depth are recorded as interference fringes with a CCD camera located at the optical Fourier plane. Fast Fourier transform of the digital hologram yields the depth-selected image. When the tissue is living, highly dynamic speckle is observed as fluctuating pixel intensities. The temporal autocorrelation functions are directly related to the degree of motility at depth. We have applied the cytoskeletal drugs nocodazole and colchicine to osteogenic sarcoma multicellular spheroids and observed the response holographically. Colchicine is an anticancer drug that inhibits microtubule polymerization and hence prevents spindle formation during mitosis. Nocodazole, on the other hand, depolymerizes microtubules. Both drugs preferentially inhibit rapidly-dividing cancer cells. We observe dose-response using motility as an effective contrast agent. This work opens the possibility for studies of three-dimensional motility as a multiplexed assay for drug discovery.

  16. Tetrandrine enhances the anticancer effects of arsenic trioxide in vitro.

    PubMed

    Chen, Youran; Li, Peichun; Yang, Shen; Tong, Nannan; Zhang, Jie; Zhao, Xiaoyan

    2014-05-01

    Arsenic trioxide (As2O3), an effective agent to treat leukemia and other solid tumors, is largely limited by its toxicity. QT prolongation, torsades de pointes and sudden death have been implicated in the cardiotoxicity of As2O3. The present study was designed to assess whether the combination of As2O3 and tetrandrine could generate a more powerful anti-cancer effect. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed for detecting the proliferation of HepG2 and A549 cells treated with tetrandrine and As2O3. Fluorescent microscopy measurements and flow cytometry were carried out to evaluate the apoptosis in HepG2 cells. The cell cycle arrest of HepG2 cells was also determined by flow cytometry. The cell proliferation assay in HepG2 and A549 cells indicated that tetrandrine significantly enhanced the inhibit effect of As2O3. In addition, the following Isobolograms further demonstrated that combining As2O3 with tetrandrine generated synergism action. Tetrandrine also enhanced the apoptosis, necrosis and cell cycle arrest in As2O3-treated HepG2 cells. Our present study showed that tetrandrine can dramatically enhance the anti- cancer effect induced by As2O3. Combining As2O3 with tetrandrine would be a novel strategy to treat cancer in clinical practice. PMID:24548979

  17. Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics.

    PubMed

    Law, Mary E; Corsino, Patrick E; Narayan, Satya; Law, Brian K

    2015-11-01

    Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATP-competitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATP-competitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer. PMID:26018905

  18. Anticancer activity of essential oils: a review.

    PubMed

    Bhalla, Yashika; Gupta, Vinay Kumar; Jaitak, Vikas

    2013-12-01

    Natural essential oil constituents play an important role in cancer prevention and treatment. Essential oil constituents from aromatic herbs and dietary plants include monoterpenes, sesquiterpenes, oxygenated monoterpenes, oxygenated sesquiterpenes and phenolics among others. Various mechanisms such antioxidant, antimutagenic and antiproliferative, enhancement of immune function and surveillance, enzyme induction and enhancing detoxification, modulation of multidrug resistance and synergistic mechanism of volatile constituents are responsible for their chemopreventive properties. This review covers the most recent literature to summarize structural categories and molecular anticancer mechanisms of constituents from aromatic herbs and dietary plants. PMID:23765679

  19. Potential anticancer activity of carvone in N2a neuroblastoma cell line.

    PubMed

    Ayd?n, Elanur; Türkez, Hasan; Kele?, Mevlüt Sait

    2015-08-01

    Carvone (CVN) is a monocyclic monoterpene found in the essential oils of Mentha spicata var. crispa (Lamiaceae) and Carum carvi L. (Apiaceae) plants and has been reported to have antioxidant, antimicrobial, anticonvulsant, and antitumor activities. The beneficial health properties of CVN have encouraged us to look into its anticancer activity. To the best of our knowledge, reports are not available on the anticancer activity of CVN in cultured primary rat neuron and N2a neuroblastoma (NB) cells. Therefore, the present study is an attempt toward exploring the potential anticancer activity of CVN, if any, in cultured primary rat neuron and N2a NB cells. Our results indicated that CVN (only at 25 mg/L) treatment led to an increase in the total antioxidant capacity levels in cultured primary rat neuron cells compared with control cells. Also, CVN (at concentrations higher than 100 mg/L) treatment led to an increase in the total oxidative stress levels in both cell types. The mean values of the total scores of cells showing DNA damage (for comet assay) were not found to be significantly different from the control values in both cells (p > 0.05). On the other hand, after 24 h treatment with CVN, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay showed that CVN application significantly reduced the cell viability rates in both cell types at concentrations higher than 100 mg/L. Summarizing, our data suggest that CVN represents little potential for promising anticancer agent to improve brain tumors therapy. PMID:23552268

  20. Phloretin exhibits an anticancer effect and enhances the anticancer ability of cisplatin on non-small cell lung cancer cell lines by regulating expression of apoptotic pathways and matrix metalloproteinases.

    PubMed

    Ma, Lijie; Wang, Ruixuan; Nan, Yandong; Li, Wangping; Wang, Qingwei; Jin, Faguang

    2016-02-01

    Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancer cases and the prognosis of NSCLC patients is unsatisfactory since 5-year survival rate of NSCLC is still as low as 11%. Natural compounds derived from plants with few or no side effects have been recognized as alternative or auxiliary cure for cancer patients. Phloretin is such an agent possessing various pharmacological activities; however, there is scarce information on its anticancer effects on NSCLC. It was evaluated and confirmed, in the present study, that phloretin inhibited proliferation and induced apoptosis in A549, Calu-1, H838 and H520 cells in a dose-dependent manner, phloretin also suppressed the invasion and migration of NSCLC cells. We further confirmed that phloretin dose-dependently suppressed the expression of Bcl-2, increased the protein expression of cleaved-caspase-3 and -9, and deregulated the expression of matrix metalloproteinases (MMP)-2 and -9 on gene and protein levels. Besides, evaluations revealed that phloretin enhanced the anticancer effects of cisplatin on inhibition of proliferation and induction of apoptosis in NSCLC cells. Moreover, phloretin facilitated the effects of cisplatin on deregulation of Bcl-2, MMP-2 and -9, and upregulation of cleaved-caspase-3 and -9. In conclusion, the present study demonstrated that phloretin possessed anticancer effects and enhanced the anticancer effects of cisplatin on NSCLC cell lines by suppressing proliferation, inducing apoptosis and inhibiting invasion and migration of the cells through regulating apoptotic pathways and MMPs. PMID:26692364

  1. Ruthenium complexes as antimicrobial agents.

    PubMed

    Li, Fangfei; Collins, J Grant; Keene, F Richard

    2015-04-21

    One of the major advances in medical science has been the development of antimicrobials; however, a consequence of their widespread use has been the emergence of drug-resistant populations of microorganisms. There is clearly a need for the development of new antimicrobials--but more importantly, there is the need for the development of new classes of antimicrobials, rather than drugs based upon analogues of known scaffolds. Due to the success of the platinum anticancer agents, there has been considerable interest in the development of therapeutic agents based upon other transition metals--and in particular ruthenium(II/III) complexes, due to their well known interaction with DNA. There have been many studies of the anticancer properties and cellular localisation of a range of ruthenium complexes in eukaryotic cells over the last decade. However, only very recently has there been significant interest in their antimicrobial properties. This review highlights the types of ruthenium complexes that have exhibited significant antimicrobial activity and discusses the relationship between chemical structure and biological processing--including site(s) of intracellular accumulation--of the ruthenium complexes in both bacterial and eukaryotic cells. PMID:25724019

  2. ATP-triggered anticancer drug delivery

    NASA Astrophysics Data System (ADS)

    Mo, Ran; Jiang, Tianyue; Disanto, Rocco; Tai, Wanyi; Gu, Zhen

    2014-03-01

    Stimuli-triggered drug delivery systems have been increasingly used to promote physiological specificity and on-demand therapeutic efficacy of anticancer drugs. Here we utilize adenosine-5'-triphosphate (ATP) as a trigger for the controlled release of anticancer drugs. We demonstrate that polymeric nanocarriers functionalized with an ATP-binding aptamer-incorporated DNA motif can selectively release the intercalating doxorubicin via a conformational switch when in an ATP-rich environment. The half-maximal inhibitory concentration of ATP-responsive nanovehicles is 0.24??M in MDA-MB-231 cells, a 3.6-fold increase in the cytotoxicity compared with that of non-ATP-responsive nanovehicles. Equipped with an outer shell crosslinked by hyaluronic acid, a specific tumour-targeting ligand, the ATP-responsive nanocarriers present an improvement in the chemotherapeutic inhibition of tumour growth using xenograft MDA-MB-231 tumour-bearing mice. This ATP-triggered drug release system provides a more sophisticated drug delivery system, which can differentiate ATP levels to facilitate the selective release of drugs.

  3. PEGylated Silk Nanoparticles for Anticancer Drug Delivery.

    PubMed

    Wongpinyochit, Thidarat; Uhlmann, Petra; Urquhart, Andrew J; Seib, F Philipp

    2015-11-01

    Silk has a robust clinical track record and is emerging as a promising biopolymer for drug delivery, including its use as nanomedicine. However, silk-based nanomedicines still require further refinements for full exploitation of their potential; the application of "stealth" design principals is especially necessary to support their evolution. The aim of this study was to develop and examine the potential of PEGylated silk nanoparticles as an anticancer drug delivery system. We first generated B. mori derived silk nanoparticles by driving ?-sheet assembly (size 104 ± 1.7 nm, zeta potential -56 ± 5.6 mV) using nanoprecipitation. We then surface grafted polyethylene glycol (PEG) to the fabricated silk nanoparticles and verified the aqueous stability and morphology of the resulting PEGylated silk nanoparticles. We assessed the drug loading and release behavior of these nanoparticles using clinically established and emerging anticancer drugs. Overall, PEGylated silk nanoparticles showed high encapsulation efficiency (>93%) and a pH-dependent release over 14 days. Finally, we demonstrated significant cytotoxicity of drug loaded silk nanoparticles applied as single and combination nanomedicines to human breast cancer cells. In conclusion, these results, taken together with prior silk nanoparticle data, support a viable future for silk-based nanomedicines. PMID:26418537

  4. Evaluating Medicinal Plants for Anticancer Activity

    PubMed Central

    Solowey, Elisha; Lichtenstein, Michal; Sallon, Sarah; Paavilainen, Helena; Solowey, Elaine; Lorberboum-Galski, Haya

    2014-01-01

    Plants have been used for medical purposes since the beginning of human history and are the basis of modern medicine. Most chemotherapeutic drugs for cancer treatment are molecules identified and isolated from plants or their synthetic derivatives. Our hypothesis was that whole plant extracts selected according to ethnobotanical sources of historical use might contain multiple molecules with antitumor activities that could be very effective in killing human cancer cells. This study examined the effects of three whole plant extracts (ethanol extraction) on human tumor cells. The extracts were from Urtica membranacea (Urticaceae), Artemesia monosperma (Asteraceae), and Origanum dayi post (Labiatae). All three plant extracts exhibited dose- and time-dependent killing capabilities in various human derived tumor cell lines and primary cultures established from patients' biopsies. The killing activity was specific toward tumor cells, as the plant extracts had no effect on primary cultures of healthy human cells. Cell death caused by the whole plant extracts is via apoptosis. Plant extract 5 (Urtica membranacea) showed particularly strong anticancer capabilities since it inhibited actual tumor progression in a breast adenocarcinoma mouse model. Our results suggest that whole plant extracts are promising anticancer reagents. PMID:25478599

  5. Investigating the optimal size of anticancer nanomedicine.

    PubMed

    Tang, Li; Yang, Xujuan; Yin, Qian; Cai, Kaimin; Wang, Hua; Chaudhury, Isthier; Yao, Catherine; Zhou, Qin; Kwon, Mincheol; Hartman, James A; Dobrucki, Iwona T; Dobrucki, Lawrence W; Borst, Luke B; Lezmi, Stéphane; Helferich, William G; Ferguson, Andrew L; Fan, Timothy M; Cheng, Jianjun

    2014-10-28

    Nanomedicines (NMs) offer new solutions for cancer diagnosis and therapy. However, extension of progression-free interval and overall survival time achieved by Food and Drug Administration-approved NMs remain modest. To develop next generation NMs to achieve superior anticancer activities, it is crucial to investigate and understand the correlation between the physicochemical properties of NMs (particle size in particular) and their interactions with biological systems to establish criteria for NM optimization. Here, we systematically evaluated the size-dependent biological profiles of three monodisperse drug-silica nanoconjugates (NCs; 20, 50, and 200 nm) through both experiments and mathematical modeling and aimed to identify the optimal size for the most effective anticancer drug delivery. Among the three NCs investigated, the 50-nm NC shows the highest tumor tissue retention integrated over time, which is the collective outcome of deep tumor tissue penetration and efficient cancer cell internalization as well as slow tumor clearance, and thus, the highest efficacy against both primary and metastatic tumors in vivo. PMID:25316794

  6. Investigating the optimal size of anticancer nanomedicine

    PubMed Central

    Tang, Li; Yang, Xujuan; Yin, Qian; Cai, Kaimin; Wang, Hua; Chaudhury, Isthier; Yao, Catherine; Zhou, Qin; Kwon, Mincheol; Hartman, James A.; Dobrucki, Iwona T.; Dobrucki, Lawrence W.; Borst, Luke B.; Lezmi, Stéphane; Helferich, William G.; Ferguson, Andrew L.; Fan, Timothy M.; Cheng, Jianjun

    2014-01-01

    Nanomedicines (NMs) offer new solutions for cancer diagnosis and therapy. However, extension of progression-free interval and overall survival time achieved by Food and Drug Administration-approved NMs remain modest. To develop next generation NMs to achieve superior anticancer activities, it is crucial to investigate and understand the correlation between the physicochemical properties of NMs (particle size in particular) and their interactions with biological systems to establish criteria for NM optimization. Here, we systematically evaluated the size-dependent biological profiles of three monodisperse drug–silica nanoconjugates (NCs; 20, 50, and 200 nm) through both experiments and mathematical modeling and aimed to identify the optimal size for the most effective anticancer drug delivery. Among the three NCs investigated, the 50-nm NC shows the highest tumor tissue retention integrated over time, which is the collective outcome of deep tumor tissue penetration and efficient cancer cell internalization as well as slow tumor clearance, and thus, the highest efficacy against both primary and metastatic tumors in vivo. PMID:25316794

  7. Detection of Alkylating Agents using Electrical and Mechanical Means

    NASA Astrophysics Data System (ADS)

    Gerchikov, Yulia; Borzin, Elena; Gannot, Yair; Shemesh, Ariel; Meltzman, Shai; Hertzog-Ronen, Carmit; Tal, Shay; Stolyarova, Sara; Nemirovsky, Yael; Tessler, Nir; Eichen, Yoav

    2011-08-01

    Alkylating agents are reactive molecules having at least one polar bond between a carbon atom and a good leaving group. These often simple molecules are frequently used in organic synthesis, as sterilizing agents in agriculture and even as anticancer agents in medicine. Unfortunately, for over a century, some of the highly reactive alkylating agents are also being used as blister chemical warfare agents. Being relatively simple to make, the risk is that these will be applied by terrorists as poor people warfare agents. The detection and identification of such alkylating agents is not a simple task because of their high reactivity and simple structure of the reactive site. Here we report on new approaches to the detection and identification of such alkylating agents using electrical (organic field effect transistors) and mechanical (microcantilevers) means.

  8. Biological Agents

    MedlinePLUS

    ... Statistics Training Publications Newsroom Small Business Anti-Retaliation Biological Agents This page requires that javascript be enabled ... and Health Topics A-Z Index What's New Biological agents include bacteria, viruses, fungi, other microorganisms and ...

  9. Combined bacterial and viral treatment: a novel anticancer strategy

    PubMed Central

    2015-01-01

    An idea for a new combination therapy will be described herein. It is a proposition to combine viral and bacterial anticancer therapies and make them fight cancer in concert. We analyzed biological anticancer therapies and found overlapping advantages and disadvantages which led us to the conclusion that the combination therapy has the potential to create a new therapeutic quality. It is surprising how many weaknesses of viral anticancer therapy are the strengths of bacterial anticancer therapies and the other way round. We review the facts behind this concept and try to assess its value. We propose a few strategies how to combine these two therapies but as far as the review can go, final answers will have to come from the experiments. This review is the first attempt to describe a new strategy and understand the means for this idea but also to raise new questions and discuss new ways to look at anti-cancer treatment. PMID:26648783

  10. Combining emerging agents in advanced breast cancer.

    PubMed

    Luu, Thehang; Chung, Cathie; Somlo, George

    2011-01-01

    Newer treatments have improved survival for patients with metastatic breast cancer over the last two decades, and a battery of new cytotoxic and targeted therapies is continuing to enhance this trend. This review outlines recent data and ongoing research in this area, by highlighting new developments (regarding approved but relatively new classes of cytotoxic and targeted agents) and also new classes of targeted therapy that are undergoing clinical evaluation. Mechanisms for synergy between agents are discussed where data are available, as is information on the rationale behind the development of agents that inhibit angiogenesis, DNA repair, histone deacetylases, heat shock proteins, or various signaling pathways in tumor proliferation. The abundance of clinical research surrounding anticancer agents, together with ongoing cancer biology research, is expected to further increase the available pool of therapeutic options for metastatic breast cancer. Concomitantly, in the absence of an effective targeted monotherapy, a better understanding of the interplay between biologic and cytotoxic anticancer agents will improve our ability to rationally design combination regimens with better efficacy and tolerability. PMID:21543509

  11. Combining Emerging Agents in Advanced Breast Cancer

    PubMed Central

    Chung, Cathie

    2011-01-01

    Newer treatments have improved survival for patients with metastatic breast cancer over the last two decades, and a battery of new cytotoxic and targeted therapies is continuing to enhance this trend. This review outlines recent data and ongoing research in this area, by highlighting new developments (regarding approved but relatively new classes of cytotoxic and targeted agents) and also new classes of targeted therapy that are undergoing clinical evaluation. Mechanisms for synergy between agents are discussed where data are available, as is information on the rationale behind the development of agents that inhibit angiogenesis, DNA repair, histone deacetylases, heat shock proteins, or various signaling pathways in tumor proliferation. The abundance of clinical research surrounding anticancer agents, together with ongoing cancer biology research, is expected to further increase the available pool of therapeutic options for metastatic breast cancer. Concomitantly, in the absence of an effective targeted monotherapy, a better understanding of the interplay between biologic and cytotoxic anticancer agents will improve our ability to rationally design combination regimens with better efficacy and tolerability. PMID:21543509

