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Sample records for anticancer agent podophyllotoxin

  1. Synthesis and comparative evaluation of 4-oxa- and 4-aza-podophyllotoxins as antiproliferative microtubule destabilizing agents.

    PubMed

    Chernysheva, Natalia B; Tsyganov, Dmitry V; Philchenkov, Alex A; Zavelevich, Michael P; Kiselyov, Alex S; Semenov, Roman V; Semenova, Marina N; Semenov, Victor V

    2012-04-01

    A series of novel 4-oxa-podophyllotoxin derivatives 7 featuring the intact lactone ring D and various substituents in rings B and E has been synthesized and evaluated in a phenotypic sea urchin embryo assay along with the representative 4-aza-analogs 5 for their antimitotic and microtubule destabilizing activity. The most active compounds exhibited myristicin-derived or a 3',5'-dimethoxy substitution pattern in the ring E and a 6-methoxy moiety replacing the methylenedioxy ring A. Compounds 5xb, 5xe, 5yb, 7xa, 7xb, and 7xc showed potent antiproliferative effects in the NCI60 cytotoxicity screen. Notably, growth of the multi-drug resistant NCI/ADR-RES cells was more affected by these agents than the parent OVCAR-8 cell line. Although generally 4-oxa-podophyllotoxins were less potent than the respective 4-aza-derivatives in these assays, stability of the former series towards oxidation may prove to be of interest for the development of anticancer agents with in vivo activity. PMID:22370267

  2. Anticancer Properties of an Important Drug Lead Podophyllotoxin Can Be Efficiently Mimicked by Diverse Heterocyclic Scaffolds Accessible via One-Step Synthesis

    PubMed Central

    Magedov, Igor V.; Frolova, Liliya; Manpadi, Madhuri; Bhoga, Uma devi; Tang, Hong; Evdokimov, Nikolai M.; George, Olivia; Georgiou, Kathy Hadje; Renner, Steffen; Getlic, Matthäus; Kinnibrugh, Tiffany L.; Fernandes, Manuel A.; Van slambrouck, Severine; Steelant, Wim F. A.; Shuster, Charles B.; Rogelj, Snezna; van Otterlo, Willem A. L.; Kornienko, Alexander

    2011-01-01

    Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on beta-tubulin, provided a theoretical understanding of these successful experimental findings. PMID:21615090

  3. 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

  4. Synthetic and application perspectives of azapodophyllotoxins: alternative scaffolds of podophyllotoxin.

    PubMed

    Kumar, A; Kumar, V; Alegria, A E; Malhotra, S V

    2011-01-01

    Podophyllotoxin (1) has been known to possess anti-tumor activity and is still considered an important lead for research and development of antineoplastic agents. Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. These agents are also used in combination therapies with other drugs. Due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. These issues provide strong impetus to a search for analogues of 1 with simplified structures, which can be accessible via short synthetic sequences from simple starting materials. Even if such initial compounds might have diminished cytotoxic potencies compared with the parent cyclolignan, the ease of preparation of carefully designed libraries of analogues would lead to more informative SAR studies and expeditious structure optimization. In this regard, during the last two decades considerable efforts have been made to synthesize aza- analogs of podophyllotoxin, i. e. aza-podophyllotoxins, with hetero atoms at different positions of the podophyllotoxin skeleton, while keeping the basic podophyllotoxin structure. Recently, there have been significant efforts towards the convenient synthesis of aza-analogs of 1. The use of multicomponent reactions (MCRs) and the synergies of ultrasound and microwave irradiations have increased the synthetic speed and variety of azapodophyllotoxins which are and will be available to be tested against a diverse population of carcinomas and other diseases. It has been reported that several aza-podophyllotoxins retain a great fraction of the cytotoxicity associated with the parent lignan. This review focuses on the strategies towards synthesis of various aza-podophyllotoxin analogues and their biological activities. PMID:21824101

  5. Synthetic and Application Perspectives of Azapodophyllotoxins: Alternative Scaffolds of Podophyllotoxin

    PubMed Central

    Kumar, A.; Kumar, V.; Alegria, A.E.; Malhotra, S.V.

    2012-01-01

    Podophyllotoxin (1) has been known to possess anti-tumor activity and is still considered an important lead for research and development of antineoplastic agents. Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. These agents are also used in combination therapies with other drugs. Due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. These issues provide strong impetus to a search for analogues of 1 with simplified structures, which can be accessible via short synthetic sequences from simple starting materials. Even if such initial compounds might have diminished cytotoxic potencies compared with the parent cyclolignan, the ease of preparation of carefully designed libraries of analogues would lead to more informative SAR studies and expeditious structure optimization. In this regard, during the last two decades considerable efforts have been made to synthesize aza- analogs of podophyllotoxin, i. e. aza-podophyllotoxins, with hetero atoms at different positions of the podophyllotoxin skeleton, while keeping the basic podophyllotoxin structure. Recently, there have been significant efforts towards the convenient synthesis of aza-analogs of 1. The use of multicomponent reactions (MCRs) and the synergies of ultrasound and microwave irradiations have increased the synthetic speed and variety of azapodophyllotoxins which are and will be available to be tested against a diverse population of carcinomas and other diseases. It has been reported that several aza-podophyllotoxins retain a great fraction of the cytotoxicity associated with the parent lignan. This review focuses on the strategies towards synthesis of various aza-podophyllotoxin analogues and their biological activities. PMID:21824101

  6. 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

  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. Heterocyclic chalcone analogues as potential anticancer agents.

    PubMed

    Sharma, Vikas; Kumar, Vipin; Kumar, Pradeep

    2013-03-01

    Chalcones, aromatic ketones and enones acting as the precursor for flavonoids such as Quercetin, are known for their anticancer effects. Although, parent chalcones consist of two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl system, various synthetic compounds possessing heterocyclic rings like pyrazole, indole etc. are well known and proved to be effective anticancer agents. In addition to their use as anticancer agents in cancer cell lines, heterocyclic analogues are reported to be effective even against resistant cell lines. In this connection, we hereby highlight the potential of various heterocyclic chalcone analogues as anticancer agents with a brief summary about therapeutic potential of chalcones, mechanism of anticancer action of various chalcone analogues, and current and future prospects related to the chalcones-derived anticancer research. Furthermore, some key points regarding chalcone analogues have been reviewed by analyzing their medicinal properties. PMID:22721390

  9. 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...

  10. Endophytic Fungus from Sinopodophyllum emodi (Wall.) Ying that Produces Podophyllotoxin.

    PubMed

    Liang, Zizhen; Zhang, Jia; Zhang, Xuan; Li, Jinjie; Zhang, Xiaoqian; Zhao, Changqi

    2016-02-01

    The aryltetralin lactone podophyllotoxin, which exhibits pronounced antineoplastic activity, is used as the precursor of the following three clinical anticancer drugs: Etoposide™, Etopophos™ and Teniposide™. The natural occurrence of this arylnaphthalene lignan is scarce and unable to meet the ever-rising demand in the medical industry. Thus, developing alternative sources for the production of podophyllotoxin is extremely urgent. This is the first report of the production of podophyllotoxin from endophytic Alternaria tenuissima isolated from Sinopodophyllum emodi (Wall.) Ying. The identification of podophyllotoxin was performed using high-performance liquid chromatography and liquid chromatography-mass spectrometry (MS)-MS and confirmed by comparison with authentic standards. PMID:26306574

  11. Glutamic acid as anticancer agent: An overview

    PubMed Central

    Dutta, Satyajit; Ray, Supratim; Nagarajan, K.

    2013-01-01

    The objective of the article is to highlight various roles of glutamic acid like endogenic anticancer agent, conjugates to anticancer agents, and derivatives of glutamic acid as possible anticancer agents. Besides these emphases are given especially for two endogenous derivatives of glutamic acid such as glutamine and glutamate. Glutamine is a derivative of glutamic acid and is formed in the body from glutamic acid and ammonia in an energy requiring reaction catalyzed by glutamine synthase. It also possesses anticancer activity. So the transportation and metabolism of glutamine are also discussed for better understanding the role of glutamic acid. Glutamates are the carboxylate anions and salts of glutamic acid. Here the roles of various enzymes required for the metabolism of glutamates are also discussed. PMID:24227952

  12. Synthesis and quantitative structure-activity relationship (QSAR) study of novel isoxazoline and oxime derivatives of podophyllotoxin as insecticidal agents.

    PubMed

    Wang, Yi; Shao, Yonghua; Wang, Yangyang; Fan, Lingling; Yu, Xiang; Zhi, Xiaoyan; Yang, Chun; Qu, Huan; Yao, Xiaojun; Xu, Hui

    2012-08-29

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, 33 isoxazoline and oxime derivatives of podophyllotoxin modified in the C and D rings were synthesized and their structures were characterized by Proton nuclear magnetic resonance ((1)H NMR), high-resolution mass spectrometry (HRMS), electrospray ionization-mass spectrometry (ESI-MS), optical rotation, melting point (mp), and infrared (IR) spectroscopy. The stereochemical configurations of compounds 5e, 5f, and 9f were unambiguously determined by X-ray crystallography. Their insecticidal activity was evaluated against the pre-third-instar larvae of northern armyworm, Mythimna separata (Walker), in vivo. Compounds 5e, 9c, 11g, and 11h especially exhibited more promising insecticidal activity than toosendanin, a commercial botanical insecticide extracted from Melia azedarach . A genetic algorithm combined with multiple linear regression (GA-MLR) calculation is performed by the MOBY DIGS package. Five selected descriptors are as follows: one two-dimensional (2D) autocorrelation descriptor (GATS4e), one edge adjacency indice (EEig06x), one RDF descriptor (RDF080v), one three-dimensional (3D) MoRSE descriptor (Mor09v), and one atom-centered fragment (H-052) descriptor. Quantitative structure-activity relationship studies demonstrated that the insecticidal activity of these compounds was mainly influenced by many factors, such as electronic distribution, steric factors, etc. For this model, the standard deviation error in prediction (SDEP) is 0.0592, the correlation coefficient (R(2)) is 0.861, and the leave-one-out cross-validation correlation coefficient (Q(2)loo) is 0.797. PMID:22891988

  13. Histone deacetylase inhibitors: emerging anticancer therapeutic agents?

    PubMed

    Kristeleit, Rebecca; Fong, Peter; Aherne, G Wynne; de Bono, Johann

    2005-09-01

    Histone deacetylase inhibitors are novel anticancer agents in clinical development that target the family of histone deacetylase (HDAC) enzymes responsible for deacetylating core nucleosomal histones and other proteins. The precise mechanisms resulting in the antiproliferative biologic effects of these agents are not yet known, but there are several proposed mechanistic models, including transcriptional and nontranscriptional processes. Clinical experience with these agents indicates that they are generally well tolerated, and anticancer activity has been observed in early clinical trials in several tumor types including non-small-cell lung cancer. The development of these agents continues, with an emphasis on the discovery of HDAC isoform-selective compounds. Successful future development relies on clearer understanding of the dominant mechanisms involved in the observed antiproliferative effects. PMID:16159416

  14. Mitochondrially targeted anti-cancer agents.

    PubMed

    Biasutto, Lucia; Dong, Lan-Feng; Zoratti, Mario; Neuzil, Jiri

    2010-11-01

    Cancer is an ever-increasing problem that is yet to be harnessed. Frequent mutations make this pathology very variable and, consequently, a considerable challenge. Intriguingly, mitochondria have recently emerged as novel targets for cancer therapy. A group of agents with anti-cancer activity that induce apoptosis by way of mitochondrial destabilisation, termed mitocans, have been a recent focus of research. Of these compounds, many are hydrophobic agents that associate with various sub-cellular organelles. Clearly, modification of such structures with mitochondria-targeting moieties, for example tagging them with lipophilic cations, would be expected to enhance their activity. This may be accomplished by the addition of triphenylphosphonium groups that direct such compounds to mitochondria, enhancing their activity. In this paper, we will review agents that possess anti-cancer activity by way of destabilizing mitochondria and their possible targets. We propose that mitochondrial targeting, in particular where the agent associates directly with the target, results in more specific and efficient anti-cancer drugs of potential high clinical relevance. PMID:20601192

  15. Spirooxindoles: Promising scaffolds for anticancer agents.

    PubMed

    Yu, Bin; Yu, De-Quan; Liu, Hong-Min

    2015-06-01

    The search for novel anticancer agents with more selectivity and lower toxicity continues to be an area of intensive investigation. The unique structural features of spirooxindoles together with diverse biological activities have made them privileged structures in new drug discovery. Among them, spiro-pyrrolidinyl oxindoles have been extensively studied as potent inhibitors of p53-MDM2 interaction, finally leading to the identification of MI-888, which could achieve rapid, complete and durable tumor regression in xenograft models of human cancer with oral administration and is in advanced preclinical research for cancer therapy. This review highlights recent progress of biologically active spirooxindoles for their anticancer potentials, mainly focusing on the discussions of SARs and modes of action. This article also aims to discuss potential further directions on the development of more potent analogues for cancer therapy. PMID:24994707

  16. Reengineered tricyclic anti-cancer agents.

    PubMed

    Kastrinsky, David B; Sangodkar, Jaya; Zaware, Nilesh; Izadmehr, Sudeh; Dhawan, Neil S; Narla, Goutham; Ohlmeyer, Michael

    2015-10-01

    The phenothiazine and dibenzazepine tricyclics are potent neurotropic drugs with a documented but underutilized anti-cancer side effect. Reengineering these agents (TFP, CPZ, CIP) by replacing the basic amine with a neutral polar functional group (e.g., RTC-1, RTC-2) abrogated their CNS effects as demonstrated by in vitro pharmacological assays and in vivo behavioral models. Further optimization generated several phenothiazines and dibenzazepines with improved anti-cancer potency, exemplified by RTC-5. This new lead demonstrated efficacy against a xenograft model of an EGFR driven cancer without the neurotropic effects exhibited by the parent molecules. Its effects were attributed to concomitant negative regulation of PI3K-AKT and RAS-ERK signaling. PMID:26372073

  17. Organoiridium complexes: anticancer agents and catalysts.

    PubMed

    Liu, Zhe; Sadler, Peter J

    2014-04-15

    Iridium is a relatively rare precious heavy metal, only slightly less dense than osmium. Researchers have long recognized the catalytic properties of square-planar Ir(I) complexes, such as Crabtree's hydrogenation catalyst, an organometallic complex with cyclooctadiene, phosphane, and pyridine ligands. More recently, chemists have developed half-sandwich pseudo-octahedral pentamethylcyclopentadienyl Ir(III) complexes containing diamine ligands that efficiently catalyze transfer hydrogenation reactions of ketones and aldehydes in water using H2 or formate as the hydrogen source. Although sometimes assumed to be chemically inert, the reactivity of low-spin 5d(6) Ir(III) centers is highly dependent on the set of ligands. Cp* complexes with strong σ-donor C^C-chelating ligands can even stabilize Ir(IV) and catalyze the oxidation of water. In comparison with well developed Ir catalysts, Ir-based pharmaceuticals are still in their infancy. In this Account, we review recent developments in organoiridium complexes as both catalysts and anticancer agents. Initial studies of anticancer activity with organoiridium complexes focused on square-planar Ir(I) complexes because of their structural and electronic similarity to Pt(II) anticancer complexes such as cisplatin. Recently, researchers have studied half-sandwich Ir(III) anticancer complexes. These complexes with the formula [(Cp(x))Ir(L^L')Z](0/n+) (with Cp* or extended Cp* and L^L' = chelated C^N or N^N ligands) have a much greater potency (nanomolar) toward a range of cancer cells (especially leukemia, colon cancer, breast cancer, prostate cancer, and melanoma) than cisplatin. Their mechanism of action may involve both an attack on DNA and a perturbation of the redox status of cells. Some of these complexes can form Ir(III)-hydride complexes using coenzyme NAD(P)H as a source of hydride to catalyze the generation of H2 or the reduction of quinones to semiquinones. Intriguingly, relatively unreactive organoiridium complexes containing an imine as a monodentate ligand have prooxidant activity, which appears to involve catalytic hydride transfer to oxygen and the generation of hydrogen peroxide in cells. In addition, researchers have designed inert Ir(III) complexes as potent kinase inhibitors. Octahedral cyclometalated Ir(III) complexes not only serve as cell imaging agents, but can also inhibit tumor necrosis factor α, promote DNA oxidation, generate singlet oxygen when photoactivated, and exhibit good anticancer activity. Although relatively unexplored, organoiridium chemistry offers unique features that researchers can exploit to generate novel diagnostic agents and drugs with new mechanisms of action. PMID:24555658

  18. Organoiridium Complexes: Anticancer Agents and Catalysts

    PubMed Central

    2014-01-01

    Conspectus Iridium is a relatively rare precious heavy metal, only slightly less dense than osmium. Researchers have long recognized the catalytic properties of square-planar IrI complexes, such as Crabtree’s hydrogenation catalyst, an organometallic complex with cyclooctadiene, phosphane, and pyridine ligands. More recently, chemists have developed half-sandwich pseudo-octahedral pentamethylcyclopentadienyl IrIII complexes containing diamine ligands that efficiently catalyze transfer hydrogenation reactions of ketones and aldehydes in water using H2 or formate as the hydrogen source. Although sometimes assumed to be chemically inert, the reactivity of low-spin 5d6 IrIII centers is highly dependent on the set of ligands. Cp* complexes with strong σ-donor C∧C-chelating ligands can even stabilize IrIV and catalyze the oxidation of water. In comparison with well developed Ir catalysts, Ir-based pharmaceuticals are still in their infancy. In this Account, we review recent developments in organoiridium complexes as both catalysts and anticancer agents. Initial studies of anticancer activity with organoiridium complexes focused on square-planar IrI complexes because of their structural and electronic similarity to PtII anticancer complexes such as cisplatin. Recently, researchers have studied half-sandwich IrIII anticancer complexes. These complexes with the formula [(Cpx)Ir(L∧L′)Z]0/n+ (with Cp* or extended Cp* and L∧L′ = chelated C∧N or N∧N ligands) have a much greater potency (nanomolar) toward a range of cancer cells (especially leukemia, colon cancer, breast cancer, prostate cancer, and melanoma) than cisplatin. Their mechanism of action may involve both an attack on DNA and a perturbation of the redox status of cells. Some of these complexes can form IrIII-hydride complexes using coenzyme NAD(P)H as a source of hydride to catalyze the generation of H2 or the reduction of quinones to semiquinones. Intriguingly, relatively unreactive organoiridium complexes containing an imine as a monodentate ligand have prooxidant activity, which appears to involve catalytic hydride transfer to oxygen and the generation of hydrogen peroxide in cells. In addition, researchers have designed inert IrIII complexes as potent kinase inhibitors. Octahedral cyclometalated IrIII complexes not only serve as cell imaging agents, but can also inhibit tumor necrosis factor α, promote DNA oxidation, generate singlet oxygen when photoactivated, and exhibit good anticancer activity. Although relatively unexplored, organoiridium chemistry offers unique features that researchers can exploit to generate novel diagnostic agents and drugs with new mechanisms of action. PMID:24555658

  19. 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

  20. 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

  1. 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

  2. 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

  3. Plant antimicrobial peptides as potential anticancer agents.

    PubMed

    Guzmán-Rodríguez, Jaquelina Julia; Ochoa-Zarzosa, Alejandra; López-Gómez, Rodolfo; López-Meza, Joel E

    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

  4. 4-Nerolidylcatechol analogues as promising anticancer agents.

    PubMed

    Cortez, Alane Pereira; de Ávila, Renato Ivan; da Cunha, Carla Rosane Mendanha; Santos, Alexandre Pereira; Menegatti, Ricardo; Rezende, Kênnia Rocha; Valadares, Marize Campos

    2015-10-15

    4-Nerolidylcatechol (1) is an isolated compound from Pothomorphe umbellata L. (Piperaceae) with promising antitumor cells properties. However it presents lability under light and room temperatures. Many efforts have been directed towards discovering anticancer agents endowed with cytotoxic activities. Here, we evaluated cytotoxic effects of 4-NRC analogues (LQFMs 2-6) and the cell death pathways induced by these compounds in multidrug-resistant K562 cells. Compounds (2-6) exhibited cytotoxic activities in a concentration-dependent manner against leukaemic cells, specially the compounds (3) and (5). Additionally, compounds (1), (3) and (5) promoted marked alterations on the cell morphology, including nuclear changes as demonstrated by Hoescht 33342 staining. Moreover, these compounds promoted apoptosis induction in K562 cells by phosphatidylserine exposure, increase of sub-G1 cells and modulation of the caspases-3/7, -8 and -9 activation. In addition, the pancaspase inhibitor z-VAD-fmk partially reduced the apoptosis induced by the compounds (1) and (5)-induced, suggesting caspase-dependent and caspase-independent cell death pathways. Compounds (1) and (5) also modified the cell cycle progression by G0/G1 and S arrest, respectively. Furthermore, compounds (1), (3) and (5) promoted mitochondrial dysfunction associated to accumulation of cytosolic cytochrome c and modulated the NF-ĸB activation. In addition, unlike their analogues, 4-NRC (1) also promoted a significant cyclin D1 inhibition. Together, these data suggest that the mechanism of cell death of 4-NRC and its analogues (3) and (5) occurs by apoptosis through mitochondrial mechanisms. Considering that LQFMs are biocompatible synthetic analogues produced by molecular simplification of (1) without the chiral centre, which is associated with the instability found in compound (1), we suggest that these compounds are promising candidates for further pre-clinical studies. PMID:26297972

  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 γ-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-α, 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. Snake venom: a potent anticancer agent.

    PubMed

    Jain, Deepika; Kumar, Sudhir

    2012-01-01

    Since cancer is one of the leading causes of death worldwide, and there is an urgent need to find better treatment. In recent years remarkable progress has been made towards the understanding of proposed hallmarks of cancer development and treatment. Treatment modalities comprise radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy. Currently, the use of chemotherapeutics remains the predominant option for clinical control. However, one of the major problems with successful cancer therapy using chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. This has led to the increased use of anticancer drugs developed from natural resources. The biodiversity of venoms and toxins makes them a unique source from which novel therapeutics may be developed. In this review, the anticancer potential of snake venom is discussed. Some of the included molecules are under clinical trial and may find application for anticancer drug development in the near future. PMID:23244070

  7. Indenoindolone derivatives as topoisomerase II-inhibiting anticancer agents.

    PubMed

    Kashyap, Maneesh; Kandekar, Somnath; Baviskar, Ashish T; Das, Dipon; Preet, Ranjan; Mohapatra, Purusottam; Satapathy, Shakti Ranjan; Siddharth, Sumit; Guchhait, Sankar K; Kundu, Chanakya N; Banerjee, Uttam C

    2013-02-15

    Based on known heterocyclic topoisomerase II inhibitors and anticancer agents, various indenoindolone derivatives were predicted as potential topoisomerase II-inhibiting anticancer agents. They are hydrazones, (thio)semicarbazones, and oximes of indenoindolones, and indenoindolols. These derivatives with suitable substitutions exhibited potent specific inhibition of human DNA TopoIIα while not showing inhibition of topoisomerase I and DNA intercalation, despite the fact that parent indenoindolones are known poor/moderate inhibitors of topoisomerase II. The potent topoisomerase II inhibitor indenoindolone derivatives exhibited good anticancer activities compared to etoposide and 5-fluorouracil, and relatively low toxicity to normal cells. These derivatizations of indenoindolones were found to result in enhancement of anticancer activities. PMID:23321564

  8. Nephrotoxicity of recent anti-cancer agents

    PubMed Central

    Lameire, Norbert

    2014-01-01

    Cancer patients may develop a variety of kidney lesions that impair not only their immediate survival but also limit the adequate treatment of the underlying malignant process. This review summarizes the nephrotoxic potential of some of the most recently developed anti-cancer drugs, focusing on those interfering with the vascular endothelial growth factor and epidermal growth factor receptor pathways and mammalian target of rapamycin inhibitors. Thrombotic microangiopathy (haemolytic-uraemic syndrome), proteinuria, hypertension and magnesium depletion are the most common side effects. Also the risk for developing acute kidney injury in patients with advanced prostate cancer undergoing androgen deprivation therapy is discussed. PMID:25859345

  9. Production of anti-cancer agent using microbial biotransformation.

    PubMed

    Roh, Changhyun; Kang, ChanKyu

    2014-01-01

    Microbial biotransformation is a great model system to produce drugs and biologically active compounds. In this study, we elucidated the fermentation and production of an anti-cancer agent from a microbial process for regiospecific hydroxylation of resveratrol. Among the strains examined, a potent strain showed high regiospecific hydroxylation activity to produce piceatannol. In a 5 L (w/v 3 L) jar fermentation, this wild type Streptomyces sp. in the batch system produced 205 mg of piceatannol (i.e., 60% yields) from 342 mg of resveratrol in 20 h. Using the product, an in vitro anti-cancer study was performed against a human cancer cell line (HeLa). It showed that the biotransformed piceatannol possessed a significant anticancer activity. This result demonstrates that a biotransformation screening method might be of therapeutic interest with respect to the identification of anti-cancer drugs. PMID:25325153

  10. Marine-derived anticancer agents in clinical trials.

    PubMed

    Schwartsmann, Gilberto; Da Rocha, Adriana Brondani; Mattei, Jane; Lopes, RafaelMartins

    2003-08-01

    Anticancer agents may be derived either from the isolation of an active lead compound occurring spontaneously in nature or by novel chemical synthesis in the laboratory. There are examples of successful drugs being derived from both sources, which have had a profound impact on the natural history of various types of cancer. The treatment of lymphomas and acute leukaemias with the use of combination chemotherapy, including anthracyclines and vinca alkaloids, are examples of the contribution of nature. In contrast, agents such as 5-fluorouracil, methotrexate and more recently, the humanised anti-CD20 antibody rituximab and the tyrosine kinase inhibitor imatinib are examples of synthetic compounds, which were designed with a clear rationale, that are routinely used in patients with solid tumours and haematological malignancies. Until recently, the tradition in natural product-derived anticancer drug development was to rely almost exclusively on the screening of terrestrial sources (plant extracts and fermentation products) for their cytotoxic properties. Although C-nucleosides obtained from Caribbean sponge were the initial inspiration for the synthesis of antiviral substituted nucleosides and the successful anticancer agent citarabine, active against leukaemias and lymphomas, the contribution of marine compounds as a source of anticancer agents was modest. In recent years, the improvements in the technology of deep-sea collection and aquaculture added to the growing recognition of the tremendous biodiversity present in the marine world, and has contributed to the growing interest of exploring the oceans as a potential source of new anticancer candidates. This is reflected in the number of marine-derived compounds undergoing preclinical and early clinical development. In this paper, the authors discuss the available literature on anticancer agents that have reached clinical trials, such as didemnin B, aplidine, dolastatin-10, bryostatin-1 and ecteinascidin-743 (ET-743, trabectedin), as well as other promising compounds still undergoing tests in the laboratory. PMID:12882622

  11. 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

  12. 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

  13. Ferrocene incorporated selenoureas as anticancer agents.

    PubMed

    Hussain, Raja Azadar; Badshah, Amin; Pezzuto, John M; Ahmed, Nadeem; Kondratyuk, Tamara P; Park, Eun-Jung

    2015-07-01

    For a compound to be a best chemopreventive agent it should be a descent DNA binder and at the same time should be active against any of the three stages of carcinogenesis i.e. cancer initiation, cancer propagation and tumor growth. Most of the problems associated with chemotherapy can be overcome if the chemopreventive agent is active against all the three stages of cancer development. Cancer may be initiated by higher concentration of free radicals, inflammating agents and phase I enzymes (Cytochrome P450) in the body. Cancer propagation can be very efficiently controlled by inducing the phase II enzymes (glutathione S-transferases (GSTs), UDP-glucuronosyl transferases, and quinone reductases) in the body and cancer termination depends on the killing of the faulty cells i.e. cytotoxic actions. This article reports comprehensively the comparative DNA binding studies (with, cyclic voltammetry, UV-vis spectroscopy and viscometry), antioxidant activities (DPPH scavenging), anti-inflammatory activities (nitrite inhibition), phase I enzyme inhibition activities (aromatase inhibition), phase II enzyme induction studies (quinone reductase induction) and cytotoxic studies against neuroblastoma (MYCN2 and SK-N-SH), liver cancer (Hepa 1c1c7) and breast cancer (MCF-7) of seventeen ferrocene incorporated selenoureas. PMID:25966308

  14. 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

  15. Discovery of new anticancer agents from higher plants

    PubMed Central

    Pan, Li; Chai, Hee-Byung; Kinghorn, A. Douglas

    2012-01-01

    1. ABSTRACT Small organic molecules derived from higher plants have been one of the mainstays of cancer chemotherapy for approximately the past half a century. In the present review, selected single chemical entity natural products of plant origin and their semi-synthetic derivatives currently in clinical trials are featured as examples of new cancer chemotherapeutic drug candidates. Several more recently isolated compounds obtained from plants showing promising in vivo biological activity are also discussed in terms of their potential as anticancer agents, with many of these obtained from species that grow in tropical regions. Since extracts of only a relatively small proportion of the ca. 300,000 higher plants on earth have been screened biologically to date, bioactive compounds from plants should play an important role in future anticancer drug discovery efforts. PMID:22202049

  16. 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....