  12. Anticancer therapeutic potential of Mn porphyrin/ascorbate system.

    PubMed

    Tovmasyan, Artak; Sampaio, Romulo S; Boss, Mary-Keara; Bueno-Janice, Jacqueline C; Bader, Bader H; Thomas, Milini; Reboucas, Julio S; Orr, Michael; Chandler, Joshua D; Go, Young-Mi; Jones, Dean P; Venkatraman, Talaignair N; Haberle, Sinisa; Kyui, Natalia; Lascola, Christopher D; Dewhirst, Mark W; Spasojevic, Ivan; Benov, Ludmil; Batinic-Haberle, Ines

    2015-12-01

    Ascorbate (Asc) as a single agent suppressed growth of several tumor cell lines in a mouse model. It has been tested in a Phase I Clinical Trial on pancreatic cancer patients where it exhibited no toxicity to normal tissue yet was of only marginal efficacy. The mechanism of its anticancer effect was attributed to the production of tumoricidal hydrogen peroxide (H2O2) during ascorbate oxidation catalyzed by endogenous metalloproteins. The amount of H2O2 could be maximized with exogenous catalyst that has optimized properties for such function and is localized within tumor. Herein we studied 14 Mn porphyrins (MnPs) which differ vastly with regards to their redox properties, charge, size/bulkiness and lipophilicity. Such properties affect the in vitro and in vivo ability of MnPs (i) to catalyze ascorbate oxidation resulting in the production of H2O2; (ii) to subsequently employ H2O2 in the catalysis of signaling proteins oxidations affecting cellular survival pathways; and (iii) to accumulate at site(s) of interest. The metal-centered reduction potential of MnPs studied, E1/2 of Mn(III)P/Mn(II)P redox couple, ranged from -200 to +350mV vs NHE. Anionic and cationic, hydrophilic and lipophilic as well as short- and long-chained and bulky compounds were explored. Their ability to catalyze ascorbate oxidation, and in turn cytotoxic H2O2 production, was explored via spectrophotometric and electrochemical means. Bell-shape structure-activity relationship (SAR) was found between the initial rate for the catalysis of ascorbate oxidation, vo(Asc)ox and E1/2, identifying cationic Mn(III) N-substituted pyridylporphyrins with E1/2>0mV vs NHE as efficient catalysts for ascorbate oxidation. The anticancer potential of MnPs/Asc system was subsequently tested in cellular (human MCF-7, MDA-MB-231 and mouse 4T1) and animal models of breast cancer. At the concentrations where ascorbate (1mM) and MnPs (1 or 5µM) alone did not trigger any alteration in cell viability, combined treatment suppressed cell viability up to 95%. No toxicity was observed with normal human breast epithelial HBL-100 cells. Bell-shape relationship, essentially identical to vo(Asc)oxvs E1/2, was also demonstrated between MnP/Asc-controlled cytotoxicity and E1/2-controlled vo(Asc)ox. Magnetic resonance imaging studies were conducted to explore the impact of ascorbate on T1-relaxivity. The impact of MnP/Asc on intracellular thiols and on GSH/GSSG and Cys/CySS ratios in 4T1 cells was assessed and cellular reduction potentials were calculated. The data indicate a significant increase in cellular oxidative stress induced by MnP/Asc. Based on vo(Asc)oxvs E1/2 relationships and cellular toxicity, MnTE-2-PyP(5+) was identified as the best catalyst among MnPs studied. Asc and MnTE-2-PyP(5+) were thus tested in a 4T1 mammary mouse flank tumor model. The combination of ascorbate (4g/kg) and MnTE-2-PyP(5+) (0.2mg/kg) showed significant suppression of tumor growth relative to either MnTE-2-PyP(5+) or ascorbate alone. About 7-fold higher accumulation of MnTE-2-PyP(5+) in tumor vs normal tissue was found to contribute largely to the anticancer effect. PMID:26496207

  13. Gut microbiome and anticancer immune response: really hot Sh*t!

    PubMed

    Viaud, S; Daillère, R; Boneca, I G; Lepage, P; Langella, P; Chamaillard, M; Pittet, M J; Ghiringhelli, F; Trinchieri, G; Goldszmid, R; Zitvogel, L

    2015-02-01

    The impact of gut microbiota in eliciting innate and adaptive immune responses beneficial for the host in the context of effective therapies against cancer has been highlighted recently. Chemotherapeutic agents, by compromising, to some extent, the intestinal integrity, increase the gut permeability and selective translocation of Gram-positive bacteria in secondary lymphoid organs. There, anticommensal pathogenic Th17 T-cell responses are primed, facilitating the accumulation of Th1 helper T cells in tumor beds after chemotherapy as well as tumor regression. Importantly, the redox equilibrium of myeloid cells contained in the tumor microenvironment is also influenced by the intestinal microbiota. Hence, the anticancer efficacy of alkylating agents (such as cyclophosphamide) and platinum salts (oxaliplatin, cis-platin) is compromised in germ-free mice or animals treated with antibiotics. These findings represent a paradigm shift in our understanding of the mode of action of many compounds having an impact on the host-microbe mutualism. PMID:24832470

  14. Anticancer activity of Aristolochia ringens Vahl. (Aristolochiaceae)

    PubMed Central

    Akindele, Abidemi James; Wani, Zahoor; Mahajan, Girish; Sharma, Sadhana; Aigbe, Flora Ruth; Satti, Naresh; Adeyemi, Olufunmilayo Olaide; Mondhe, Dilip Manikrao

    2014-01-01

    Cancer is a leading cause of death worldwide and sustained focus is on the discovery and development of newer and better tolerated anticancer drugs especially from plants. The sulforhodamine B (SRB) in vitro cytotoxicity assay, sarcoma-180 (S-180) ascites and solid tumor, and L1210 lymphoid leukemia in vivo models were used to investigate the anticancer activity of root extracts of Aristolochia ringens Vahl. (Aristolochiaceae; ??? m? d?u líng). AR-A001 (IC50 values of 20 ?g/mL, 22 ?g/mL, 3 ?g/mL, and 24 ?g/mL for A549, HCT-116, PC3, and THP-1 cell lines, respectively), and AR-A004 (IC50 values of 26 ?g/mL, 19.5 ?g/mL, 12 ?g/mL, 28 ?g/mL, 30 ?g/mL, and 22 ?g/mL for A549, HCT-116, PC3, A431, HeLa, and THP-1, respectively), were observed to be significantly active in vitro. Potency was highest with AR-A001 and AR-A004 for PC3 with IC50 values of 3 ?g/mL and 12 ?g/mL, respectively. AR-A001 and AR-A004 produced significant (p < 0.05–0.001) dose-dependent inhibition of tumor growth in the S-180 ascites model with peak effects produced at the highest dose of 120 mg/kg. Inhibition values were 79.51% and 89.98% for AR-A001 and AR-A004, respectively. In the S-180 solid tumor model, the inhibition of tumor growth was 29.45% and 50.50% for AR-A001 (120 mg/kg) and AR-A004 (110 mg/kg), respectively, compared to 50.18% for 5-fluorouracil (5-FU; 20 mg/kg). AR-A001 and AR-A004 were also significantly active in the leukemia model with 211.11% and 155.56% increase in mean survival time (MST) compared to a value of 211.11% for 5-FU. In conclusion, the ethanolic (AR-A001) and dichloromethane:methanol (AR-A004) root extracts of AR possess significant anticancer activities in vitro and in vivo. PMID:26151007

  15. Oral nano-delivery of anticancer ginsenoside 25-OCH3-PPD, a natural inhibitor of the MDM2 oncogene: Nanoparticle preparation, characterization, in vitro and in vivo anti-prostate cancer activity, and mechanisms of action

    PubMed Central

    Sarkar, Sushanta; Nag, Subhasree; Walbi, Ismail A.; Wang, Shu; Zhao, Yuqing; Wang, Wei; Zhang, Ruiwen

    2015-01-01

    The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the efficiency of MDM2 targeting, anticancer efficacy, pharmacokinetics, and safety were evaluated in in vitro and in vivo models of human prostate cancer. Our results indicated that, compared with the unencapsulated GS25, GS25NP demonstrated better MDM2 inhibition, improved oral bioavailability and enhanced in vitro and in vivo activities. In conclusion, the validated nano-formulation for GS25 oral delivery improves its molecular targeting, oral bioavailability and anticancer efficacy, providing a basis for further development of GS25 as a novel agent for cancer therapy and prevention. PMID:26041888

  16. Therapeutic aptamers: developmental potential as anticancer drugs

    PubMed Central

    Lee, Ji Won; Kim, Hyun Jung; Heo, Kyun

    2015-01-01

    Aptamers, composed of single-stranded DNA or RNA oligonucleotides that interact with target molecules through a specific three-dimensional structure, are selected from pools of combinatorial oligonucleotide libraries. With their high specificity and affinity for target proteins, ease of synthesis and modification, and low immunogenicity and toxicity, aptamers are considered to be attractive molecules for development as anticancer therapeutics. Two aptamers - one targeting nucleolin and a second targeting CXCL12 - are currently undergoing clinical trials for treating cancer patients, and many more are under study. In this mini-review, we present the current clinical status of aptamers and aptamer-based cancer therapeutics. We also discuss advantages, limitations, and prospects for aptamers as cancer therapeutics. [BMB Reports 2015; 48(4): 234-237] PMID:25560701

  17. Nanocarriers for delivery of platinum anticancer drugs?

    PubMed Central

    Oberoi, Hardeep S.; Nukolova, Natalia V.; Kabanov, Alexander V.; Bronich, Tatiana K.

    2014-01-01

    Platinum based anticancer drugs have revolutionized cancer chemotherapy, and continue to be in widespread clinical use especially for management of tumors of the ovary, testes, and the head and neck. However, several dose limiting toxicities associated with platinum drug use, partial anti-tumor response in most patients, development of drug resistance, tumor relapse, and many other challenges have severely limited the patient quality of life. These limitations have motivated an extensive research effort towards development of new strategies for improving platinum therapy. Nanocarrier-based delivery of platinum compounds is one such area of intense research effort beginning to provide encouraging preclinical and clinical results and may allow the development of the next generation of platinum chemotherapy. This review highlights current understanding on the pharmacology and limitations of platinum compounds in clinical use, and provides a comprehensive analysis of various platinum–polymer complexes, micelles, dendrimers, liposomes and other nanoparticles currently under investigation for delivery of platinum drugs. PMID:24113520

  18. Functional vesicles formed by anticancer drug assembly.

    PubMed

    Zhu, Wenjun; Fang, Shuo; Zhang, Yemin; Li, Xinsong

    2015-01-15

    In this Letter, a new type of nitrogen mustard conjugate vesicles is developed to improve the stability and efficiency of anticancer drug. Benzoic acid nitrogen mustard-peptide (AAAK) conjugate was designed and synthesized, which was found to self-assemble into vesicles in water. The formation of the vesicles was confirmed by dynamic light scattering (DLS), transmission electron microscopy (TEM) and circular dichroism (CD). The degradation data revealed that the benzoic acid nitrogen mustard peptide (AAAK) conjugate vesicles are more stable than the parent drug in aqueous solution. Furthermore, MTT assay revealed that the free drug conjugate has similar antitumor activity against MCF-7, Hela, HepG-2 cell lines compared with the parent drug. The benzoic acid nitrogen mustard-peptide conjugate vesicles may have potential in the treatment of cancers. PMID:25515557

  19. Mechanisms of the Anticancer Effects of Isothiocyanates.

    PubMed

    Fofaria, Neel M; Ranjan, Alok; Kim, Sung-Hoon; Srivastava, Sanjay K

    2015-01-01

    Cancer results from aberrant signaling pathways that result in uncontrolled cellular proliferation. The epidemiological studies have shown a strong inverse correlation between dietary consumption of cruciferous vegetables and incidences of cancer. Isothiocyanates (ITCs) are present in cruciferous vegetables like broccoli, cabbage, watercress, etc. and are identified as the major active constituents. Several mechanistic studies have demonstrated chemopreventive and chemotherapeutic activity of ITCs against various tumor types. ITCs exert anticancer activity by suppressing various critical hallmarks of cancer like cellular proliferation, angiogenesis, apoptosis, metastasis, etc., in vitro as well as in preclinical animal model. ITCs also generate reactive oxygen species to induce apoptosis in cancer cells. Due to promising preclinical results, few ITCs have also advanced to clinical trials. This chapter provides a candid review on the chemopreventive and chemotherapeutic activity of various major ITCs. PMID:26298458

  20. New Norcantharidin Analogs: Synthesis and Anticancer Activity.

    PubMed

    Pachuta-Stec, Anna; Szuster-Ciesielska, Agnieszka

    2015-12-01

    The reaction of direct condensation between S-ethyl-N-(7-oxabicyclo-[2.2.1]heptane-2,3-dicarbonyl)isothiosemicarbazide (1) and primary amines was used for synthesizing new N-substituted amides of 3-(3-ethylthio-1,2,4-triazol-5-yl)-7-oxabicyclo-[2.2.1]heptane-2-carboxylic acid (2-12) as norcantharadin analogs. Moreover, the anticancer activity of the obtained compounds was studied. Among all compounds, the N-3-methylbutyl amide of 3-(3-ethylthio-1,2,4-triazol-5-yl)-7-oxabicyclo-[2.2.1]heptane-2-carboxylic acid (4) presented selective in vitro toxic and antiproliferative effects against the human hepatoma cell line Hep3B, without affecting normal human liver stellate cells (LX-2 cell line). PMID:26548647

  1. 21st International Congress on Anticancer Treatment.

    PubMed

    Magné, Nicolas; Pacaut, Cécile; Chargari, Cyrus

    2010-05-01

    The 21st International Congress on Anticancer Treatment, endorsed by the American Society of Clinical Oncology, was held in Paris (France) 1-5 February 2010. It was led and jointly sponsored by Gabriel Hortobagyi and David Khayat and by the University of Texas MD Anderson Cancer Center (TX, USA) and the Hôpital de la Pitié Salpêtrière (Paris, France), respectively. The meeting provided complete updates and innovations in the management of various cancers and supportive care. This well-recognized annual international educational and scientific conference brought together the leading scientists from across the world to share their skills and expertise by participating in this high-quality meeting. This congress provides an exceptional opportunity to meet with fellow professionals and discuss new educational case studies. In the present article, we have highlighted particularly pertinent sessions concerning hot topics for the new areas of cancer. PMID:20469995

  2. Anticancer Mechanism of Sulfur-Containing Compounds.

    PubMed

    De Gianni, Elena; Fimognari, Carmela

    2015-01-01

    Fruit and vegetables have traditionally represented a main source for the discovery of many biologically active substances with therapeutic values. Among the many bioactive compounds identified over the years, sulfur-containing compounds, which are present especially in the genera Allium and Brassica, have been showing a protective effect against different types of cancer. Many in vitro and in vivo studies reported that apoptosis is crucial for the anticancer effects of sulfur-containing compounds. Garlic and onion compounds and isothiocyanates contained in Brassica vegetables are able to modulate apoptosis by a wide range of mechanisms. This chapter will give an overview on the induction of apoptosis by sulfur-containing compounds in cancer cells and their different molecular mechanisms. Finally, the potential clinical implications of their proapoptotic effects will be discussed. PMID:26298460

  3. Anticancer Properties of Distinct Antimalarial Drug Classes

    PubMed Central

    Hooft van Huijsduijnen, Rob; Guy, R. Kiplin; Chibale, Kelly; Haynes, Richard K.; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A.; Vennerstrom, Jonathan L.; Yuthavong, Yongyuth; Wells, Timothy N. C.

    2013-01-01

    We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings. PMID:24391728

  4. The Conyza triloba extracts with high chlorophyll content and free radical scavenging activity had anticancer activity in cell lines.

    PubMed

    El-Sayed, Wael M; Hussin, Warda A; Mahmoud, Ahmed A; AlFredan, Mohamed A

    2013-01-01

    The discovery of anticancer agents paradigm has been shifted to natural resources to overcome the toxicity of many synthetic agents at early clinical stages. In the present study, the antimutagenic, anticancer, phytochemistry, and free radical scavenging activities of five extracts of Conyza triloba were investigated. Extracts II (water : methanol), III (methylene chloride), and IV (methylene chloride : methanol) had the highest chlorophyll content and the highest superoxide scavenging, and metal chelating activities comparable to that of trolox. They also showed DPPH(•) scavenging activities better than that of ? -tocopherol. Virtually all extracts exerted a strong (>40% reduction) antimutagenic activity against sodium azide and benzopyrene. Extracts II, III, and IV showed a remarkable growth inhibition profile with GI50 of 0.07-0.87 ?g for Hepa1c1c7 and H4IIE1, A549, HT29, and PC3 cell lines and totally abated the growth of all cell lines, except for the breast cells, at 0.3-7.0 ?g. The present study found a strong correlation between the chlorophyll content of Conyza extracts and their DDPH scavenging, metal chelating, and in vitro cytotoxic and cytostatic activities most probably through triggering apoptosis. This study could offer a platform for future studies and help selecting the vital features that identify the extract with potential anticancer activities. PMID:23781512

  5. The Conyza triloba Extracts with High Chlorophyll Content and Free Radical Scavenging Activity Had Anticancer Activity in Cell Lines

    PubMed Central

    El-Sayed, Wael M.; Hussin, Warda A.; Mahmoud, Ahmed A.; AlFredan, Mohamed A.

    2013-01-01

    The discovery of anticancer agents paradigm has been shifted to natural resources to overcome the toxicity of many synthetic agents at early clinical stages. In the present study, the antimutagenic, anticancer, phytochemistry, and free radical scavenging activities of five extracts of Conyza triloba were investigated. Extracts II (water?:?methanol), III (methylene chloride), and IV (methylene chloride?:?methanol) had the highest chlorophyll content and the highest superoxide scavenging, and metal chelating activities comparable to that of trolox. They also showed DPPH• scavenging activities better than that of ?-tocopherol. Virtually all extracts exerted a strong (>40% reduction) antimutagenic activity against sodium azide and benzopyrene. Extracts II, III, and IV showed a remarkable growth inhibition profile with GI50 of 0.07–0.87??g for Hepa1c1c7 and H4IIE1, A549, HT29, and PC3 cell lines and totally abated the growth of all cell lines, except for the breast cells, at 0.3–7.0??g. The present study found a strong correlation between the chlorophyll content of Conyza extracts and their DDPH scavenging, metal chelating, and in vitro cytotoxic and cytostatic activities most probably through triggering apoptosis. This study could offer a platform for future studies and help selecting the vital features that identify the extract with potential anticancer activities. PMID:23781512

  6. Evaluation of Anticancer, Antioxidant, and Possible Anti-inflammatory Properties of Selected Medicinal Plants Used in Indian Traditional Medication

    PubMed Central

    Shaikh, Rafik; Pund, Mahesh; Dawane, Ashwini; Iliyas, Sayyed

    2014-01-01

    The present study was carried out to evaluate the anticancer, antioxidant, and possible anti-inflammatory properties of diverse medicinal plants frequently used in Indian traditional medication. The selected botanicals such as Soymida fembrifuga (Roxb.) A. Juss. (Miliaceae), Tinospora cordifolia (Willd.) Miers. (Menispermaceae), Lavandula bipinnata (L.) O. Ktze. (Lamiaceae), and Helicteres isora L. (Sterculiaceae) extracted in different solvents were evaluated for their in vitro anticancer and antioxidant activities. The results obtained indicate that H. isora has potent cytotoxic activity toward the selected cancer cells such as HeLa-B75 (34.21 ± 0.24%), HL-60 (30.25 ± 1.36%), HEP-3B (25.36 ± 1.78%), and PN-15 (29.21 ± 0.52%). Interestingly, the selected botanicals selectively inhibited cyclooxygenase-2 (COX-2) more than (COX-1), which are the key enzymes implicated in inflammation. COX-2 inhibition was observed to be in the range of 19.66-49.52% as compared to COX-1 inhibition (3.93-19.61%). The results of the antioxidant study revealed that the selected plants were found to be effective 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl (OH), and superoxide radical (SOR) scavenging agents. High-performance thin layer chromatography (HPTLC) fingerprint of flavonoids was used as a measure of quality control of the selected plant samples. The results of the present findings strengthen the potential of the selected plants as a resource for the discovery of novel anticancer, anti-inflammatory, and antioxidant agents. PMID:25379467

  7. Uptake, internalization and nuclear translocation of radioimmunotherapeutic agents.

    PubMed

    Hillyar, Christopher R T; Cornelissen, Bart; Vallis, Katherine A

    2014-03-01

    Radioimmunotherapy (RIT) agents that incorporate short-range particle-emitting radionuclides exploit the high linear energy transfer of ?-particles and Auger electrons. Both are densely ionizing, generate complex DNA double-strand breaks and so are profoundly cytotoxic. Internalizing RIT agents enter tumor cells through receptor-mediated endocytosis and by incorporation of cell-penetrating peptides. Once internalized, some RIT agents mediate escape from endosomes and/or translocate to the nucleus. In the classical nuclear import pathway, ?/?-importins recognize nuclear localization sequences in RIT agents. Translocation through nuclear pores enables RIT agents to bind to nuclear targets induced by, for example, cellular stress, growth factors or anticancer therapy, such as ?H2AX or p27(KIP-1). This review discusses RIT agents designed to exploit the mechanisms underlying these complex processes and compares them with noninternalizing RIT agents. PMID:24592956

  8. Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines.

    PubMed

    Greish, Khaled

    2007-01-01

    Over the past two decades cancer has ascended the causes of human death to be number one or two in many nations world wide. A major limitation inherent to most conventional anticancer chemotherapeutic agents is their lack of tumor selectivity. One way to achieve selective drug targeting to solid tumors is to exploit abnormalities of tumor vasculature, namely, hypervascularisation; aberrant vascular architecture; extensive production of vascular permeability factors stimulating extravasation within tumor tissues; and lack of lymphatic drainage. Maeda and his colleagues have extensively studied tumor vascular abnormalities in terms of active and selective delivery of anticancer drugs to tumor tissues, notably defining the enhanced permeability and retention effect (EPR effect) of macromolecular drugs in solid tumors. Due to their large molecular size, nanosized macromolecular anticancer drugs administered intravenously (i.v.) escape renal clearance. Often they can not penetrate the tight endothelial junctions of normal blood vessels, but they can extravasate in tumour vasculature and become trapped in the tumor vicinity. With time the tumor concentration will build up reaching several folds higher than that of the plasma due to lack of efficient lymphatic drainage in solid tumor; an ideal application for EPR-based selective anticancer drug delivery. Establishing this principle hastened development of various polymer conjugates and polymeric micelles as well as multifunctional nanoparticles for targeted cancer chemotherapy. Indeed this selective high local concentration of nanosized anticancer drugs in tumor tissues has proven superior in therapeutic effect with minimal side effects in both preclinical and clinical settings. In this review the mechanisms and factors involved in the EPR effect, as well as the uniqueness of nanoscale drugs for tumor targeting through EPR effect, will be discussed in detail. PMID:17671892

  9. Lobelia chinensis: chemical constituents and anticancer activity perspective.

    PubMed

    Chen, Mei-Wan; Chen, Wen-Rong; Zhang, Jin-Ming; Long, Xiao-Ying; Wang, Yi-Tao

    2014-02-01

    Research has demonstrated that many chemical constituents dominated by piperidine alkaloids and flavonoids, such as lobelanidine, lobeline, and lobelanine, have been obtained from Lobelia chinensis Lour. Experimental studies and clinical applications have also indicated that L. chinensis possesses a number of pharmacological activities (e.g., diuretic, choleretic, breathing excitement, anti-venom, anti-bacterial, and anticancer). This paper focuses on the properties, chemical constituents, and anticancer activity of L. chinensis to clarify the connection among them, and identify the active anticancer compounds. This work serves as the foundation for further research and development of L. chinensis. PMID:24636059

  10. Intelligence Artificielle Agents Intelligents

    E-print Network

    Bouzy, Bruno

    Intelligence Artificielle Agents Intelligents Bruno Bouzy http Descartes #12;Agents intelligents Agents intelligents Agents et environnement Rationalit´e PEAS Types d'environnement Structure des agents Conclusion 2 / 21 Intelligence artificielle #12;Agents intelligents Agents intelligents

  11. Novel molecular, cytotoxical, and immunological study on promising and selective anticancer activity of Mung bean sprouts

    PubMed Central

    2012-01-01

    Background The anticancer and immunomodulatory activity of mung bean sprouts (MBS) and the underlying mechanisms against human cervical and hepatocarcinoma cancer cells were explored. Methods MBS cytotoxicity and MBS-induced anticancer cytokines, TNF-? and IFN-? from cancer cells, and immunological cytokines, IL-4, IFN-?, and IL-10 from peripheral mononuclear cells (PMNC) were assessed by MTS and ELISA assays. Apoptotic cells were investigated by flow cytometry. The expression level of apoptotic genes (Bax, BCL-2, Capsases 7–9) and cell cycle regulatory genes (cyclin D, E, and A) and tumor suppressor proteins (p27, p21, and p53) was assessed by real-time qPCR in the cancer cells treated with extract IC50. Results The cytotoxicity on normal human cells was significantly different from HeLa and HepG2 cells, 163.97 ± 5.73, 13.3 ± 0.89, and 14.04 ± 1.5 mg/ml, respectively. The selectivity index (SI) was 12.44 ± 0.83 for HeLa and 11.94 ± 1.2 for HepG2 cells. Increased levels of TNF-? and IFN-? were observed in the treated HeLa and HepG2 culture supernatants when compared with untreated cells. MBS extract was shown to be an immunopolarizing agent by inducing IFN? and inhibiting IL-4 production by PBMC; this leads to triggering of CMI and cellular cytotoxicity. The extract induced apoptosis, in a dose and time dependent manner, in treated HeLa and HepG2, but not in untreated, cells (P < 0.05). The treatment significantly induced cell cycle arrest in G0/G1 in HeLa cells. The percentage of cells in G0/G1 phase of the treated HeLa cells increased from 62.87 ± 2.1%, in untreated cells, to 80.48 ± 2.97%. Interestingly, MBS IC50 induced the expression of apoptosis and tumor suppressor related genes in both HeLa and HepG2 cells. MBS extract succeeded in inducing cdk-inhibitors, p21, p53, and p27 in HeLa cells while it induced only p53 in HepG2 cells (P < 0.05). This is a clue for the cell type- specific interaction of the studied extract. These proteins inhibit the cyclin-cdk complexes apart from the presence of some other components that might stimulate some cyclins such as cyclin E, A, and D. Conclusion MBS extract was shown to be a potent anticancer agent granting new prospects of anticancer therapy using natural products. PMID:23122182

  12. 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

  13. Investigations into the Mechanisms of Cell Death: The Common Link between Anticancer Nanotherapeutics and Nanotoxicology

    NASA Astrophysics Data System (ADS)

    Minocha, Shalini

    Nanotoxicology and anticancer nanotherapeutics are essentially two sides of the same coin. The nanotoxicology discipline deals with the nanoparticle (NP)-induced toxicity and mechanisms of cell death in healthy cells, whereas anticancer agents delivered via nano-based approaches aim to induce cell death in abnormally proliferating cancer cells. The objectives of the studies presented herein were two-fold; to (a) systematically study the physico-chemical properties and cell death mechanisms of model NPs and (b) utilize the knowledge gained from cell death-nanotoxicity studies in developing a potentially novel anticancer nanotherapeutic agent. For the first objective, the effect of a distinguishing characteristic, i.e., surface carbon coating on the matched pairs of carbon-coated and non-coated copper and nickel NPs (Cu, C-Cu, Ni and C-Ni) on the physico-chemical properties and toxicity in A549 alveolar epithelial cells were evaluated. The effect of carbon coating on particle size, zeta potential, oxidation state, cellular uptake, release of soluble metal and concentration dependent toxicity of Cu and Ni NPs was systematically evaluated. A significant effect of carbon coating was observed on the physico-chemical properties, interaction with cellular membranes, and overall toxicity of the NPs. C-Cu NPs, compared to Cu NPs, showed four-fold lower release of soluble copper, ten-fold higher cellular uptake and protection against surface oxidation. In toxicity assays, C-Cu NPs induced higher mitochondrial damage than Cu NPs whereas Cu NPs were associated with a significant damage to plasma membrane integrity. Nickel and carbon coated nickel NPs were less toxic compared to Cu and C-Cu NPs. Thus, by studying the effect of carbon coating, correlations between physico-chemical properties and toxicity of NPs were established. The second objective was focused on utilizing nano-based approaches for the intracellular delivery of an anticancer agent, Cytochrome c (Cyt c), to breast cancer cells for inducing apoptosis. Cytochrome c is an endogenous mitochondrial protein and upon its release to cytosol, leads to apoptotic cell death. Although the mechanism by which Cyt c induces apoptosis theoretically makes it an attractive anti-cancer therapeutic agent, the lack of physicochemical characteristics required for successful cell permeation requires the use of delivery systems such as nanocarriers to facilitate its intracellular delivery. Cytochrome c, being a protein, is susceptible to changes in structural integrity and aggregation which might occur upon exposure to organic solvents and high shear/stress conditions, often used during nanoparticle preparation. Furthermore, successful delivery to cell cytosol requires endosomal release. Therefore, to deliver Cyt c intracellularly, while maintaining conditions for its stability, entrapment was performed using a film hydration method with 1,2-dioleoyl-3-trimethylammonium-propane and cholesterol (DOTAP-Chol) liposomes. It was shown that modulation of hydration buffer pH from 7 to 8.5 increased entrapment of Cyt c in DOTAP-Chol liposomes from 2% to 30%. The optimized formulation showed apoptotic activity in MDA-MB-231 cells. It was also shown that no aggregation, secondary and heme crevice structure change and deamidation was observed for Cyt c released from optimized formulation and that released Cyt c retained apoptotic activity after storage of formulation for twenty eight days at 4 °C.

  14. Heat-Shock Protein 90 (Hsp90) as Anticancer Target for Drug Discovery: An Ample Computational Perspective.

    PubMed

    Kumalo, Hezekiel M; Bhakat, Soumendranath; Soliman, Mahmoud E

    2015-11-01

    There are over 100 different types of cancer, and each is classified based on the type of cell that is initially affected. If left untreated, cancer can result in serious health problems and eventually death. Recently, the paradigm of cancer chemotherapy has evolved to use a combination approach, which involves the use of multiple drugs each of which targets an individual protein. Inhibition of heat-shock protein 90 (Hsp90) is one of the novel key cancer targets. Because of its ability to target several signaling pathways, Hsp90 inhibition emerged as a useful strategy to treat a wide variety of cancers. Molecular modeling approaches and methodologies have become 'close counterparts' to experiments in drug design and discovery workflows. A wide range of molecular modeling approaches have been developed, each of which has different objectives and outcomes. In this review, we provide an up-to-date systematic overview on the different computational models implemented toward the design of Hsp90 inhibitors as anticancer agents. Although this is the main emphasis of this review, different topics such as background and current statistics of cancer, different anticancer targets including Hsp90, and the structure and function of Hsp90 from an experimental perspective, for example, X-ray and NMR, are also addressed in this report. To the best of our knowledge, this review is the first account, which comprehensively outlines various molecular modeling efforts directed toward identification of anticancer drugs targeting Hsp90. We believe that the information, methods, and perspectives highlighted in this report would assist researchers in the discovery of potential anticancer agents. PMID:25958815

  15. Cellular responses against DNA damaged by platinum anticancer drugs

    E-print Network

    Jung, Yongwon, 1977-

    2005-01-01

    The anticancer activity of platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin is mediated by their ability to attack DNA such that generated adducts trigger numerous cellular responses. A better understanding ...

  16. Chemistry and Biology of Deoxynyboquinone, a Potent Anticancer Compound

    E-print Network

    Hergenrother, Paul J.

    S1 Chemistry and Biology of Deoxynyboquinone, a Potent Anticancer Compound Joseph S. Bair, Rahul Biotechnology. Anti-HSP70 monoclonal mouse antibody (SPA-810) and anti-HMOX-1 rabbit polyclonal antibody (SPA

  17. OLIGODEOXYNUCLEOTIDES AS ANTI-CANCER THERAPEUTICS AND DIAGNOSTICS

    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.

  18. Potential Anticancer Properties and Mechanisms of Action of Withanolides.

    PubMed

    Samadi, Abbas K

    2015-01-01

    Plant-based Ayurvedic medicine has been practiced in India for thousands of years for the treatment of a variety of disorders. They are rich sources of bioactive compounds potentially useful for prevention and treatment of cancer. Withania somnifera (commonly known as Ashwagandha in Ayurvedic medicine) is a widely used medicinal plant whose anticancer value was recognized after isolation of steroidal compounds withanolides from the leaves of this shrub. Withaferin A is the first member of withanolides to be isolated, and it is the most abundant withanolide present in W. somnifera. Its cancer-protective role has now been established using chemically induced and oncogene-driven rodent cancer models. The present review summarizes the key preclinical studies demonstrating anticancer effects of withaferin along with its molecular targets and mechanisms related to its anticancer effects. Anticancer potential of other withanolides is also discussed. PMID:26298456

  19. Mechanism Based Anticancer Drugs that Degrade Sp Transcription Factors 

    E-print Network

    Chadalapaka, Gayathri

    2013-03-14

    Curcumin is the active component of tumeric, and this polyphenolic compound has been extensively investigated as an anticancer drug that modulates multiple pathways and genes. We demonstrated that curcumin inhibited 253JB-V and KU7 bladder cancer...

  20. Quantitative High-Throughput Drug Screening Identifies Novel Classes of Drugs with Anticancer Activity in Thyroid Cancer Cells: Opportunities for Repurposing

    PubMed Central

    Zhang, Lisa; He, Mei; Zhang, Yaqin; Nilubol, Naris; Shen, Min

    2012-01-01

    Context: Despite increased understanding of the pathogenesis and targets for thyroid cancer and other cancers, developing a new anticancer chemical agent remains an expensive and long process. An alternative approach is the exploitation of clinically used and/or bioactive compounds. Objective: Our objective was to identify agents with an anticancer effect in thyroid cancer cell lines using quantitative high-throughput screening (qHTS). Design: We used the newly assembled National Institutes of Health Chemical Genomic Center's pharmaceutical collection, which contains 2816 clinically approved drugs and bioactive compounds to perform qHTS. Results: Multiple agents, across a variety of therapeutic categories and with different modes of action, were found to have an antiproliferative effect. We found the following therapeutic categories were the most enriched categories with antiproliferative activity: cardiotonic and antiobesity agents. Sixteen agents had an efficacy of greater than 60% and a 50% inhibitory concentration (IC50) in the nanomolar range. We validated the results of the qHTS using two agents (bortezomib and ouabain) in additional cell lines representing different histological subtypes of thyroid cancer and with different mutations (BRAF V600E, RET/PTC1, p53, PTEN). Both agents induced apoptosis, and ouabain also caused cell cycle arrest. Conclusions: To our knowledge, this is the first study to use qHTS of a large drug library to identify candidate drugs for anticancer therapy. Our results indicate such a screening approach can lead to the discovery of novel agents in different therapeutic categories and drugs with nonclassic chemotherapy mode of action. Our approach could lead to drug repurposing and accelerate clinical trials of compounds with well-established pharmacokinetics and toxicity profiles. PMID:22170715

  1. Phytonutrients as therapeutic agents.

    PubMed

    Gupta, Charu; Prakash, Dhan

    2014-09-01

    Nutrients present in various foods plays an important role in maintaining the normal functions of the human body. The major nutrients present in foods include carbohydrates, proteins, lipids, vitamins, and minerals. Besides these, there are some bioactive food components known as "phytonutrients" that play an important role in human health. They have tremendous impact on the health care system and may provide medical health benefits including the prevention and/or treatment of disease and various physiological disorders. Phytonutrients play a positive role by maintaining and modulating immune function to prevent specific diseases. Being natural products, they hold a great promise in clinical therapy as they possess no side effects that are usually associated with chemotherapy or radiotherapy. They are also comparatively cheap and thus significantly reduce health care cost. Phytonutrients are the plant nutrients with specific biological activities that support human health. Some of the important bioactive phytonutrients include polyphenols, terpenoids, resveratrol, flavonoids, isoflavonoids, carotenoids, limonoids, glucosinolates, phytoestrogens, phytosterols, anthocyanins, ?-3 fatty acids, and probiotics. They play specific pharmacological effects in human health such as anti-microbial, anti-oxidants, anti-inflammatory, antiallergic, anti-spasmodic, anti-cancer, anti-aging, hepatoprotective, hypolipidemic, neuroprotective, hypotensive, diabetes, osteoporosis, CNS stimulant, analgesic, protection from UVB-induced carcinogenesis, immuno-modulator, and carminative. This mini-review attempts to summarize the major important types of phytonutrients and their role in promoting human health and as therapeutic agents along with the current market trend and commercialization. PMID:25051278

  2. Comparison of phenanthriplatin, a novel monofunctional platinum based anticancer drug candidate, with cisplatin, a classic bifunctional anticancer drug

    E-print Network

    Li, Meiyi, S.M. Massachusetts Institute of Technology

    2012-01-01

    Nucleotide excision repair, a DNA repair mechanism, is the major repair pathway responsible for removal of platinum-based anticancer drugs. In this study, 146 bp duplexes were prepared containing either a site-specific ...