  17. 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

  18. Recent advances in the new generation taxane anticancer agents.

    PubMed

    Geney, R; Chen, J; Ojima, I

    2005-03-01

    Recent advances in the design and preclinical evaluations of promising new generation taxane anticancer agents are reviewed in this article. Paclitaxel and docetaxel are two of the most important anticancer drugs today. However, recent reports have shown that treatment with these drugs often encounters undesirable side effects as well as drug resistance. Therefore, it is important to develop new taxane anticancer agents with fewer side effects, superior pharmacological properties, and improved activity against drug-resistant human cancers. Structure-activity relationship (SAR) studies led to the discovery of a series of highly active second-generation taxanes. One of them, "Ortataxel" (SB-T-101131, IDN5109, BAY59-8862), exhibits excellent activity against a variety of drug-sensitive and drug-resistant cancer cell lines, as well as human tumor xenografts in mice. It is orally active and is currently in phase II clinical trials. Photoaffinity labeling of microtubules and P-glycoprotein using photoreactive radiolabeled taxoids has disclosed the drug-binding domain of tubulin as well as Pgp. Together with information on microtubule-bound fluorine-labeled taxoids obtained by solid-state NMR studies, the bioactive conformation of paclitaxel and taxoids appears to emerge. Novel taxane-monoclonal antibody (mAb) immunoconjugates, have shown highly promising results for the tumor-specific delivery and release of an extremely cytotoxic, second-generation taxane. Also, another novel series of second generation taxanes conjugated with n-3 polyunsaturated fatty acids, e.g. decosahexaenoic acid (DHA), has exhibited impressive antitumor activity with minimum general toxicity against the highly drug-resistant DLD-1 human colon cancer xenografts in SCID mice. PMID:16787308

  19. Novel marine-derived anti-cancer agents.

    PubMed

    Adrian, Thomas E

    2007-01-01

    There is an immense diversity of marine plants and animals from which an estimated 14,000 pharmacologically active compounds have been isolated. However, in terms of clinically useful anti-cancer agents, the oceans remain as a largely untapped resource. Indeed, there are currently only two compounds used in the clinic that are derived from marine sources. These are cytarabine, which is a deoxycitidine analogue and aplidine, which has both growth inhibitory and anti-angiogenic effects. This situation is likely to change rather dramatically in the near future, as attention has focused on the vast diversity of available agents from marine organisms. The increased pace of activity in this area has resulted in a several clinical trials of promising compounds with the probability that these will be followed by other drugs currently under preclinical development. PMID:18045195

  20. 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 μM) and 12h (IC50: 1.12-2.03 μM) showed superior potency to etoposide (IC50: 2.03 to >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. 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

  2. Clinical development of histone deacetylase inhibitors as anticancer agents.

    PubMed

    Drummond, Daryl C; Noble, Charles O; Kirpotin, Dmitri B; Guo, Zexiong; Scott, Gary K; Benz, Christopher C

    2005-01-01

    Acetylation is a key posttranslational modification of many proteins responsible for regulating critical intracellular pathways. Although histones are the most thoroughly studied of acetylated protein substrates, histone acetyltransferases (HATs) and deacetylases (HDACs) are also responsible for modifying the activity of diverse types of nonhistone proteins, including transcription factors and signal transduction mediators. HDACs have emerged as uncredentialed molecular targets for the development of enzymatic inhibitors to treat human cancer, and six structurally distinct drug classes have been identified with in vivo bioavailability and intracellular capability to inhibit many of the known mammalian members representing the two general types of NAD+-independent yeast HDACs, Rpd3 (HDACs 1, 2, 3, 8) and Hda1 (HDACs 4, 5, 6, 7, 9a, 9b, 10). Initial clinical trials indicate that HDAC inhibitors from several different structural classes are very well tolerated and exhibit clinical activity against a variety of human malignancies; however, the molecular basis for their anticancer selectivity remains largely unknown. HDAC inhibitors have also shown preclinical promise when combined with other therapeutic agents, and innovative drug delivery strategies, including liposome encapsulation, may further enhance their clinical development and anticancer potential. An improved understanding of the mechanistic role of specific HDACs in human tumorigenesis, as well as the identification of more specific HDAC inhibitors, will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment. PMID:15822187

  3. Comprehensive Review on Betulin as a Potent Anticancer Agent

    PubMed Central

    Kiełbus, Michał; 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

  4. Discovery of Natural Product Anticancer Agents from Biodiverse Organisms

    PubMed Central

    Kinghorn, A. Douglas; Chin, Young-Won; Swanson, Steven M.

    2010-01-01

    For over 40 years, small organic molecules derived naturally from microbes and plants have provided a number of useful cancer chemotherapeutic drugs. The search for naturally occurring lead compounds of this type has continued in recent years, with the constituents of marine fauna and flora as well as those of terrestrial microorganisms and plants being investigated for their anti-cancer activities. In the present short review, selected new compounds or their derivatives are described that have obtained for the first time recently from organisms of diverse biological origin, with potential use as cancer chemotherapeutic agents. It may be seen that such promising lead compounds tend to rapidly generate considerable interest among scientists such as synthetic organic chemists and biologists. Consequently, the supply of a given precious natural product sample may be enhanced, and it may be possible to determine a preliminary notion of structure-activity relationships and of its potential mechanism of action. PMID:19333864

  5. Small mitochondria-targeting molecules as anti-cancer agents

    PubMed Central

    Wang, Feng; Ogasawara, Marcia A.; Huang, Peng

    2009-01-01

    Alterations in mitochondrial structure and functions have long been observed in cancer cells. Targeting mitochondria as a cancer therapeutic strategy has gained momentum in the recent years. The signaling pathways that govern mitochondrial function, apoptosis and molecules that affect mitochondrial integrity and cell viability have been important topics of the recent review in the literature. In this article, we first briefly summarize the rationale and biological basis for developing mitochondrial-targeted compounds as potential anticancer agents, and then provide key examples of small molecules that either directly impact mitochondria or functionally affect the metabolic alterations in cancer cells with mitochondrial dysfunction. The main focus is on the small molecular weight compounds with potential applications in cancer treatment. We also summarize information on the drug developmental stages of the key mitochondria-targeted compounds and their clinical trial status. The advantages and potential shortcomings of targeting the mitochondria for cancer treatment are also discussed. PMID:19995573

  6. T-oligo as an anticancer agent in colorectal cancer

    SciTech Connect

    Wojdyla, Luke; Stone, Amanda L.; Sethakorn, Nan; Uppada, Srijayaprakash B.; Devito, Joseph T.; Bissonnette, Marc; Puri, Neelu

    2014-04-04

    Highlights: • T-oligo induces cell cycle arrest, senescence, apoptosis, and differentiation in CRC. • Treatment with T-oligo downregulates telomere-associated proteins. • T-oligo combined with an EGFR-TKI additively inhibits cellular proliferation. • T-oligo has potential as an effective therapeutic agent for CRC. - Abstract: In the United States, there will be an estimated 96,830 new cases of colorectal cancer (CRC) and 50,310 deaths in 2014. CRC is often detected at late stages of the disease, at which point there is no effective chemotherapy. Thus, there is an urgent need for effective novel therapies that have minimal effects on normal cells. T-oligo, an oligonucleotide homologous to the 3′-telomere overhang, induces potent DNA damage responses in multiple malignant cell types, however, its efficacy in CRC has not been studied. This is the first investigation demonstrating T-oligo-induced anticancer effects in two CRC cell lines, HT-29 and LoVo, which are highly resistant to conventional chemotherapies. In this investigation, we show that T-oligo may mediate its DNA damage responses through the p53/p73 pathway, thereby inhibiting cellular proliferation and inducing apoptosis or senescence. Additionally, upregulation of downstream DNA damage response proteins, including E2F1, p53 or p73, was observed. In LoVo cells, T-oligo induced senescence, decreased clonogenicity, and increased expression of senescence associated proteins p21, p27, and p53. In addition, downregulation of POT1 and TRF2, two components of the shelterin protein complex which protects telomeric ends, was observed. Moreover, we studied the antiproliferative effects of T-oligo in combination with an EGFR tyrosine kinase inhibitor, Gefitinib, which resulted in an additive inhibitory effect on cellular proliferation. Collectively, these data provide evidence that T-oligo alone, or in combination with other molecularly targeted therapies, has potential as an anti-cancer agent in CRC.

  7. Quinones as mutagens, carcinogens, and anticancer agents: introduction and overview

    SciTech Connect

    Smith, M.T.

    1985-01-01

    Quinones are widespread in the environment, occurring both naturally and as pollutants. Human exposure to them is, therefore, extensive. Quinones also form an important class of toxic metabolites generated as a result of the metabolism of phenols and related compounds, including phenol itself, 1-naphthol, and diethylstilbesterol. The mechanisms by which quinones exert their toxic effects are complex, but two processes appear to be centrally involved: the direct arylation of sulfhydryls, and the generation of active oxygen species via redox cycling. Certain quinones have been shown to be mutagenic via the formation of active oxygen species and others via their conversion to DNA-binding semiquinone free radicals. Paradoxically, quinones are not only mutagenic and therefore potentially carcinogenic, they are also effective anticancer agents. Classic examples are Adriamycin (doxorubicin hydrochloride) and mitomycin C, but other less complex quinones also show effective antitumor activity. The design of novel quinones that are more selective in their toxicity to human tumor cells and whose mechanism of action if understood seems a promising approach in cancer treatment, especially if host toxicity can be prevented via the use of chemoprotective agents.

  8. Parasporins as new natural anticancer agents: a review.

    PubMed

    Okassov, Almas; Nersesyan, Armen; Kitada, Sakae; Ilin, Alexander

    2015-01-01

    In 1999 Mizuki and co-authors studied for the first time the parasporal inclusion proteins extracted from B. thuringiensis strains (a Gram-positive, soil-dwelling bacterium) for cytotoxic activity against human leukaemia T-cells. Later some other proteins with this unusual property to recognize human leukemic cells were isolated from this strain of bacteria and named parasporins. At present 6 types of parasporins are identified and characterized. This review summarizes the properties of these new potentially useful antitumor agents of natural origin. Various types of parasporins possess unique cytotoxic mechanisms against cancer cells. The cytotoxic activity for cancer cells makes parasporins possible candidates for anticancer agents in clinical oncology. Recently, genetic engineering was applied for the production of parasporins and the gene responsible for the production of the proteins was expressed in E. coli. However, there are virtually no data regarding the cytotoxic (antitumor) activity of parasporins in vivo. These relatively new cytotoxic proteins warrant further investigation, especially in rodents, for possible application in clinical oncology. PMID:25778289

  9. T-oligo as an anticancer agent in colorectal cancer

    PubMed Central

    Stone, Amanda L.; Sethakorn, Nan; Uppada, Srijayaprakash B.; Devito, Joseph T.; Bissonnette, Marc

    2016-01-01

    In the United States, there will be an estimated 96,830 new cases of colorectal cancer (CRC) and 50,310 deaths in 2014. CRC is often detected at late stages of the disease, at which point there is no effective chemotherapy. Thus, there is an urgent need for effective novel therapies that have minimal effects on normal cells. T-oligo, an oligonucleotide homologous to the 3'-telomere overhang, induces potent DNA damage responses in multiple malignant cell types, however, its efficacy in CRC has not been studied. This is the first investigation demonstrating T-oligo-induced anticancer effects in two CRC cell lines, HT-29 and LoVo, which are highly resistant to conventional chemotherapies. In this investigation, we show that T-oligo may mediate its DNA damage responses through the p53/p73 pathway, thereby inhibiting cellular proliferation and inducing apoptosis or senescence. Additionally, upregulation of downstream DNA damage response proteins, including E2F1, p53 or p73, was observed. In LoVo cells, T-oligo induced senescence, decreased clonogenicity, and increased expression of senescence associated proteins p21, p27, and p53. In addition, downregulation of POT1 and TRF2, two components of the shelterin protein complex which protects telomeric ends, was observed. Moreover, we studied the antiproliferative effects of T-oligo in combination with an EGFR tyrosine kinase inhibitor, Gefitinib, which resulted in an additive inhibitory effect on cellular proliferation. Collectively, these data provide evidence that T-oligo alone, or in combination with other molecularly targeted therapies, has potential as an anti-cancer agent in CRC. PMID:24632202

  10. Apoptosis of human gastric cancer SGC-7901 cells induced by podophyllotoxin

    PubMed Central

    JI, CHEN-FENG; JI, YU-BIN

    2014-01-01

    Numerous studies have demonstrated that podophyllotoxin and its derivatives exhibit antitumor effects. The aim of the present study was to investigate SGC-7901 cell apoptosis and the underlying mechanism induced by podophyllotoxin. SGC-7901 cells were treated with varying concentrations of podophyllotoxin. MTT assays and flow cytometry were used to evaluate the effects of podophyllotoxin on the proliferation and apoptosis of SGC-7901 cells, while fluorescence inverted microscopy was used to observe the morphology of SGC-7901 cells that had been dyed with Hoechst 33258. In addition, laser scanning confocal microscopy was used to analyze the mitochondrial membrane potential (MMP) of SGC-7901 cells dyed with Rhodamine 123. Western blotting was performed to analyze the expression levels of cytochrome c (cyt-c), caspase-9 and caspase-3 in the SGC-7901 cells. The results indicated that podophyllotoxin was capable of inhibiting growth and inducing the apoptosis of SGC-7901 cells in a dose-dependent manner, causing cell cycle arrest at the G2/M phase. After 48 h of treatment, the apoptotic morphology of SGC-7901 cells was clear, exhibiting cell protuberance, concentrated cytoplasms and apoptotic bodies. Following 24 h of treatment, the MMP of the SGC-7901 cells decreased. In addition, after 48 h, the expression of cyt-c was shown to be upregulated, while the expression levels of pro-caspase-9 and pro-caspase-3 in the SGC-7901 cells were shown to be downregulated. In conclusion, apoptosis can be induced in SGC-7901 cells by podophyllotoxin, potentially via a mitochondrial pathway, indicating that podophyllotoxin may be a potent agent for cancer treatment. PMID:24940431

  11. 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

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

    PubMed

    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

  13. 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

  14. 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

  15. Rational Design, Synthesis, and Biological Evaluation of Third Generation α-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 (ΔGbind) 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

  16. Compound A398, a novel podophyllotoxin analogue: cytotoxicity and induction of apoptosis in human leukemia cells.

    PubMed

    Silveira, Alethéia L; Faheina-Martins, Glaúcia V; Maia, Raquel C; Araújo, Demetrius A M

    2014-01-01

    Despite advances in oncology research, cancer is one of the leading causes of death worldwide. Thus, there is a demand for the development of more selective and effective antitumor agents. This study showed that A398, a novel podophyllotoxin analogue, was cytotoxic to the HT-29, MCF-7, MOLT-4 and HL-60 tumor cell lines, being less active in human peripheral blood mononuclear cells and normal cell lines FGH and IEC-6. Tests using the HepG2 lineage indicated that its metabolites do not contribute to its cytotoxicity. In the HL-60 cells, A398 induced apoptosis in a time and concentration-dependent manner, promoting mitochondrial depolarization, inhibition of Bcl-2, phosphatidylserine exposure, activation of caspases -8, -9 and -3, and DNA fragmentation. The production of reactive oxygen species does not seem to be a crucial event for the apoptotic process. Pretreatment with specific inhibitors of kinases ERK1/2, JNK and p38 resulted in an increased percentage of death induced by A398. These results indicate that the compound induced apoptosis through activation of intrinsic and extrinsic death pathways with the mechanism involving the inhibition of the MAPKs and Bcl-2. Taken together, our findings suggest that A398 has an anticancer potential, proving itself to be a candidate for preclinical studies. PMID:25221997

  17. 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

  18. Non-covalent carriage of anticancer agents by humanized antibody trastuzumab.

    PubMed

    Yadav, Arpita; Sharma, Sweta; Yadav, Veejendra Kumar

    2016-05-01

    This article explores the internalization and non-covalent carriage of small molecule anticancer agents like vinca alkaloids by humanized monoclonal antibody trastuzumab. Such carriage is marked by significant reduction in side effects and increased therapeutic value of these anticancer agents. This study is coherent with few clinical observations of enhanced efficiency of these anticancer agents when co-administered with therapeutic antibodies. This study will also serve as the foundation for screening a database of anticancer agents for possible compounds that may be co-delivered alongwith the antibody. Based on this study vincristine conformation inside antibody and its charge environment may be used as descriptors for screening purposes. Graphical Abstract This article describes the use of immunotherapeutic agents for enhancing the bioavailability and efficacy of small molecule anticancer agents. The internalization and non-covalent carriage of vinca alkaloids by humanized antibody trastuzumab has been investigated utilizing flexible ligand molecular docking and molecular dynamics simulation studies coupled with MMGBSA binding energy calculations. The study concludes efficient non-covalent carriage without probability of premature expulsion. It is recommended that vincristine conformation and charge distribution may be used for screening library of compounds for possible mAb cargo. PMID:27109707

  19. Photosensitizers binding to nucleic acids as anticancer agents.

    PubMed

    Xodo, Luigi E; Cogoi, Susanna; Rapozzi, Valentina

    2016-02-01

    Cationic porphyrins (Prs) and phthalocyanines (Pcs) are strong photosensitizers that have drawn much attention for their potential in photodynamic therapy. These compounds have the interesting property of binding to nucleic acids, in particular G-rich quadruplex-forming sequences in DNA and RNA. In this review, we highlight their potential as anticancer drugs. PMID:26807879

  20. 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

  1. Which botanicals or other unconventional anticancer agents should we take to clinical trial?

    PubMed Central

    Vickers, Andrew J.

    2008-01-01

    There is significant public and scientific interest as regards unconventional anticancer agents (“CAM agents”). This paper describes five principles pertaining to the question of which CAM agents should be taken to clinical trial: 1) Very many CAM agents have been proposed as cancer treatments, far more than could possibly be studied in clinical trials; 2) Claims by patients or practitioners are generally unhelpful in choosing which CAM agents to test; 3) Laboratory studies can help determine which CAM agents to take to trial, and with which co-interventions; 4) Preliminary laboratory studies are essential to confirm safety before trials can be considered;. 5) The vast majority of anticancer CAM agents will be ineffective: our aim should be to discard agents from consideration as rapidly as possible. PMID:17761132

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

    PubMed

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

    2013-03-01

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

  3. Asymmetric synthesis and evaluation of α-quaternary chiral lactam derivatives as novel anticancer agents.

    PubMed

    Lee, Hwanhyuk; Hwang, Su Jung; Jung, Jisung; Hong, Suckchang; Lee, Myungmo; Park, Hyeung-geun; Lee, Hyo-Jong; Park, Yohan

    2014-10-01

    Asymmetric synthesis of α-quaternary chiral lactam derivatives as novel anticancer agents and evaluation of their cytotoxic potentials and spectrums are reported. Among the developed lactam derivatives, the most active new compounds (S)-4m and (S)-4n synthesized via asymmetric phase-transfer catalytic alkylation in very high optical yields (98 % ee) show promising in vitro anticancer activities with low micromolar IC50 values against colon, uterus, lung, and breast human cancer cells. PMID:24185506

  4. Potential role of garcinol as an anticancer agent.

    PubMed

    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

  5. Nanomicellar carriers for targeted delivery of anticancer agents

    PubMed Central

    Zhang, Xiaolan; Huang, Yixian; Li, Song

    2014-01-01

    Clinical application of anticancer drugs is limited by problems such as low water solubility, lack of tissue-specificity and toxicity. Formulation development represents an important approach to these problems. Among the many delivery systems studied, polymeric micelles have gained considerable attention owing to ease in preparation, small sizes (10–100 nm), and ability to solubilize water-insoluble anticancer drugs and accumulate specifically at the tumors. This article provides a brief review of several promising micellar systems and their applications in tumor therapy. The emphasis is placed on the discussion of the authors’ recent work on several nanomicellar systems that have both a delivery function and antitumor activity, named dual-function drug carriers. PMID:24341817

  6. Synthesis and insecticidal activity of new oxime derivatives of podophyllotoxin-based phenazines against Mythimna separata Walker.

    PubMed

    Zhi, Xiaoyan; Yang, Chun; Yu, Xiang; Xu, Hui

    2014-12-15

    To discover new natural-product-based insecticidal agents, a series of novel oxime derivatives of podophyllotoxin-based phenazines modified in the C, D and E rings of podophyllotoxin were prepared and tested as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1 mg/mL. The steric configuration of IIIc was unambiguously confirmed by single-crystal X-ray diffraction analysis. Compounds IIIa-d, and IIIi exhibited an equal or higher insecticidal activity than toosendanin. PMID:25467160

  7. A Theoretical Model for the Hormetic Dose-response Curve for Anticancer Agents.

    PubMed

    Yoshimasu, Tatsuya; Ohashi, Takuya; Oura, Shoji; Kokawa, Yozo; Kawago, Mitsumasa; Hirai, Yoshimitsu; Miyasaka, Miwako; Nishiguchi, Haruka; Kawashima, Sayoko; Yata, Yumi; Honda, Mariko; Fujimoto, Takahiro; Okamura, Yoshitaka

    2015-11-01

    In the present article, we quantitatively evaluated the dose-response relationship of hormetic reactions of anticancer agents in vitro. Serial dilutions of gemcitabine, cisplatin, 5-fluorouracil, vinorelbine, and paclitaxel were administered to the A549 non-small-cell lung cancer cell line. The bi-phasic sigmoidal curve with hormetic and cytotoxic effects is given by the formula y=(a-b/(1+exp(c(*)log(x)-d)))/(1+exp(e(*)log(x)-f)), that was used to perform a non-linear least square regression. The dose-responses of the five anticancer agents were fitted to this equation. Gemcitabine and 5-fluorouracil, which had the lowest ED50 for their hormetic reaction, had the most pronounced promotive effects out of the five anticancer agents tested. The hormetic reaction progressed exponentially with culturing time. Our theoretical model will be useful in predicting how hormetic reactions affect patients with malignant tumors. PMID:26504007

  8. 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

  9. Design and synthesis of harzialactone analogues: promising anticancer agents.

    PubMed

    Pawar, Vishwas U; Ghosh, Sougata; Chopade, Balu A; Shinde, Vaishali S

    2010-12-15

    New homologues of harzialactone were synthesized using D-glucose as chiral template. Wittig reaction to introduce aromatic moiety in 10 and chemoselective anomeric oxidation of 13 were used as key reactions in our synthesis. Anticancer activity of these target molecules was assessed against five cancer cell lines, P388D1, HL60, COLO-205, Zr-75-1 and HeLa. Both compound 5 and 6, showed significant activity against colon cancer (COLO-205) and cervical cancer (HeLa) and moderate with others. To the best of our knowledge, this is the first report of harzialactone analogues as potent inhibitors of human colon and cervical cancer. PMID:21074431

  10. Erlotinib hydro-chloride: an anti-cancer agent.

    PubMed

    Selvanayagam, S; Sridhar, B; Ravikumar, K

    2008-01-01

    In the cation of the title compound, C(22)H(24)N(3)O(4) (+)·Cl(-), an active ingredient of the anti-cancer drug also known as Tarceva, the quinazoline ring system is planar within 0.044 (3) Å. The dihedral angle formed by the mean planes of the two six-membered quinazoline rings is 3.2 (1)°. Both N-bound H atoms participate in N-H⋯Cl bonds, which link the ions into infinite chains running along the b axis. C-H⋯O inter-actions involving neighboring cations provide additional stabilization of these aggregates. PMID:21202412

  11. 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

  12. Phytochemicals and Biogenic Metallic Nanoparticles as Anticancer Agents

    PubMed Central

    Rao, Pasupuleti Visweswara; Nallappan, Devi; Madhavi, Kondeti; Rahman, Shafiqur; Jun Wei, Lim; Gan, Siew Hua

    2016-01-01

    Cancer is a leading cause of death worldwide. Several classes of drugs are available to treat different types of cancer. Currently, researchers are paying significant attention to the development of drugs at the nanoscale level to increase their target specificity and to reduce their concentrations. Nanotechnology is a promising and growing field with multiple subdisciplines, such as nanostructures, nanomaterials, and nanoparticles. These materials have gained prominence in science due to their size, shape, and potential efficacy. Nanomedicine is an important field involving the use of various types of nanoparticles to treat cancer and cancerous cells. Synthesis of nanoparticles targeting biological pathways has become tremendously prominent due to the higher efficacy and fewer side effects of nanodrugs compared to other commercial cancer drugs. In this review, different medicinal plants and their active compounds, as well as green-synthesized metallic nanoparticles from medicinal plants, are discussed in relation to their anticancer activities. PMID:27057273

  13. Phytochemicals and Biogenic Metallic Nanoparticles as Anticancer Agents.

    PubMed

    Rao, Pasupuleti Visweswara; Nallappan, Devi; Madhavi, Kondeti; Rahman, Shafiqur; Jun Wei, Lim; Gan, Siew Hua

    2016-01-01

    Cancer is a leading cause of death worldwide. Several classes of drugs are available to treat different types of cancer. Currently, researchers are paying significant attention to the development of drugs at the nanoscale level to increase their target specificity and to reduce their concentrations. Nanotechnology is a promising and growing field with multiple subdisciplines, such as nanostructures, nanomaterials, and nanoparticles. These materials have gained prominence in science due to their size, shape, and potential efficacy. Nanomedicine is an important field involving the use of various types of nanoparticles to treat cancer and cancerous cells. Synthesis of nanoparticles targeting biological pathways has become tremendously prominent due to the higher efficacy and fewer side effects of nanodrugs compared to other commercial cancer drugs. In this review, different medicinal plants and their active compounds, as well as green-synthesized metallic nanoparticles from medicinal plants, are discussed in relation to their anticancer activities. PMID:27057273

  14. Chrysin-piperazine conjugates as antioxidant and anticancer agents.

    PubMed

    Patel, Rahul V; Mistry, Bhupendra; Syed, Riyaz; Rathi, Anuj K; Lee, Yoo-Jung; Sung, Jung-Suk; Shinf, Han-Seung; Keum, Young-Soo

    2016-06-10

    Synthesis of 7-(4-bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one intermediate treating chrysin with 1,4-dibromobutane facilitated combination of chrysin with a wide range of piperazine moieties which were equipped via reacting the corresponding amines with bis(2-chloroethyl)amine hydrochloride in diethylene glycol monomethyl ether solvent. Free radical scavenging potential of prepared products was analyzed in vitro adopting DPPH and ABTS bioassay in addition to the evaluation of in vitro anticancer efficacies against cervical cancer cell lines (HeLa and CaSki) and an ovarian cancer cell line SK-OV-3 using SRB assay. Bearable toxicity of 7a-w was examined employing Madin-Darby canine kidney (MDCK) cell line. In addition, cytotoxic nature of the presented compounds was inspected utilizing Human bone marrow derived mesenchymal stem cells (hBM-MSCs). Overall, 7a-w indicated remarkable antioxidant power in scavenging DPPH(·) and ABTS(·+), particularly analogs 7f, 7j, 7k, 7l, 7n, 7q, 7v, 7w have shown promising free radical scavenging activity. Analogs 7j and 7o are identified to be highly active candidates against HeLa and CaSki cell lines, whereas 7h and 7l along with 7j proved to be very sensitive towards ovarian cancer cell line SKOV-3. None of the newly prepared scaffolds showed cytotoxic nature toward hBM-MSCs cells. From the structure-activity point of view, nature and position of the electron withdrawing and electron donating functional groups on the piperazine core may contribute to the anticipated antioxidant and anticancer action. Different spectroscopic techniques (FT-IR, (1)H NMR, (13)C NMR, Mass) and elemental analysis (CHN) were utilized to confirm the desired structure of final compounds. PMID:26924226

  15. 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

  16. A Highly Efficient Approach To Construct (epi)-Podophyllotoxin-4-O-glycosidic Linkages as well as Its Application in Concise Syntheses of Etoposide and Teniposide.

    PubMed

    Liu, Hui; Liao, Jin-Xi; Hu, Yang; Tu, Yuan-Hong; Sun, Jian-Song

    2016-03-18

    By taking full advantage of the mild promotion conditions of an ortho-alkynylbenzoate glycosylation protocol, a highly efficient approach to construct the challenging (epi)-podophyllotoxin 4-O-glycosidic linkages was devised under the activation of a catalytic amount of a Au(I) complex. The novel method enjoys a quite broad substrate scope in terms of both glycosyl donors and podophyllotoxin derivative acceptors, providing the desired glycosides in excellent yields. Based on the new approach, concise syntheses of clinically used anticancer reagents etoposide and teniposide were accomplished, and the overall yields counting from easily available starting materials could reach as high as 18% and 9%, respectively. PMID:26916150

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

    DOE PAGESBeta

    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.; et al

    2015-11-05

    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 mitochondrialmore » 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.« less

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

    SciTech Connect

    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.

    2015-11-05

    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.

  19. 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

  20. Discovery of novel isatin-dehydroepiandrosterone conjugates as potential anticancer agents.

    PubMed

    Ke, Shaoyong; Shi, Liqiao; Yang, Ziwen

    2015-10-15

    A series of isatin-dehydroepiandrosterone hybrids were synthesised via a convenient condensation procedure, and which were evaluated for their potential anticancer activities. The preliminary assays indicated that some of the newly obtained compounds exhibited good antitumor activities against human hepatocellular liver carcinoma (HepG2), heptoma (Huh-7), melanoma (A875) and 5-fluorouracil-resistant human hepatocellular carcinoma (BEL-7402/5-FU) cell lines compared with 5-fluorouracil (5-FU), which might be considered as promising lead scaffold for further design and synthesis of highly potential anticancer agents. PMID:26320625

  1. Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.

    PubMed

    Pace, Jennifer R; DeBerardinis, Albert M; Sail, Vibhavari; Tacheva-Grigorova, Silvia K; Chan, Kelly A; Tran, Raymond; Raccuia, Daniel S; Wechsler-Reya, Robert J; Hadden, M Kyle

    2016-04-28

    Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold. PMID:27014922

  2. Garlic-derived anticancer agents: structure and biological activity of ajoene.

    PubMed

    Kaschula, Catherine H; Hunter, Roger; Parker, M Iqbal

    2010-01-01

    Garlic has been used throughout the centuries to treat infections, heart disease, and cancer. Ajoene is one of the main compounds formed from heating crushed garlic as a mixture of E- and Z-isomers (E- and Z-4,5,9-trithiadodeca-1,6,11-triene 9-oxide). Ajoene possesses a broad spectrum of biological activities that include anticancer activity. It's cytotoxicity towards cancer cells is postulated to occur via an apoptotic mechanism involving activation of the mitochondrial-dependent caspase cascade. Structure-activity studies on ajoene and ajoene analogues have revealed that the Z-isomer is moderately more active than the E-isomer at inhibiting in vitro tumor cell growth, suggesting that specific protein interactions may be important. Substitution of the terminal end allyl groups in ajoene for alkyl, aromatic, or heteroaromatic groups produces some analogs with superior in vitro anticancer activity to ajoene, opening up the way to developing ajoene-based anticancer agents. PMID:20108330

  3. Caffeine-hydrazones as anticancer agents with pronounced selectivity toward T-lymphoblastic leukaemia cells.

    PubMed

    Kaplánek, Robert; Jakubek, Milan; Rak, Jakub; Kejík, Zdeněk; Havlík, Martin; Dolenský, Bohumil; Frydrych, Ivo; Hajdúch, Marián; Kolář, Milan; Bogdanová, Kateřina; Králová, Jarmila; Džubák, Petr; Král, Vladimír

    2015-06-01

    We report design and synthesis of set of novel anticancer agents based on caffeine-hydrazones bearing 2-hydroxyaryl- or 2-N-heteroaryl moiety. Anticancer activity evaluation using seven cancer cell lines and two non-malignant cell lines demonstrated that several derivatives display significant anticancer activity and great selectivity index toward T-lymphoblastic leukaemia cells. In general, hydrazones bearing 2-N-heteroaryl moiety are more active and selective than those with 2-hydroxyaryl moiety. Tested compounds exhibit dose-dependent inhibition of both RNA and DNA synthesis, with some exceptions. Antimicrobial activities were tested on set of twelve bacterial and yeast strains, however prepared compounds were not active, suggesting for a molecular target specific for eukaryotic cells. PMID:25912310

  4. Synthesis and evaluation of 3-ylideneoxindole acetamides as potent anticancer agents.

    PubMed

    Chiou, Chun-Tang; Lee, Wei-Chun; Liao, Jiahn-Haur; Cheng, Jing-Jy; Lin, Lie-Chwen; Chen, Chih-Yu; Song, Jen-Shin; Wu, Ming-Hsien; Shia, Kak-Shan; Li, Wen-Tai

    2015-06-15

    Indirubin, an active component in the traditional Chinese medicine formula Danggui Longhui Wan, shows promising anticancer effects. Meisoindigo is an analog derived from indirubin, which is less toxic and appears to be even more potent against cancer. In considering meisoindigo as a structural template for the development of new drugs, we designed and synthesized a series of 3-ylideneoxindole acetamides as novel anticancer agents. The acetamides were then evaluated for in vitro and in vivo anticancer activities. The 3-ylideneoxindole acetamides were found to have better anticancer activity than was indirubin-3'-oxime in several cancer cell lines and also displayed a spectrum of activity similar to that of the drug candidate roscovitine, a CDK inhibitor. Among the 3-ylideneoxindole acetamides, compound 10 showed particularly good efficacy. Cell cycle analysis further revealed that compound 10 arrested cells in the G1 phase and caused an increase in the sub-G1 population, indicating that the apoptosis pathway had been induced. In addition, exposure of cells to compound 10 led to the upregulation of the cell-cycle regulator cyclin D1, which was sustained at a high level. In contrast, the same compound induced a short-term elevation in the level of cyclin E, which was followed by a rapid decrease and the attenuation of Rb phosphorylation. Furthermore, a docking model suggests that compound 10 binds to the active site of CDK4. In testing the therapeutic potency of compound 10 on CT26-xenografted BALB/c mice, a significant reduction in tumor size comparable to that of cisplatin was found when administrated via the i.p. route. The mice presented no loss of body weight, indicating that this compound possesses low toxicity. In the future, we are planning in vivo investigations of these new active anticancer agents to better elucidate active mechanisms at the cellular level and thus benefit the development of anticancer therapies. PMID:25988923

  5. Development of anticancer agents targeting the Wnt/β-catenin signaling

    PubMed Central

    Zhang, Xiangqian; Hao, Jijun

    2015-01-01

    Wnt/β-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/β-catenin pathway. Here we systematically review the potential therapeutic agents that have been developed to date for inhibition of the Wnt/β-catenin cascade as well as current status of clinical trials of some of these agents. PMID:26396911

  6. Monocarboxylate transporter 1 inhibitors as potential anticancer agents.

    PubMed

    Gurrapu, Shirisha; Jonnalagadda, Sravan K; Alam, Mohammad A; Nelson, Grady L; Sneve, Mary G; Drewes, Lester R; Mereddy, Venkatram R

    2015-05-14

    Potent monocarboxylate transporter 1 inhibitors (MCT1) have been developed based on α-cyano-4-hydroxycinnamic acid template. Structure-activity relationship studies demonstrate that the introduction of p-N, N-dialkyl/diaryl, and o-methoxy groups into cyanocinnamic acid has maximal MCT1 inhibitory activity. Systemic toxicity studies in healthy ICR mice with few potent MCT1 inhibitors indicate normal body weight gains in treated animals. In vivo tumor growth inhibition studies in colorectal adenocarcinoma (WiDr cell line) in nude mice xenograft models establish that compound 27 exhibits single agent activity in inhibiting the tumor growth. PMID:26005533

  7. Investigation of Vietnamese plants for potential anticancer agents

    PubMed Central

    Pérez, Lynette Bueno; Still, Patrick C.; Naman, C. Benjamin; Ren, Yulin; Pan, Li; Chai, Hee-Byung; Carcache de Blanco, Esperanza J.; Ninh, Tran Ngoc; Van Thanh, Bui; Swanson, Steven M.; Soejarto, Djaja D.

    2014-01-01

    Higher plants continue to afford humankind with many new drugs, for a variety of disease types. In this review, recent phytochemical and biological progress is presented for part of a collaborative multi-institutional project directed towards the discovery of new antitumor agents. The specific focus is on bioactive natural products isolated and characterized structurally from tropical plants collected in Vietnam. The plant collection, identification, and processing steps are described, and the natural products isolated from these species are summarized with their biological activities. PMID:25395897

  8. Structure-activity relationships of 2'-modified-4'-selenoarabinofuranosyl-pyrimidines as anticancer agents.

    PubMed

    Kim, Jin-Hee; Yu, Jinha; Alexander, Varughese; Choi, Jung Hee; Song, Jayoung; Lee, Hyuk Woo; Kim, Hea Ok; Choi, Jungwon; Lee, Sang Kook; Jeong, Lak Shin

    2014-08-18

    Based on the potent anticancer activity of the D-arabino-configured cytosine nucleoside ara-C, novel 2'-substituted-4'-selenoarabinofuranosyl pyrimidines 3a-3u, comprising azido, fluoro, and hydroxyl substituents at C-2' were designed, synthesized, and evaluated for anticancer activity. The 2'-azido group was stereoselectively introduced by the Mitsunobu reaction using diphenylphosphoryl azide (DPPA), and the 2'-fluoro group was stereoselectively introduced through the double inversions of stereochemistry via the episelenium intermediate, which was formed by the participation of the selenium atom. Among the compounds tested, the 2'-fluoro derivative 3t (X=NH2, Y=H, R=F) was found to be the most potent anticancer agent and showed more potent anticancer activity than the control, ara-C in all tested human cancer cell lines (HCT116, A549, SNU638, T47D, and PC-3) except the leukemia cell lines (K562). The anticancer activity of the 2'-substituted-4'-selenonucleosides is in the following order: 2'-F>2'-OH>2'-N3. PMID:24956556

  9. 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

  10. Discovery of isoerianin analogues as promising anticancer agents.

    PubMed

    Messaoudi, Samir; Hamze, Abdallah; Provot, Olivier; Tréguier, Bret; Rodrigo De Losada, Jordi; Bignon, Jérôme; Liu, Jian-Miao; Wdzieczak-Bakala, Joanna; Thoret, Sylviane; Dubois, Joëlle; Brion, Jean-Daniel; Alami, Mouad

    2011-03-01

    The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly inhibits tubulin polymerization in the micromolar range. Moreover, isoerianin leads to G2/M phase cell-cycle arrest in H1299 and K562 cancer cells, and strongly induces apoptosis. Isoerianin also disrupts the vessel-like structures formed by human umbilical vein endothelial cells (HUVECs) in vitro, suggesting that this compound may act as a vascular disrupting agent. It clearly appears that in this compound series, the 1,1-ethane bridge encountered in isoerianin derivatives can replace the 1,2-ethane bridge of natural erianin with no loss of activity. This reinforces the bioisosteric replacement approach in the combretastatin series previously reported by our research group. PMID:21360820

  11. 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...

  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 α-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism. PMID:26521302

  13. Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine*

    PubMed Central

    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 α-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism. PMID:26521302

  14. 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 α-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

  15. The application of click chemistry in the synthesis of agents with anticancer activity

    PubMed Central

    Ma, Nan; Wang, Ying; Zhao, Bing-Xin; Ye, Wen-Cai; Jiang, Sheng

    2015-01-01

    The copper(I)-catalyzed 1,3-dipolar cycloaddition between alkynes and azides (click chemistry) to form 1,2,3-triazoles is the most popular reaction due to its reliability, specificity, and biocompatibility. This reaction has the potential to shorten procedures, and render more efficient lead identification and optimization procedures in medicinal chemistry, which is a powerful modular synthetic approach toward the assembly of new molecular entities and has been applied in anticancer drugs discovery increasingly. The present review focuses mainly on the applications of this reaction in the field of synthesis of agents with anticancer activity, which are divided into four groups: topoisomerase II inhibitors, histone deacetylase inhibitors, protein tyrosine kinase inhibitors, and antimicrotubule agents. PMID:25792812

  16. Adding pharmacogenomics to the development of new marine-derived anticancer agents

    PubMed Central

    Jimeno, José; Aracil, Miguel; Tercero, Juan Carlos

    2006-01-01

    Nature has always been a highly productive tool in the development of anticancer therapies. Renewed interest in the potential of this tool has recently been sparked by the realization that the marine ecosystem can be used for the discovery and development of new compounds with clinical potential in advanced resistant tumors. These compounds can be incorporated into combination approaches in a chronic therapy scenario. Our marine anticancer program is using the sea to develop new agents with activity in resistant solid tumors and to identify new cellular targets for therapeutic intervention. This review describes the integration of different pharmacogenomic tools in the development of Yondelis™, Aplidin® and Kahalalide F, three marine-derived compounds currently in Phase II or III development. Our results are reinforcing the targeted selectivity of these agents and opening the gates for customized therapies in cancer patients in the near future. PMID:16401350

  17. 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.

  18. Current development of the second generation of mTOR inhibitors as anticancer agents

    PubMed Central

    Zhou, Hong-Yu; Huang, Shi-Le

    2012-01-01

    The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, acts as a “master switch” for cellular anabolic and catabolic processes, regulating the rate of cell growth and proliferation. Dysregulation of the mTOR signaling pathway occurs frequently in a variety of human tumors, and thus, mTOR has emerged as an important target for the design of anticancer agents. mTOR is found in two distinct multiprotein complexes within cells, mTORC1 and mTORC2. These two complexes consist of unique mTOR-interacting proteins and are regulated by different mechanisms. Enormous advances have been made in the development of drugs known as mTOR inhibitors. Rapamycin, the first defined inhibitor of mTOR, showed effectiveness as an anticancer agent in various preclinical models. Rapamycin analogues (rapalogs) with better pharmacologic properties have been developed. However, the clinical success of rapalogs has been limited to a few types of cancer. The discovery that mTORC2 directly phosphorylates Akt, an important survival kinase, adds new insight into the role of mTORC2 in cancer. This novel finding prompted efforts to develop the second generation of mTOR inhibitors that are able to target both mTORC1 and mTORC2. Here, we review the recent advances in the mTOR field and focus specifically on the current development of the second generation of mTOR inhibitors as anticancer agents. PMID:22059905

  19. [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

  20. 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

  1. Potential anticancer agents. I. Synthesis of isoxazole moiety containing quinazoline derivatives and preliminarily in vitro anticancer activity.

    PubMed

    Yong, Jian-Ping; Lu, Can-Zhong; Wu, Xiaoyuan

    2015-01-01

    14 new structures of isoxazole-moiety-containing quinazoline derivatives(3a~3n) were synthesized for the first time and characterized by IR, (1)H NMR, (13)C NMR, ESI-MS. Subsequently, their in vitro anticancer activity against A549, HCT116 and MCF-7 cell lines was preliminarily evaluated using the MTT method. Among them, most compounds showed good to excellent anticancer activity, especially 3d, 3i, 3k and 3m exhibited the more potent anticancer activity against A549, HCT116 and MCF-7 cell lines, which can be regarded as the promising drug candidates for development of anticancer drugs. PMID:25142319

  2. Carnosol: a promising anti-cancer and anti-inflammatory agent.

    PubMed

    Johnson, Jeremy J

    2011-06-01

    The Mediterranean diet and more specifically certain meats, fruits, vegetables, and olive oil found in certain parts of the Mediterranean region have been associated with a decreased cardiovascular and diabetes risk. More recently, several population based studies have observed with these lifestyle choices have reported an overall reduced risk for several cancers. One study in particular observed an inverse relationship between consumption of Mediterranean herbs such as rosemary, sage, parsley, and oregano with lung cancer. In light of these findings there is a need to explore and identify the anti-cancer properties of these medicinal herbs and to identify the phytochemicals therein. One agent in particular, carnosol, has been evaluated for anti-cancer property in prostate, breast, skin, leukemia, and colon cancer with promising results. These studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFκB), apoptotic related proteins, phosphatidylinositol-3-kinase (PI3 K)/Akt, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and is well tolerated when administered to animals. This mini-review reports on the pre-clinical studies that have been performed to date with carnosol describing mechanistic, efficacy, and safety/tolerability studies as a cancer chemoprevention and anti-cancer agent. PMID:21382660

  3. 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-κB and AP-1), MAPK-pathway, and detoxification enzymes like SOD, catalase, glutathione peroxidase, and glutathione reductase has also been discussed. PMID:25003106

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

    PubMed

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

    2011-02-01

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

  5. 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

  6. 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

  7. The effect of mitochondrially targeted anticancer agents on mitochondrial (super)complexes.

    PubMed

    Vondrusova, Magdalena; Bezawork-Geleta, Ayanachew; Sachaphibulkij, Karishma; Truksa, Jaroslav; Neuzil, Jiri

    2015-01-01

    The mitochondrial respiratory chain is organized into dynamic high molecular weight complexes that associate to form supercomplexes. The function of these SCs is to minimize the production of reactive oxygen species (ROS) generated during electron transfer within them and to efficiently transfer electrons to complex IV. These supra-molecular structures as well as whole mitochondria are stress-responsive and respond to mitochondrially targeted anti-cancer agent by destabilization and induction of massive production of ROS leading to apoptosis. We have recently developed mitochondrially targeted anti-cancer agents epitomized by the mitochondrially targeted analogue of the redox-silent compound vitamin E succinate, which belongs to the group of agents that kill cancer cells via their mitochondria-destabilizing activity, referred to as mitocans. To understand the molecular mechanism of the effect of such agents, the use of native blue gel electrophoresis and clear native electrophoresis coupled with in-gel activity assays, are methods of choice. The relevant methodology is described in this chapter. PMID:25634277

  8. Vitamin E analogs, a novel group of "mitocans," as anticancer agents: the importance of being redox-silent.

    PubMed

    Neuzil, Jiri; Tomasetti, Marco; Zhao, Yan; Dong, Lan-Feng; Birringer, Marc; Wang, Xiu-Fang; Low, Pauline; Wu, Kun; Salvatore, Brian A; Ralph, Steven J

    2007-05-01

    The search for a selective and efficient anticancer agent for treating all neoplastic disease has yet to deliver a universally suitable compound(s). The majority of established anticancer drugs either are nonselective or lose their efficacy because of the constant mutational changes of malignant cells. Until recently, a largely neglected target for potential anticancer agents was the mitochondrion, showing a considerable promise for future clinical applications. Vitamin E (VE) analogs, epitomized by alpha-tocopheryl succinate, belong to the group of "mitocans" (mitochondrially targeted anticancer drugs). They are selective for malignant cells, cause destabilization of their mitochondria, and suppress cancer in preclinical models. This review focuses on our current understanding of VE analogs in the context of their proapoptotic/anticancer efficacy and suggests that their effect on mitochondria may be amplified by modulation of alternative pathways operating in parallel. We show here that the analogs of VE that cause apoptosis (which translates into their anticancer efficacy) generally do not possess antioxidant (redox) activity and are prototypical of the mitocan group of anticancer compounds. Therefore, by analogy to Oscar Wilde's play The Importance of Being Earnest, we use the motto in the title "the importance of being redox-silent" to emphasize an essentially novel paradigm for cancer therapy, in which redox-silence is a prerequisite property for most of the anticancer activities described in this communication. PMID:17220355

  9. Polylactide-co-glycolide nanoparticles for controlled delivery of anticancer agents

    PubMed Central

    Dinarvand, R; Sepehri, N; Manoochehri, S; Rouhani, H; Atyabi, F

    2011-01-01

    The effectiveness of anticancer agents may be hindered by low solubility in water, poor permeability, and high efflux from cells. Nanomaterials have been used to enable drug delivery with lower toxicity to healthy cells and enhanced drug delivery to tumor cells. Different nanoparticles have been developed using different polymers with or without surface modification to target tumor cells both passively and/or actively. Polylactide-co-glycolide (PLGA), a biodegradable polyester approved for human use, has been used extensively. Here we report on recent developments concerning PLGA nanoparticles prepared for cancer treatment. We review the methods used for the preparation and characterization of PLGA nanoparticles and their applications in the delivery of a number of active agents. Increasing experience in the field of preparation, characterization, and in vivo application of PLGA nanoparticles has provided the necessary momentum for promising future use of these agents in cancer treatment, with higher efficacy and fewer side effects. PMID:21720501

  10. Polylactide-co-glycolide nanoparticles for controlled delivery of anticancer agents.

    PubMed

    Dinarvand, R; Sepehri, N; Manoochehri, S; Rouhani, H; Atyabi, F

    2011-01-01

    The effectiveness of anticancer agents may be hindered by low solubility in water, poor permeability, and high efflux from cells. Nanomaterials have been used to enable drug delivery with lower toxicity to healthy cells and enhanced drug delivery to tumor cells. Different nanoparticles have been developed using different polymers with or without surface modification to target tumor cells both passively and/or actively. Polylactide-co-glycolide (PLGA), a biodegradable polyester approved for human use, has been used extensively. Here we report on recent developments concerning PLGA nanoparticles prepared for cancer treatment. We review the methods used for the preparation and characterization of PLGA nanoparticles and their applications in the delivery of a number of active agents. Increasing experience in the field of preparation, characterization, and in vivo application of PLGA nanoparticles has provided the necessary momentum for promising future use of these agents in cancer treatment, with higher efficacy and fewer side effects. PMID:21720501

  11. 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

  12. 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

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

    NASA Astrophysics Data System (ADS)

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

    2010-03-01

    Poly(lactide-co-glycolide) (PLA50GA50) 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 PLA50GA50 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) (PLA50GA50) at inherent viscosity of 0.89 dL/g as preliminary studies for anticancer agent delivery.