  3. Potential anticancer properties of bioactive compounds of Gymnema sylvestre and its biofunctionalized silver nanoparticles

    PubMed Central

    Arunachalam, Kantha Deivi; Arun, Lilly Baptista; Annamalai, Sathesh Kumar; Arunachalam, Aarrthy M

    2015-01-01

    Background Gymnema sylvestre is an ethno-pharmacologically important medicinal plant used in many polyherbal formulations for its potential health benefits. Silver nanoparticles (SNPs) were biofunctionalized using aqueous leaf extracts of G. sylvestre. The anticancer properties of the bioactive compounds and the biofunctionalized SNPs were compared using the HT29 human adenoma colon cancer cell line. Methods The preliminary phytochemical screening for bioactive compounds from aqueous extracts revealed the presence of alkaloids, triterpenes, flavonoids, steroids, and saponins. Biofunctionalized SNPs were synthesized using silver nitrate and characterized by ultraviolet–visible spectroscopy, scanning electron microscopy, energy-dispersive X-ray analysis, Fourier transform infrared spectroscopy, and X-ray diffraction for size and shape. The characterized biofunctionalized G. sylvestre were tested for its in vitro anticancer activity against HT29 human colon adenocarcinoma cells. Results The biofunctionlized G. sylvestre SNPs showed the surface plasmon resonance band at 430 nm. The scanning electron microscopy images showed the presence of spherical nanoparticles of various sizes, which were further determined using the Scherrer equation. In vitro cytotoxic activity of the biofunctionalized green-synthesized SNPs (GSNPs) indicated that the sensitivity of HT29 human colon adenocarcinoma cells for cytotoxic drugs is higher than that of Vero cell line for the same cytotoxic agents and also higher than the bioactive compound of the aqueous extract. Conclusion Our results show that the anticancer properties of the bioactive compounds of G. sylvestre can be enhanced through biofunctionalizing the SNPs using the bioactive compounds present in the plant extract without compromising their medicinal properties. PMID:25565802

  4. Anticancer activity of botanical alkyl hydroquinones attributed to topoisomerase II poisoning

    SciTech Connect

    Huang, C.-P.; Fang, W.-H.; Lin, L.-I.; Chiou, Robin Y.; Kan, L.-S.; Chi, N.-H.; Chen, Y.-R.; Lin, T.-Y.; Lin, S.-B.

    2008-03-15

    Cytotoxic alkyl hydroquinone compounds have been isolated from many plants. We previously isolated 3 structurally similar cytotoxic alkyl hydroquinone compounds from the sap of the lacquer tree Rhus succedanea L. belonging to the sumac family, which have a long history of medicinal use in Asia. Each has an unsaturated alkyl chain attached to the 2-position of a hydroquinone ring. One of these isolates, 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. We found that HQ17(3) was a topoisomerase (Topo) II poison. It irreversibly inhibited Topo II{alpha} activity through the accumulation of Topo II-DNA cleavable complexes. A cell-based assay showed that HQ17(3) inhibited the growth of leukemia HL-60 cells with an EC{sub 50} of 0.9 {mu}M, inhibited the topoisomerase-II-deficient cells HL-60/MX2 with an EC{sub 50} of 9.6 {mu}M, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 {mu}M. These results suggest that Topo II is the cellular drug target. In HL-60 cells, HQ17(3) promptly inhibited DNA synthesis, induced chromosomal breakage, and led to cell death with an EC{sub 50} about one-tenth that of hydroquinone. Pretreatment of the cells with N-acetylcysteine could not attenuate the cytotoxicity and DNA damage induced by HQ17(3). However, N-acetylcysteine did significantly reduce the cytotoxicity of hydroquinone. In F344 rats, intraperitoneal injection of HQ17(3) for 28 days induced no clinical signs of toxicity. These results indicated that HQ17(3) is a potential anticancer agent, and its structural features could be a model for anticancer drug design.

  5. Anti-cancer activity of curcumin loaded nanoparticles in prostate cancer

    PubMed Central

    Yallapu, Murali M.; Khan, Sheema; Maher, Diane M.; Ebeling, Mara C.; Sundram, Vasudha; Chauhan, Neeraj; Ganju, Aditya; Balakrishna, Swati; Gupta, Brij K.; Zafar, Nadeem; Jaggi, Meena; Chauhan, Subhash C.

    2014-01-01

    Prostate cancer is the most commonly diagnosed cancer disease in men in the Unites States and its management remains challenge in everyday oncology practice. Thus, advanced therapeutic strategies are required to treat prostate cancer patients. Curcumin (CUR) is a promising anticancer agent for various cancer types. The objective of this study was to evaluate therapeutic potential of novel poly(lactic-co-glycolic acid)- CUR nanoparticles (PLGA-CUR NPs) for prostate cancer treatment. Our results indicate that PLGA-CUR NPs efficiently internalize in prostate cancer cells and release biologically active CUR in cytosolic compartment of cells for effective therapeutic activity. Cell proliferation (MTS), clonogenic, and Western blot analyses reveal that PLGA-CUR NPs can effectively inhibit proliferation and colony formation ability of prostate cancer cells than free CUR. PLGA-CUR NPs showed superior tumor regression compared to CUR in xenograft mice. Further investigations reveal that PLGA-CUR NPs inhibit nuclear ?-catenin and AR expression in cells and in tumor xenograft tissues. It also suppresses STAT3 and AKT phosphorylation and leads to apoptosis via inhibition of key anti-apoptotic proteins, MCL-1, Bcl-xL and caused induction of PARP cleavage. Additionally, PLGA-CUR NPs significant downregulation of oncogenic miR21 and up-regulation of miR-205 was observed with PLGA-CUR NPs treatment as determined by RT-PCR and in situ hybridization analyses. A superior anti-cancer potential was attained with PSMA antibody conjugated PLGA-CUR NPs in prostate cancer cells and a significant tumor targeting of 131I labelled PSMA antibody was achieved with PLGA-CUR NPs in prostate cancer xenograft mice model. In conclusion, PLGA-CUR NPs can significantly accumulate and exhibit superior anticancer activity in prostate cancer. PMID:25028336

  6. From body art to anticancer activities: perspectives on medicinal properties of henna.

    PubMed

    Pradhan, Rohan; Dandawate, Prasad; Vyas, Alok; Padhye, Subhash; Biersack, Bernhard; Schobert, Rainer; Ahmad, Aamir; Sarkar, Fazlul H

    2012-12-01

    Nature has been a rich source of therapeutic agents for thousands of years and an impressive number of modern drugs have been isolated from natural sources based on the uses of these plants in traditional medicine. Henna is one such plant commonly known as Persian Henna or Lawsonia inermis, a bushy, flowering tree, commonly found in Australia, Asia and along the Mediterranean coasts of Africa. Paste made from the leaves of Henna plant has been used since the Bronze Age to dye skin, hairs and fingernails especially at the times of festivals. In recent times henna paste has been used for body art paintings and designs in western countries. Despite such widespread use in dyeing and body art painting, Henna extracts and constituents possess numerous biological activities including antioxidant, anti-inflammatory, antibacterial and anticancer activities. The active coloring and biologically active principle of Henna is found to be Lawsone (2- hydroxy-1, 4-naphthoquinone) which can serve as a starting building block for synthesizing large number of therapeutically useful compounds including Atovaquone, Lapachol and Dichloroallyl lawsone which have been shown to possess potent anticancer activities. Some other analogs of Lawsone have been found to exhibit other beneficial biological properties such as antioxidant, anti-inflammatory, antitubercular and antimalarial. The ability of Lawsone to undergo the redox cycling and chelation of trace metal ions has been thought to be partially responsible for some of its biological activities. Despite such diverse biological properties and potent anticancer activities the compound has remained largely unexplored and hence in the present review we have summarized the chemistry and biological activities of Lawsone along with its analogs and metal complexes. PMID:23140289

  7. Effect of Cellular Location of Human Carboxylesterase 2 on CPT-11 Hydrolysis and Anticancer Activity

    PubMed Central

    Hsieh, Yuan-Ting; Lin, Hsuan-Pei; Chen, Bing-Mae; Huang, Ping-Ting; Roffler, Steve R.

    2015-01-01

    CPT-11 is an anticancer prodrug that is clinically used for the treatment of metastatic colorectal cancer. Hydrolysis of CPT-11 by human carboxylesterase 2 (CE2) generates SN-38, a topoisomerase I inhibitor that is the active anti-tumor agent. Expression of CE2 in cancer cells is under investigation for the tumor-localized activation of CPT-11. CE2 is normally expressed in the endoplasmic reticulum of cells but can be engineered to direct expression of active enzyme on the plasma membrane or as a secreted form. Although previous studies have investigated different locations of CE2 expression in cancer cells, it remains unclear if CE2 cellular location affects CPT-11 anticancer activity. In the present study, we directly compared the influence of CE2 cellular location on substrate hydrolysis and CPT-11 cytotoxicity. We linked expression of CE2 and enhanced green fluorescence protein (eGFP) via a foot-and-mouth disease virus 2A (F2A) peptide to facilitate fluorescence-activated cell sorting to achieve similar expression levels of ER-located, secreted or membrane-anchored CE2. Soluble CE2 was detected in the medium of cells that expressed secreted and membrane-anchored CE2, but not in cells that expressed ER-retained CE2. Cancer cells that expressed all three forms of CE2 were more sensitive to CPT-11 as compared to unmodified cancer cells, but the membrane-anchored and ER-retained forms of CE2 were consistently more effective than secreted CE2. We conclude that expression of CE2 in the ER or on the membrane of cancer cells is suitable for enhancing CPT-11 anticancer activity. PMID:26509550

  8. Anticancer activity of selected Colocasia gigantia fractions.

    PubMed

    Pornprasertpol, Apichai; Sereemaspun, Amornpun; Sooklert, Kanidta; Satirapipatkul, Chutimon; Sukrong, Suchada

    2015-01-01

    The objective of this study is to investigate the anticancer potential of the extract of Colocasia gigantea C. gigantea), a plant member of the Araceae family. In the present study, we investigated the cytotoxic activity of C. gigantea extract on cervical cancer (Hela) and human white blood cells (WBC) in vitro. The authors then identified the bioactive ingredients that demonstrated cytotoxicity on tested cells and evaluated those bioactive ingredients using the bioassay-guided fractionation method. The results showed that not all parts of C. gigantea promote cytotoxic activity. The dichloromethane leaf fraction showed significant cell proliferation effect on Hela cells, but not on WBCs. Only the n-hexane tuber fraction (Fr. 1T) exhibited significant cytotoxicity on Hela cells (IC50 = 585 ?g/ml) and encouraged WBC cell proliferation. From GC-Mass spectrometry, 4,22-Stigmastadiene-3-one, Diazoprogesterone, 9-Octadecenoic acid (Z)-, hexyl ester and Oleic Acid were the components of Fr 1T that demonstrated cytotoxic potential. In conclusion, C. gigantea's Fr 1T shows potential for cervical cancer treatment. PMID:25764620

  9. Macrocyclic trichothecenes as antifungal and anticancer compounds.

    PubMed

    de Carvalho, Maira Peres; Weich, Herbert; Abraham, Wolf-Rainer

    2016-01-01

    Trichothecenes are sesquiterpenoid metabolites produced by fungi and species of the plant genus Baccharis, family Asteraceae. They comprise a tricyclic core with an epoxide at C-12 and C-13 and can be grouped into non-macrocyclic and macrocyclic compounds. While many of these compounds are of concern in agriculture, the macrocyclic metabolites have been evaluated as antiviral, anti-cancer, antimalarial and antifungal compounds. Some known cytotoxic responses on eukaryotic cells include inhibition of protein, DNA and RNA syntheses, interference with mitochondrial function, effects on cell division and membranes. These targets however have been elucidated essentially employing non-macrocyclic trichothecenes and only one or two closely related macrocyclic compounds. For several macrocyclic trichothecenes high selectivity against fungal species and against cancer cell lines have been reported suggesting that the macrocycle and its stereochemistry are of crucial importance regarding biological activity and selectivity. This review is focused on compounds belonging to the macrocyclic type, where a cyclic diester or triester ring binds to the trichothecane moiety at C-4 and C- 15 leading to natural products belonging to the groups of satratoxins, verrucarins, roridins, myrotoxins and baccharinoids. Their biological activities, cytotoxic mechanisms and structure-activity relationships (SAR) are discussed. From the reported data it becomes evident that even small changes in the molecules can lead to pronounced effects on biological activity or selectivity against cancer cells lines. Understanding the underlying mechanisms may help to design highly specific drugs for cancer therapy. PMID:26572613

  10. Potential Anticancer Properties of Grape Antioxidants

    PubMed Central

    Zhou, Kequan; Raffoul, Julian J.

    2012-01-01

    Dietary intake of foods rich in antioxidant properties is suggested to be cancer protective. Foods rich in antioxidant properties include grape (Vitis vinifera), one of the world's largest fruit crops and most commonly consumed fruits in the world. The composition and cancer-protective effects of major phenolic antioxidants in grape skin and seed extracts are discussed in this review. Grape skin and seed extracts exert strong free radical scavenging and chelating activities and inhibit lipid oxidation in various food and cell models in vitro. The use of grape antioxidants are promising against a broad range of cancer cells by targeting epidermal growth factor receptor (EGFR) and its downstream pathways, inhibiting over-expression of COX-2 and prostaglandin E2 receptors, or modifying estrogen receptor pathways, resulting in cell cycle arrest and apoptosis. Interestingly, some of these activities were also demonstrated in animal models. However, in vivo studies have demonstrated inconsistent antioxidant efficacy. Nonetheless, a growing body of evidence from human clinical trials has demonstrated that consumption of grape, wine and grape juice exerts many health-promoting and possible anti-cancer effects. Thus, grape skin and seed extracts have great potential in cancer prevention and further investigation into this exciting field is warranted. PMID:22919383

  11. Molecular mechanisms underlying anticancer effects of myricetin.

    PubMed

    Devi, Kasi Pandima; Rajavel, Tamilselvam; Habtemariam, Solomon; Nabavi, Seyed Fazel; Nabavi, Seyed Mohammad

    2015-12-01

    Dietary guidelines published in the past two decades have acknowledged the beneficial effects of myricetin, an important and common type of herbal flavonoid, against several human diseases such as inflammation, cardiovascular pathologies, and cancer. An increasing number of studies have shown the beneficial effects of myricetin against different types of cancer by modifying several cancer hallmarks including aberrant cell proliferation, signaling pathways, apoptosis, angiogenesis, and tumor metastasis. Most importantly, myricetin interacts with oncoproteins such as protein kinase B (PKB) (Akt), Fyn, MEK1, and JAK1-STAT3 (Janus kinase-signal transducer and activator of transcription 3), and it attenuates the neoplastic transformation of cancer cells. In addition, myricetin exerts antimitotic effects by targeting the overexpression of cyclin-dependent kinase 1 (CDK1) in liver cancer. Moreover, it also targets the mitochondria and promotes different kinds of cell death in various cancer cells. In the present paper, a critical review of the available literature is presented to identify the molecular targets underlying the anticancer effects of myricetin. PMID:26455550

  12. Sesamin synergistically potentiates the anticancer effects of ?-tocotrienol in mammary cancer cell lines.

    PubMed

    Akl, Mohamed R; Ayoub, Nehad M; Abuasal, Bilal S; Kaddoumi, Amal; Sylvester, Paul W

    2013-01-01

    ?-Tocotrienol and sesamin are phytochemicals that display potent anticancer activity. Since sesamin inhibits the metabolic degradation of tocotrienols, studies were conducted to determine if combined treatment with sesamin potentiates the antiproliferative effects of ?-tocotrienol on neoplastic mouse (+SA) and human (MCF-7 and MDA-MB-231) mammary cancer cells. Results showed that treatment with ?-tocotrienol or sesamin alone induced a significant dose-responsive growth inhibition, whereas combination treatment with these agents synergistically inhibited the growth of +SA, MCF-7 and MDA-MB-231 mammary cancer cells, while similar treatment doses were found to have little or no effect on normal (mouse CL-S1 and human MCF-10A) mammary epithelial cell growth or viability. However, sesamin synergistic enhancement of ?-tocotrienol-induced anticancer effects was not found to be mediated from a reduction in ?-tocotrienol metabolism. Rather, combined treatment with subeffective doses of ?-tocotrienol and sesamin was found to induce G1 cell cycle arrest, and a corresponding decrease in cyclin D1, CDK2, CDK4, CDK6, phospho-Rb, and E2F1 levels, and increase in p27 and p16 levels. Additional studies showed that the antiproliferative effect of combination treatment did not initiate apoptosis or result in a decrease in mammary cancer cell viability. Taken together, these findings indicate that the synergistic antiproliferative action of combined ?-tocotrienol and sesamin treatment in mouse and human mammary cancer cells is cytostatic, not cytotoxic, and results from G1 cell cycle arrest. PMID:23266736

  13. Characterization of the Phytochemical Constituents of Taif Rose and Its Antioxidant and Anticancer Activities

    PubMed Central

    Abdel-Hameed, El-Sayed S.; Bazaid, Salih A.; Salman, Mahmood S.

    2013-01-01

    Ward Taifi (Taif rose) is considered one of the most important economic products of Taif, Saudi Arabia. In this study both fresh and dry Taif rose were biologically and phytochemically investigated. The 80% methanol extracts and n-butanol fractions of dry and fresh Taif rose had high radical scavenging activity toward artificial 1,1-diphenyl picrylhydrazyl (DPPH)• radical with SC50 values range 5.86?12.24?µg/ml whereas the aqueous fractions showed weak activity. All samples had in vitro anticancer activity toward HepG2 with IC50 < 20?µg/ml which fall within the criteria of the American Cancer Institute. High positive correlation appeared between the antioxidant activity and total phenolics whereas there is no correlation between total phenolics and anticancer activity. The LC-ESI(? ve)-MS analysis of all extracts indicate the presence of phenolic compounds belonging to hydrolysable tannins and flavonol glycosides. In conclusion, the presence of this is considered to be the first phytochemical report that identifies the major compounds in dry and fresh roses using HPLC-ESI-MS. The methanol extracts and its n-butanol and aqueous fractions for both fresh and dry Taif rose could be used as preventive and therapeutic effective natural agents for diseases in which free radicals involved after more in vitro and in vivo studies. PMID:24282813

  14. Anticancer property of bromelain with therapeutic potential in malignant peritoneal mesothelioma.

    PubMed

    Pillai, Krishna; Akhter, Javed; Chua, Terence C; Morris, David Lawson

    2013-05-01

    Bromelain is a mixture of proteolytic enzymes that is capable of hydrolyzing glycosidic linkages in glycoprotein. Glycoprotein's are ubiquitously distributed throughout the body and serve a variety of physiologic functions. Faulty glycosylation of proteins may lead to cancer. Antitumor properties of bromelain have been demonstrated in both, in vitro and in vivo studies, along with scanty anecdotal human studies. Various mechanistic pathways have been proposed to explain the anticancer properties of bromelain. However, proteolysis by bromelain has been suggested as a main pathway by some researchers. MUC1 is a glycoprotein that provides tumor cells with invasive, metastatic, and chemo-resistant properties. To date, there is no study that examines the effect of bromelain on MUC1. However, the viability of MUC1 expressing pancreatic and breast cancer cells are adversely affected by bromelain. Further, the efficacy of cisplatin and 5-FU are enhanced by adjuvant treatment with bromelain, indicating that the barrier function of MUC1 may be affected. Other studies have also indicated that there is a greater accumulation of 5-FU in the cell compartment on treatment with 5-FU and bromelain. Malignant peritoneal mesothelioma (MPM) expresses MUC1 and initial studies have shown that the viability of MPM cells is adversely affected by exposure to bromelain. Further, bromelain in combination with either 5-FU or cisplatin, the efficacy of the chemotherapeutic drug is enhanced. Hence, current evidence indicates that bromelain may have the potential of being developed into an effective anticancer agent for MPM. PMID:23570457

  15. Base excision repair: contribution to tumorigenesis and target in anticancer treatment paradigms

    PubMed Central

    Illuzzi, Jennifer L.; Wilson, David M.