  14. Discovery and development of the anticancer agent salinosporamide A (NPI-0052).

    PubMed

    Fenical, William; Jensen, Paul R; Palladino, Michael A; Lam, Kin S; Lloyd, G Kenneth; Potts, Barbara C

    2009-03-15

    The discovery of the anticancer agent salinosporamide A (NPI-0052) resulted from the exploration of new marine environments and a commitment to the potential of the ocean to yield new natural products for drug discovery and development. Driving the success of this process was the linkage of academic research together with the ability and commitment of industry to undertake drug development and provide the resources and expertise to advance the entry of salinosporamide A (NPI-0052) into human clinical trials. This paper offers a chronicle of the important events that facilitated the rapid clinical development of this exciting molecule. PMID:19022674

  15. DFT-based QSAR study and molecular design of AHMA derivatives as potent anticancer agents

    NASA Astrophysics Data System (ADS)

    Chen, Jincan; Shen, Yong; Liao, Siyan; Chen, Lanmei; Zheng, Kangcheng

    A quantitative structure-activity relationship (QSAR) of 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA) derivatives and their alkylcarbamates as potent anticancer agents has been studied using density functional theory (DFT), molecular mechanics (MM+), and statistical methods. In the best established QSAR equation, the energy (ENL) of the next lowest unoccupied molecular orbital (NLUMO) and the net charges (QFR) of the first atom of the substituent R, as well as the steric parameter (MR2) of subsituent R2 are the main independent factors contributing to the anticancer activity of the compounds. A new scheme determining outliers by ?leave-one-out? (LOO) cross-validation coefficient (q2n-i) was suggested and successfully used. The fitting correlation coefficient (R2) and the ?LOO? cross-validation coefficient (q2) values for the training set of 25 compounds are 0.881 and 0.829, respectively. The predicted activities of 5 compounds in the test set using this QSAR model are in good agreement with their experimental values, indicating that this model has excellent predictive ability. Based on the established QSAR equation, 10 new compounds with rather high anticancer activity much greater than that of 34 compounds have been designed and await experimental verification.

  16. 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.

  17. 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

  18. 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

  19. 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

  20. The role of alpha tocopheryl succinate (?-TOS) as a potential anticancer agent.

    PubMed

    Angulo-Molina, Aracely; Reyes-Leyva, Julio; Lpez-Malo, Aurelio; Hernndez, Jess

    2014-01-01

    In recent years, efforts to improve cancer therapy have focused on developing new anticancer agents, such as mitocans. These agents include vitamin E analogues and suppress cancer by inducing apoptosis by targeting mitochondria. Alpha tocopheryl succinate (?-TOS) is the most effective form of vitamin E analogues causing inhibition of proliferation and apoptosis of cancer cells. Both in vitro and in vivo studies have demonstrated that ?-TOS selectively kills tumor cells with little or no effect on normal cells. Treatment with ?-TOS shows great promise for future clinical applications, as it causes cell death, at least in part, by selectively inducing apoptosis by mitochondrial destabilization. This review presents an overview of perspectives on ?-TOS and the potential uses of ?-TOS in cancer treatment and other clinical applications. PMID:24364743

  1. 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

  2. Novel C6-substituted 1,3,4-oxadiazinones as potential anti-cancer agents

    PubMed Central

    Jung, Yujin; Yun, Hye Jeong; Min, Hye-Young; Lee, Ho Jin; Pham, Phuong Chi; Moon, Jayoung; Kwon, Dah In; Lim, Bumhee; Suh, Young-Ger; Lee, Jeeyeon; Lee, Ho-Young

    2015-01-01

    The insulin-like growth factor 1 receptor (IGF-1R) is a membrane receptor tyrosine kinase over-expressed in a number of tumors. However, combating resistance is one of the main challenges in the currently available IGF-1R inhibitor-based cancer therapies. Increased Src activation has been reported to confer resistance to anti-IGF-1R therapeutics in various tumor cells. An urgent unmet need for IGF-1R inhibitors is to suppress Src rephosphorylation induced by current anti-IGF-1R regimens. In efforts to develop effective anticancer agents targeting the IGF-1R signaling pathway, we explored 2-aryl-1,3,4-oxadiazin-5-ones as a novel scaffold that is structurally unrelated to current tyrosine kinase inhibitors (TKIs). The compound, LL-2003, exhibited promising antitumor effects in vitro and in vivo; it effectively suppressed IGF-1R and Src and induced apoptosis in various non-small cell lung cancer cells. Further optimizations for enhanced potency in cellular assays need to be followed, but our strategy to identify novel IGF-1R/Src inhibitors may open a new avenue to develop more efficient anticancer agents. PMID:26515601

  3. 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

  4. New synthetic aliphatic sulfonamido-quaternary ammonium salts as anticancer chemotherapeutic agents.

    PubMed

    Song, Doona; Yang, Jee Sun; Oh, Changmok; Cui, Shuolin; Kim, Bo-Kyung; Won, Misun; Lee, Jang-ik; Kim, Hwan Mook; Han, Gyoonhee

    2013-11-01

    RhoB is expressed during tumor cell proliferation, survival, invasion, and metastasis. In malignant progression, the expression levels of RhoB are commonly attenuated. RhoB is known to be linked to the regulation of the PI3K/Akt survival pathways. Based on aliphatic amido-quaternary ammonium salts that induce apoptosis via up-regulation of RhoB, we synthesized novel aliphatic sulfonamido-quaternary ammonium salts. These new synthetic compounds were evaluated for their biological activities using an in vitro RhoB promoter assay in HeLa cells, and in a growth inhibition assay using human cancer cell lines including PC-3, NUGC-3, MDA-MB-231, ACHN, HCT-15, and NCI-H23. Compound 5b (ethyl-dimethyl-{3-[methyl-(tetradecane-1-sulfonyl)-amino]-propyl}-ammonium; iodide) was the most promising anticancer agent in the series, based upon the potency of growth inhibition and RhoB promotion. These new aliphatic sulfonamido-quaternary ammonium salts could be a valuable series for development of new anticancer chemotherapeutic agents. PMID:24095759

  5. Toad Glandular Secretions and Skin Extractions as Anti-Inflammatory and Anticancer Agents

    PubMed Central

    Tan, C. K.; Hashimi, Saeed M.; Zulfiker, Abu Hasanat Md.; Wei, Ming Q.

    2014-01-01

    Toad glandular secretions and skin extractions contain many natural agents which may provide a unique resource for novel drug development. The dried secretion from the auricular and skin glands of Chinese toad (Bufo bufo gargarizans) is named Chansu, which has been used in Traditional Chinese Medicine (TCM) for treating infection and inflammation for hundreds of years. The sterilized hot water extraction of dried toad skin is named Huachansu (Cinobufacini) which was developed for treating hepatitis B virus (HBV) and several types of cancers. However, the mechanisms of action of Chansu, Huachansu, and their constituents within are not well reported. Existing studies have suggested that their anti-inflammation and anticancer potential were via targeting Nuclear Factor (NF)-κB and its signalling pathways which are crucial hallmarks of inflammation and cancer in various experimental models. Here, we review some current studies of Chansu, Huachansu, and their compounds in terms of their use as both anti-inflammatory and anticancer agents. We also explored the potential use of toad glandular secretions and skin extractions as alternate resources for treating human cancers in combinational therapies. PMID:24734105

  6. Nano-Fenton Reactors as a New Class of Oxidative Stress Amplifying Anticancer Therapeutic Agents.

    PubMed

    Kwon, Byeongsu; Han, Eunji; Yang, Wonseok; Cho, Wooram; Yoo, Wooyoung; Hwang, Junyeon; Kwon, Byoung-Mog; Lee, Dongwon

    2016-03-01

    Cancer cells, compared to normal cells, are under oxidative stress associated with an elevated level of reactive oxygen species (ROS) and are more vulnerable to oxidative stress induced by ROS generating agents. Thus, manipulation of the ROS level provides a logical approach to kill cancer cells preferentially, without significant toxicity to normal cells, and great efforts have been dedicated to the development of strategies to induce cytotoxic oxidative stress for cancer treatment. Fenton reaction is an important biological reaction in which irons convert hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals that escalate ROS stress. Here, we report Fenton reaction-performing polymer (PolyCAFe) micelles as a new class of ROS-manipulating anticancer therapeutic agents. Amphiphilic PolyCAFe incorporates H2O2-generating benzoyloxycinnamaldehyde and iron-containing compounds in its backbone and self-assembles to form micelles that serve as Nano-Fenton reactors to generate cytotoxic hydroxyl radicals, killing cancer cells preferentially. When intravenously injected, PolyCAFe micelles could accumulate in tumors preferentially to remarkably suppress tumor growth, without toxicity to normal tissues. This study demonstrates the tremendous translatable potential of Nano-Fenton reactors as a new class of anticancer drugs. PMID:26888039

  7. An efficient in vitro system for somatic embryogenesis and podophyllotoxin production in Podophyllum hexandrum Royle.

    PubMed

    Rajesh, Manoharan; Sivanandhan, Ganeshan; Jeyaraj, Murugaraj; Chackravarthy, Rajan; Manickavasagam, Markandan; Selvaraj, N; Ganapathi, Andy

    2014-09-01

    Podophyllum hexandrum Royle known as Indian mayapple is an important medicinal plant found only in higher altitudes (2,700 to 4,200 m) of the Himalayas. The highly valued anticancer drug Podophyllotoxin is obtained from the roots of this plant. Due to over exploitation, this endemic plant species is on the verge of extinction. In vitro culture for efficient regeneration and the production of podophyllotoxin is an important research priority for this plant. Hence, in the present study, an efficient plant regeneration system for mass multiplication through somatic embryogenesis was developed. We have screened P. hexandrum seeds collected from three different regions in the Himalayas to find their regenerative potentials. These variants showed variation in germination percentage as well as somatic embryogenic frequency. The seeds collected from the Milam area of Pithoragarh district showed better germination response (99.3%) on Murashige and Skoog (MS) medium fortified with Gibberellic acid (GA3 [5 mg/l]) and higher direct somatic embryogenic frequency (89.6%). Maximum production of embryogenic callus (1.2 g fresh weight [FW]) was obtained when cotyledons containing the direct somatic embryo clusters were cultured in MS medium supplemented with 2,4-dichlorophenoxyacetic acid (2,4-D [1.5 mg/l]) after 4 week of culture in complete darkness. In the present investigation, somatic embryogenesis was accomplished either by direct organogenesis or callus mediated pathways. The latter method resulted in a higher frequency of somatic embryo induction in hormone-free MS medium yielding 47.7 embryos/50 mg of embryogenic callus and subsequent germination in MS medium supplemented with GA3 (5 mg/l). Seventy-nine percent of embryos attained complete maturity and germinated into normal plants with well-developed roots. Systematic histological analysis revealed the origin of somatic embryo and their ontogenesis. The higher level of podophyllotoxin (1.8 mg/g dry weight [DW]) was recorded in germinated somatic embryos when compared to field grown plants. The present system can be widely used for mass propagation, transgenic recovery, and podophyllotoxin production for commercial utilization. PMID:24633328

  8. Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study.

    PubMed

    Rana, Sandeep; Blowers, Elizabeth C; Tebbe, Calvin; Contreras, Jacob I; Radhakrishnan, Prakash; Kizhake, Smitha; Zhou, Tian; Rajule, Rajkumar N; Arnst, Jamie L; Munkarah, Adnan R; Rattan, Ramandeep; Natarajan, Amarnath

    2016-05-26

    Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-μM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents. PMID:27077228

  9. Phytantriol based liquid crystal provide sustained release of anticancer drug as a novel embolic agent.

    PubMed

    Qin, Lingzhen; Mei, Liling; Shan, Ziyun; Huang, Ying; Pan, Xin; Li, Ge; Gu, Yukun; Wu, Chuanbin

    2016-02-01

    Phytantriol has received increasing amount of attention in drug delivery system, however, the ability of the phytantriol based liquid crystal as a novel embolic agent to provide a sustained release delivery system is yet to be comprehensively demonstrated. The purpose of this study was to prepare a phytantriol-based cubic phase precursor solution loaded with anticancer drug hydroxycamptothecine (HCPT) and evaluate its embolization properties, in vitro drug release and cytotoxicity. Phase behavior of the phytantriol-solvent-water system was investigated by visual inspection and polarized light microscopy, and no phase transition was observed in the presence of HCPT within the studied dose range. Water uptake by the phytantriol matrices was determined gravimetrically, suggesting that the swelling complied with the second order kinetics. In vitro evaluation of embolic efficacy indicated that the isotropic solution displayed a satisfactory embolization effect. In vitro drug release results showed a sustained-release up to 30 days and the release behavior was affected by the initial composition and drug loading. Moreover, the in vitro cytotoxicity and anticancer activity were evaluated by MTT assay. No appreciable mortality was observed for NIH 3T3 cells after 48 h exposure to blank formulations, and the anticancer activity of HCPT-loaded formulations to HepG2 and SMMC7721 cells was strongly dependent on the drug loading and treatment time. Taken together, these results indicate that phytantriol-based cubic phase embolic gelling solution is a promising potential carrier for HCPT delivery to achieve a sustained drug release by vascular embolization, and this technology may be potential for clinical applications. PMID:26035332

  10. Synthesis, biological evaluation and mechanism studies of deoxytylophorinine and its derivatives as potential anticancer agents.

    PubMed

    Lv, Haining; Ren, Jinhong; Ma, Shuanggang; Xu, Song; Qu, Jing; Liu, Zhenjia; Zhou, Qing; Chen, Xiaoguang; Yu, Shishan

    2012-01-01

    Previous studies indicated that (+)-13a-(S)-deoxytylophorinine (1) showed profound anti-cancer activities both in vitro and in vivo and could penetrate the blood brain barrier to distribute well in brain tissues. CNS toxicity, one of the main factors to hinder the development of phenanthroindolizidines, was not obviously found in 1. Based on its fascinating activities, thirty-four derivatives were designed, synthesized; their cytotoxic activities in vitro were tested to discover more excellent anticancer agents. Considering the distinctive mechanism of 1 and interesting SAR of deoxytylophorinine and its derivatives, the specific impacts of these compounds on cellular progress as cell signaling transduction pathways and cell cycle were proceeded with seven representative compounds. 1 as well as three most potent compounds, 9, 32, 33, and three less active compounds, 12, 16, 35, were selected to proform this study to have a relatively deep view of cancer cell growth-inhibitory characteristics. It was found that the expressions of phospho-Akt, Akt, phospho-ERK, and ERK in A549 cells were greater down-regulated by the potent compounds than by the less active compounds in the Western blot analysis. To the best of our knowledge, this is the first report describing phenanthroindolizidines alkaloids display influence on the crucial cell signaling proteins, ERK. Moreover, the expressions of cyclin A, cyclin D1 and CDK2 proteins depressed more dramatically when the cells were treated with 1, 9, 32, and 33. Then, these four excellent compounds were subjected to flow cytometric analysis, and an increase in S-phase was observed in A549 cells. Since the molecular level assay results of Western blot for phospho-Akt, Akt, phospho-ERK, ERK, and cyclins were relevant to the potency of compounds in cellular level, we speculated that this series of compounds exhibit anticancer activities through blocking PI3K and MAPK signaling transduction pathways and interfering with the cell cycle progression. PMID:22276180

  11. 2-Hydroxypropyl-β-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-β-cyclodextrin (HP-β-CyD) is a cyclic oligosaccharide that is widely used as an enabling excipient in pharmaceutical formulations, but also as a cholesterol modifier. HP-β-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-β-CyD itself might have anticancer effects. This study provides evidence that HP-β-CyD inhibits leukemic cell proliferation at physiologically available doses. First, we identified the potency of HP-β-CyD in vitro against various leukemic cell lines derived from acute myeloid leukemia (AML), acute lymphoblastic leukemia and chronic myeloid leukemia (CML). HP-β-CyD treatment reduced intracellular cholesterol resulting in significant leukemic cell growth inhibition through G2/M cell-cycle arrest and apoptosis. Intraperitoneal injection of HP-β-CyD significantly improved survival in leukemia mouse models. Importantly, HP-β-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-β-CyD. Systemic administration of HP-β-CyD to mice had no significant adverse effects. These data suggest that HP-β-CyD is a promising anticancer agent regardless of disease or cellular characteristics. PMID:26535909

  12. Preclinical pharmacology of the natural product anticancer agent bryostatin 1, an activator of protein kinase C.

    PubMed

    Zhang, X; Zhang, R; Zhao, H; Cai, H; Gush, K A; Kerr, R G; Pettit, G R; Kraft, A S

    1996-02-15

    Bryostatin 1, a natural product anticancer agent isolated from a marine bryozoan, has been shown in tissue culture to activate protein kinase C. This agent has recently undergone Phase I testing in humans given either as a bolus i.v. injection or a continuous infusion. To understand how bryostatin 1 might be used best as an anticancer agent, a study of the pharmacokinetics, tissue distribution, metabolism, and elimination of bryostatin 1 in mice was undertaken, using [C26-3H]-labeled bryostatin 1. Following i.v. administration, the plasma disappearance curve for bryostatin 1 could be described by a two-compartment model, with half-lives of 1.05 and 22.97 h, respectively. In contrast, the plasma disappearance curve for bryostatin 1 administered i.p. was better described by a first order absorption one-compartment model, with an absorption half-life of 0.81 h and an elimination half-life of 28.76 h, respectively. The majority of radioactivity in plasma was associated with the intact drug for up to 24 h after dosing. In the first 12 h after i.v administration, urinary excretion represented the major pathway of elimination, with 23.0 +/- 1.9% (mean +/- SD) of the administered dose excreted. Within 72 h after i.v. administration, approximately equal amounts of radioactivity (40%) were excreted in feces compared to urine. Bryostatin 1 was widely distributed in many organs but concentrated in the lung, liver, gastrointestinal tract, and fatty tissue. The concentration in the gastrointestinal tract, along with the fecal excretion, suggests the possibility of enterohepatic circulation of this drug. In summary, this study demonstrates that bryostatin 1 is relatively stable in vivo, widely distributed but concentrated in some major tissues, and rapidly excreted first through urine and at later times through the feces. The data from this animal study should be useful in the design of future human trials with this anticancer drug. PMID:8631017

  13. 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

  14. Withaferin-A—A Natural Anticancer Agent with Pleitropic Mechanisms of Action

    PubMed Central

    Lee, In-Chul; Choi, Bu Young

    2016-01-01

    Cancer, being the second leading cause of mortality, exists as a formidable health challenge. In spite of our enormous efforts, the emerging complexities in the molecular nature of disease progression limit the real success in finding an effective cancer cure. It is now conceivable that cancer is, in fact, a progressive illness, and the morbidity and mortality from cancer can be reduced by interfering with various oncogenic signaling pathways. A wide variety of structurally diverse classes of bioactive phytochemicals have been shown to exert anticancer effects in a large number of preclinical studies. Multiple lines of evidence suggest that withaferin-A can prevent the development of cancers of various histotypes. Accumulating data from different rodent models and cell culture experiments have revealed that withaferin-A suppresses experimentally induced carcinogenesis, largely by virtue of its potent anti-oxidative, anti-inflammatory, anti-proliferative and apoptosis-inducing properties. Moreover, withaferin-A sensitizes resistant cancer cells to existing chemotherapeutic agents. The purpose of this review is to highlight the mechanistic aspects underlying anticancer effects of withaferin-A. PMID:26959007

  15. Withaferin-A-A Natural Anticancer Agent with Pleitropic Mechanisms of Action.

    PubMed

    Lee, In-Chul; Choi, Bu Young

    2016-01-01

    Cancer, being the second leading cause of mortality, exists as a formidable health challenge. In spite of our enormous efforts, the emerging complexities in the molecular nature of disease progression limit the real success in finding an effective cancer cure. It is now conceivable that cancer is, in fact, a progressive illness, and the morbidity and mortality from cancer can be reduced by interfering with various oncogenic signaling pathways. A wide variety of structurally diverse classes of bioactive phytochemicals have been shown to exert anticancer effects in a large number of preclinical studies. Multiple lines of evidence suggest that withaferin-A can prevent the development of cancers of various histotypes. Accumulating data from different rodent models and cell culture experiments have revealed that withaferin-A suppresses experimentally induced carcinogenesis, largely by virtue of its potent anti-oxidative, anti-inflammatory, anti-proliferative and apoptosis-inducing properties. Moreover, withaferin-A sensitizes resistant cancer cells to existing chemotherapeutic agents. The purpose of this review is to highlight the mechanistic aspects underlying anticancer effects of withaferin-A. PMID:26959007

  16. 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 α-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

  17. Hsp90-functionalized polypyrrole nanotube FET sensor for anti-cancer agent detection.

    PubMed

    Kwon, Oh Seok; Hong, Tae-Joon; Kim, Sang Kyu; Jeong, Jae-Hoon; Hahn, Ji-Sook; Jang, Jyongsik

    2010-02-15

    A rapid and efficient strategy to detect novel heat shock protein 90 (Hsp90) inhibitors as anti-cancer agents was developed with field-effect transistor (FET) sensor based on carboxylated polypyrrole nanotubes (CPNTs). First of all, the CPNTs were successfully fabricated by using cylindrical micelle templates in a water-in-oil emulsion system, and the functional carboxyl groups were effectively incorporated into the polymer backbone during the polymerization by using pyrrole-3-carboxylic acid (P3CA) as a co-monomer. A liquid-ion gated FET-type sensor was readily constructed on the basis of CPNTs as the conductive channel. The CPNTs were covalently immobilized onto the microelectrode substrate to maintain stable electrical contact between the CPNTs and the microelectrodes in the liquid phase. Subsequently, Hsp90 was attached to the CPNTs surface through condensation reactions between the terminal amino groups in Hsp90 amino acid residues and the carboxyl groups on the CPNTs. The Hsp90-conjugated CPNT FET sensor provided a convenient and sensitive method to observe the affinity between Hsp90 to Hsp90 inhibitors in real-time. This result suggests that the FET sensor will open up the potential application for new anti-cancer drug discovery (Hsp90 inhibitors) after a judicious optimization. PMID:19914055

  18. Synthesis and Evaluation of Novel Erlotinib-NSAID Conjugates as More Comprehensive Anticancer Agents.

    PubMed

    Zhang, Yanmei; Tortorella, Micky D; Liao, Jinxi; Qin, Xiaochu; Chen, Tingting; Luo, Jinfeng; Guan, Jiantong; Talley, John J; Tu, Zhengchao

    2015-10-01

    A series of novel anticancer agents were designed and synthesized based on coupling of different nonsteroidal anti-inflammatory drugs (NSAIDs) with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers where both EGFR overexpression and inflammation play a direct role in disease progression. PMID:26487917

  19. Histone deacetylase inhibitors: a new wave of molecular targeted anticancer agents.

    PubMed

    Budillon, Alfredo; Di Gennaro, Elena; Bruzzese, Francesca; Rocco, Monia; Manzo, Giuseppe; Caraglia, Michele

    2007-06-01

    Epigenetics as well as post-translational modifications of proteins are emerging as novel attractive targets for anti-cancer therapy. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two classes of enzymes regulating histone acetylation and whose altered activity has been identified in several cancers. In particular, imbalance in histone acetylation can lead to changes in chromatin structure and transcriptional dysregulation of genes that are involved in the control of proliferation, cell-cycle progression, differentiation and/or apoptosis. In addition, several non histone protein substrates such as transcription factors, chaperone proteins or tubulin, undergo acetylation as key post-translation modification regulating their half-life and function. On this regard, several inhibitors of HDAC, selected by academic as well as industrial research, have been recently shown to induce growth arrest and apoptosis in a variety of human cancer cells and have been patented as anti-cancer agents. Although several clinical studies with HDAC inhibitors are ongoing, their mechanism of action cannot be solely attributed to the level of histone acetylation and molecular basis for their tumor selectivity remains unknown, presenting a challenge for the cancer research community. PMID:18221057

  20. Nucleotide Binding Preference of the Monofunctional Platinum Anticancer-Agent Phenanthriplatin.

    PubMed

    Riddell, Imogen A; Johnstone, Timothy C; Park, Ga Young; Lippard, Stephen J

    2016-05-23

    The monofunctional platinum anticancer agent phenanthriplatin generates covalent adducts with the purine bases guanine and adenine. Preferential nucleotide binding was investigated by using a polymerase stop assay and linear DNA amplification with a 163-base pair DNA double helix. Similarly to cisplatin, phenanthriplatin forms the majority of adducts at guanosine residues, but significant differences in both the number and position of platination sites emerge when comparing results for the two complexes. Notably, the monofunctional complex generates a greater number of polymerase-halting lesions at adenosine residues than does cisplatin. Studies with 9-methyladenine reveal that, under abiological conditions, phenanthriplatin binds to the N(1) or N(7) position of 9-methyladenine in approximately equimolar amounts. By contrast, comparable reactions with 9-methylguanine afforded only the N(7) -bound species. Both of the 9-methyladenine linkage isomers (N(1) and N(7) ) exist as two diastereomeric species, arising from hindered rotation of the aromatic ligands about their respective platinum-nitrogen bonds. Eyring analysis of rate constants extracted from variable-temperature NMR spectroscopic data revealed that the activation energies for ligand rotation in the N(1) -bound platinum complex and the N(7) -linkage isomers are comparable. Finally, a kinetic analysis indicated that phenanthriplatin reacts more rapidly, by a factor of eight, with 9-methylguanine than with 9-methyladenine, suggesting that the distribution of lesions formed on double-stranded DNA is kinetically controlled. In addition, implications for the potent anticancer activity of phenanthriplatin are discussed herein. PMID:27111128

  1. 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

  2. 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

  3. Drug-induced interstitial lung diseases associated with molecular-targeted anticancer agents.

    PubMed

    Gemma, Akihiko

    2009-02-01

    Little was known about drug-induced interstitial lung disease (ILD) when acute ILD-type events developed in several Japanese patients treated with gefitinib. A better understanding of drug-induced ILD is required, including more reliable data about the incidence of events associated with different treatments and identification of the risk factors for this type of ILD. Recent advances in imaging, molecular examination, and pathology have been used in postmarketing surveillance studies designed and conducted by an independent academic team to define the risk and to increase the amount of evidence about ILD related to various molecularly targeted anticancer agents. These studies may shed light on the underlying mechanisms of drug-induced ILD and appropriate evidence-based strategies that can be used to prevent or manage these events. PMID:19305103

  4. 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.