    2015-01-01

    Cancer treatments often lose their effectiveness due to the development of multiple drug resistance. Thus, identification of key proteins involved in the tumorigenic process and the survival mechanism(s), coupled with the design of novel therapeutic compounds (such as small molecule inhibitors), are essential steps towards the establishment of improved anticancer treatment strategies. DNA repair pathways and their proteins have been exposed as potential targets for combinatorial anticancer therapies that involve DNA-interactive cytotoxins, such as alkylating agents, because of their central role in providing resistance against DNA damage. In addition, an understanding of the tumor-specific genetics and associated DNA repair capacity has allowed research scientists and clinicians to begin to devise more targeted treatment strategies based on the concept of synthetic lethality. In this review, the repair mechanisms, as well as the links to cancer progression and treatment, of three key proteins that function in the base excision repair pathway, i.e. APE1, POL?, and FEN1, are discussed. PMID:22788768

  16. Purification, structural characterization and anticancer activity of the novel polysaccharides from Rhynchosia minima root.

    PubMed

    Jia, Xuejing; Zhang, Chao; Qiu, Jianfeng; Wang, Lili; Bao, Jiaolin; Wang, Kai; Zhang, Yulin; Chen, Meiwan; Wan, Jianbo; Su, Huanxing; Han, Jianping; He, Chengwei

    2015-11-01

    Three novel acidic polysaccharides termed PRM1, PRM3 and PRM5 were purified from Rhynchosia minima root using DEAE-52 cellulose and sephadex G-150 column chromatography. Their structures were characterized by ultraviolet (UV) and Fourier transform infrared (FTIR) spectrometry, gel permeation chromatography (GPC), gas chromatography-mass spectrometry (GC-MS), and differential scanning colorimeter (DSC) analysis. The uronic acid contents of PRM1, PRM3 and PRM5 were 30.7%, 12.7% and 47.7%, respectively. PRM1 (143.2 kDa), PRM3 (105.3 kDa) and PRM5 (162.1 kDa) were heteropolysaccharides because they were composed of arabinose, mannose, glucose and galactose. Their enthalpy values were 201.0, 111.0 and 206.8 J/g, respectively. PRM3 and PRM1 exhibited strong in vitro anticancer activity against lung cancer A549 and liver cancer HepG2 cells in a dose-dependent manner. These findings suggested that PRM1 and PRM3 could be potentially developed as natural anticancer agents. PMID:26256325

  17. Garcinol: Current status of its anti-oxidative, anti-inflammatory and anti-cancer effects.

    PubMed

    Liu, Chaoqun; Ho, Paul Chi-Lui; Wong, Fang Cheng; Sethi, Gautam; Wang, Ling Zhi; Goh, Boon Cher

    2015-06-28

    Garcinol is the main medicinal component of the dried fruit rind of Garcinia indica (G. indica), which has traditionally been extensively used to treat gastric ailments and skin irritation. In vitro studies of garcinol revealed its potential therapeutic effects, such as its anti-oxidative, anti-inflammatory and anti-cancer properties. Similarly, in vivo studies in animal models also demonstrated the efficacy of garcinol for the treatment of various inflammatory and cancerous conditions. Despite being well tolerated in preclinical studies, the toxicological profile of garcinol remains elusive. More importantly, systematic pharmacokinetics (PK) studies of garcinol to establish an appropriate route of administration and its effective concentration range under physiological conditions have not yet been performed. PK studies play an essential role in translating the preclinical findings of garcinol from cell line models and animal species to humans, thereby facilitating dose selection, the characterization of the therapeutic index, identification of a metabolic pathway, and the determination of garcinol's potency and tolerability. This paper reviews the current studies of garcinol as a potential anti-oxidant, anti-inflammatory and anti-cancer agent and highlights the importance of performing preclinical PK and toxicological studies on garcinol for its development pipeline. PMID:25796441

  18. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin

    PubMed Central

    Chan, Pan F.; Srikannathasan, Velupillai; Huang, Jianzhong; Cui, Haifeng; Fosberry, Andrew P.; Gu, Minghua; Hann, Michael M.; Hibbs, Martin; Homes, Paul; Ingraham, Karen; Pizzollo, Jason; Shen, Carol; Shillings, Anthony J.; Spitzfaden, Claus E.; Tanner, Robert; Theobald, Andrew J.; Stavenger, Robert A.; Bax, Benjamin D.; Gwynn, Michael N.

    2015-01-01

    New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a ‘pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested. PMID:26640131

  19. Synthesis and Biological Evaluation of Novel 3-Alkylpyridine Marine Alkaloid Analogs with Promising Anticancer Activity

    PubMed Central

    Gonçalves, Alessandra Mirtes Marques Neves; de Lima, Aline Brito; Barbosa, Maria Cristina da Silva; de Camargos, Luiz Fernando; de Oliveira, Júlia Teixeira; Barbosa, Camila de Souza; Villar, José Augusto Ferreira Perez; Costa, André Carvalho; da Silva, Isabella Viana Gomes; Silva, Luciana Maria; Varotti, Fernando de Pilla; dos Santos, Fabio Vieira; Viana, Gustavo Henrique Ribeiro

    2014-01-01

    Cancer continues to be one of the most important health problems worldwide, and the identification of novel drugs and treatments to address this disease is urgent. During recent years, marine organisms have proven to be a promising source of new compounds with action against tumoral cell lines. Here, we describe the synthesis and anticancer activity of eight new 3-alkylpyridine alkaloid (3-APA) analogs in four steps and with good yields. The key step for the synthesis of these compounds is a Williamson etherification under phase-transfer conditions. We investigated the influence of the length of the alkyl chain attached to position 3 of the pyridine ring on the cytotoxicity of these compounds. Biological assays demonstrated that compounds with an alkyl chain of ten carbon atoms (4c and 5c) were the most active against two tumoral cell lines: RKO-AS-45-1 and HeLa. Micronucleus and TUNEL assays showed that both compounds are mutagenic and induce apoptosis. In addition, Compound 5c altered the cellular actin cytoskeleton in RKO-AS-45-1 cells. The results suggest that Compounds 4c and 5c may be novel prototype anticancer agents. PMID:25089949

  20. Targeting MKK3 as a novel anticancer strategy: molecular mechanisms and therapeutical implications

    PubMed Central

    Baldari, S; Ubertini, V; Garufi, A; D'Orazi, G; Bossi, G

    2015-01-01

    Mitogen-activated protein kinase kinase 3 (MAP2K3, MKK3) is a member of the dual specificity protein kinase group that belongs to the MAP kinase kinase family. This kinase is activated by mitogenic or stress-inducing stimuli and participates in the MAP kinase-mediated signaling cascade, leading to cell proliferation and survival. Several studies highlighted a critical role for MKK3 in tumor progression and invasion, and we previously identified MKK3 as transcriptional target of mutant (mut) p53 to sustain cell proliferation and survival, thus rendering MKK3 a promising target for anticancer therapies. Here, we found that targeting MKK3 with RNA interference, in both wild-type (wt) and mutp53-carrying cells, induced endoplasmic reticulum stress and autophagy that, respectively, contributed to stabilize wtp53 and degrade mutp53. MKK3 depletion reduced cancer cell proliferation and viability, whereas no significant effects were observed in normal cellular context. Noteworthy, MKK3 depletion in combination with chemotherapeutic agents increased tumor cell response to the drugs, in both wtp53 and mutp53 cancer cells, as demonstrated by enhanced poly (ADP-ribose) polymerase cleavage and reduced clonogenic ability in vitro. In addition, MKK3 depletion reduced tumor growth and improved biological response to chemotherapeutic in vivo. The overall results indicate MKK3 as a novel promising molecular target for the development of more efficient anticancer treatments in both wtp53- and mutp53-carrying tumors. PMID:25633290

  1. Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect

    PubMed Central

    Johnstone, Ricky W.; Prince, H. Miles

    2010-01-01

    Summary The histone deacetylase inhibitors (HDACi) have demonstrated anticancer efficacy across a range of malignancies, most impressively in the hematological cancers. It is uncertain whether this clinical efficacy is attributable predominantly to their ability to induce apoptosis and differentiation in the cancer cell, or to their ability to prime the cell to other pro-death stimuli such as those from the immune system. HDACi-induced apoptosis occurs through altered expression of genes encoding proteins in both intrinsic and extrinsic apoptotic pathways; through effects on the proteasome/aggresome systems; through the production of reactive oxygen species, possibly by directly inducing DNA damage; and through alterations in the tumor microenvironment. In addition HDACi increase the immunogenicity of tumor cells and modulate cytokine signaling and potentially T-cell polarization in ways that may contribute the anti-cancer effect in vivo. Here, we provide an overview of current thinking on the mechanisms of HDACi activity, with attention given to the hematological malignancies as well as scientific observations arising from the clinical trials. We also focus on the immune effects of these agents. PMID:21161327

  2. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity.

    PubMed

    Barretina, Jordi; Caponigro, Giordano; Stransky, Nicolas; Venkatesan, Kavitha; Margolin, Adam A; Kim, Sungjoon; Wilson, Christopher J; Lehár, Joseph; Kryukov, Gregory V; Sonkin, Dmitriy; Reddy, Anupama; Liu, Manway; Murray, Lauren; Berger, Michael F; Monahan, John E; Morais, Paula; Meltzer, Jodi; Korejwa, Adam; Jané-Valbuena, Judit; Mapa, Felipa A; Thibault, Joseph; Bric-Furlong, Eva; Raman, Pichai; Shipway, Aaron; Engels, Ingo H; Cheng, Jill; Yu, Guoying K; Yu, Jianjun; Aspesi, Peter; de Silva, Melanie; Jagtap, Kalpana; Jones, Michael D; Wang, Li; Hatton, Charles; Palescandolo, Emanuele; Gupta, Supriya; Mahan, Scott; Sougnez, Carrie; Onofrio, Robert C; Liefeld, Ted; MacConaill, Laura; Winckler, Wendy; Reich, Michael; Li, Nanxin; Mesirov, Jill P; Gabriel, Stacey B; Getz, Gad; Ardlie, Kristin; Chan, Vivien; Myer, Vic E; Weber, Barbara L; Porter, Jeff; Warmuth, Markus; Finan, Peter; Harris, Jennifer L; Meyerson, Matthew; Golub, Todd R; Morrissey, Michael P; Sellers, William R; Schlegel, Robert; Garraway, Levi A

    2012-03-29

    The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens. PMID:22460905

  3. Theoretical demonstration of the potentiality of boron nitride nanotubes to encapsulate anticancer molecule.

    PubMed

    El Khalifi, Mohammed; Duverger, Eric; Gharbi, Tijani; Boulahdour, Hatem; Picaud, Fabien

    2015-11-28

    Anticancer drug transport is now becoming an important scientific challenge since it would allow localizing the drug release near the tumor cell, avoiding secondary medical effects. We present theoretical results, based on density functional theory and molecular dynamics simulations, which demonstrate the stability of functionalized single (10,10) boron nitride nanotubes (BNNTs) filled with anticancer molecule such as carboplatin (CPT). For this functionalized system we determine the dependence of the adsorption energy on the molecule displacement near the inner BNNTs surface, together with their local morphological and electrical changes and compare the values to the adsorption energy obtained on the outer surface. Quantum simulations show that the most stable physisorption state is located inside the nanotube, with no net charge transfer. This demonstrates that chemotherapeutic encapsulation is the most favorable way to transport drug molecules. The solvent effect and dispersion repulsion contributions are then taken into account using molecular dynamics simulations. Our results confirm that carboplatin therapeutic agents are not affected when they are adsorbed inside BNNTs by the surrounding water molecules. PMID:26498990

  4. Recent developments in mushrooms as anti-cancer therapeutics: a review.

    PubMed

    Patel, Seema; Goyal, Arun

    2012-03-01

    From time immemorial, mushrooms have been valued by humankind as a culinary wonder and folk medicine in Oriental practice. The last decade has witnessed the overwhelming interest of western research fraternity in pharmaceutical potential of mushrooms. The chief medicinal uses of mushrooms discovered so far are as anti-oxidant, anti-diabetic, hypocholesterolemic, anti-tumor, anti-cancer, immunomodulatory, anti-allergic, nephroprotective, and anti-microbial agents. The mushrooms credited with success against cancer belong to the genus Phellinus, Pleurotus, Agaricus, Ganoderma, Clitocybe, Antrodia, Trametes, Cordyceps, Xerocomus, Calvatia, Schizophyllum, Flammulina, Suillus, Inonotus, Inocybe, Funlia, Lactarius, Albatrellus, Russula, and Fomes. The anti-cancer compounds play crucial role as reactive oxygen species inducer, mitotic kinase inhibitor, anti-mitotic, angiogenesis inhibitor, topoisomerase inhibitor, leading to apoptosis, and eventually checking cancer proliferation. The present review updates the recent findings on the pharmacologically active compounds, their anti-tumor potential, and underlying mechanism of biological action in order to raise awareness for further investigations to develop cancer therapeutics from mushrooms. The mounting evidences from various research groups across the globe, regarding anti-tumor application of mushroom extracts unarguably make it a fast-track research area worth mass attention. PMID:22582152

  5. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin.

    PubMed

    Chan, Pan F; Srikannathasan, Velupillai; Huang, Jianzhong; Cui, Haifeng; Fosberry, Andrew P; Gu, Minghua; Hann, Michael M; Hibbs, Martin; Homes, Paul; Ingraham, Karen; Pizzollo, Jason; Shen, Carol; Shillings, Anthony J; Spitzfaden, Claus E; Tanner, Robert; Theobald, Andrew J; Stavenger, Robert A; Bax, Benjamin D; Gwynn, Michael N

    2015-01-01

    New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a 'pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested. PMID:26640131

  6. Structure-activity relationship study of novel anticancer aspirin-based compounds

    PubMed Central

    JOSEPH, STANCY; NIE, TING; HUANG, LIQUN; ZHOU, HUI; ATMAKUR, KRISHNAIAH; GUPTA, RAMESH C.; JOHNSON, FRANCIS; RIGAS, BASIL

    2013-01-01

    We performed a structure-activity relationship (SAR) study of a novel aspirin (ASA) derivative, which shows strong anticancer activity in vitro and in vivo. A series of ASA-based benzyl esters (ABEs) were synthesized and their inhibitory activity against human colon (HT-29 and SW480) and pancreatic (BxPC-3 and MIA PaCa-2) cancer cell lines was evaluated. The ABEs that we studied largely comprise organic benzyl esters bearing an ASA or acyloxy group (X) at the meta or para position of the benzyl ring and one of four different leaving groups. The nature of the salicyloyl/acyloxy function, the leaving group, and the additional substituents affecting the electron density of the benzyl ring, all were influential determinants of the inhibitory activity on cancer cell growth for each ABE. Positional isomerism also played a significant role in this effect. The mechanism of action of these compounds appears consistent with the notion that they generate either a quinone methide or an m-oxybenzyl zwitterion (or an m-hydroxybenzyl cation), which then reacts with a nucleophile, mediating their biological effect. Our SAR study provides an insight into the biological properties of this novel class of compounds and underscores their potential as anticancer agents. PMID:21805049

  7. Anticancer efficacy of deguelin in human prostate cancer cells targeting glycogen synthase kinase-3 ?/?-catenin pathway.

    PubMed

    Thamilselvan, Vijayalakshmi; Menon, Mani; Thamilselvan, Sivagnanam

    2011-12-15

    Activation of survival pathways has been associated with chemoresistance and progression of androgen independence which places a major obstacle to successful treatment of metastatic prostate cancer. Deguelin, a rotenoid isolated from Mundulea sericea, has an anticancer effect against several types of cancers; however, the mechanism of its antitumor effects on prostate cancer is not well understood. The aim of our study was to elucidate the effect of deguelin on the growth of prostate cancer cells and its putative mechanism of action. Deguelin decreased the viability of both androgen-dependent and -independent prostate cancer cells but not normal prostate epithelial cells. Downregulation of phosphorylated Akt and GSK-3? by deguelin promoted proteosomal degradation of ?-catenin that resulted in decreased nuclear accumulation and inhibited transactivation of ?-catenin-responsive genes. Deguelin-induced downregulation of proliferative (cyclin D1 and c-myc) and antiapoptotic proteins (Mcl-1, Bcl-xL and survivin) in prostate cancer cells culminated in the induction of apoptosis, inhibition of DNA synthesis and cell growth, altered membrane integrity, marked reduction of invasiveness, inhibition of anchorage-dependent and -independent colony formation. Our data demonstrated for the first time that deguelin inhibits the growth and survival of human androgen-independent prostate cancer cells, and its anticancer and antimetastatic activity occurs, at least in part through downregulating GSK-3?/?-catenin signaling pathway and antiapoptotic survival proteins. Taken together our study indicates that deguelin may have translational potential as therapeutic agent for advanced or metastatic prostate cancer. PMID:21472727

  8. Classification of stimuli-responsive polymers as anticancer drug delivery systems.

    PubMed

    Taghizadeh, Bita; Taranejoo, Shahrouz; Monemian, Seyed Ali; Salehi Moghaddam, Zoha; Daliri, Karim; Derakhshankhah, Hossein; Derakhshani, Zaynab

    2015-02-01

    Although several anticancer drugs have been introduced as chemotherapeutic agents, the effective treatment of cancer remains a challenge. Major limitations in the application of anticancer drugs include their nonspecificity, wide biodistribution, short half-life, low concentration in tumor tissue and systemic toxicity. Drug delivery to the tumor site has become feasible in recent years, and recent advances in the development of new drug delivery systems for controlled drug release in tumor tissues with reduced side effects show great promise. In this field, the use of biodegradable polymers as drug carriers has attracted the most attention. However, drug release is still difficult to control even when a polymeric drug carrier is used. The design of pharmaceutical polymers that respond to external stimuli (known as stimuli-responsive polymers) such as temperature, pH, electric or magnetic field, enzymes, ultrasound waves, etc. appears to be a successful approach. In these systems, drug release is triggered by different stimuli. The purpose of this review is to summarize different types of polymeric drug carriers and stimuli, in addition to the combination use of stimuli in order to achieve a better controlled drug release, and it discusses their potential strengths and applications. A survey of the recent literature on various stimuli-responsive drug delivery systems is also provided and perspectives on possible future developments in controlled drug release at tumor site have been discussed. PMID:24547737

  9. From antimicrobial to anticancer peptides. A review

    PubMed Central

    Gaspar, Diana; Veiga, A. Salomé; Castanho, Miguel A. R. B.