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

    PubMed

    Damio, Mariana C F C B; Pasqualoto, Kerly F M; Ferreira, Adilson K; Teixeira, Sarah F; Azevedo, Ricardo A; Barbuto, Jos A M; Palace-Berl, Fanny; Franchi-Junior, Gilberto C; Nowill, Alexandre E; Tavares, Maurcio 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 (M) 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

  6. [The biological point of view on pharmacogenetics of anticancer agents in colorectal cancer].

    PubMed

    Laurent-Puig, Pierre; Livre, Astrid; Ducreux, Michel; Loriot, Marie-Anne

    2008-10-01

    Several drugs have been developed and demonstrated similar efficacy in colorectal cancer treatment therefore with choice, time comes for decision. The biologist will have to provide the tools allowing to clarify this choice. Among the tools available, those of pharmacogenetics and pharmacogenomics appear most promising and recent examples allow to illustrate their clinical interest. The pharmacogenetics of anti-cancer agents presents a clinical characteristic, which requires to hold into account the genetic variations not only of host cells but also of those of the tumor cells. Among the most conclusive examples one is that of the prediction of severe neutropenia induced by the irinotecan among patients homozygous for * 28 allele of UGT1A1 enzyme which conjugates SN38 active compound of irinotecan, the other one is the presence of a KRAS mutated allele in tumor cell to predict resistance to anti EGFR antibodies in the treatment of colorectal metastatic cancer. PMID:19004723

  7. Evaluation of 2-(methylaminosulfonyl)-1-(arylsulfonyl)-1-methylhydrazines as anticancer agents.

    PubMed

    Sanyal, U; De, R; Dutta, S; Das, H; Ghost, M

    1993-01-01

    Seven new 2-(methylaminosulfonyl)-1-(arylsulfonyl)-1-methylhydrazines were prepared. The anticancer activity of these compounds was assessed in murine Ehrlich ascites carcinoma (EAC) by in vivo screening. Moderate in vivo activity in EAC was exhibited by three compounds. All of them were screened in vitro against a battery of human tumor cell lines at the National Cancer Institute (NCI), USA. One of them, compound 3a has displayed highly significant specificity in the renal tumor cell line RXF 393. These three compounds were also assessed for in vitro anti-HIV activity at the NCI, however, they have not reached the criteria of significant activity. The alkylating activity of the compounds was determined by measuring the absorbance of the alkylated product of 4-(4-nitrobenzyl)pyridine. It has been found that they are capable of acting as chemical alkylating agents. PMID:8272148

  8. Molecular Basis for the Inhibition of Human NMPRTase, a Novel Target for Anticancer Agents

    SciTech Connect

    Khan,J.; Tao, X.; Tong, L.

    2006-01-01

    Nicotinamide phosphoribosyltransferase (NMPRTase) has a crucial role in the salvage pathway of NAD{sup +} biosynthesis, and a potent inhibitor of NMPRTase, FK866, can reduce cellular NAD+ levels and induce apoptosis in tumors. We have determined the crystal structures at up to 2.1-Angstroms resolution of human and murine NMPRTase, alone and in complex with the reaction product nicotinamide mononucleotide or the inhibitor FK866. The structures suggest that Asp219 is a determinant of substrate specificity of NMPRTase, which is confirmed by our mutagenesis studies. FK866 is bound in a tunnel at the interface of the NMPRTase dimer, and mutations in this binding site can abolish the inhibition by FK866. Contrary to current knowledge, the structures show that FK866 should compete directly with the nicotinamide substrate. Our structural and biochemical studies provide a starting point for the development of new anticancer agents.

  9. 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.

  10. Design, Synthesis, and Biological Evaluation of Novel Selenium (Se-NSAID) Molecules as Anticancer Agents.

    PubMed

    Plano, Daniel; Karelia, Deepkamal N; Pandey, Manoj K; Spallholz, Julian E; Amin, Shantu; Sharma, Arun K

    2016-03-10

    The synthesis and anticancer evaluation of novel selenium-nonsteroidal anti-inflammatory drug (Se-NSAID) hybrid molecules are reported. The Se-aspirin analogue 8 was identified as the most effective agent in reducing the viability of different cancer cell lines, particularly colorectal cancer (CRC) cells, was more selective toward cancer cells than normal cells, and was >10 times more potent than 5-FU, the current therapy for CRC. Compound 8 inhibits CRC growth via the inhibition of the cell cycle in G1 and G2/M phases and reduces the cell cycle markers like cyclin E1 and B1 in a dose dependent manner; the inhibition of the cell cycle may be dependent on the ability of 8 to induce p21 expression. Furthermore, 8 induces apoptosis by activating caspase 3/7 and PARP cleavage, and its longer exposure causes increase in intracellular ROS levels in CRC cells. Taken together, 8 has the potential to be developed further as a chemotherapeutic agent for CRC. PMID:26750401

  11. Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug

    PubMed Central

    Crespo-Ortiz, Maria P.; Wei, Ming Q.

    2012-01-01

    Improvement of quality of life and survival of cancer patients will be greatly enhanced by the development of highly effective drugs to selectively kill malignant cells. Artemisinin and its analogs are naturally occurring antimalarials which have shown potent anticancer activity. In primary cancer cultures and cell lines, their antitumor actions were by inhibiting cancer proliferation, metastasis, and angiogenesis. In xenograft models, exposure to artemisinins substantially reduces tumor volume and progression. However, the rationale for the use of artemisinins in anticancer therapy must be addressed by a greater understanding of the underlying mechanisms involved in their cytotoxic effects. The primary targets for artemisinin and the chemical base for its preferential effects on heterologous tumor cells need yet to be elucidated. The aim of this paper is to provide an overview of the recent advances and new development of this class of drugs as potential anticancer agents. PMID:22174561

  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 α-methylene-γ-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. 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

  14. Scaffold hybridization in generation of indenoindolones as anticancer agents that induce apoptosis with cell cycle arrest at G2/M phase.

    PubMed

    Kashyap, Maneesh; Das, Dipon; Preet, Ranjan; Mohapatra, Purusottam; Satapathy, Shakti Ranjan; Siddharth, Sumit; Kundu, Chanakya N; Guchhait, Sankar K

    2012-04-01

    Scaffold hybridization of several natural and synthetic anticancer leads led to the consideration of indenoindolones as potential novel anticancer agents. A series of these compounds were prepared by a diversity-feasible synthetic method. They were found to possess anticancer activities with higher potency compared to etoposide and 5-fluorouracil in kidney cancer cells (HEK 293) and low toxicity to corresponding normal cells (Vero). They exerted apoptotic effect with blocking of cell cycle at G2/M phase. PMID:22381050

  15. Vitamin E analogues as a novel group of mitocans: anti-cancer agents that act by targeting mitochondria.

    PubMed

    Neuzil, Jiri; Dong, Lan-Feng; Ramanathapuram, Lalitha; Hahn, Tobias; Chladova, Miroslava; Wang, Xiu-Fang; Zobalova, Renata; Prochazka, Lubomir; Gold, Mikhal; Freeman, Ruth; Turanek, Jaroslav; Akporiaye, Emmanuel T; Dyason, Jeffrey C; Ralph, Stephen J

    2007-01-01

    Mitochondria have recently emerged as new and promising targets for cancer prevention and therapy. One of the reasons for this is that mitochondria are instrumental to many types of cell death and often lie downstream from the initial actions of anti-cancer drugs. Unlike the tumour suppressor gene encoding p53 that is notoriously prone to inactivating mutations but whose function is essential for induction of apoptosis by DNA-targeting agents (such as doxorubicin or 5-fluorouracil), mitochondria present targets that are not so compromised by genetic mutation and whose targeting overcomes problems with mutations of upstream targets such as p53. We have recently proposed a novel class of anti-cancer agents, mitocans that exert their anti-cancer activity by destabilising mitochondria, promoting the selective induction of apoptotic death in tumour cells. In this communication, we review recent findings on mitocans and propose a common basis for their mode of action in inducing apoptosis of cancer cells. We use as an example the analogues of vitamin E that are proving to be cancer cell-specific and may soon be developed into efficient anti-cancer drugs. PMID:17499351

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

    PubMed Central

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

    2016-01-01

    Diclofenac (DCF) is a well-known and widely used non-steroidal anti-inflammatory drug (NSAID), with a range of actions which are of interest in an oncological context. While there has long been an interest in the use of NSAIDs in chemoprevention, there is now emerging evidence that such drugs may have activity in a treatment setting. DCF, which is a potent inhibitor of COX-2 and prostaglandin E2 synthesis, displays a range of effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity and tumour metabolism. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. Based on this evidence the case is made for further clinical investigation of the anticancer effects of DCF, particularly in combination with other agents - with a range of possible multi-drug and multi-modality combinations outlined in the supplementary materials accompanying the main paper. PMID:26823679

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

    PubMed

    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

  18. Synthesis and biological evaluation of new naphthalene substituted thiosemicarbazone derivatives as potent antifungal and anticancer agents.

    PubMed

    Altıntop, Mehlika Dilek; Atlı, Özlem; Ilgın, Sinem; Demirel, Rasime; Özdemir, Ahmet; Kaplancıklı, Zafer Asım

    2016-01-27

    New thiosemicarbazone derivatives (1-10) were obtained via the reaction of 4-(naphthalen-1-yl)thiosemicarbazide with fluoro-substituted aromatic aldehydes. The synthesized compounds were evaluated for their in vitro antifungal effects against pathogenic yeasts and molds using broth microdilution assay. Ames and umuC assays were carried out to determine the genotoxicity of the most effective antifungal derivatives. Furthermore, all compounds were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cell lines using XTT test. Among these derivatives, 4-(naphthalen-1-yl)-1-(2,3-difluorobenzylidene)thiosemicarbazide (1) and 4-(naphthalen-1-yl)-1-(2,5-difluorobenzylidene)thiosemicarbazide (3) can be identified as the most promising antifungal derivatives due to their notable inhibitory effects on Candida species and no cytotoxicity against NIH/3T3 mouse embryonic fibroblast cell line. According to Ames and umuC assays, compounds 1 and 3 were classified as non-mutagenic compounds. On the other hand, 4-(naphthalen-1-yl)-1-(2,4-difluorobenzylidene)thiosemicarbazide (2) can be considered as the most promising anticancer agent against A549 cell line owing to its notable inhibitory effect on A549 cells with an IC50 value of 31.25 μg/mL when compared with cisplatin (IC50 = 16.28 μg/mL) and no cytotoxicity against NIH/3T3 cells. PMID:26706351

  19. Recent developments in l-asparaginase discovery and its potential as anticancer agent.

    PubMed

    Shrivastava, Abhinav; Khan, Abdul Arif; Khurshid, Mohsin; Kalam, Mohd Abul; Jain, Sudhir K; Singhal, Pradeep K

    2016-04-01

    l-Asparaginase (EC3.5.1.1) is an enzyme, which is used for treatment of acute lymphoblastic leukaemia (ALL) and other related blood cancers from a long time. This enzyme selectively hydrolyzes the extracellular amino acid l-asparagine into l-aspartate and ammonia, leading to nutritional deficiencies, protein synthesis inhibition, and ultimately death of lymphoblastic cells by apoptosis. Currently, bacterial asparaginases are used for treatment purpose but offers scepticism due to a number of toxicities, including thrombosis, pancreatitis, hyperglycemia, and hepatotoxicity. Resistance towards bacterial asparaginase is another major disadvantage during cancer management. This situation attracted attention of researchers towards alternative sources of l-asparaginase, including plants and fungi. Present article discusses about potential of l-asparaginase as an anticancer agent, its mechanism of action, and adverse effects related to current asparaginase formulations. This article also provides an outlook for recent developments in l-asparaginase discovery from alternative sources and their potential as a less toxic alternative to current formulations. PMID:25630663

  20. 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 ∼100μm 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

  1. Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents.

    PubMed

    Milelli, Andrea; Tumiatti, Vincenzo; Micco, Marialuisa; Rosini, Michela; Zuccari, Guendalina; Raffaghello, Lizzia; Bianchi, Giovanna; Pistoia, Vito; Fernando Díaz, J; Pera, Benet; Trigili, Chiara; Barasoain, Isabel; Musetti, Caterina; Toniolo, Marianna; Sissi, Claudia; Alcaro, Stefano; Moraca, Federica; Zini, Maddalena; Stefanelli, Claudio; Minarini, Anna

    2012-11-01

    Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets. PMID:22819507

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

    PubMed

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

    2016-03-23

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

  3. 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 (μs). 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 μm skin thickness), which were retarded for 900 μm 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

  4. 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

  5. General pharmacological properties, developmental toxicity, and analgesic activity of gambogic acid, a novel natural anticancer agent.

    PubMed

    Zhao, Li; Zhen, Chen; Wu, Zhaoqiu; Hu, Rong; Zhou, Changlin; Guo, Qinglong

    2010-01-01

    In this article, the general pharmacological toxicity of gambogic acid (GA), a new anticancer agent, on the dog cardiovascular and respiratory system and the mouse central nervous system (CNS) were observed. The developmental toxicity and analgesic activities of GA were also investigated in rats and mice. Results showed that GA did not cause any toxic symptoms on blood pressure (i.e., mean arterial pressure), heart rate (HR), and respiratory frequency. However, a high dose of GA showed slight side effects on the mouse CNS. Further, evidence of maternal and developmental toxicity was observed in a dose-dependent manner. The maternal body-weight gain, as well as the birth weights and live birth index, were decreased significantly in the treatment groups. The inhibitory effects of GA on fetal skeletal development were also found. No obvious effects of GA on external alterations and visceral alterations were shown. In the analgesic experiments, GA showed significant analgesic activity in the acetic-acid-induced writhing study in a dose-dependent manner. This mechanism might be related to its anti-inflammation properties. PMID:20001662

  6. 3D-QSAR of Benzothiazole Derivatives as Potent Anticancer Agents

    NASA Astrophysics Data System (ADS)

    Chen, Jin-can; Shen, Yong; Qian, Li; Chen, Lan-mei; Zheng, Kang-cheng

    2007-04-01

    Comparative molecular field analysis (CoMFA) method was applied to study three-dimensional quantitative structure activity relationship (3D-QSAR) of a series of benzothiazole derivatives as potent anticancer agents. The CoMFA model of cross-validation and the partial-least-square (PLS) model of non cross-validation have been well established. The best CoMFA model gives a good cross-validation coefficient of 0.642 and a conventional correlation coefficient of 0.976. Moreover, the estimated standard error is 0.161 and the statistical square deviation ratio F(3,20) is 111.4. The statistical parameters of the best CoMFA model show this model is reasonable and has predictive ability. The CoMFA results suggest that an electron-withdrawing group or atom (e.g. F atom) linking to the first atom (C19) of substituent R can increase the positive charges of C19 and its ?-site atoms, which lie in the blue-colored regions in the electrostatic field contour map of CoMFA, and thus can improve the activity of the compound. Meanwhile, selecting an R with an appropriate volume is also advantageous for improving the activity.

  7. Bridging academic science and clinical research in the search for novel targeted anti-cancer agents

    PubMed Central

    Matter, Alex

    2015-01-01

    This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials. PMID:26779369

  8. Repurposing Drugs in Oncology (ReDO)-diclofenac as an anti-cancer agent.

    PubMed

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

    2016-01-01

    Diclofenac (DCF) is a well-known and widely used non-steroidal anti-inflammatory drug (NSAID), with a range of actions which are of interest in an oncological context. While there has long been an interest in the use of NSAIDs in chemoprevention, there is now emerging evidence that such drugs may have activity in a treatment setting. DCF, which is a potent inhibitor of COX-2 and prostaglandin E2 synthesis, displays a range of effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity and tumour metabolism. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. Based on this evidence the case is made for further clinical investigation of the anticancer effects of DCF, particularly in combination with other agents - with a range of possible multi-drug and multi-modality combinations outlined in the supplementary materials accompanying the main paper. PMID:26823679

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

    PubMed Central

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

    2016-01-01

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

  10. Antitumor Agents 252. Application of Validated QSAR Models to Database Mining: Discovery of Novel Tylophorine Derivatives as Potential Anticancer Agents

    PubMed Central

    Zhang, Shuxing; Wei, Linyi; Bastow, Ken; Zheng, Weifan; Brossi, Arnold; Lee, Kuo-Hsiung; Tropsha, Alexander

    2009-01-01

    A combined approach of validated QSAR modeling and virtual screening was successfully applied to the discovery of novel tylophrine derivatives as anticancer agents. QSAR models have been initially developed for 52 chemically diverse phenanthrine-based tylophrine derivatives (PBTs) with known experimental EC50 using chemical topological descriptors (calculated with the MolConnZ program) and variable selection k nearest neighbor (kNN) method. Several validation protocols have been applied to achieve robust QSAR models. The original dataset was divided into multiple training and test sets, and the models were considered acceptable only if the leave-one-out cross-validated R2 (q2) values were greater than 0.5 for the training sets and the correlation coefficient R2 values were greater than 0.6 for the test sets. Furthermore, the q2 values for the actual dataset were shown to be significantly higher than those obtained for the same dataset with randomized target properties (Y-randomization test), indicating that models were statistically significant. Ten best models were then employed to mine a commercially available ChemDiv Database (ca. 500K compounds) resulting in 34 consensus hits with moderate to high predicted activities. Ten structurally diverse hits were experimentally tested and eight were confirmed active with the highest experimental EC50 of 1.8µM implying an exceptionally high hit rate (80%). The same ten models were further applied to predict EC50 for four new PBTs, and the correlation coefficient (R2) between the experimental and predicted EC50 for these compounds plus eight active consensus hits was shown to be as high as 0.57. Our studies suggest that the approach combining validated QSAR modeling and virtual screening could be successfully used as a general tool for the discovery of novel biologically active compounds. PMID:17340042

  11. Synthesis and evaluation of naphthalene-based thiosemicarbazone derivatives as new anticancer agents against LNCaP prostate cancer cells.

    PubMed

    Altintop, Mehlika Dilek; Sever, Belgin; Özdemir, Ahmet; Kuş, Gökhan; Oztopcu-Vatan, Pinar; Kabadere, Selda; Kaplancikli, Zafer Asim

    2016-06-01

    Fourteen new naphthalene-based thiosemicarbazone derivatives were designed as anticancer agents against LNCaP human prostate cancer cells and synthesized. MTT assay indicated that compounds 6, 8 and 11 exhibited inhibitory effect on LNCaP cells. Among these compounds, 4-(naphthalen-1-yl)-1-[1-(4-hydroxyphenyl)ethylidene)thiosemicarbazide (6), which caused more than 50% death on LNCaP cells, was chosen for flow cytometric analysis of apoptosis. Flow cytometric analysis pointed out that compound 6 also showed apoptotic effect on LNCaP cells. Compound 6 can be considered as a promising anticancer agent against LNCaP cells owing to its potent cytotoxic activity and apoptotic effect. PMID:25826149

  12. 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.

  13. Synthesis and Biological Evaluation of Quinazoline Derivatives as Potential Anticancer Agents (II).

    PubMed

    Yong, Jianping; Lu, Canzhong; Wu, Xiaoyuan

    2015-01-01

    Under the guidance of our previous work, we synthesized 21 new structures of quinazolines (3a~3u) and evaluated their in vitro anticancer activity against A549, HCT116 and MCF-7 cell lines using the MTT method. Most compounds showed good to excellent anticancer activity. In particular, 3o (regarded as erlotinib analogues) has marked anticancer activity against A549, HCT116 and MCF-7 cell lines (IC50s: 4.26, 3.92 and 0.14 μM, respectively) as compared with the standard anticancer drug gefitinib (IC50s: 17.9, 21.55 and 20.68 μM, respectively), and which can be regarded as the best candidate for development of anticancer drugs. PMID:26008189

  14. Ginsenosides as Anticancer Agents: In vitro and in vivo Activities, Structure–Activity Relationships, and Molecular Mechanisms of Action

    PubMed Central

    Nag, Subhasree Ashok; Qin, Jiang-Jiang; Wang, Wei; Wang, Ming-Hai; Wang, Hui; Zhang, Ruiwen

    2012-01-01

    Conventional chemotherapeutic agents are often toxic not only to tumor cells but also to normal cells, limiting their therapeutic use in the clinic. Novel natural product anticancer compounds present an attractive alternative to synthetic compounds, based on their favorable safety and efficacy profiles. Several pre-clinical and clinical studies have demonstrated the anticancer potential of Panax ginseng, a widely used traditional Chinese medicine. The anti-tumor efficacy of ginseng is attributed mainly to the presence of saponins, known as ginsenosides. In this review, we focus on how ginsenosides exert their anticancer effects by modulation of diverse signaling pathways, including regulation of cell proliferation mediators (CDKs and cyclins), growth factors (c-myc, EGFR, and vascular endothelial growth factor), tumor suppressors (p53 and p21), oncogenes (MDM2), cell death mediators (Bcl-2, Bcl-xL, XIAP, caspases, and death receptors), inflammatory response molecules (NF-κB and COX-2), and protein kinases (JNK, Akt, and AMP-activated protein kinase). We also discuss the structure–activity relationship of various ginsenosides and their potentials in the treatment of various human cancers. In summary, recent advances in the discovery and evaluation of ginsenosides as cancer therapeutic agents support further pre-clinical and clinical development of these agents for the treatment of primary and metastatic tumors. PMID:22403544

  15. Ginsenosides as Anticancer Agents: In vitro and in vivo Activities, Structure-Activity Relationships, and Molecular Mechanisms of Action.

    PubMed

    Nag, Subhasree Ashok; Qin, Jiang-Jiang; Wang, Wei; Wang, Ming-Hai; Wang, Hui; Zhang, Ruiwen

    2012-01-01

    Conventional chemotherapeutic agents are often toxic not only to tumor cells but also to normal cells, limiting their therapeutic use in the clinic. Novel natural product anticancer compounds present an attractive alternative to synthetic compounds, based on their favorable safety and efficacy profiles. Several pre-clinical and clinical studies have demonstrated the anticancer potential of Panax ginseng, a widely used traditional Chinese medicine. The anti-tumor efficacy of ginseng is attributed mainly to the presence of saponins, known as ginsenosides. In this review, we focus on how ginsenosides exert their anticancer effects by modulation of diverse signaling pathways, including regulation of cell proliferation mediators (CDKs and cyclins), growth factors (c-myc, EGFR, and vascular endothelial growth factor), tumor suppressors (p53 and p21), oncogenes (MDM2), cell death mediators (Bcl-2, Bcl-xL, XIAP, caspases, and death receptors), inflammatory response molecules (NF-?B and COX-2), and protein kinases (JNK, Akt, and AMP-activated protein kinase). We also discuss the structure-activity relationship of various ginsenosides and their potentials in the treatment of various human cancers. In summary, recent advances in the discovery and evaluation of ginsenosides as cancer therapeutic agents support further pre-clinical and clinical development of these agents for the treatment of primary and metastatic tumors. PMID:22403544

  16. A new and efficient strategy for the synthesis of podophyllotoxin and its analogues.

    PubMed

    Wu, Yingming; Zhang, Hongbin; Zhao, Yuanhong; Zhao, Jingfeng; Chen, Jingbo; Li, Liang

    2007-03-29

    [structure: see text]. An efficient and stereoselective strategy for the total synthesis of podophyllotoxin was developed. This route leads to podophyllotoxin 1 in only 12 steps with 29% overall yield. A notable feature of this synthetic strategy is the use of the cascade addition-alkylation to ensure the key C1-C2 stereochemistry that is pivotal for the synthesis of podophyllotoxin. PMID:17326644

  17. Coumarins as anticancer agents: a review on synthetic strategies, mechanism of action and SAR studies.

    PubMed

    Thakur, Anuradha; Singla, Ramit; Jaitak, Vikas

    2015-08-28

    Coumarins are fused benzene and pyrone ring systems which prompt biological investigation to assess their potential therapeutic significance. It possesses immeasurable anticancer potential with minimum side effects depending on the substitutions on the basic nucleus. Coumarins have a tremendous ability to regulate diverse range of cellular pathways that can be explored for selective anticancer activity. This is the first standalone review that emphasis on the assorted retrosynthetic approaches, important targets for molecularly targeted cancer therapy and structure activity relationship studies that highlight the chemical groups responsible for evoking the anticancer potential of coumarin derivatives reported from 2011 to 2014. PMID:26188907

  18. Blechnum Orientale Linn - a fern with potential as antioxidant, anticancer and antibacterial agent

    PubMed Central

    2010-01-01

    Background Blechnum orientale Linn. (Blechnaceae) is used ethnomedicinally for the treatment of various skin diseases, stomach pain, urinary bladder complaints and sterilization of women. The aim of the study was to evaluate antioxidant, anticancer and antibacterial activity of five solvent fractions obtained from the methanol extract of the leaves of Blechnum orientale Linn. Methods Five solvent fractions were obtained from the methanol extract of B. orientale through successive partitioning with petroleum ether, chloroform, ethyl acetate, butanol and water. Total phenolic content was assessed using Folin-Ciocalteu's method. The antioxidant activity was determined by measuring the scavenging activity of DPPH radicals. Cytotoxic activity was tested against four cancer cell lines and a non-malignant cell using MTT assay. Antibacterial activity was assessed using the disc diffusion and broth microdilution assays. Standard phytochemical screening tests for saponins, tannins, terpenoids, flavonoids and alkaloids were also conducted. Results The ethyl acetate, butanol and water fractions possessed strong radical scavenging activity (IC50 8.6-13.0 μg/ml) and cytotoxic activity towards human colon cancer cell HT-29 (IC50 27.5-42.8 μg/ml). The three extracts were also effective against all Gram-positive bacteria tested: Bacillus cereus, Micrococcus luteus, methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) and Stapylococcus epidermidis(minimum inhibitory concentration MIC 15.6-250 μg/ml; minimum bactericidal concentration MBC 15.6-250 μg/ml). Phytochemical analysis revealed the presence of flavonoids, terpenoids and tannins. Ethyl acetate and butanol fractions showed highest total phenolic content (675-804 mg gallic acid equivalent/g). Conclusions The results indicate that this fern is a potential candidate to be used as an antioxidant agent, for colon cancer therapy and for treatment of MRSA infections and other MSSA/Gram-positive bacterial infectious diseases. PMID:20429956

  19. 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

  20. The role of aziridinyl cyclophosphazenes and related compounds as anticancer agents. A tentative quantum mechanical approach

    NASA Astrophysics Data System (ADS)

    Guerch, Guy; Faucher, Jean-Paul; Graffeuil, Marcel; Levy, Gaston; Labarre, Jean-Francois

    The electronic structures of the various conformations and allotropie species of two promising anticancer drugs, namely MYKO 63 and SOAz, have been calculated using the CNDO/2 approximation. The results allow prediction of the acidity (in the Lewis sense) of the aziridinyl-bearing atoms of the drugs which corresponds to the optimum anticancer activity possible upon coordination to DNA, as the Lewis-base target.