    2013-01-01

    Antimicrobial peptides (AMPs) are part of the innate immune defense mechanism of many organisms. Although AMPs have been essentially studied and developed as potential alternatives for fighting infectious diseases, their use as anticancer peptides (ACPs) in cancer therapy either alone or in combination with other conventional drugs has been regarded as a therapeutic strategy to explore. As human cancer remains a cause of high morbidity and mortality worldwide, an urgent need of new, selective, and more efficient drugs is evident. Even though ACPs are expected to be selective toward tumor cells without impairing the normal body physiological functions, the development of a selective ACP has been a challenge. It is not yet possible to predict antitumor activity based on ACPs structures. ACPs are unique molecules when compared to the actual chemotherapeutic arsenal available for cancer treatment and display a variety of modes of action which in some types of cancer seem to co-exist. Regardless the debate surrounding the definition of structure-activity relationships for ACPs, great effort has been invested in ACP design and the challenge of improving effective killing of tumor cells remains. As detailed studies on ACPs mechanisms of action are crucial for optimizing drug development, in this review we provide an overview of the literature concerning peptides' structure, modes of action, selectivity, and efficacy and also summarize some of the many ACPs studied and/or developed for targeting different solid and hematologic malignancies with special emphasis on the first group. Strategies described for drug development and for increasing peptide selectivity toward specific cells while reducing toxicity are also discussed. PMID:24101917

  10. Cancer cell-oriented migration of mesenchymal stem cells engineered with an anticancer gene (PTEN): an imaging demonstration

    PubMed Central

    Yang, Zhuo-Shun; Tang, Xiang-Jun; Guo, Xing-Rong; Zou, Dan-Dan; Sun, Xu-Yong; Feng, Jing-Bo; Luo, Jie; Dai, Long-Jun; Warnock, Garth L

    2014-01-01

    Background Mesenchymal stem cells (MSCs) have been considered to hold great potential as ideal carriers for the delivery of anticancer agents since the discovery of their tumor tropism. This study was performed to demonstrate the effects of phosphatase and tensin homolog (PTEN) engineering on MSCs’ capacity for cancer cell-oriented migration. Methods MSCs were engineered with a PTEN-bearing plasmid and the expression was confirmed with Western blotting. A human glioma cell line (DBTRG) was used as the target cell; DBTRG cell-oriented migration of MSCs was monitored with a micro speed photographic system. Results The expression of transfected PTEN in MSCs was identified by immunoblotting analysis and confirmed with cell viability assessment of target cells. The DBTRG cell-oriented migration of PTEN-engineered MSCs was demonstrated by a real-time dynamic monitoring system, and a phagocytosis-like action of MSCs was also observed. Conclusion MSCs maintained their capacity for cancer cell-directed migration after they were engineered with anticancer genes. This study provides the first direct evidence of MSCs’ tropism post-anticancer gene engineering. PMID:24669193

  11. [Chemical evaluation by cancer cell line panel and its role in molecular target-based anticancer drug screening].

    PubMed

    Yamori, Takao

    2004-04-01

    Mechanism-based or target-based evaluation of chemicals is important in the discovery and development of anticancer drugs. A new scale for the mechanism-oriented evaluation is acquired by creating a database of drugs that includes their activities concerning growth inhibition against a set of cancer cell lines and by employing a specific data-mining method (Paull KD, et al: J Natl Cancer Inst 81: 1088-1092, 1989). According to this principle, we have established a new system for drug evaluation using a panel of 39 human cancer cell lines, JFCR-39 Cell Line Panel. The JFCR-39 Cell Line Panel is a system combining a wet system (drug-sensitivity test) and a dry system (data base and its mining), and can predict the mechanism of action of chemicals. Therefore, it is useful in anticancer drug discovery. The JFCR-39 Cell Line Panel now plays an important role as a core drug evaluation system in the molecular target-based drug screening conducted by Screening Committee of New Anticancer Agents supported by Grant-in-Aid for Scientific Research on Priority Area "Cancer" from The Ministry of Education, Culture, Sports, Science and Technology, Japan. I outlined the JFCR-39 Cell Line Panel in this review. PMID:15114687

  12. 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; Pot??ková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Ma?ecki, Jan G.; Sajewicz, Mieczys?aw; Ratuszna, Alicja; Muchowicz, Angelika; Go??b, Jakub; Šim?nek, 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. Anticancer and antitumor potential of fucoidan and fucoxanthin, two main metabolites isolated from brown algae.

    PubMed

    Zorofchian Moghadamtousi, Soheil; Karimian, Hamed; Khanabdali, Ramin; Razavi, Mahboubeh; Firoozinia, Mohammad; Zandi, Keivan; Abdul Kadir, Habsah

    2014-01-01

    Seaweed is one of the largest producers of biomass in marine environment and is a rich arsenal of active metabolites and functional ingredients with valuable beneficial health effects. Being a staple part of Asian cuisine, investigations on the crude extracts of Phaeophyceae or brown algae revealed marked antitumor activity, eliciting a variety of research to determine the active ingredients involved in this potential. The sulfated polysaccharide of fucoidan and carotenoid of fucoxanthin were found to be the most important active metabolites of brown algae as potential chemotherapeutic or chemopreventive agents. This review strives to provide detailed account of all current knowledge on the anticancer and antitumor activity of fucoidan and fucoxanthin as the two major metabolites isolated from brown algae. PMID:24526922

  14. Anticancer Role of PPAR? Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

    PubMed Central

    Simpson-Haidaris, P. J.; Pollock, S. J.; Ramon, S.; Guo, N.; Woeller, C. F.; Feldon, S. E.; Phipps, R. P.

    2010-01-01

    The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-? agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPAR? agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPAR? agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPAR? and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow. PMID:20204067

  15. Synthesis, molecular docking and anticancer studies of peptides and iso-peptides.

    PubMed

    Jabeen, Farukh; Panda, Siva S; Kondratyuk, Tamara P; Park, Eun-Jung; Pezzuto, John M; Ihsan-ul-Haq; Hall, C Dennis; Katritzky, Alan R

    2015-08-01

    Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimerization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinski's Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA-MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results. PMID:26048799

  16. Autophagy in Cancer Chemoprevention: Identification of Novel Autophagy Modulators with Anticancer Potential.

    PubMed

    Lao, Yuanzhi; Xu, Naihan

    2016-01-01

    Cancer cells have the ability to tolerate extreme conditions, autophagy-related stress tolerance enables cancer cells to survive by maintaining energy production that leads to cell growth and therapeutic resistance. Insufficient activation of autophagy in nutrient-deprived cancer cells may sensitize cancer cells to a broad array of chemotherapeutic agents and ionizing radiation. Therefore, identification of novel autophagy modulators with lower toxicity and better therapeutic index would be beneficial for cancer therapy. Here, we describe several currently used biochemical methods to assess autophagic activity and lysosomal function in cultured cancer cells. We also discuss both in vitro and in vivo assays to clarify the anticancer potential of novel autophagy modulators. PMID:26608298

  17. The wisdom of crowds and the repurposing of artesunate as an anticancer drug

    PubMed Central

    Augustin, Yolanda; Krishna, Sanjeev; Kumar, Devinder; Pantziarka, Pan

    2015-01-01

    Artesunate, a semi-synthetic and water-soluble artemisinin-derivative used as an anti-malarial agent, has attracted the attention of cancer researchers due to a broad range of anti-cancer activity including anti-angiogenic, immunomodulatory and treatment-sensitisation effects. In addition to pre-clinical evidence in a range of cancers, a recently completed randomised blinded trial in colorectal cancer has provided a positive signal for further clinical investigation. Used perioperatively artesunate appears to reduce the rate of disease recurrence - and the Neo-Art trial, a larger Phase II RCT, is seeking to confirm this positive effect. However, artesunate is a generic medication, and as with other trials of repurposed drugs, the Neo-Art trial does not have commercial sponsorship. In an innovative move, the trial is seeking funds directly from members of the public via a crowd-funding strategy that may have resonance beyond this single trial. PMID:26557887

  18. Anticancer and Antitumor Potential of Fucoidan and Fucoxanthin, Two Main Metabolites Isolated from Brown Algae

    PubMed Central

    Zorofchian Moghadamtousi, Soheil; Karimian, Hamed; Khanabdali, Ramin; Razavi, Mahboubeh; Firoozinia, Mohammad; Abdul Kadir, Habsah

    2014-01-01

    Seaweed is one of the largest producers of biomass in marine environment and is a rich arsenal of active metabolites and functional ingredients with valuable beneficial health effects. Being a staple part of Asian cuisine, investigations on the crude extracts of Phaeophyceae or brown algae revealed marked antitumor activity, eliciting a variety of research to determine the active ingredients involved in this potential. The sulfated polysaccharide of fucoidan and carotenoid of fucoxanthin were found to be the most important active metabolites of brown algae as potential chemotherapeutic or chemopreventive agents. This review strives to provide detailed account of all current knowledge on the anticancer and antitumor activity of fucoidan and fucoxanthin as the two major metabolites isolated from brown algae. PMID:24526922

  19. Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma.

    PubMed

    Oberoi, Rajneet K; Parrish, Karen E; Sio, Terence T; Mittapalli, Rajendar K; Elmquist, William F; Sarkaria, Jann N

    2016-01-01

    Glioblastoma (GBM) is a lethal and aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. Molecularly targeted agents hold great promise in treating these genetically heterogeneous tumors, yet have produced disappointing results. One reason for the clinical failure of these novel therapies can be the inability of the drugs to achieve effective concentrations in the invasive regions beyond the bulk tumor. In this review, we describe the influence of the blood-brain barrier on the distribution of anticancer drugs to both the tumor core and infiltrative regions of GBM. We further describe potential strategies to overcome these drug delivery limitations. Understanding the key factors that limit drug delivery into brain tumors will guide future development of approaches for enhanced delivery of effective drugs to GBM. PMID:26359209

  20. PI3K Functions in Cancer Progression, Anticancer Immunity and Immune Evasion by Tumors

    PubMed Central

    Dituri, Francesco; Mazzocca, Antonio; Giannelli, Gianluigi; Antonaci, Salvatore

    2011-01-01

    The immunological surveillance of tumors relies on a specific recognition of cancer cells and their associate antigens by leucocytes of innate and adaptive immune responses. However, a dysregulated cytokine release can lead to, or be associated with, a failure in cell-cell recognition, thus, allowing cancer cells to evade the killing system. The phosphatidylinositol 3-kinase (PI3K) pathway regulates multiple cellular processes which underlie immune responses against pathogens or malignant cells. Conversely, there is accumulating evidence that the PI3K pathway is involved in the development of several malignant traits of cancer cells as well as their escape from immunity. Herein, we review the counteracting roles of PI3K not only in antitumor immune response but also in the mechanisms that cancer cells use to avoid leukocyte attack. In addition, we discuss, from antitumor immunological point of view, the potential benefits and disadvantages arising from use of anticancer pharmacological agents targeting the PI3K pathway. PMID:22046194

  1. Evaluation of Extrahepatic Perfusion of Anticancer Drugs in the Right Gastric Arterial Region on Fused Images Using Combined CT/SPECT: Is Extrahepatic Perfusion Predictive of Gastric Toxicity?

    SciTech Connect

    Ikeda, Osamu Tamura, Yoshitaka; Nakasone, Yutaka; Shiraishi, Shinya; Kawanaka, Kouichi; Tomiguchi, Seiji; Morishita, Shouji; Takamori, Hiroshi; Chikamoto, Akira; Kanemitsu, Keiichirou; Yamashita, Yasuyuki

    2007-06-15

    Background. Hepatic arterial infusion (HAI) chemotherapy is effective for treating primary and metastatic carcinomas of the liver. Since hepatic arteries also supply the stomach and duodenum, HAI may result in unwanted infusion into the upper gastrointestinal tract and consequent gastric toxicity. Using fused images obtained with a combined SPECT/CT system, we assessed extrahepatic perfusion (EHP) and its correlation with gastrointestinal toxicity in patients receiving HAI. Methods. We studied 41 patients with primary or metastatic carcinoma of the liver who received HAI chemotherapy consisting of 5-fluorouracil and cisplatin. All underwent abdominal SPECT using a {sup 99m}Tc-MAA (185 MBq) instrument and an injection rate of 0.1 ml/min, identical to the chemotherapy infusion rate. Delivery was through an implantable port. We analyzed the distribution of the anticancer agent on fused images and the relationship between EHP of the right gastric arterial region and gastric toxicity. All patients underwent esophagogastroduodenoscopy (EGDS). Results. Of the 41 patients, 11 (27%) manifested enhancement of the duodenal and gastric pyloric region on fused images. EGDS at the time of reservoir placement detected gastric ulcers in 10 of these patients. Conclusion. Fusion imaging with combined SPECT/CT reflects the actual distribution of the infused anticancer agents. The detection of EHP on fused images is predictive of the direct gastric toxicity from anticancer agents in patients undergoing HAI.

  2. Anticancer activity of pyrithione zinc in oral cancer cells identified in small molecule screens and xenograft model: Implications for oral cancer therapy.

    PubMed

    Srivastava, Gunjan; Matta, Ajay; Fu, Guodong; Somasundaram, Raj Thani; Datti, Alessandro; Walfish, Paul G; Ralhan, Ranju

    2015-10-01

    Oral squamous cell carcinoma (OSCC) patients diagnosed in late stages have limited chemotherapeutic options, underscoring the great need for development of new anticancer agents for more effective disease management. We aimed to identify novel anticancer agents for OSCC using quantitative high throughput assays for screening six chemical libraries consisting of 5170 small molecule inhibitors. In depth characterization resulted in identification of pyrithione zinc (PYZ) as the most effective cytotoxic agent inhibiting cell proliferation and inducing apoptosis in OSCC cells in vitro. Further, treatment with PYZ reduced colony forming, migration and invasion potential of oral cancer cells in a dose-dependent manner. PYZ treatment also led to altered expression of several key components of the major signaling pathways including PI3K/AKT/mTOR and WNT/?-catenin in OSCC cells. In addition, treatment with PYZ also reduced expression of 14-3-3?, 14-3-3?, cyclin D1, c-Myc and pyruvate kinase M2 (PKM2), proteins identified in our earlier studies to be involved in development and progression of OSCCs. Importantly, PYZ treatment significantly reduced tumor xenograft volume in immunocompromised NOD/SCID/Crl mice without causing apparent toxicity to normal tissues. Taken together, we demonstrate in vitro and in vivo efficacy of PYZ in OSCC. In conclusion, we identified PYZ in HTS assays and demonstrated in vitro and in vivo pre-clinical efficacy of PYZ as a novel anticancer therapeutic candidate in OSCC. PMID:26115765

  3. 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

  4. CancerPPD: a database of anticancer peptides and proteins.

    PubMed

    Tyagi, Atul; Tuknait, Abhishek; Anand, Priya; Gupta, Sudheer; Sharma, Minakshi; Mathur, Deepika; Joshi, Anshika; Singh, Sandeep; Gautam, Ankur; Raghava, Gajendra P S

    2015-01-01

    CancerPPD (http://crdd.osdd.net/raghava/cancerppd/) is a repository of experimentally verified anticancer peptides (ACPs) and anticancer proteins. Data were manually collected from published research articles, patents and from other databases. The current release of CancerPPD consists of 3491 ACP and 121 anticancer protein entries. Each entry provides comprehensive information related to a peptide like its source of origin, nature of the peptide, anticancer activity, N- and C-terminal modifications, conformation, etc. Additionally, CancerPPD provides the information of around 249 types of cancer cell lines and 16 different assays used for testing the ACPs. In addition to natural peptides, CancerPPD contains peptides having non-natural, chemically modified residues and D-amino acids. Besides this primary information, CancerPPD stores predicted tertiary structures as well as peptide sequences in SMILES format. Tertiary structures of peptides were predicted using the state-of-art method, PEPstr and secondary structural states were assigned using DSSP. In order to assist users, a number of web-based tools have been integrated, these include keyword search, data browsing, sequence and structural similarity search. We believe that CancerPPD will be very useful in designing peptide-based anticancer therapeutics. PMID:25270878

  5. Anticancer Activity of Metal Complexes: Involvement of Redox Processes

    PubMed Central

    Jungwirth, Ute; Kowol, Christian R.; Keppler, Bernhard K.; Hartinger, Christian G.; Berger, Walter; Heffeter, Petra

    2012-01-01

    Cells require tight regulation of the intracellular redox balance and consequently of reactive oxygen species for proper redox signaling and maintenance of metal (e.g., of iron and copper) homeostasis. In several diseases, including cancer, this balance is disturbed. Therefore, anticancer drugs targeting the redox systems, for example, glutathione and thioredoxin, have entered focus of interest. Anticancer metal complexes (platinum, gold, arsenic, ruthenium, rhodium, copper, vanadium, cobalt, manganese, gadolinium, and molybdenum) have been shown to strongly interact with or even disturb cellular redox homeostasis. In this context, especially the hypothesis of “activation by reduction” as well as the “hard and soft acids and bases” theory with respect to coordination of metal ions to cellular ligands represent important concepts to understand the molecular modes of action of anticancer metal drugs. The aim of this review is to highlight specific interactions of metal-based anticancer drugs with the cellular redox homeostasis and to explain this behavior by considering chemical properties of the respective anticancer metal complexes currently either in (pre)clinical development or in daily clinical routine in oncology. PMID:21275772

  6. CancerPPD: a database of anticancer peptides and proteins

    PubMed Central

    Tyagi, Atul; Tuknait, Abhishek; Anand, Priya; Gupta, Sudheer; Sharma, Minakshi; Mathur, Deepika; Joshi, Anshika; Singh, Sandeep; Gautam, Ankur; Raghava, Gajendra P.S.