  1. Structural elaboration of a natural product: identification of 3,3'-diindolylmethane aminophosphonate and urea derivatives as potent anticancer agents.

    PubMed

    Kandekar, Somnath; Preet, Ranjan; Kashyap, Maneesh; Renu Prasad, M U; Mohapatra, Purusottam; Das, Dipon; Satapathy, Shakti Ranjan; Siddharth, Sumit; Jain, Vaibhav; Choudhuri, Maitrayee; Kundu, Chanakya N; Guchhait, Sankar K; Bharatam, Prasad V

    2013-11-01

    An approach involving rational structural elaboration of the biologically active natural product diindolylmethane (DIM) with the incorporation of aminophosphonate and urea moieties toward the discovery of potent anticancer agents was considered. A four-step approach for the synthesis of DIM aminophosphonate and urea derivatives was established. These novel compounds showed potent anticancer activities in two representative kidney and colon cancer cell lines, low toxicity to normal cells, higher potency than the parent natural product DIM and etoposide, and potent inhibition of cancer cell migration. Biophysical and immunological studies, including DAPI nuclear staining, western blot analysis with apoptotic protein markers, flow cytometry, immunocytochemistry, and comet assays of the two most potent compounds revealed good efficacies in apoptosis and DNA damage. It was found that down-regulation of nuclear factor κB (NF-κB p65) could be an important mode of action in apoptosis, and the two most potent derivatives were found to be more potent than parent compound DIM in the down-regulation of NF-κB. Our results show the importance of structural elaboration of DIM by rational incorporation of aminophosphonate and urea moieties to produce potent anticancer agents; they also suggest that this approach using other structurally simple bioactive natural products as scaffolds holds promise for future drug discovery and development. PMID:23983049

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

    PubMed

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

    2014-05-01

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

  3. Pharmacokinetic Properties of Anticancer Agents for the Treatment of Central Nervous System Tumors: Update of the Literature.

    PubMed

    Jacus, Megan O; Daryani, Vinay M; Harstead, K Elaine; Patel, Yogesh T; Throm, Stacy L; Stewart, Clinton F

    2016-03-01

    Despite significant improvement in outcomes for patients with hematologic malignancies and solid tumors over the past 10years, patients with primary or metastatic brain tumors continue to have a poor prognosis. A primary reason for this is the inability of many chemotherapeutic drugs to penetrate into the brain and brain tumors at concentrations high enough to exert an antitumor effect because of unique barriers and efflux transporters. Several studies have been published recently examining the central nervous system pharmacokinetics of various anticancer drugs in patients with primary and metastatic brain tumors. To summarize recent advances in the field, this review critically presents studies published within the last 9years examining brain and cerebrospinal fluid penetration of clinically available anticancer agents for patients with central nervous system tumors. PMID:26293618

  4. Bioassay-Guided Isolation of Sesquiterpene Coumarins from Ferula narthex Bioss: A New Anticancer Agent

    PubMed Central

    Alam, Mahboob; Khan, Ajmal; Wadood, Abdul; Khan, Ayesha; Bashir, Shumaila; Aman, Akhtar; Jan, Abdul Khaliq; Rauf, Abdur; Ahmad, Bashir; Khan, Abdur Rahman; Farooq, Umar

    2016-01-01

    The main objective of cancer management with chemotherapy (anticancer drugs) is to kill the neoplastic (cancerous) cell instead of a normal healthy cell. The bioassay-guided isolation of two new sesquiterpene coumarins (compounds 1 and 2) have been carried out from Ferula narthex collected from Chitral, locally known as “Raw.” Anticancer activity of crude and all fractions have been carried out to prevent carcinogenesis by using MTT assay. The n-hexane fraction showed good activity with an IC50 value of 5.434 ± 0.249 μg/mL, followed by crude MeFn extract 7.317 ± 0.535 μg/mL, and CHCl3 fraction 9.613 ± 0.548 μg/mL. Compounds 1 and 2 were isolated from chloroform fraction. Among tested pure compounds, compound 1 showed good anticancer activity with IC50 value of 14.074 ± 0.414 μg/mL. PASS (Prediction of Activity Spectra) analysis of the compound 1 was carried out, in order to predicts their binding probability with anti-cancer target. As a results the compound 1 showed binding probability with human histone acetyltransferase with Pa (probability to be active) value of 0.303. The compound 1 was docked against human histone acetyltransferase (anti-cancer drug target) by using molecular docking simulations. Molecular docking results showed that compound 1 accommodate well in the anti-cancer drug target. Moreover the activity support cancer chemo preventive activity of different compounds isolated from the genus Ferula, in accordance with the previously reported anticancer activities of the genus. PMID:26909039

  5. Bioassay-Guided Isolation of Sesquiterpene Coumarins from Ferula narthex Bioss: A New Anticancer Agent.

    PubMed

    Alam, Mahboob; Khan, Ajmal; Wadood, Abdul; Khan, Ayesha; Bashir, Shumaila; Aman, Akhtar; Jan, Abdul Khaliq; Rauf, Abdur; Ahmad, Bashir; Khan, Abdur Rahman; Farooq, Umar

    2016-01-01

    The main objective of cancer management with chemotherapy (anticancer drugs) is to kill the neoplastic (cancerous) cell instead of a normal healthy cell. The bioassay-guided isolation of two new sesquiterpene coumarins (compounds 1 and 2) have been carried out from Ferula narthex collected from Chitral, locally known as "Raw." Anticancer activity of crude and all fractions have been carried out to prevent carcinogenesis by using MTT assay. The n-hexane fraction showed good activity with an IC50 value of 5.434 ± 0.249 μg/mL, followed by crude MeFn extract 7.317 ± 0.535 μg/mL, and CHCl3 fraction 9.613 ± 0.548 μg/mL. Compounds 1 and 2 were isolated from chloroform fraction. Among tested pure compounds, compound 1 showed good anticancer activity with IC50 value of 14.074 ± 0.414 μg/mL. PASS (Prediction of Activity Spectra) analysis of the compound 1 was carried out, in order to predicts their binding probability with anti-cancer target. As a results the compound 1 showed binding probability with human histone acetyltransferase with Pa (probability to be active) value of 0.303. The compound 1 was docked against human histone acetyltransferase (anti-cancer drug target) by using molecular docking simulations. Molecular docking results showed that compound 1 accommodate well in the anti-cancer drug target. Moreover the activity support cancer chemo preventive activity of different compounds isolated from the genus Ferula, in accordance with the previously reported anticancer activities of the genus. PMID:26909039

  6. Curcumin-albumin conjugates as an effective anti-cancer agent with immunomodulatory properties.

    PubMed

    Aravind, S R; Krishnan, Lissy K

    2016-05-01

    Curcumin (diferuloylmethane) is an active ingredient in turmeric (Curcuma longa) with anti-inflammatory, antioxidant, chemopreventive, chemosensitization, and radiosensitization properties. Conjugation of curcumin (Curc) to albumin (Alb) has been found to increase the aqueous solubility of the drug. The current study aimed to prove the safe use of the Curc-Alb conjugate in animals and to demonstrate that it retains drug action both in vitro and in vivo. Dalton's lymphoma ascites (DLA) cell viability was inhibited by the Curc-Alb conjugate in a dose dependent manner in vitro, as evidenced by the MTT assay. Administration of up to 11.4mg of conjugated curcumin per kg body weight to healthy animals was non-toxic both in terms of lethality and weight loss. Histological analysis of vital organs (kidney, liver and spleen) also did not show toxic effects. Favorable immuno-modulatory activity was observed after continuous administration of sub-acute doses of the conjugate which caused increase in total leukocyte count, platelet count, and viable cell count in bone marrow, and enhanced proliferation of lymphocyte in vitro upon culture. In vivo studies in the DLA tumor model in mice demonstrated that conjugated drug induces tumor reduction and prevention. Significant tumor reduction was observed when the Curc-Alb conjugate was administered intraperitoneally in DLA-induced mice after 1day (prevention therapy) and 7days (reduction therapy) of tumor induction. There was significant reduction in both tumor volume and tumor cell numbers in the treated animals as well as a marked increase in their mean survival time and percent increase in life span. The effect was greater when the conjugate was administered soon after inducing the tumor as compared to when treatment was started after allowing tumor to grow for 7days. Thus, the results of the present study suggest that curcumin albumin conjugate has immunomodulatory and tumor growth inhibition properties. The study postulates the drug form has the potential to be used as an anticancer agent in affected human subjects. PMID:26927614

  7. 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 μg/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 μg equiv/g), urinary bladder contents at 3 h (89.636 μg 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 μg equiv/g), small intestine at 3 h (16.946 μg equiv/g), Harderian gland at 3 h (12.332 μg equiv/g) and pancreas at 3 h (12.635 μg equiv/g). Concentrations in the cerebrum (1.978 μg equiv/g), cerebellum (2.109 μg equiv/g), medulla (1.797 μg equiv/g) and spinal cord (1.510 μg 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 100μCi IV dose of [14C]VNP40101M were well within the medical guidelines for maximum radioactivity exposures in human subjects. PMID:25798740

  8. 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

  9. Exploring Polymeric Micelles for Improved Delivery of Anticancer Agents: Recent Developments in Preclinical Studies

    PubMed Central

    Tan, Chalet; Wang, Yingzhe; Fan, Wei

    2013-01-01

    As versatile drug delivery systems, polymeric micelles have demonstrated particular strength in solubilizing hydrophobic anticancer drugs while eliminating the use of toxic organic solvents and surfactants. However, the true promise of polymeric micelles as drug carriers for cancer therapy resides in their potential ability to preferentially elevate drug exposure in the tumor and achieve enhanced anticancer efficacy, which still remains to be fully exploited. Here, we review various micellar constructs that exhibit the enhanced permeation and retention effect in the tumor, the targeting ligands that potentiate the anticancer efficacy of micellar drugs, and the polyplex micelle systems suitable for the delivery of plasmid DNA and small interference RNA. Together, these preclinical studies in animal models help us further explore polymeric micelles as emerging drug carriers for targeted cancer therapy. PMID:24300405

  10. Synthesis of aryl dihydrothiazol acyl shikonin ester derivatives as anticancer agents through microtubule stabilization.

    PubMed

    Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua

    2015-07-15

    The high incidence of cancer and the side effects of traditional anticancer drugs motivate the search for new and more effective anticancer drugs. In this study, we synthesized 17 kinds of aryl dihydrothiazol acyl shikonin ester derivatives and evaluated their anticancer activity through MTT assay. Among them, C13 showed better antiproliferation activity with IC50=3.14 ± 0.21 μM against HeLa cells than shikonin (IC50=5.75 ± 0.47 μM). We then performed PI staining assay, cell cycle distribution, and cell apoptosis analysis for C13 and found that it can cause cell arrest in G2/M phase, which leads to cell apoptosis. This derivative can also reduce the adhesive ability of HeLa cells. Docking simulation and confocal microscopy assay results further indicated that C13 could bind well to the tubulin at paclitaxel binding site, leading to tubulin polymerization and mitotic disruption. PMID:25957661

  11. Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent

    PubMed Central

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

    2014-01-01

    Mebendazole, a well-known anti-helminthic drug in wide clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical studies across a number of different cancer types. Significantly, there are also two case reports of anti-cancer activity in humans. The data are summarised and discussed in relation to suggested mechanisms of action. Based on the evidence presented, it is proposed that mebendazole would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of mebendazole as an anti-cancer therapeutic is warranted. A number of possible combinations with other drugs are discussed in the Appendix. PMID:25075217

  12. Design, Synthesis and Biological Evaluation of Novel 5H-Chromenopyridines as Potential Anti-Cancer Agents.

    PubMed

    Banerjee, Souvik; Wang, Jin; Pfeffer, Susan; Ma, Dejian; Pfeffer, Lawrence M; Patil, Shivaputra A; Li, Wei; Miller, Duane D

    2015-01-01

    A novel series of 5H-chromenopyridines was identified as anticancer agents in our continuing effort to discover and develop new small molecule anti-proliferative agents. Based on our initial lead SP-6-27 compound, we designed and synthesized novel tricyclic 5H-thiochromenopyridine and 5H-chromenopyridine analogs to evaluate the impact of an additional ring, as well as conformational flexibility on cytotoxic activity against human melanoma and glioma cell lines. All of the 5H-thiochromenopyridines have been achieved in good yields (89%-93%) using a single-step, three-component cyclization without the need for purification. The 5H-chromenopyridine analog of the potent 5H-thiochromenopyride was obtained in a good yield upon purification. All newly-prepared 5H-thiochromenopyridines showed good to moderate cytotoxicity against three melanoma and two glioma cell lines (3-15 μM). However, the 5H-chromenopyridine analogue that we prepared in our laboratory lost cytotoxic activity. The moderate cytotoxic activity of 5H-thiochromenopyridines shows the promise of developing chromenopyridines as potential anticancer agents. PMID:26393554

  13. Evaluation of bishexadecyltrimethyl ammonium palladium tetrachloride based dual functional colloidal carrier as an antimicrobial and anticancer agent.

    PubMed

    Kaur, Gurpreet; Kumar, Sandeep; Dilbaghi, Neeraj; Kaur, Baljinder; Kant, Ravi; Guru, Santosh Kumar; Bhushan, Shashi; Jaglan, Sundeep

    2016-04-12

    We have developed a dual function carrier using bishexadecyltrimethyl ammonium palladium tetrachloride, which has anticancer as well as antibacterial activity, using a ligand insertion method with a simple and easy work procedure. The complex is prepared by a simple and cost effective method using hexadecyltrimethyl ammonium chloride and palladium chloride under controlled stoichiometry. Herein, we report the aggregation (self assembly) of the metallosurfactant having palladium as a counter ion, in aqueous medium along with its binding affinity with bovine serum albumin. The palladium surfactant has exhibited excellent antimicrobial efficacy against fungus and bacteria (both Gram-positive and Gram-negative bacteria). Cytotoxicity of palladium surfactant against cancerous (Human leukemia HL-60, pancreatic MIA-Pa-Ca-2 and prostate cancer PC-3) and healthy cells (fR2 human breast epithelial cells) was also evaluated using MTT assay. The present dual functional moiety shows a low IC50 value and has potential to be used as an anticancer agent. Our dual function carrier which itself possesses antimicrobial and anticancer activity represents a simple and effective system and can also be utilized as a drug carrier in the future. PMID:26961498

  14. The novel microtubule-interfering agent TZT-1027 enhances the anticancer effect of radiation in vitro and in vivo

    PubMed Central

    Akashi, Y; Okamoto, I; Suzuki, M; Tamura, K; Iwasa, T; Hisada, S; Satoh, T; Nakagawa, K; Ono, K; Fukuoka, M

    2007-01-01

    TZT-1027 is a novel anticancer agent that inhibits microtubule polymerisation and manifests potent antitumour activity in preclinical models. We have examined the effect of TZT-1027 on cell cycle progression as well as the anticancer activity of this drug both in vitro and in vivo. With the use of tsFT210 cells, which express a temperature-sensitive mutant of Cdc2, we found that TZT-1027 arrests cell cycle progression in mitosis, the phase of the cell cycle most sensitive to radiation. A clonogenic assay indeed revealed that TZT-1027 increased the sensitivity of H460 cells to γ-radiation, with a dose enhancement factor of 1.2. Furthermore, TZT-1027 increased the radiosensitivity of H460 and A549 cells in nude mice, as revealed by a marked delay in tumour growth and an enhancement factor of 3.0 and 2.2, respectively. TZT-1027 also potentiated the induction of apoptosis in H460 cells by radiation both in vitro and in vivo. Histological evaluation of H460 tumours revealed that TZT-1027 induced morphological damage to the vascular endothelium followed by extensive central tumour necrosis. Our results thus suggest that TZT-1027 enhances the antitumour effect of ionising radiation, and that this action is attributable in part to potentiation of apoptosis induction and to an antivascular effect. Combined treatment with TZT-1027 and radiation therefore warrants investigation in clinical trials as a potential anticancer strategy. PMID:17473826

  15. Lesson Learned from Nature for the Development of Novel Anti-Cancer Agents: Implication of Isoflavone, Curcumin, and their Synthetic Analogs

    PubMed Central

    Sarkar, Fazlul H.; Li, Yiwei; Wang, Zhiwei; Padhye, Subhash

    2011-01-01

    In recent years, naturally occurring dietary compounds have received greater attention in the field of cancer prevention and treatment research. Among them, isoflavone genistein and curcumin are very promising anti-cancer agents because of their non-toxic and potent anti-cancer properties. However, it is important to note that the low water solubility, poor in vivo bioavailability and unacceptable pharmacokinetic profile of these natural compounds limit their efficacy as anti-cancer agents for solid tumors. Therefore, the development of synthetic analogs of isoflavone and curcumin based on the structure-activity assay, and the encapsulation of isoflavone and curcumin with liposome or nanoparticle for enhancing the anti-tumor activity of these natural agents, is an exciting area of research. Emerging in vitro and in vivo studies clearly suggest that these analogs and formulations of natural compounds could be much more potent for the prevention and/or treatment of various cancers. In this review article, we will summarize the current knowledge regarding the anti-cancer effect of natural compounds and their analogs, the regulation of cell signaling by these agents, and the structure-activity relationship for better design of novel anti-cancer agents, which could open newer avenues for the prevention of tumor progression and/or treatment of human malignancies. PMID:20345353

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

    PubMed

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

    2015-08-01

    Βeta-sitosterol (β-SITO), a phytosterol present in pomegranate, peanut, corn oil, almond, and avocado, has been recognized to offer health benefits and potential clinical uses. β-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 β-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 β-SITO with tubulin. A polymer mass assay comparing the effects of β-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 β-SITO with tubulin. Although β-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 β-SITO with tubulin. Based on the results from the biochemical assays, we computationally modeled the binding of β-SITO with tubulin. Using molecular docking followed by molecular dynamic simulations, we found that β-SITO binds tubulin at a novel site (which we call the 'SITO site') adjacent to the colchicine and noscapine sites. Our data suggest that β-SITO is a potent anticancer compound that interferes with microtubule assembly dynamics by binding to a novel site on tubulin. PMID:25912799

  17. Photophysical characterization of anticancer drug valrubicin in rHDL nanoparticles and its use as an imaging agent.

    PubMed

    Shah, Sunil; Chib, Rahul; Raut, Sangram; Bermudez, Jaclyn; Sabnis, Nirupama; Duggal, Divya; Kimball, Joseph D; Lacko, Andras G; Gryczynski, Zygmunt; Gryczynski, Ignacy

    2016-02-01

    Nanoparticles are target-specific drug delivery agents that are increasingly used in cancer therapy to enhance bioavailability and to reduce off target toxicity of anti-cancer agents. Valrubicin is an anti-cancer drug, currently approved only for vesicular bladder cancer treatment because of its poor water solubility. On the other hand, valrubicin carrying reconstituted high density lipoprotein (rHDL) nanoparticles appear ideally suited for extended applications, including systemic cancer chemotherapy. We determined selected fluorescence properties of the free (unencapsulated) drug vs. valrubicin incorporated into rHDL nanoparticles. We have found that upon encapsulation into rHDL nanoparticles the quantum yield of valrubicin fluorescence increased six fold while its fluorescence lifetime increased about 2 fold. Accordingly, these and potassium iodide (KI) quenching data suggest that upon incorporation, valrubicin is localized deep in the interior of the nanoparticle, inside the lipid matrix. Fluorescence anisotropy of the rHDL valrubicin nanoparticles was also found to be high along with extended rotational correlation time. The fluorescence of valrubicin could also be utilized to assess its distribution upon delivery to prostate cancer (PC3) cells. Overall the fluorescence properties of the rHDL: valrubicin complex reveal valuable novel characteristics of this drug delivery vehicle that may be particularly applicable when used in systemic (intravenous) therapy. PMID:26735001

  18. Synthesis and biological evaluation of new rhodanine analogues bearing 2-chloroquinoline and benzo[h]quinoline scaffolds as anticancer agents.

    PubMed

    Ramesh, Vadla; Ananda Rao, Boddu; Sharma, Pankaj; Swarna, B; Thummuri, Dinesh; Srinivas, Kolupula; Naidu, V G M; Jayathirtha Rao, Vaidya

    2014-08-18

    Several rhodanine derivatives (9-39) were synthesized for evaluation of their potential as anticancer agents. Villsmeier cyclization to synthesize aza-aromatic aldehydes, rhodanine derivatives preparation and Knoevenagel type of condensation between the rhodanines and aza-aromatic aldehydes are key steps used for the synthesis of 31 compounds. In vitro antiproliferative activity of the synthesized rhodanine derivatives (9-39) was studied on a panel of six human tumor cell lines viz. HGC, MNK-74, MCF-7, MDAMB-231, DU-145 and PC-3 cell lines. Some of the compounds were capable of inhibiting the proliferation of cancer cell lines at a micromolar concentration. Six compounds are found to be potent against HGC cell lines; compound 15 is found to be active against HGC - Gastric, MCF7 - Breast Cancer and DU145 - Prostate Cancer cell lines; compound 39 is potent against MNK-74; four compounds are found to be potent against MCF-7 cell lines; three compounds are active against MDAMB-231; nine compounds are found to be potent against DU-145; three compounds are active against PC-3 cell lines. These compounds constitute a promising starting point for the development of novel and more potent anticancer agents in future. PMID:24996143

  19. Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II.

    PubMed

    Neuzil, Jiri; Dyason, Jeffrey C; Freeman, Ruth; Dong, Lan-Feng; Prochazka, Lubomir; Wang, Xiu-Fang; Scheffler, Immo; Ralph, Stephen J

    2007-02-01

    Recently mitochondria in cancer cells have emerged as the Achilles heel for tumour destruction. Anti-cancer agents specifically targeting cancer cell mitochondria are referred to as 'mitocans'. These compounds act by destabilising these organelles, unleashing their apoptogenic potential, resulting in the efficient death of malignant cells and suppression of tumour growth. Importantly, at least some mitocans are selective for cancer cells, and these are represented by the group of redox-silent vitamin E analogues, epitomised by alpha-tocopheryl succinate (alpha-TOS). This compound has proven itself in pre-clinical models to be an efficient anti-cancer agent, targeting complex II of the respiratory chain to displace ubiquinone binding. We propose that disrupting the electron flow of mitochondrial complex II results in generation of superoxide, triggering mitochondrial destabilisation and initiation of apoptotic pathways. Moreover, alpha-TOS is selective for cancer cells with their reduced anti-oxidant defenses and lower esterase activity than the normal (non-malignant) counterparts. In this mini-review we discuss the emerging significance of mitocans, as exemplified by alpha-TOS. PMID:17294131

  20. [Intraarterial bolus infusion followed by rapid removal of anticancer agents with hemocarboperfusion under local hyperthermia in advanced hepatic cancer].

    PubMed

    Agishi, T; Nakazawa, H; Teraoka, S; Fuchinoue, S; Okumura, T; Ota, K; Akimoto, S; Hamano, K

    1986-04-01

    Reported herein is a new multidisciplinary treatment modality for unresectable hepatic cancer in which local hyperthermia and intraarterial infusion of bolus anticancer agent are simultaneously undertaken while anticancer agent leaking from the hepatic bed into the general circulation is rapidly removed by charcoal hemoperfusion. Local hyperthermia induced by exposure to 13.56-MHz radiofrequency waves was conducted between one and one and a half hours once or twice a week. During the hyperthermia treatment, a bolus of either 1 mg/kg Mitomycin C or 2 mg/kg Adriamycin was injected into the hepatic artery via a Vascular Access Port, the catheter portion of which had been surgically inserted into the hepatic artery and the reservoir of which had been implanted subcutaneously. In general, a regular dose of 6 mg of Mitomycin C was injected into the Vascular Access Port during the following hyperthermia procedures. In seven of nine patients (78%) treated with this method, a marked reduction in tumor size of more than 50% was observed on computed tomograms. A light to moderate degree of side effects such as leukocytopenia, thrombocytopenia, liver dysfunction or hair loss were noticed after the bolus infusion, but were not so serious as to threaten the patients' lives. PMID:3089174

  1. Synthesis and biological evaluation of andrographolide analogues as anti-cancer agents.

    PubMed

    Preet, Ranjan; Chakraborty, Biswajit; Siddharth, Sumit; Mohapatra, Purusottam; Das, Dipon; Satapathy, Shakti Ranjan; Das, Supriya; Maiti, Nakul C; Maulik, Prakas R; Kundu, Chanakya Nath; Chowdhury, Chinmay

    2014-10-01

    A new family of andrographolide analogues were synthesized and screened in vitro against kidney (HEK-293) and breast (MCF-7) cancer cells. The anti-cancer effects of the active analogues (2b, 2c and 4c) were determined by multiple cell based assays such as MTT, immunostaining, FACS, western blotting and transcriptional inhibition of NF-κB activity. Importantly, these compounds were found to possess higher anti-cancer potency than andrographolide and low toxicity to normal (VERO and MCF-10A) cells. Increased level of Bax/Bcl-xL ratio, caspase 3, and sub G1 population, higher expression level of tumor suppressor protein p53 and lower expression level of NF-κB suggested potent apoptotic property of the active analogues. Data revealed that the andrographolide derivative-mediated cell death in cancer cells was p53 dependent. PMID:25078313

  2. Evernia prunastri and Pseudoevernia furfuraceae lichens and their major metabolites as antioxidant, antimicrobial and anticancer agents.

    PubMed

    Kosanić, Marijana; Manojlović, Nedeljko; Janković, Slobodan; Stanojković, Tatjana; Ranković, Branislav

    2013-03-01

    The aim of this study is to investigate chemical composition of acetone extracts of the lichens Evernia prunastri and Pseudoevernia furfuraceae and in vitro antioxidant, antimicrobial, and anticancer activities of these extracts and some their major metabolites. HPLC-UV method was used for identification of secondary metabolites. Antioxidant activity was evaluated by free radical scavenging, superoxide anion radical scavenging, reducing power and determination of total phenolic compounds. As a result of the study physodic acid had largest antioxidant activities. Total content of phenol in extracts was determined as pyrocatechol equivalent. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration by the broth microdilution method. The most active was also physodic acid. Anticancer activity was tested against FemX (human melanoma) and LS174 (human colon carcinoma) cell lines using MTT method. PMID:23220145

  3. 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

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

    PubMed

    Romero-Canelón, Isolda; Mos, Magdalena; Sadler, Peter J

    2015-10-01

    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

  5. 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

  6. [Quod medicina aliis, aliis est acre venenum**--venoms as a source of anticancer agents].

    PubMed

    Kucińska, Małgorzata; Ruciński, Piotr; Murias, Marek

    2013-01-01

    Natural product derived from plants and animals were used in folk medicine for centuries. The venoms produced by animals for hunting of self-defence are rich in bioactive compounds with broad spectrum of biological activity. The papers presents the most promising compounds isolated from venoms of snakes, scorpions and toads. For these compounds both: mechanism of anticancer activity as well as possibilities of clinical use are presented. PMID:24466712

  7. Structure-activity relationship for Fe(III)-salen-like complexes as potent anticancer agents.

    PubMed

    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 (R (2) train = 0.99, RMSE = 0.138, and Q (2) LOO = 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

  8. 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.

  9. New 3'-O-aromatic acyl-5-fluoro-2'-deoxyuridine derivatives as potential anticancer agents.

    PubMed

    Szymańska-Michalak, Agnieszka; Wawrzyniak, Dariusz; Framski, Grzegorz; Kujda, Marta; Zgoła, Paulina; Stawinski, Jacek; Barciszewski, Jan; Boryski, Jerzy; Kraszewski, Adam

    2016-06-10

    New aromatic and aliphatic 3'-O-acyl-5-fluoro-2'-deoxyuridine derivatives were synthesized and evaluated as candidates for prodrugs against various cancer cell lines. As the most promising candidate for antimalignant therapeutics was found a dual-acting acyl derivative 7h, which apparently released not only the known anticancer nucleoside, 5-fluoro-2'-deoxyuridine (FdU), but also an additional active metabolite, acetylsalicylic acid, reinforcing thus therapeutic effect of FdU. Promising therapeutic indices showed also some aromatic dicarboxylic acids derivatives decorated with FdU esters (11 and 12). PMID:26994842

  10. Synthesis and biological evaluation of new securinine analogues as potential anticancer agents.

    PubMed

    Perez, Marc; Ayad, Tahar; Maillos, Philippe; Poughon, Valérie; Fahy, Jacques; Ratovelomanana-Vidal, Virginie

    2016-02-15

    A series of new securinine analogues was prepared by Heck reaction from readily accessible securinine and commercially available iodoarenes. The in vitro cytotoxicity of the prepared compounds was assayed against a panel of four cancer cell lines: A375, A549, HCT-116 and HL-60 showing promising growth inhibition with excellent IC50 values in the nanomolar range. The plasmatic stability of the most potent analogue was also investigated demonstrating that they might serve as valuable leads for the development of anticancer drugs. PMID:26793989

  11. Anticancer/Antiviral Agent Akt Inhibitor-IV Massively Accumulates in Mitochondria and Potently Disrupts Cellular Bioenergetics

    PubMed Central

    2015-01-01

    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 λmax = 388 nm, emission λmax = 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 μM, 5 min) by confocal laser scanning microscopy, with excitation at 405 nm, revealed extensive accumulation in mitochondria. Treatment of Jurkat lymphocytes with 1 μM AKTIV for 15 min caused accumulation to over 250 μM in these organelles, whereas treatment with 5 μM 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

  12. Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary

    PubMed Central

    Takahashi, Ryoko; Mabuchi, Seiji; Kawano, Mahiru; Sasano, Tomoyuki; Matsumoto, Yuri; Kuroda, Hiromasa; Kozasa, Katsumi; Hashimoto, Kae; Sawada, Kenjiro; Kimura, Tadashi

    2016-01-01

    Objective The objective of this study was to evaluate the antitumor effects of lurbinectedin as a single agent or in combination with existing anticancer agents for clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histological subtype. Methods Using human ovarian CCC cell lines, the antitumor effects of lurbinectedin, SN-38, doxorubicin, cisplatin, and paclitaxel as single agents were assessed using the MTS assay. Then, the antitumor effects of combination therapies involving lurbinectedin and 1 of the other 4 agents were evaluated using isobologram analysis to examine whether these combinations displayed synergistic effects. The antitumor activity of each treatment was also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines. Finally, we determined the effects of mTORC1 inhibition on the antitumor activity of lurbinectedin-based chemotherapy. Results Lurbinectedin exhibited significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. An examination of mouse CCC cell xenografts revealed that lurbinectedin significantly inhibits tumor growth. Among the tested combinations, lurbinectedin plus SN-38 resulted in a significant synergistic effect. This combination also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Everolimus significantly enhanced the antitumor activity of lurbinectedin-based chemotherapies. Conclusions Lurbinectedin, a new agent that targets active transcription, exhibits antitumor activity in CCC when used as a single agent and has synergistic antitumor effects when combined with irinotecan. Our results indicate that lurbinectedin is a promising agent for treating ovarian CCC, both as a first-line treatment and as a salvage treatment for recurrent lesions that develop after platinum-based or paclitaxel treatment. PMID:26986199

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

    PubMed

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

    2015-07-15

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

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

    PubMed Central

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

    2015-01-01

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

  15. 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: 1.00-2.71μM). 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 10μM. 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

  16. Immune response to haptenized tumor antigen as possible mechanism of anticancer action of hypoxic bioreductive agents at low doses.

    PubMed

    Schepetkin, I

    1999-08-01

    Possible anticancer effect mechanism of hypoxic bioreductive agents (HBA) at low nongenotoxic doses are reviewed. Experimental and clinical investigations show the process which can develop step-by-step when injecting HBA into the tumor-bearing organism resulting in the stimulation of antitumor immunity: HBA activation in hypoxic tumor tissue, conjugation of activated HBA with proteins of tumor cells, antigen processing, presentation of neoantigen epitops in association with major histocompatibility complex-I and cytolysis of these tumor cells by T-killers. The present process can be a variant of the delayed-type hypersensitivity reaction in the tumor region. The direct regulating influence of HBA on immunocompetent and/or tumor cells as a result of interaction of these drugs with superficial or intercellular receptors is supposed to be realized additively with this process. It is concluded that the ability of HBA to selective activation in tumor tissue and formation of immunogenic conjugates with tumor proteins can be a starting-point for developing drugs with immuno-modulation anticancer properties. PMID:10850314

  17. Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data

    PubMed Central

    Cheng, H-W; Liang, Y-H; Kuo, Y-L; Chuu, C-P; Lin, C-Y; Lee, M-H; Wu, A T H; Yeh, C-T; Chen, E I-T; Whang-Peng, J; Su, C-L; Huang, C-YF

    2015-01-01

    Glioblastoma (GBM) is a common and malignant tumor with a poor prognosis. Glioblastoma stem cells (GSCs) have been reported to be involved in tumorigenesis, tumor maintenance and therapeutic resistance. Thus, to discover novel candidate therapeutic drugs for anti-GBM and anti-GSCs is an urgent need. We hypothesized that if treatment with a drug could reverse, at least in part, the gene expression signature of GBM and GSCs, this drug may have the potential to inhibit pathways essential in the formation of GBM and thereby treat GBM. Here, we collected 356 GBM gene signatures from public databases and queried the Connectivity Map. We systematically evaluated the in vitro antitumor effects of 79 drugs in GBM cell lines. Of the drugs screened, thioridazine was selected for further characterization because it has potent anti-GBM and anti-GSCs properties. When investigating the mechanisms underlying the cytocidal effects of thioridazine, we found that thioridazine induces autophagy in GBM cell lines, and upregulates AMPK activity. Moreover, LC3-II was upregulated in U87MG sphere cells treated with thioridazine. In addition, thioridazine suppressed GBM tumorigenesis and induced autophagy in vivo. We not only repurposed the antipsychotic drug thioridazine as a potent anti-GBM and anti-GSCs agent, but also provided a new strategy to search for drugs with anticancer and anticancer stem cell properties. PMID:25950483

  18. Role of cytochrome P450 activity in the fate of anticancer agents and in drug resistance: focus on tamoxifen, paclitaxel and imatinib metabolism.

    PubMed

    Rochat, Bertrand

    2005-01-01

    Although activity of cytochrome P450 isoenzymes (CYPs) plays a major role in the fate of anticancer agents in patients, there are relatively few clinical studies that evaluate drug metabolism with therapeutic outcome. Nevertheless, many clinical reports in various non-oncology fields have shown the dramatic importance of CYP activity in therapeutic efficacy, safety and interindividual variability of drug pharmacokinetics. Moreover, variability of drug metabolism in the liver as well as in cancer cells must also be considered as a potential factor mediating cancer resistance. This review underlines the role of drug metabolism mediated by CYPs in pharmacokinetic variability, drug resistance and safety. As examples, biotransformation pathways of tamoxifen, paclitaxel and imatinib are reviewed. This review emphasises the key role of therapeutic drug monitoring as a complementary tool of investigation to in vitro data. For instance, pharmacokinetic data of anticancer agents have not often been published within subpopulations of patients who show ultra-rapid, extensive or poor metabolism (e.g. due to CYP2D6 and CYP2C19 genotypes). Besides kinetic variability in the systemic circulation, induction of CYP activity may participate in creating drug resistance by speeding up the cancer agent degradation specifically in the target cells. For one cancer agent, various mechanisms of resistance are usually identified within different cell clones. This review also tries to emphasise that drug resistance mediated by CYP activity in cancer cells should be taken into consideration to a greater degree. The unequivocal identification of the metabolising enzymes involved in clinical conditions will eventually allow improvement and individualisation of anticancer agent therapy, i.e. drug dosage and selection. In addition, a more complete understanding of the metabolism of anticancer agents will assist in the prediction of drug-drug interactions, as anticancer agent combinations are becoming more prevalent. PMID:15828850

  19. 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

  20. 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

  1. Synthesis and Structure–Activity Relationship Study of 1-Phenyl-1-(quinazolin-4-yl)ethanols as Anticancer Agents

    PubMed Central

    2015-01-01

    A quinazoline derivative PVHD121 (1a) was shown to have strong antiproliferative activity against various tumor-derived cell lines, including A549 (lung), NCI-H460 (lung), HCT116 (colon), MCF7 (breast), PC3 (prostate), and HeLa (cervical) cells with IC50 values from 0.1 to 0.3 μM. A structure–activity relationship (SAR) study at the 2- and 4-position of the quinazoline core lead to the discovery of more potent anticancer agents (14, 16, 17, 19, 24, and 31). The results of an in vitro tubulin polymerization assay and fluorescent-based colchicine site competition assay with purified tubulin indicated that 1a inhibits tubulin polymerization by binding to the colchicine site. PMID:25815147

  2. 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

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

    PubMed Central

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

    2016-01-01

    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

  4. Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN-007 in Orthotopic Mouse Xenografts

    PubMed Central

    Coutinho de Souza, Patricia; Mallory, Samantha; Smith, Nataliya; Saunders, Debra; Li, Xiao-Nan; McNall-Knapp, Rene Y.; Fung, Kar-Ming; Towner, Rheal A.

    2015-01-01

    Pediatric glioblastomas (pGBM), although rare, are one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. Here, we describe the use of conventional and advanced in vivo magnetic resonance imaging (MRI) techniques to assess a novel orthotopic xenograft pGBM mouse (IC-3752GBM patient-derived culture) model, and to monitor the effects of the anti-cancer agent OKN-007 as an inhibitor of pGBM tumor growth. Immunohistochemistry support data is also presented for cell proliferation and tumor growth signaling. OKN-007 was found to significantly decrease tumor volumes (p<0.05) and increase animal survival (p<0.05) in all OKN-007-treated mice compared to untreated animals. In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05). OKN-007 also significantly reduced lipid tumor metabolism in responsive animals [(Lip1.3 and Lip0.9)-to-creatine ratio (p<0.05)], as well as significantly decrease tumor cell proliferation (p<0.05) and microvessel density (p<0.05). Furthermore, in relationship to the PDGFRα pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-α (platelet-derived growth factor receptor-α) (p<0.05) immunoexpression, and significantly increase decorin expression (p<0.05) in responsive mice. This study indicates that OKN-007 may be an effective anti-cancer agent for some patients with pGBMs by inhibiting cell proliferation and angiogenesis, possibly via the PDGFRα pathway, and could be considered as an additional therapy for pediatric brain tumor patients. PMID:26248280

  5. Development History and Concept of an Oral Anticancer Agent S-1 (TS-1®): Its Clinical Usefulness and Future Vistas

    PubMed Central

    Shirasaka, Tetsuhiko

    2009-01-01

    Dushinsky et al. left a great gift to human beings with the discovery of 5-fluorouracil (5-FU). Approximately 50 years have elapsed from that discovery to the development of S-1 (TS-1®). The concept of developing an anticancer agent that simultaneously possesses both efficacy-enhancing and adverse reaction-reducing effects could be achieved only with a three-component combination drug. S-1 is an oral anticancer agent containing two biochemical modulators for 5-FU and tegafur (FT), a metabolically activated prodrug of 5-FU. The first modulator, 5-chloro-2,4-dihydroxypyridine (CDHP), enhances the pharmacological actions of 5-FU by potently inhibiting its degradation. The second modulator, potassium oxonate (Oxo), localizing in mucosal cells of the gastrointestinal (GI) tract after oral administration, reduces the incidence of GI toxicities by suppressing the activation of 5-FU in the GI tract. Thus, S-1 combines FT, CDHP and Oxo at a molar ratio of 1:0.4:1. In 1999–2007, S-1 was approved for the treatment of the following seven cancers: gastric, head and neck, colorectal, non-small cell lung, breast, pancreatic and biliary tract cancers. ‘S-1 and low-dose cisplatin therapy’ without provoking Grade 3 non-hematologic toxicities was proposed to enhance its clinical usefulness. Furthermore, ‘alternate-day S-1 regimen’ may improve the dosing schedule for 5-FU by utilizing its strongly time-dependent mode of action; the former is characterized by the low incidences of myelotoxicity and non-hematologic toxicities (e.g. ≤Grade 1 anorexia, fatigue, stomatitis, nausea, vomiting and taste alteration). These two approaches are considered to allow long-lasting therapy with S-1. PMID:19052037

  6. Investigating the cellular fate of a DNA-targeted platinum-based anticancer agent by orthogonal double-click chemistry.

    PubMed

    Qiao, Xin; Ding, Song; Liu, Fang; Kucera, Gregory L; Bierbach, Ulrich

    2014-03-01

    Confocal fluorescence microscopy was used to study a platinum-based anticancer agent in intact NCI-H460 lung cancer cells. Orthogonal copper-catalyzed azide-alkyne cycloaddition (click) reactions were used to simultaneously determine the cell-cycle-specific localization of the azide-functionalized platinum-acridine agent 1 and monitor its effects on nucleic acid metabolism. Copper-catalyzed postlabeling showed advantages over copper-free click chemistry using a dibenzocyclooctyne (DIBO)-modified reporter dye, which produced high background levels in microscopic images and failed to efficiently label platinum adducts in chromatin. Compound 1 was successfully labeled with the fluorophore DIBO to yield 1* (characterized by in-line high-performance liquid chromatography/electrospray mass spectrometry). 1 and 1* show a high degree of colocalization in the confocal images, but the ability of 1* to target the (compacted) chromatin was markedly reduced, most likely owing to the steric bulk introduced by the DIBO tag. Nuclear platinum levels correlated inversely with the ability of the cells to synthesize DNA and cause cell cycle arrest, as confirmed by bivariate flow cytometry analysis. In addition, a decrease in the level of cellular transcription, shrinkage of the nucleolar regions, and redistribution of RNA into the cytosol were observed. Postlabeling in conjunction with colocalization experiments is a useful tool for studying the cell killing mechanism of this type of DNA-targeted agent. PMID:24407462

  7. 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.

  8. Design and synthesis of diamide-coupled benzophenones as potential anticancer agents.

    PubMed

    Zabiulla; Shamanth Neralagundi, H G; Bushra Begum, A; Prabhakar, B T; Khanum, Shaukath Ara

    2016-06-10

    A series of diamide-coupled benzophenone, 2-(4-benzoyl-phenoxy)-N-{2-[2-(4-benzoyl-phenoxy)-acetylamino]-phenyl}-acetamide analogues (9a-l) were synthesized by multistep reactions and all compounds were well characterized. Among the series (9a-l), compound 9k with three methyl groups at ortho position in rings A, B, and D and bromo group at the para position in ring E was selected as a lead compound by screening through multiple cancer cell types by in-vitro cytotoxic and antiproliferative assay systems. Also, the cytotoxic nature of the compound 9k resulted the regression of the tumor growth in-vivo, which could be due to decreased vascularisation in the peritoneum lining of the mice which regress the tumor growth. The results were reconfirmed in-vivo chorioallantoic membrane model which indicates a scope of developing 9k into potent anticancer drug in near future. PMID:27027818

  9. Are the antagonists of the renin-angiotensin system also anticancer agents?

    PubMed

    Lonati, Chiara; Morganti, Alberto

    2015-06-01

    The antagonists of the renin-angiotensin system (RAS) have gained increasing popularity in the last two decades due to their indisputable efficacy in a number of cardiovascular disorders, coupled with an unsurpassed tolerability. However some years ago a partial and non-predefined meta-analysis raised the possibility that angiotensin receptor antagonists in particular may increase the incidence of cancer. This observation, although not confirmed by subsequent, larger analyses, caused a remarkable and understandable concern even outside the medical community. Herein we will summarize the available evidence pro and con the hypothesis of a carcinogenetic activity of RAS antagonists coming to the conclusion that these drugs may actually exert an anticancer action. PMID:24916368

  10. Lipophilic Statins as Anticancer Agents: Molecular Targeted Actions and Proposal in Advanced Gynaecological Malignancies.

    PubMed

    Gizzo, Salvatore; Quaranta, Michela; Nardelli, Giovanni Battista; Noventa, Marco

    2015-01-01

    Despite adequate surgery, women affected by advanced-stage gynaecological cancers (ovarian/ endometrial malignancies) carry an extremely poor prognosis; an improved oncological prognosis could largely depend upon the enhancement of adjuvant treatment. Recent data showed that, among women affected by endometrial/ovarian malignancies, a reduced cancer-related mortality was noted in statin-users compared to non-users, suggesting the need for clinical trials to define the anticancerproperties of statins. In vitro/in vivo evidences suggest a potential chemo-preventive effect through induction of cancer-cell apoptosis and inhibition of cancer-cell growth, proliferation, invasion, and metastasis. The potential oncological impact of this discovery compels us to investigate all possible molecular targets for anticancer activities of statins in order to identify a rationale in proposing their administration in association with standard chemotherapy/radiotherapy protocols after adequate surgical-treatment for advanced-stages gynaecological malignancies. PMID:25901529

  11. Membranes affinity of promising anticancer agent DB-67 determined by fluorescence spectra analysis

    NASA Astrophysics Data System (ADS)

    Ziomkowska, Blanka; Cyrankiewicz, Michał; Kruszewski, Stefan; Siuda, Ryszard

    2005-08-01

    Camptothecins are fluorescent compounds which exhibit anticancer properties. A disadvantage which seriously limits application of camptothecins in antitumor chemotherapy is the hydrolysis of these compounds. They convert into inactive carboxylate forms. The process of hydrolysis is inhibited when the molecules of camptothecin are bound to cell membranes. So it is desirable that camptothecins molecules bind easily to membranes. A quantitative measure of drugs affinity to membranes is the association constant. To determine the association constant to membranes the lipid bilayers i.e. liposomes are used as model membranes. In this work affinity of hydroxycamptothecin DB-67 to model membranes is determined. Fluorescence spectra of this analogue change in presence of liposomes: the fluorescence intensity is bigger and besides green band the blue band appears. The spectra of hydroxycamptothecins change over lipids concentration. On the basis of this changes the association constant to membranes is calculated.

  12. Membranes affinity of 10-hydroxycamptothecin and SN-38, anticancer agents, determined by fluorescence spectra analysis

    NASA Astrophysics Data System (ADS)

    Cyrankiewicz, Michał; Ziomkowska, Blanka; Kruszewski, Stefan; Siuda, Ryszard

    2006-02-01

    Camptothecins are fluorescent compounds which exhibit anticancer properties. A disadvantage which seriously limits application of camptothecins in antitumor chemotherapy is the hydrolysis of these compounds. They convert into inactive carboxylate forms. The process of hydrolysis is inhibited when the molecules of camptothecin are bound to cell membranes. So it is desirable that camptothecins molecules bind easily to membranes. A quantitative measure of drugs affinity to membranes is the association constant. To determine this parameter the small unilamellar lipids vesicles i.e. unilamellar liposomes are used as model membranes. The affinities of 10-hydroxycamptothecin and SN-38 to model membranes are determined in this work. Fluorescence spectra of these analogues change in presence of liposomes: the fluorescence intensity increases and besides green band the blue band appears. The spectra of 10-hydroxycamptothecins and SN-38 change over lipids concentration. On the basis of these changes the association constants to membranes are determined.

  13. New triarylpyrazoles as broad-spectrum anticancer agents: design, synthesis, and biological evaluation.

    PubMed

    El-Gamal, Mohammed I; Park, Yi Seul; Chi, Dae Yoon; Yoo, Kyung Ho; Oh, Chang-Hyun

    2013-07-01

    A new series of diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold was designed and synthesized. Their in vitro antiproliferative activities against NCI-60 cell line panel were tested. Most of the compounds showed strong and broad-spectrum antiproliferative activities. Compound 18 exerted sub-micromolar IC50 values over all the subpanels of nine different cancer types. Its IC50 value over MDA-MB-435 melanoma cell line was 27 nM. Compounds 10-13, 22, and 23 possessing urea spacer exerted lethal effect over the NCI-60 panel with mean %inhibitions more than 100% in single-dose testing. Compounds 13 and 23 with urea linker and 3',5'-bis(trifluoromethyl)phenyl terminal ring showed the highest mean %inhibition over the NCI-60 panel in single-dose testing, and showed high potencies and broad-spectrum anticancer activities in five-dose testing. PMID:23732996

  14. Rational development of histone deacetylase inhibitors as anticancer agents: a review.

    PubMed

    Acharya, Milin R; Sparreboom, Alex; Venitz, Jrgen; Figg, William D

    2005-10-01

    The epigenome is defined by DNA methylation patterns and the associated post-translational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The histone deacetylases (HDACs) play a major role in keeping the balance between the acetylated and deacetylated states of chromatin and eventually regulate gene expression. Recent developments in understanding the cancer cell cycle, specifically the interplay with chromatin control, are providing opportunities for developing mechanism-based therapeutic drugs. Inhibitors of HDACs are under considerable exploration, in part because of their potential roles in reversing the silenced genes in transformed tumor cells by modulating transcriptional processes. This review is an effort to summarize the nonclinical and clinical status of HDAC inhibitors currently under development in anticancer therapy. PMID:15955865

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

    PubMed

    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, (1)H- and (13)C-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. PMID:25706598

  16. Lappaol F, a novel anticancer agent isolated from plant arctium Lappa L.

    PubMed

    Sun, Qing; Liu, Kanglun; Shen, Xiaoling; Jin, Weixin; Jiang, Lingyan; Sheikh, M Saeed; Hu, Yingjie; Huang, Ying

    2014-01-01

    In an effort to search for new cancer-fighting therapeutics, we identified a novel anticancer constituent, Lappaol F, from plant Arctium Lappa L. Lappaol F suppressed cancer cell growth in a time- and dose-dependent manner in human cancer cell lines of various tissue types. We found that Lappaol F induced G(1) and G(2) cell-cycle arrest, which was associated with strong induction of p21 and p27 and reduction of cyclin B1 and cyclin-dependent kinase 1 (CDK1). Depletion of p21 via genetic knockout or short hairpin RNA (shRNA) approaches significantly abrogated Lappaol F-mediated G(2) arrest and CDK1 and cyclin B1 suppression. These results suggest that p21 seems to play a crucial role in Lappaol F-mediated regulation of CDK1 and cyclin B1 and G(2) arrest. Lappaol F-mediated p21 induction was found to occur at the mRNA level and involved p21 promoter activation. Lappaol F was also found to induce cell death in several cancer cell lines and to activate caspases. In contrast with its strong growth inhibitory effects on tumor cells, Lappaol F had minimal cytotoxic effects on nontumorigenic epithelial cells tested. Importantly, our data also demonstrate that Lappaol F exhibited strong growth inhibition of xenograft tumors in nude mice. Lappaol F was well tolerated in treated animals without significant toxicity. Taken together, our results, for the first time, demonstrate that Lappaol F exhibits antitumor activity in vitro and in vivo and has strong potential to be developed as an anticancer therapeutic. PMID:24222662

  17. 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

  18. Proof of concept for inhibiting metastasis: circulating tumor cell-triggered localized release of anticancer agent via a structure-switching aptamer.