    2015-01-01

    CancerPPD (http://crdd.osdd.net/raghava/cancerppd/) is a repository of experimentally verified anticancer peptides (ACPs) and anticancer proteins. Data were manually collected from published research articles, patents and from other databases. The current release of CancerPPD consists of 3491 ACP and 121 anticancer protein entries. Each entry provides comprehensive information related to a peptide like its source of origin, nature of the peptide, anticancer activity, N- and C-terminal modifications, conformation, etc. Additionally, CancerPPD provides the information of around 249 types of cancer cell lines and 16 different assays used for testing the ACPs. In addition to natural peptides, CancerPPD contains peptides having non-natural, chemically modified residues and D-amino acids. Besides this primary information, CancerPPD stores predicted tertiary structures as well as peptide sequences in SMILES format. Tertiary structures of peptides were predicted using the state-of-art method, PEPstr and secondary structural states were assigned using DSSP. In order to assist users, a number of web-based tools have been integrated, these include keyword search, data browsing, sequence and structural similarity search. We believe that CancerPPD will be very useful in designing peptide-based anticancer therapeutics. PMID:25270878

  7. Sunscreening Agents

    PubMed Central

    Martis, Jacintha; Shobha, V; Sham Shinde, Rutuja; Bangera, Sudhakar; Krishnankutty, Binny; Bellary, Shantala; Varughese, Sunoj; Rao, Prabhakar; Naveen Kumar, B.R.

    2013-01-01

    The increasing incidence of skin cancers and photodamaging effects caused by ultraviolet radiation has increased the use of sunscreening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Many sunscreen compounds are in use, but their safety and efficacy are still in question. Efficacy is measured through indices, such as sun protection factor, persistent pigment darkening protection factor, and COLIPA guidelines. The United States Food and Drug Administration and European Union have incorporated changes in their guidelines to help consumers select products based on their sun protection factor and protection against ultraviolet radiation, whereas the Indian regulatory agency has not yet issued any special guidance on sunscreening agents, as they are classified under cosmetics. In this article, the authors discuss the pharmacological actions of sunscreening agents as well as the available formulations, their benefits, possible health hazards, safety, challenges, and proper application technique. New technologies and scope for the development of sunscreening agents are also discussed as well as the role of the physician in patient education about the use of these agents. PMID:23320122

  8. Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer

    NASA Astrophysics Data System (ADS)

    Gao, Xiang; Wang, Bilan; Wei, Xiawei; Men, Ke; Zheng, Fengjin; Zhou, Yingfeng; Zheng, Yu; Gou, Maling; Huang, Meijuan; Guo, Gang; Huang, Ning; Qian, Zhiyong; Wei, Yuquan

    2012-10-01

    Encapsulation of hydrophobic agents in polymer micelles can improve the water solubility of cargos, contributing to develop novel drugs. Quercetin (QU) is a hydrophobic agent with potential anticancer activity. In this work, we encapsulated QU into biodegradable monomethoxy poly(ethylene glycol)-poly(?-caprolactone) (MPEG-PCL) micelles and tried to provide proof-of-principle for treating ovarian cancer with this nano-formulation of quercetin. These QU loaded MPEG-PCL (QU/MPEG-PCL) micelles with drug loading of 6.9% had a mean particle size of 36 nm, rendering the complete dispersion of quercetin in water. QU inhibited the growth of A2780S ovarian cancer cells on a dose dependent manner in vitro. Intravenous administration of QU/MPEG-PCL micelles significantly suppressed the growth of established xenograft A2780S ovarian tumors through causing cancer cell apoptosis and inhibiting angiogenesis in vivo. Furthermore, the anticancer activity of quercetin on ovarian cancer cells was studied in vitro. Quercetin treatment induced the apoptosis of A2780S cells associated with activating caspase-3 and caspase-9. MCL-1 downregulation, Bcl-2 downregulation, Bax upregulation and mitochondrial transmembrane potential change were observed, suggesting that quercetin may induce apoptosis of A2780S cells through the mitochondrial apoptotic pathway. Otherwise, quercetin treatment decreased phosphorylated p44/42 mitogen-activated protein kinase and phosphorylated Akt, contributing to inhibition of A2780S cell proliferation. Our data suggested that QU/MPEG-PCL micelles were a novel nano-formulation of quercetin with a potential clinical application in ovarian cancer therapy.

  9. Reduced graphene oxide–silver nanoparticle nanocomposite: a potential anticancer nanotherapy

    PubMed Central

    Gurunathan, Sangiliyandi; Han, Jae Woong; Park, Jung Hyun; Kim, Eunsu; Choi, Yun-Jung; Kwon, Deug-Nam; Kim, Jin-Hoi

    2015-01-01

    Background Graphene and graphene-based nanocomposites are used in various research areas including sensing, energy storage, and catalysis. The mechanical, thermal, electrical, and biological properties render graphene-based nanocomposites of metallic nanoparticles useful for several biomedical applications. Epithelial ovarian carcinoma is the fifth most deadly cancer in women; most tumors initially respond to chemotherapy, but eventually acquire chemoresistance. Consequently, the development of novel molecules for cancer therapy is essential. This study was designed to develop a simple, non-toxic, environmentally friendly method for the synthesis of reduced graphene oxide–silver (rGO–Ag) nanoparticle nanocomposites using Tilia amurensis plant extracts as reducing and stabilizing agents. The anticancer properties of rGO–Ag were evaluated in ovarian cancer cells. Methods The synthesized rGO–Ag nanocomposite was characterized using various analytical techniques. The anticancer properties of the rGO–Ag nanocomposite were evaluated using a series of assays such as cell viability, lactate dehydrogenase leakage, reactive oxygen species generation, cellular levels of malonaldehyde and glutathione, caspase-3 activity, and DNA fragmentation in ovarian cancer cells (A2780). Results AgNPs with an average size of 20 nm were uniformly dispersed on graphene sheets. The data obtained from the biochemical assays indicate that the rGO–Ag nanocomposite significantly inhibited cell viability in A2780 ovarian cancer cells and increased lactate dehydrogenase leakage, reactive oxygen species generation, caspase-3 activity, and DNA fragmentation compared with other tested nanomaterials such as graphene oxide, rGO, and AgNPs. Conclusion T. amurensis plant extract-mediated rGO–Ag nanocomposites could facilitate the large-scale production of graphene-based nanocomposites; rGO–Ag showed a significant inhibiting effect on cell viability compared to graphene oxide, rGO, and silver nanoparticles. The nanocomposites could be effective non-toxic therapeutic agents for the treatment of both cancer and cancer stem cells. PMID:26491296

  10. Applying Agent Technology Applying Agent Technology

    E-print Network

    Woolridge, Mike

    Kingdom N.R.Jennings@qmw.ac.uk M.Wooldridge@doc.mmu.ac.uk 1. Intelligent Agents and Multi­Agent Systems The term ``agent'', (and hence ``agent based computing'', ``agent based system'', ``multi­agent system entities. These entities range from relatively simple systems, (such as Microsoft's TIP WIZARD, which

  11. Novel anticancer polymeric conjugates of activated nucleoside analogs

    PubMed Central

    Senanayake, Thulani H.; Warren, Galya; Vinogradov, Serguei V.

    2011-01-01

    Inherent or therapy-induced drug resistance is a major clinical setback in cancer treatment. The extensive usage of cytotoxic nucleobases and nucleoside analogs in chemotherapy also results in the development of specific mechanisms of drug resistance; such as nucleoside transport or activation deficiencies. These drugs are prodrugs; and being converted into the active mono-, di- and triphosphates inside cancer cells following administration, they affect nucleic acid synthesis, nucleotide metabolism, or sensitivity to apoptosis. Previously, we have actively promoted the idea that the nanodelivery of active nucleotide species, e.g. 5?-triphosphates of nucleoside analogs, can enhance drug efficacy and reduce nonspecific toxicity. In this study we report the development of a novel type of drug nanoformulations, polymeric conjugates of nucleoside analogs, which are capable of the efficient transport and sustained release of phosphorylated drugs. These drug conjugates have been synthesized, starting from cholesterol-modified mucoadhesive polyvinyl alcohol or biodegradable dextrin, by covalent attachment of nucleoside analogs through a tetraphosphate linker. Association of cholesterol moieties in aqueous media resulted in intramolecular polymer folding and the formation of small nanogel particles containing 0.5 mmol/g of a 5?-phosphorylated nucleoside analog, e.g. 5-fluoro-2?-deoxyuridine (floxuridine, FdU), an active metabolite of anticancer drug 5-fluorouracyl (5-FU). The polymeric conjugates demonstrated rapid enzymatic release of floxuridine 5?-phosphate and much slower drug release under hydrolytic conditions (pH 1.0–7.4). Among the panel of cancer cell lines, all studied polymeric FdU-conjugates demonstrated an up to 50 times increased cytotoxicity in human prostate cancer PC-3, breast cancer MCF-7 and MDA-MB-231 cells, and more than 100 times higher efficacy against cytarabine-resistant human T-lymphoma (CEM/araC/8) and gemcitabine-resistant follicular lymphoma (RL7/G) cells as compared to free drugs. In the initial in vivo screening, both PC-3 and RL7/G subcutaneous tumor xenograft models showed enhanced sensitivity to sustained drug release from polymeric FdU-conjugate after peritumoral injections and significant tumor growth inhibition. All these data demonstrate a remarkable clinical potential of novel polymeric conjugates of phosphorylated nucleoside analogs, especially as new therapeutic agents against drug-resistant tumors. PMID:21863885

  12. A Comprehensive Review on Cyclodextrin-Based Carriers for Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs

    PubMed Central

    Gidwani, Bina; Vyas, Amber

    2015-01-01

    Most of the cytotoxic chemotherapeutic agents have poor aqueous solubility. These molecules are associated with poor physicochemical and biopharmaceutical properties, which makes the formulation difficult. An important approach in this regard is the use of combination of cyclodextrin and nanotechnology in delivery system. This paper provides an overview of limitations associated with anticancer drugs, their complexation with cyclodextrins, loading/encapsulating the complexed drugs into carriers, and various approaches used for the delivery. The present review article aims to assess the utility of cyclodextrin-based carriers like liposomes, niosomes, nanoparticles, micelles, millirods, and siRNA for delivery of antineoplastic agents. These systems based on cyclodextrin complexation and nanotechnology will camouflage the undesirable properties of drug and lead to synergistic or additive effect. Cyclodextrin-based nanotechnology seems to provide better therapeutic effect and sustain long life of healthy and recovered cells. Still, considerable study on delivery system and administration routes of cyclodextrin-based carriers is necessary with respect to their pharmacokinetics and toxicology to substantiate their safety and efficiency. In future, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents. PMID:26582104

  13. 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

  14. Cobra venom cytotoxins; apoptotic or necrotic agents?

    PubMed

    Ebrahim, Karim; Shirazi, Farshad H; Mirakabadi, Abbas Zare; Vatanpour, Hossein

    2015-12-15

    Organs homeostasis is controlled by a dynamic balance between cell proliferation and apoptosis. Failure to induction of apoptosis has been implicated in tumor development. Cytotoxin-I (CTX-I) and cytotoxin-II (CTX-II) are two physiologically active polypeptides found in Caspian cobra venom. Anticancer activity and mechanism of cell death induced by these toxins have been studied. The toxins were purified by different chromatographic steps and their cytotoxicity and pattern of cell death were determined by MTT, LDH release, acridine orange/ethidium bromide (AO/EtBr) double staining, flow cytometric analysis, caspase-3 activity and neutral red assays. The IC50 of CTX-II in MCF-7, HepG2, DU-145 and HL-60 was 4.1 ± 1.3, 21.2 ± 4.4, 9.4 ± 1.8 ?g/mL and 16.3 ± 1.9 respectively while the IC50 of this toxin in normal MDCK cell line was 54.5 ± 3.9 ?g/mL. LDH release suddenly increase after a specific toxins concentrations in all cell lines. AO/EtBr double staining, flow cytometric analysis and caspase-3 activity assay confirm dose and time-dependent induction of apoptosis by both toxins. CTX-I and CTX-II treated cells lost their lysosomal membrane integrity and couldn't uptake neutral red day. CTX-I and CTX-II showed significant anticancer activity with minimum effects on normal cells and better IC50 compared to current anticancer drug; cisplatin. They induce their apoptotic effect via lysosomal pathways and release of cathepsins to cytosol. These effects were seen in limited rage of toxins concentrations and pattern of cell death rapidly changes to necrosis by increase in toxin's concentration. In conclusion, significant apoptogenic effects of these toxins candidate them as a possible anticancer agent. PMID:26482932

  15. Ag@Ag8W4O16 nanoroasted rice beads with photocatalytic, antibacterial and anticancer activity.

    PubMed

    Selvamani, Muthamizh; Krishnamoorthy, Giribabu; Ramadoss, Manigandan; Sivakumar, Praveen Kumar; Settu, Munusamy; Ranganathan, Suresh; Vengidusamy, Narayanan

    2016-03-01

    Increasing resistance of pathogens and cancer cell line towards antibiotics and anticancer agents has caused serious health problems in the past decades. Due to these problems in recent years, researchers have tried to combine nanotechnology with material science to have intrinsic antimicrobial and anticancer activity. The metals and metal oxides were investigated with respect to their antimicrobial and anticancer effects towards bacteria and cancer cell line. In the present work metal@metal tungstate (Ag@Ag8W4O16 nanoroasted rice beads) is investigated for antibacterial activity against Escherichia coli and Staphylococcus aureus using Mueller-Hinton broth and the anticancer activity against B16F10 cell line was studied. Silver decorated silver tungstate (Ag@Ag8W4O16) was synthesized by the microwave irradiation method using Cetyl Trimethyl Ammonium Bromide (CTAB). Ag@Ag8W4O16 was characterized by using various spectroscopic techniques. The phase and crystalline nature were analyzed by using XRD. The morphological analysis was carried out using Field Emission Scanning Electron Microscopy (FE-SEM), and High Resolution Transmission Electron Microscopy (HR-TEM). Further, Fourier Transform Infrared Spectroscopy (FT-IR) and Raman spectral analysis were carried out in order to ascertain the presence of functional groups in Ag@Ag8W4O16. The optical property was investigated using Diffuse Reflectance Ultraviolet-Visible Spectroscopy (DRS-UV-Vis) and the band gap was found to be 3.08eV. Surface area of the synthesized Ag@Ag8W4O16 wasanalyzed by BET analysis and Ag@Ag8W4O16 was utilized for the degradation of organic dyes methylene blue and rhodamine B. The morphology of the Ag@Ag8W4O16 resembles roasted rice beads with breath and length in nm range. The oxidation state of tungsten (W) and silver (Ag) was investigated using X-ray photoelectron spectroscopy (XPS). PMID:26706513

  16. Synthesis of four binuclear copper(II) complexes: Structure, anticancer properties and anticancer mechanism.

    PubMed

    Qi, Jinxu; Liang, Shichu; Gou, Yi; Zhang, Zhenlei; Zhou, Zuping; Yang, Feng; Liang, Hong

    2015-05-26

    Copper (Cu) compounds are a promising candidate for next generation metal anticancer drugs and have been extensively studied. Therefore, four binuclear copper(II) compounds derived from Schiff base thiosemicarbazones (L1-L4), namely [CuCl(L1)]2 (C1), [CuNO3(L2)]2 (C2), [Cu(NCS) (L3)]2 (C3) and [Cu(CH3COO) (L4)]2 (C4) were synthesized and characterized. Four of these compounds showed very high cytotoxicity to cancer cell lines in vitro. These Cu(II) compounds strongly promoted the apoptosis of BEL-7404 cells. The formation of reactive oxygen species (ROS), change in mitochondrial membrane potential and western blot analysis revealed that Cu compounds could induce cancer cell apoptosis through the intrinsic ROS-mediated mitochondrial pathway accompanied by the regulation of Bcl-2 family proteins. PMID:25899339

  17. Anti-cancer natural products isolated from chinese medicinal herbs

    PubMed Central

    2011-01-01

    In recent years, a number of natural products isolated from Chinese herbs have been found to inhibit proliferation, induce apoptosis, suppress angiogenesis, retard metastasis and enhance chemotherapy, exhibiting anti-cancer potential both in vitro and in vivo. This article summarizes recent advances in in vitro and in vivo research on the anti-cancer effects and related mechanisms of some promising natural products. These natural products are also reviewed for their therapeutic potentials, including flavonoids (gambogic acid, curcumin, wogonin and silibinin), alkaloids (berberine), terpenes (artemisinin, ?-elemene, oridonin, triptolide, and ursolic acid), quinones (shikonin and emodin) and saponins (ginsenoside Rg3), which are isolated from Chinese medicinal herbs. In particular, the discovery of the new use of artemisinin derivatives as excellent anti-cancer drugs is also reviewed. PMID:21777476

  18. Poly(ethylene glycol) amphiphilic copolymer for anticancer drugs delivery.

    PubMed

    Feng, Runliang; Zhu, Wenxia; Teng, Fangfang; Liu, Na; Yang, Fengying; Meng, Ning; Song, Zhimei

    2015-01-01

    Poly(ethylene glycol) is a water-soluble polymer. Due to its high safety and biocompatibility, it has been widely used to prepare amphiphilic copolymers for drug delivery. These copolymers can enhance water-solubility of hydrophobic drugs, improve their pharmacokinetic parameters and control their release from corresponding nanocarriers formed by its self-assembly. Anticancer drugs have some shortcomings such as lower water-solubility, bad targeting and some serious side-effects, which limit their applications and are dangerous to patients. So encapsulation of anticancer drugs into nanocarriers originated from its copolymeric derivates can improve their absorption, distribution, metabolism and excretion with better release properties and activities against cancer cells, increase their therapeutic effects, and realize their passive or active target delivery through structure modification. Recent research development of its drug delivery systems for anticancer drugs will be discussed. PMID:25420636

  19. Plant derived and dietary phenolic antioxidants: anticancer properties.

    PubMed

    Roleira, Fernanda M F; Tavares-da-Silva, Elisiário J; Varela, Carla L; Costa, Saul C; Silva, Tiago; Garrido, Jorge; Borges, Fernanda

    2015-09-15

    In this paper, a review of the literature on the phenolic compounds with anticancer activity published between 2008 and 2012 is presented. In this overview only phenolic antioxidant compounds that display significant anticancer activity have been described. In the first part of this review, the oxidative and nitrosative stress relation with cancer are described. In the second part, the plant-derived food extracts, containing identified phenolic antioxidants, the phenolic antioxidants isolated from plants and plant-derived food or commercially available and the synthetic ones, along with the type of cancer and cells where they exert anticancer activity, are described and summarized in tables. The principal mechanisms for their anti-proliferative effects were also described. Finally, a critical analysis of the studies and directions for future research are included in the conclusion. PMID:25863633

  20. Newly synthesized podophyllotoxin derivative, LJ12, induces apoptosis and mitotic catastrophe in non-small cell lung cancer cells in vitro.

    PubMed

    Hui, Ling; Sang, Chunyan; Wang, Donghong; Wang, Xiaohui; Wang, Meiliang; Jia, Qinghua; Ma, Mingren; Chen, Shiwu

    2016-01-01

    Deoxypodophyllotoxin (DPT), an active compound isolated from a number of herbs and used in traditional medicine, has been reported to exhibit promising anti?tumor activity. A newly synthesized derivative, N-(1-oxyl?4'-demethyl-4-deoxyp odophyllic)-L?methine-4'-piperazine carbamate (LJ12) may have improved antitumor activity and fewer side effects. The present study assessed the effect of LJ12 on cell viability, apoptosis, cell cycle distribution and mitotic catastrophe in A549 human lung cancer cells in vitro. The molecular mechanisms underlying the antitumor activity of LJ12 were also examined. The results demonstrated that LJ12 reduced A549 cell viability in a time? and dose?dependent manner, with a lower half maximal inhibitory concentration of ~0.1 µM, compared with another known DPT derivative, etoposide (10 µM). Flow cytometric analysis showed that LJ12 induced tumor cell arrest at the G2/M phase of the cell cycle. The present study also observed an expected concomitant decrease in the numbers of cells cells in the G0/G1 and S phases. LJ12 was found to upregulate the protein expression levels of Cdc2 and Cyclin B1. Furthermore, LJ12 induced tumor cell apoptosis and the protein expression of B cell lymphoma?2?associated X protein, caspase?3 and p53. The present study also observed the formation of giant, multinucleated cells, indicating that LJ12 induced mitotic catastrophe in the tumor cells. These results indicated that LJ12 has anti?non?small cell lung cancer activity in vitro. Further investigations aim to develop LJ12 as a therapeutic agent for the treatment of lung cancer. PMID:26573436

  1. Selective Histone Deacetylase Inhibitors with Anticancer Activity.

    PubMed

    Ma, Nan; Luo, Ying; Wang, Ying; Liao, Chenzhong; Ye, Wen-Cai; Jiang, Sheng

    2016-01-01

    HDAC inhibitors (HDACIs), which can be used to kill cancer cells through inhibiting histone deacetylase activity or altering the structure of chromatin, have emerged as efficacious agents in the treatment of cancer. With SAHA, FK228, belinostat and panobinostat approved by the FDA, displaying satisfying activity in both haematological and solid tumors of various tissues, efforts to create selective HDACIs have been attracted attention over the past several years. Herein, we mainly review the progress of selective HDAC inhibitors including class-selective and isoform-selective HDAC inhibitors. PMID:26268343

  2. Antidiabetic Agents.

    ERIC Educational Resources Information Center

    Plummer, Nancy; Michael, Nancy, Ed.

    This module on antidiabetic agents is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

  3. 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

  4. Antioxidant and in vitro anticancer effect of 2-pyrrolidinone rich fraction of Brassica oleracea var. capitata through induction of apoptosis in human cancer cells.

    PubMed

    Thangam, Ramar; Suresh, Veeraperumal; Rajkumar, Mayan; Vincent, Jally Damien; Gunasekaran, Palani; Anbazhagan, Chinnathambi; Kaveri, Krishnasamy; Kannan, Soundarapandian

    2013-11-01

    The aim of this study was to analyze if the 2-pyrrolidinone rich fraction of Brassica oleracea var. capitata exhibiting antioxidant and in vitro anticancer activities. 2-Pyrrolidinone is an active compound present in Brassica oleracea var. capitata. Our findings explored the potential use of 2-pyrrolidinone in cancer treatment. This compound was identified and isolated by gas chromatography-mass spectrometry and high-performance liquid chromatography from the leaf of Brassica oleracea var. capitata. The resultant rich active compound exhibited in vitro cytotoxicity in HeLa and PC-3 human cancer cell lines, and it also exhibited antioxidant activity in cell free assays. DAPI staining, an apoptotic analysis and cell cycle analysis were performed to evaluate the anticancer activity of 2-pyrrolidinone against the above cell lines. The IC50 value of 2-pyrrolidinone was determined to be of 2.5?µg/ml for HeLa, 3?µg/ml for PC-3 cells at 24?h and 1.5?µg/ml for HeLa and 2?µg/ml for PC-3 cells at 48?h, respectively. However, cell cycle analysis revealed that the anti-proliferative effects of the 2-pyrrolidinone were mediated through cell cycle arrest in the G0/G1 phase. These results from the current study suggest that the 2-pyrrolidinone have potential anticancer effects, which will lead to the development of new anticancer agents for arresting cancer cells growth in vitro. PMID:23292857

  5. 21 CFR 70.51 - Advisory committee on the applicability of the anticancer clause.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... anticancer clause. 70.51 Section 70.51 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... of the anticancer clause. All requests for and procedures governing any advisory committee on the anticancer clause shall be subject to the provisions of part 14 of this chapter, and particularly subpart...

  6. 21 CFR 70.51 - Advisory committee on the applicability of the anticancer clause.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... anticancer clause. 70.51 Section 70.51 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... of the anticancer clause. All requests for and procedures governing any advisory committee on the anticancer clause shall be subject to the provisions of part 14 of this chapter, and particularly subpart...

  7. Hydrofocusing Bioreactor Produces Anti-Cancer Alkaloids

    NASA Technical Reports Server (NTRS)

    Gonda, Steve R.; Valluri, Jagan V.

    2011-01-01

    A methodology for growing three-dimensional plant tissue models in a hydrodynamic focusing bioreactor (HFB) has been developed. The methodology is expected to be widely applicable, both on Earth and in outer space, as a means of growing plant cells and aggregates thereof under controlled conditions for diverse purposes, including research on effects of gravitation and other environmental factors upon plant growth and utilization of plant tissue cultures to produce drugs in quantities greater and at costs lower than those of conventional methodologies. The HFB was described in Hydro focus - ing Bioreactor for Three-Dimensional Cell Culture (MSC-22358), NASA Tech Briefs, Vol. 27, No. 3 (March 2003), page 66. To recapitulate: The HFB offers a unique hydrofocusing capability that enables the creation of a low-shear liquid culture environment simultaneously with the herding of suspended cells and tissue assemblies and removal of unwanted air bubbles. The HFB includes a rotating cell-culture vessel with a centrally located sampling port and an internal rotating viscous spinner attached to a rotating base. The vessel and viscous spinner can be made to rotate at the same speed and direction or different speeds and directions to tailor the flow field and the associated hydrodynamic forces in the vessel in order to obtain low-shear suspension of cells and control of the locations of cells and air bubbles. For research and pharmaceutical-production applications, the HFB offers two major benefits: low shear stress, which promotes the assembly of cells into tissue-like three-dimensional constructs; and randomization of gravitational vectors relative to cells, which affects production of medicinal compounds. Presumably, apposition of plant cells in the absence of shear forces promotes cell-cell contacts, cell aggregation, and cell differentiation. Only gentle mixing is necessary for distributing nutrients and oxygen. It has been postulated that inasmuch as cells in the simulated 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.

  8. Immature, Semi-Mature, and Fully Mature Dendritic Cells: Toward a DC-Cancer Cells Interface That Augments Anticancer Immunity

    PubMed Central

    Dudek, Aleksandra M.; Martin, Shaun; Garg, Abhishek D.; Agostinis, Patrizia

    2013-01-01

    Dendritic cells (DCs) are the sentinel antigen-presenting cells of the immune system; such that their productive interface with the dying cancer cells is crucial for proper communication of the “non-self” status of cancer cells to the adaptive immune system. Efficiency and the ultimate success of such a communication hinges upon the maturation status of the DCs, attained following their interaction with cancer cells. Immature DCs facilitate tolerance toward cancer cells (observed for many apoptotic inducers) while fully mature DCs can strongly promote anticancer immunity if they secrete the correct combinations of cytokines [observed when DCs interact with cancer cells undergoing immunogenic cell death (ICD)]. However, an intermediate population of DC maturation, called semi-mature DCs exists, which can potentiate either tolerogenicity or pro-tumorigenic responses (as happens in the case of certain chemotherapeutics and agents exerting ambivalent immune reactions). Specific combinations of DC phenotypic markers, DC-derived cytokines/chemokines, dying cancer cell-derived danger signals, and other less characterized entities (e.g., exosomes) can define the nature and evolution of the DC maturation state. In the present review, we discuss these different maturation states of DCs, how they might be attained and which anticancer agents or cell death modalities (e.g., tolerogenic cell death vs. ICD) may regulate these states. PMID:24376443

  9. Synthesis and Anticancer Activity of All Known (-)-Agelastatin Sunkyu Han,

    E-print Network

    Hergenrother, Paul J.

    Synthesis and Anticancer Activity of All Known (-)-Agelastatin Alkaloids Sunkyu Han, Dustin S-by-side evaluation of all known (-)-agelastatin alkaloids against nine human cancer cell lines are described. Our concise synthesis of these alkaloids exploits the intrinsic chemistry of plausible biosynthetic precursors

  10. 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

  11. Phytochemical composition and anticancer activity of germinated wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Seed germination is a natural method to increase bioactive components that have beneficial effects on human health. Germinated wheat flour samples of a hard red wheat cultivar (Rampart) were prepared after germination of three and five days and investigated for phytochemical composition and anticanc...

  12. CNS Anticancer Drug Discovery and Development Conference White Paper.

    PubMed

    Levin, Victor A; Tonge, Peter J; Gallo, James M; Birtwistle, Marc R; Dar, Arvin C; Iavarone, Antonio; Paddison, Patrick J; Heffron, Timothy P; Elmquist, William F; Lachowicz, Jean E; Johnson, Ted W; White, Forest M; Sul, Joohee; Smith, Quentin R; Shen, Wang; Sarkaria, Jann N; Samala, Ramakrishna; Wen, Patrick Y; Berry, Donald A; Petter, Russell C

    2015-11-01

    Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric "Accelerating Drug Discovery and Development for Brain Tumors," further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward. PMID:26403167

  13. Anti-cancer Technology Summary 121 Research Drive, Suite 501

    E-print Network

    Peak, Derek

    Anti-cancer Technology Summary 121 Research Drive, Suite 501 Saskatoon, SK, S7N 1K2 Tel: (306) 966 cancers are ranked 2ed , 3ed and 11th of the most diagnosed cancers (National Cancer Institute, USA cancer cells but also healthy ones. A great opportunity exists for targeted therapies for the use solely

  14. Synthesis and evaluation of modified oximidine analogues as anticancer agents and of terephthalaldehyde-bis-guanylhydrazones as endotoxin sequestering agents

    E-print Network

    Khownium, Kriangsak

    2009-12-15

    the intermediate 42 in 70% yield. The acetate group of 42 was cleaved in the presence of CsCO 3 and Et 3 N in MeOH at 0 ?C to provide the primary alcohol 43. Subsequent Swern oxidation furnished aldehyde 44 in good yield. The macrolactone containing epoxide 45...-complex To complete the total synthesis, the triene macrocycle 60 was subjected to DDQ oxidative cleavage of the PMB ether and the resulting alcohol was oxidized with pyridinium dichromate. The crude aldehyde was converted to the vinyl iodide 65 as a single isomer...

  15. Anticancer Effect of AntiMalarial Artemisinin Compounds

    PubMed Central

    Das, AK

    2015-01-01

    The anti-malarial drug artemisinin has shown anticancer activity in vitro and animal experiments, but experience in human cancer is scarce. However, the ability of artemisinins to kill cancer cells through a variety of molecular mechanisms has been explored. A PubMed search of about 127 papers on anti-cancer effects of antimalarials has revealed that this class of drug, including other antimalarials, have several biological characteristics that include anticancer properties. Experimental evidences suggest that artemisinin compounds may be a therapeutic alternative in highly aggressive cancers with rapid dissemination, without developing drug resistance. They also exhibit synergism with other anticancer drugs with no increased toxicity toward normal cells. It has been found that semisynthetic artemisinin derivatives have much higher antitumor activity than their monomeric counterparts via mechanisms like apoptosis, arrest of cell cycle at G0/G1, and oxidative stress. The exact mechanism of activation and molecular basis of these anticancer effects are not fully elucidated. Artemisinins seem to regulate key factors such as nuclear factor-kappa B, survivin, NOXA, hypoxia-inducible factor-1?, and BMI-1, involving multiple pathways that may affect drug response, drug interactions, drug resistance, and associated parameters upon normal cells. Newer synthetic artemisinins have been developed showing substantial antineoplastic activity, but there is still limited information regarding the mode of action of these synthetic compounds. In view of the emerging data, specific interactions with established chemotherapy need to be further investigated in different cancer cells and their phenotypes and validated further using different semisynthetic and synthetic artemisinin derivatives. PMID:25861527

  16. Development and validation of an HPLC-MS/MS analytical method for quantitative analysis of TCBA-TPQ, a novel anticancer makaluvamine analog, and application in a pharmacokinetic study in rats.

    PubMed

    Yu, Jun-Xian; Voruganti, Sukesh; Li, Dan-Dan; Qin, Jiang-Jiang; Nag, Subhasree; Xu, Su; Velu, Sadanandan E; Wang, Wei; Zhang, Ruiwen

    2015-07-01

    We have recently designed and synthesized several novel iminoquinone anticancer agents that have entered preclinical development for the treatment of human cancers. Herein we developed and validated a quantitative HPLC-MS/MS analytical method for one of the lead novel anticancer makaluvamine analog, TCBA-TPQ, and conducted a pharmacokinetic study in laboratory rats. Our results indicated that the HPLC-MS/MS method was precise, accurate, and specific. Using this method, we carried out in vitro and in vivo evaluations of the pharmacological properties of TCBA-TPQ and plasma pharmacokinetics in rats. Our results provide a basis for future preclinical and clinical development of this promising anticancer marine analog. PMID:26233847

  17. MDM2 and MDM4: p53 regulators as targets in anticancer therapy

    PubMed Central

    Toledo, Franck; Wahl, Geoffrey M.

    2007-01-01

    The gene TP53, encoding transcription factor p53, is mutated or deleted in half of human cancers, demonstrating the crucial role of p53 in tumor suppression. Importantly, p53 inactivation in cancers can also result from the amplification / overexpression of its specific inhibitors MDM2 and MDM4 (also known as MDMX). The presence of wild-type p53 in those tumors with MDM2 or MDM4 overexpression stimulates the search for new therapeutic agents to selectively reactivate it. This short survey highlights recent insights into MDM2 and MDM4 regulatory functions and their implications for the design of future p53-based anticancer strategies. We now know that MDM2 and MDM4 inhibit p53 in distinct and complementary ways: MDM4 regulates p53 activity, while MDM2 mainly regulates p53 stability. Upon DNA damage, MDM2-dependent degradation of itself and MDM4 contribute significantly to p53 stabilization and activation. These and other data imply that the combined use of MDM2 and MDM4 antagonists in cancer cells expressing wild type p53 should activate p53 more significantly than agents that only antagonize MDM2, resulting in more effective anti-tumor activity. PMID:17499002

  18. Ligand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity

    PubMed Central

    Adhireksan, Zenita; Davey, Gabriela E.; Campomanes, Pablo; Groessl, Michael; Clavel, Catherine M.; Yu, Haojie; Nazarov, Alexey A.; Yeo, Charmian Hui Fang; Ang, Wee Han; Dröge, Peter; Rothlisberger, Ursula; Dyson, Paul J.; Davey, Curt A.

    2014-01-01

    Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents—the cytotoxic antiprimary tumour compound [(?6-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(?6-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]—and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel ‘atom-to-cell’ approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells. PMID:24637564

  19. Review structure- and dynamics-based computational design of anticancer drugs.

    PubMed

    Lin, Jung Hsin

    2016-01-01

    Cancer is a class of highly complex diseases involving multiple genes and multiple cross-talks between signaling networks. Cancer cells may be developed from inherited defects or acquired damages of DNA. However, many cancers are resistant to treatment, and metastasis of cancers makes the disease even more intractable. Secondary malignancies are frequently observed after cancer chemotherapy. The call for more effective cancer therapy is obligatory. Using drug-cocktails that combine multiple anti-cancer agents working in different mechanisms has been a standard treatment of cancers to overcome the drug resistance problem. More recently, design of multiple ligands (may be more easily understood as "multiple target ligands"), i.e., single agents that target multiple biomolecules in a rational manner, receives increasing attention. For those who work on computational drug design, such tasks serve as new opportunities for achieving drugs with more effective pharmacological actions, in addition to designing compounds with better binding affinity, better selectivity, or to discovering compounds that can exert their actions allosterically. Some recent methodological developments on computational drug design are reviewed, and a few recent drug design efforts on a selected set of targets (topoisomerases, Ras proteins, protein kinases, and histone deacetylases) toward cancer treatment and cancer prevention are summarized. © 2015 Wiley Periodicals, Inc. Biopolymers 105: 2-9, 2015. PMID:26385494

  20. Luteolin nanoparticle in chemoprevention – in vitro and in vivo anticancer activity

    PubMed Central

    Majumdar, Debatosh; Jung, Kyung-Ho; Zhang, Hongzheng; Nannapaneni, Sreenivas; Wang, Xu; Amin, A.R.M Ruhul; Chen, Zhengjia; Chen, Zhuo (G).; Shin, Dong M.

    2013-01-01

    Cancer prevention (chemoprevention) by using naturally occurring dietary agents has gained immense interest due to the broad safety window of these compounds. However, many of these compounds are hydrophobic and poorly soluble in water. They frequently display low bioavailability, poor systemic delivery, and low efficacy. To circumvent this problem, we explored a novel approach towards chemoprevention using nanotechnology to deliver luteolin, a natural compound present in green vegetables. We formulated water soluble polymer-encapsulated Nano-Luteolin from hydrophobic luteolin, and studied its anticancer activity against lung cancer and head and neck cancer. In vitro studies demonstrated that, like luteolin, Nano-Luteolin inhibited the growth of lung cancer cells (H292 cell line) and squamous cell carcinoma of head and neck (SCCHN) cells (Tu212 cell line). In Tu212 cells, the IC50 value of Nano-Luteolin was 4.13?M, and that of luteolin was 6.96?M. In H292 cells, the IC50 of luteolin was 15.56?M, and Nano-Luteolin was 14.96?M. In vivo studies using a tumor xenograft mouse model demonstrated that Nano-Luteolin has a significant inhibitory effect on the tumor growth of SCCHN in comparison to luteolin. Our results suggest that nanoparticle delivery of naturally occurring dietary agents like luteolin has many advantages and may have potential application in chemoprevention in clinical settings. PMID:24403290