    PubMed

    Chen, Nandi; Yang, Xiaohai; Wang, Qing; Jian, Lixin; Shi, Hui; Qin, Shiya; Wang, Kemin; Huang, Jin; Liu, Wenjing

    2016-05-21

    Existing drug delivery systems were not suitable for killing cells in the circulatory system specifically. Herein, we developed a novel localized drug delivery strategy, in which the release of anticancer agents was specifically triggered by circulating tumor cells. Meanwhile, damage to non-target cells was avoided. PMID:27121864

  19. 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 μM (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

  20. 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 α (TNF-α) 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

  1. Synthesis of novel anticancer agents through opening of spiroacetal ring of diosgenin.

    PubMed

    Hamid, A A; Hasanain, Mohammad; Singh, Arjun; Bhukya, Balakishan; Omprakash; Vasudev, Prema G; Sarkar, Jayanta; Chanda, Debabrata; Khan, Feroz; Aiyelaagbe, O O; Negi, Arvind S

    2014-09-01

    Diosgenin has been modified to furostane derivatives after opening the F-spiroacetal ring. The aldehyde group at C26 in derivative 8 was unexpectedly transformed to the ketone 9. The structure of ketone 9 was confirmed by spectroscopy and finally by X-ray crystallography. Five of the diosgenin derivatives showed significant anticancer activity against human cancer cell lines. The most potent molecule of this series i.e. compound 7, inhibited cellular growth by arresting the population at G0/G1 phase of cell division cycle. Cells undergo apoptosis after exposure to the derivative 7 which was evident by increase in sub G0 population in cell cycle analysis. Docking experiments showed caspase-3 and caspase-9 as possible molecular targets for these compounds. This was further validated by cleavage of PARP, a caspase target in apoptotic pathway. Compound 7 was found non-toxic up to 1000mg/kg dose in acute oral toxicity in Swiss albino mice. PMID:24929045

  2. The Use of 1α,25-Dihydroxyvitamin D3 as an Anticancer Agent

    PubMed Central

    Marcinkowska, Ewa; Wallace, Graham R.; Brown, Geoffrey

    2016-01-01

    The notion that vitamin D can influence the incidence of cancer arose from epidemiological studies. The major source of vitamin D in the organism is skin production upon exposure to ultra violet-B. The very first observation of an inverse correlation between exposure of individuals to the sun and the likelihood of cancer was reported as early as 1941. In 1980, Garland and Garland hypothesised, from findings from epidemiological studies of patients in the US with colon cancer, that vitamin D produced in response to sun exposure is protective against cancer as opposed to sunlight per se. Later studies revealed inverse correlations between sun exposure and the occurrence of prostate and breast cancers. These observations prompted laboratory investigation of whether or not vitamin D had an effect on cancer cells. Vitamin D is not active against cancer cells, but the most active metabolite 1α,25-dihydroxyvitamin D3 (1,25D) has profound biological effects. Here, we review the anticancer action of 1,25D, clinical trials of 1,25D to date and the prospects of the future therapeutic use of new and low calcaemic analogues. PMID:27187375

  3. Nanoemulsion formulations for anti-cancer agent piplartine-Characterization, toxicological, pharmacokinetics and efficacy studies.

    PubMed

    Fofaria, Neel M; Qhattal, Hussaini Syed Sha; Liu, Xinli; Srivastava, Sanjay K

    2016-02-10

    Piplartine (PL) is an alkaloid found in black-pepper and known for its anticancer activity, however, due to poor solubility and lack of proper formulation, its use for oral administration is a challenge. The objective of this study was to formulate PL into nanoemulsion drug delivery system for oral delivery and thereafter evaluate toxicity, pharmacokinetics and therapeutic efficacy. Optimized nanoemulsions were formulated by self-emulsification as well as by homogenization-sonication method. Two nanoemulsions enhanced the solubility of PL with low polydispersity index and high stability. Both PL loaded nanoemulsions exhibited enhanced dissolution, cellular permeability and cytotoxic effects as compared to pure PL. Formulation of PL into nanoemulsions did not obstruct its cellular uptake in cancer cells. Blank or PL loaded nanoemulsions did not exhibited toxicity in mice upon daily oral administration for 60 days. Pharmacokinetics of PL followed a two-compartment model after intravenous administration. PL loaded nanoemulsions showed 1.5-fold increase in oral bioavailability as compared to free PL. Finally, PL loaded nanoemulsions showed marked anti-tumor activity at a dose of 10mg/kg in melanoma tumor bearing mice. In conclusion, for the first time we have developed a stable nanoemulsion delivery system for oral administration of PL, which enhanced its solubility, oral bioavailability and anti-tumor efficacy. PMID:26642946

  4. The Use of 1α,25-Dihydroxyvitamin D₃ as an Anticancer Agent.

    PubMed

    Marcinkowska, Ewa; Wallace, Graham R; Brown, Geoffrey

    2016-01-01

    The notion that vitamin D can influence the incidence of cancer arose from epidemiological studies. The major source of vitamin D in the organism is skin production upon exposure to ultra violet-B. The very first observation of an inverse correlation between exposure of individuals to the sun and the likelihood of cancer was reported as early as 1941. In 1980, Garland and Garland hypothesised, from findings from epidemiological studies of patients in the US with colon cancer, that vitamin D produced in response to sun exposure is protective against cancer as opposed to sunlight per se. Later studies revealed inverse correlations between sun exposure and the occurrence of prostate and breast cancers. These observations prompted laboratory investigation of whether or not vitamin D had an effect on cancer cells. Vitamin D is not active against cancer cells, but the most active metabolite 1α,25-dihydroxyvitamin D₃ (1,25D) has profound biological effects. Here, we review the anticancer action of 1,25D, clinical trials of 1,25D to date and the prospects of the future therapeutic use of new and low calcaemic analogues. PMID:27187375

  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. Design, synthesis and biological evaluation of novel sesquiterpene mustards as potential anticancer agents.

    PubMed

    Xu, Yuan-Zhen; Gu, Xue-Yan; Peng, Shou-Jiao; Fang, Jian-Guo; Zhang, Ying-Mei; Huang, De-Jun; Chen, Jian-Jun; Gao, Kun

    2015-04-13

    Several novel series of sesquiterpene mustards (SMs) bearing nitrogen mustard and glutathione (GSH)-reactive α-methylene-γ-butyrolactone groups were successfully prepared for the first time and showed excellent antiproliferative activities in vitro. Among them, compounds 2e and 2g displayed the highest antiproliferative properties with IC50 values ranging from 2.5 to 8.7 μM. The selectivity of these two compounds was evaluated by SRB method against human cancer and normal hepatic cells (HepG2 and L02). The induction of apoptosis and effects on the cell cycle distribution with compounds 2e and 2g were investigated by Hoechst 33,258 staining and flow cytometry, which exhibited that they could induce selective cell apoptosis and cell cycle arrest in HepG2 and L02 cells. In addition, further investigation showed that compounds 2e and 2g could obviously inhibit the proliferation of HepG2 cells by inducing significant DNA cross-linking and depleting GSH in cell media. The good cytotoxicity and selectivity of compounds 2e and 2g pointed them as promising leads for anticancer drug design. PMID:25771034

  7. Synthesis, cytotoxic activity evaluation and HQSAR study of novel isosteviol derivatives as potential anticancer agents.

    PubMed

    Liu, Cong-Jun; Yu, Shu-Ling; Liu, Yan-Ping; Dai, Xing-Jie; Wu, Ya; Li, Rui-Jun; Tao, Jing-Chao

    2016-06-10

    A series of novel isosteviol derivatives bearing amino alcohol and thiourea fragments have been stereo-selectively synthesized and screened for their in vitro cytotoxic activities against three human cancer cell lines (HCT-116, HGC-27 and JEKO-1). The results demonstrated that these compounds exhibited prominent cytotoxicities. Especially, the compound Iw displayed the most potent anticancer activities against HCT-116 cell with IC50 value of 1.450 μM. On the basis of this bioassay results, these derivatives were further investigated by the hologram quantitative structure-activity relationship (HQSAR) technique. The optimal HQSAR model with q(2) = 0.663, r(2) = 0.895, SEE = 0.179 was generated using A/B/H/Ch as fragment distinction parameters and 4-7 as fragment size. This model was employed to predict the cytotoxic activities of test set compounds, and the predicted values were in good agreement with the experimental results. The contribution maps derived from the optimal model explained the individual atomic contribution to the total activity of single molecule. PMID:26994841

  8. 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 μM 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

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

    PubMed

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

    2011-03-01

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

  10. Assessment of Performance of Manufacturing Procedures in a Unit for Production of Investigational Anticancer Agents, Using a Mixed Effects Analysis

    PubMed Central

    van der Schoot, S. C.; Huitema, A. D. R.; Beijnen, J. H.

    2007-01-01

    Purpose To identify the magnitude and sources of variability of a generic, aseptic manufacturing process for experimental anticancer agents employed at our facility, and to estimate the effects on product quality. Materials and Methods In-process and quality control data of all products manufactured according to this generic process (composed of weighing, dissolution, filtration, filling, semi-stoppering and lyophilization) over a 3-year period were retrospectively analyzed using mixed-effects analysis. Results Variability in the filling process was shown to be marginal and of minor importance for product quality in terms of content and content uniformity. An overall content of 101% was found with batch-to-batch and vial-to-vial variability up to 4.21% and 2.57%, respectively. Estimation of the overall batch failure revealed that structural bias in content and a high batch-to-batch variability in content were the most prominent factors determining batch failure. Furthermore, content and not content uniformity was shown to be most important parameter influencing batch failure. Calculated Process Capability Indices (CpKs) calculated for each product showed that the process is capable of manufacturing products which will routinely comply with the specification of 90110% for content. However, the CpK values decreased dramatically using the specification of 95105% as required for approved drug products. Conclusion These results indicate that at the early stage of product development less tight specification limits must be applied to prevent unnecessary batch rejection of investigational agents. PMID:17245647

  11. 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.

  12. Co-delivery of chemosensitizing siRNA and an anticancer agent via multiple monocomplexation-induced hydrophobic association.

    PubMed

    Lee, Eunjung; Oh, Changhwoa; Kim, In-San; Kwon, Ick Chan; Kim, Sehoon

    2015-07-28

    Synergistic combination of gene targeting and chemotherapy by co-delivering siRNA and anticancer drugs has widely been investigated to develop siRNA-based therapeutics for cancer treatment. Despite clinical potential of this approach, big challenges still remain such as delivery efficiency or stability/biocompatibility of the siRNA delivery system. Here we report a simple and biocompatible co-delivering formulation based on a unique complexation method, i.e., multiple monocomplexation-induced hydrophobic association between Bcl-2 targeting siRNA and a monocationic anticancer agent (benzethonium chloride, BZT). A colloidal formulation of the hydrophobically associated multiple monocomplex (HMplex) composed of siRNA, BZT and Pluronic F-68 was spontaneously constructed by physical mixing of the ternary constituents. In vitro and in vivo studies revealed that the ternary HMplex with a low charge ratio (N/P=4) possesses a tightly complexed stable nanostructure with Pluronic surface and small colloidal size less than 10nm, which allowed for 1) suitable protection of siRNA in serum-rich physiological environment, 2) efficient intracellular transfection into the cytoplasm, and 3) successful peritumoral co-delivery into the tumor tissue with dense interstitial matrix. Compared to non-targeting HMplexes between scrambled siRNA and BZT, Bcl-2 targeting HMplexes enhanced significantly both mRNA down-regulation by siRNA and apoptosis induction by BZT, and thus greatly suppressed the tumor volume when administered to highly aggressive and resistant human breast cancer xenografts (MDA-MB-231) in mice. These results elucidate that the co-complexed siRNA and BZT were liberated by intracellular decomplexation to trigger a synergistically combined therapeutic action. The successful siRNA/chemodrug co-delivery in vivo via peritumoral route and the greatly promoted therapeutic efficacy thereby represent the clinical potential of HMplexes for adjuvant locoregional cancer treatment by gene-targeted combination therapy. PMID:25979325

  13. PTHrP attenuates osteoblast cell death and apoptosis induced by a novel class of anti-cancer agents.

    PubMed

    Chukkapalli, Sahiti; Levi, Edi; Rishi, Arun K; Datta, Nabanita S

    2016-03-01

    The effectiveness of chemotherapeutic agents often limits their use due to their negative effects on normal cells. Apoptosis regulatory protein (CARP)-1 functional mimetics (CFMs) belong to a novel class of compounds that possess anti-cancer properties with potential utility in breast and other cancers. In this study, we investigated the growth inhibitory action of CFM-4 and -5 in bone-forming osteoblasts and role of a skeletal regulator, parathyroid hormone (PTH)-related peptide (PTHrP), which is frequently associated with oncologic pathologies. MC3T3E1-clone4 (MC-4) or primary osteoblasts were treated with CFMs. Western blots were performed to determine specific protein expressions. MTT, TUNEL assay, ethidium bromide/acridine orange staining, and ApoAlert caspase profiling were used to investigate cell viability and apoptosis of osteoblasts. Immunofluorescence staining was performed to observe intracellular localization of CARP-1. Our studies revealed that CFM-4 and -5 suppressed growths of mature differentiated, but not proliferating, MC-4 cells and PTHrP attenuated this effect. Mechanistically, induction of CARP-1 protein by CFM-4 and -5 was partially decreased by PTHrP. While CARP-1 increased by CFM-4 or -5 correlated with activated caspase-3, PTHrP remarkably blocked caspase-3 activation. PTHrP also influenced translocation of CFM-induced CARP-1 from the nucleus to the cytoplasm. Our data identify a new function of PTHrP in maintaining osteoblast homeostasis in chemotherapy and define a role of CARP-1 in this process. The crosstalk of PTHrP and CFM-4 and -5 signaling highlights the importance of CFMs as potential anti-cancer therapeutics in breast and other cancers which adversely affect bone. PMID:26260694

  14. Scaffold-hopping strategy: synthesis and biological evaluation of 5,6-fused bicyclic heteroaromatics to identify orally bioavailable anticancer agents.

    PubMed

    Tung, Yen-Shih; Coumar, Mohane Selvaraj; Wu, Yu-Shan; Shiao, Hui-Yi; Chang, Jang-Yang; Liou, Jing-Ping; Shukla, Paritosh; Chang, Chun-Wei; Chang, Chi-Yen; Kuo, Ching-Chuan; Yeh, Teng-Kuang; Lin, Chin-Yu; Wu, Jian-Sung; Wu, Su-Ying; Liao, Chun-Chen; Hsieh, Hsing-Pang

    2011-04-28

    Utilizing scaffold-hopping drug-design strategy, we sought to identify a backup drug candidate for BPR0L075 (1), an indole-based anticancer agent. For this purpose, 5,6-fused bicyclic heteroaromatic scaffolds were designed and synthesized through shuffling of the nitrogen from the N-1 position or by insertion of one or two nitrogen atoms into the indole core of 1. Among these, 7-azaindole core 12 showed potent in vitro anticancer activity and improved oral bioavailability (F = 35%) compared with 1 (F < 10%). PMID:21434659

  15. In vitro and in vivo evaluation of organometallic gold(i) derivatives as anticancer agents.

    PubMed

    García-Moreno, Elena; Tomás, Alejandro; Atrián-Blasco, Elena; Gascón, Sonia; Romanos, Eduardo; Rodriguez-Yoldi, M Jesus; Cerrada, Elena; Laguna, Mariano

    2016-02-14

    Alkyne gold(i) derivatives with the water soluble phosphanes PTA (1,3,5-triaza-7-phosphaadamantane) and DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) were described and their anticancer potential against the colon cancer cell line Caco-2 (PD7 and TC7 clones) was studied. Strong antiproliferative effects are found, for all the new complexes, to be even more pronounced than for the reference drug cisplatin, and similar to auranofin. The interaction of these derivatives with bovine serum albumin (BSA) was studied by fluorescence spectroscopy. The types of quenching and binding constants were determined by a fluorescence quenching method. Moderate values of the binding constants are calculated for the tested derivatives indicating that these complexes can be stored and carried easily by this protein in the body. The study of the thermodynamic parameters in the case of [Au(C[triple bond, length as m-dash]CCH2Spyridine)(PTA)] points out to the presence of van der Waals interactions or hydrogen bonding between the metallic complex and the protein. In addition, the complex [Au(C[triple bond, length as m-dash]CCH2Spyridine)(PTA)] has shown inhibition in colon cancer proliferation of HTC-116-luc2 cell lines via the apoptotic pathway and S-phase arrest of the cell cycle. Intraperitoneal injection of this derivative in athymic nude mice inoculated with HTC-116-luc2 cells prolonged their survival and displayed moderate inhibition of the tumour growth with no subsequent organ (kidney and liver) damage after treatment. PMID:26469679

  16. Synthesis and biological evaluation of simple methoxylated chalcones as anticancer, anti-inflammatory and antioxidant agents.

    PubMed

    Bandgar, Babasaheb P; Gawande, Shrikant S; Bodade, Ragini G; Totre, Jalinder V; Khobragade, Chandrahas N

    2010-02-01

    Chalcones have been identified as interesting compounds with cytotoxicity, anti-inflammatory and antioxidant properties. In the present study, simple methoxychalcones were synthesized by Claisen-Schmidt condensation reaction and evaluated for above biological activities. The structures of the compounds were established by IR, (1)H NMR and mass spectral analysis. The data revealed that compound 3s (99-100% at 10 microM concentration) completely inhibit the selected five human cancer cell lines as compared to standard flavopiridol and gemcitabine (70-90% at 700 nM and 500 nM concentrations, respectively), followed by 3a, 3n,3o,3p,3q,3r. Among the tested compounds 3l, 3m, 3r, and 3s exhibited promising anti-inflammatory activity against TNF-alpha and IL-6 with 90-100% inhibition at 10 microM concentration. DPPH free radical scavenging activity was given by the compounds 3o, 3n, 3l, 3r, 3m, 3a, 3p, 3c and 3s at 1mM concentration. Overall, 3s was obtained as lead compound with promising anticancer, anti-inflammatory and antioxidant activities. Bioavailability of compounds were checked by in vitro cytotoxicity study and confirmed to be nontoxic. The structure activity relationship (SAR) and in silico drug relevant properties (HBDs, HBAs, PSA, cLogP, ionization potential, molecular weight, E(HOMO) and E(LUMO)) further confirmed that the compounds were potential candidates for future drug discovery study. PMID:20064725

  17. New Pyrazolopyrimidine Inhibitors of Protein Kinase D as Potent Anticancer Agents for Prostate Cancer Cells

    PubMed Central

    Tandon, Manuj; Johnson, James; Li, Zhihong; Xu, Shuping; Wipf, Peter; Wang, Qiming Jane

    2013-01-01

    The emergence of protein kinase D (PKD) as a potential therapeutic target for several diseases including cancer has triggered the search for potent, selective, and cell-permeable small molecule inhibitors. In this study, we describe the identification, in vitro characterization, structure-activity analysis, and biological evaluation of a novel PKD inhibitory scaffold exemplified by 1-naphthyl PP1 (1-NA-PP1). 1-NA-PP1 and IKK-16 were identified as pan-PKD inhibitors in a small-scale targeted kinase inhibitor library assay. Both screening hits inhibited PKD isoforms at about 100 nM and were ATP-competitive inhibitors. Analysis of several related kinases indicated that 1-NA-PP1 was highly selective for PKD as compared to IKK-16. SAR analysis showed that 1-NA-PP1 was considerably more potent and showed distinct substituent effects at the pyrazolopyrimidine core. 1-NA-PP1 was cell-active, and potently blocked prostate cancer cell proliferation by inducing G2/M arrest. It also potently blocked the migration and invasion of prostate cancer cells, demonstrating promising anticancer activities on multiple fronts. Overexpression of PKD1 or PKD3 almost completely reversed the growth arrest and the inhibition of tumor cell invasion caused by 1-NA-PP1, indicating that its anti-proliferative and anti-invasive activities were mediated through the inhibition of PKD. Interestingly, a 12-fold increase in sensitivity to 1-NA-PP1 could be achieved by engineering a gatekeeper mutation in the active site of PKD1, suggesting that 1-NA-PP1 could be paired with the analog-sensitive PKD1M659G for dissecting PKD-specific functions and signaling pathways in various biological systems. PMID:24086585

  18. 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 αβ-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

  19. Evaluation of 2-(methylaminosulfonyl)-1-(arylsulfonyl)hydrazines as anticancer agents.

    PubMed

    Ghosh, M; Dutta, S; Sanyal, U

    1999-01-01

    Seven new 2-(methylaminosulfonyl)- 1-(arylsulfonyl)hydrazines were prepared and evaluated as potential antitumor agents in vivo against murine Ehrlich ascites carcinoma (EAC). Borderline in vivo activity in EAC was exhibited by two compounds. All of them were screened in vitro against a battery of human tumor cell lines at the National Cancer Institute (NCI), USA. One of them, namely compound 2f(NSC No. 649 752) displayed highly significant specificity in two different cell lines as non-small cell lung cancer line HOP-18 and in CNS cancer line SNB-19. The compounds assessed in vitro for anti-HIV activity also at the NCI, however, have not reached the criteria of significant activity. The alkylating activity of the compounds was determined by measuring the absorbance of the alkylated product of 4-(4-nitrobenzyl)pyridine. It was found that they are capable of acting as chemical alkylating agents. PMID:10613605

  20. Design, Synthesis and Biological Evaluation of N-Acetyl-S-(pchlorophenylcarbamoyl)cysteine and Its Analogs as a Novel Class of Anticancer Agents

    PubMed Central

    Chen, Wei; Seefeldt, Teresa; Young, Alan; Zhang, Xiaoying; Guan, Xiangming

    2010-01-01

    N-Acetyl-S-(p-chlorophenylcarbamoyl)cysteine (NACC) was identified as a metabolite of sulofenur. Sulofenur was demonstrated to have broad activity against solid tumors in preclinical studies but exhibited disappointing clinical responses due to its high protein binding related adverse effects. NACC exhibited low protein binding and excellent activity against a sulofenur sensitive human colon cancer cell line. In this study, analogs of NACC were synthesized and evaluated with four human cancer cell lines. Two of the NACC analogs showed excellent activity against two human melanoma cell lines, while NACC remains the most potent of the series. All three compounds were more potent than dacarbazine, which is used extensively in treating melanoma. NACC was shown to induce apoptosis without affecting the cell cycle. Further, NACC exhibited low toxicity against monkey kidney cells. The selective anticancer activity, low toxicity, an unknown yet but unique anticancer mechanism and ready obtainability through synthesis make NACC and its analogs promising anticancer agents. PMID:21131205

  1. Synthesis and pharmacological studies of new pyrazole analogues of podophyllotoxin.

    PubMed

    Umesha, B; Basavarajuk, Y B

    2014-01-01

    The pyrazole analogues of podophyllotoxin were synthesized by the chalcone route. This route attracts the attention because of its simple operating conditions and easy availability ofthe chemicals. Initially, benzylide-neacetophenones (chalcones) were prepared in high yields by Claisen-Schmidt reaction of acetophenones with 4-(methylthio)benzaldehyde. The cyclopropyl ketones were prepared in good yields by the reaction of chalcones with trimethylsulfoxonium iodide. Tetralones were prepared in good yields by the Friedel-Craft's intramolecular cyclization reaction of cyclopropyle ketones in the presence of anhyd. stannic chloride and acetic anhydride. The tetralones on formylation to give substituted hydroxylmethylene tetralones. Condensation of substituted hydroxylmethylene tetralones with hydrazine hydrate afforded target compounds. The structures of the synthesized compounds were confirmed by IR, 'H-NMR and Mass spectral technique. The title compounds were screened for their antimitotic and antimicrobial activities. Among the synthesized compounds cyclopropyl ketones and pyrazole analogues of podophyllotoxin, compound 7-(Methytthio)-5-(4-(methylthio)phe- nyl)-4,5.-dihydro-2H-benzo[g]indazole is more active than 5-(4-(Methylthio)phenyl)-4,5-dihydro-2H-ben- zo[g]indazole, 7-Methyl-5-(4-(methylthio)phenyl)-4,5-dihydro-2H-benzo[g]indazole, 7-Methoxy-5-(4-(meth- ylthio)phenyl)-4,5-dihydro-2H-benzo[g]indazole and the key intermediate tetralones in 100, 200 and 400 ppm at 12, 18 and 24 hrs and also showed very good activity against screened bacteria and fungi compared to their standard. PMID:25898761

  2. 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

  3. In Vitro Evaluation of Oxoplatin: An Oral Platinum(IV) Anticancer Agent

    PubMed Central

    Olszewski, Ulrike; Ach, Florian; Ulsperger, Ernst; Baumgartner, Gerhard; Zeillinger, Robert; Bednarski, Patrick; Hamilton, Gerhard

    2009-01-01

    Platinum(IV) compounds like oxoplatin (cis, cis, trans-diammine-dichlorido-dihydroxido-platinum(IV)) show increased stability and therefore can be applied orally. In a panel of 38 human cancer cell lines this drug induced S-phase arrest and cell death with IC50 values 2.5-fold higher than cisplatin. Oxoplatin may be converted to cisplatin by intracellular reducing agents, however, exposure to 0.1 M HCl mimicking gastric acid yielded cis-diammine-tetrachlorido-platinum(IV) exhibiting twofold increased activity. Similar results were obtained for another platinum(IV) compound, JM 149 (ammine-dichlorido-(cyclohexylamine)-dihydroxido-platinum(IV)), but not for its parent drug JM 216/satraplatin. Genome-wide expression profiling of H526 small cell lung cancer cells treated with these platinum species revealed clear differences in the expression pattern of affected genes between oxoplatin and cisplatin. In conclusion, oxoplatin constitutes a potent oral agent that is either reduced or converted to distinct active compounds, for example, by gastric acid or acidic areas prevailing in solid tumors, in dependence of the respective pharmaceutical formulation. PMID:19587824

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

    PubMed

    Taşdemir, Demet; Karaküçük-İyidoğan, Ayşegül; Ulaşli, Mustafa; Taşkin-Tok, Tuğba; Oruç-Emre, Emİne Elçİn; 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 μM) against HGC-27 as compared with the reference compound, sindaxel (IC50 10.3 μM), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents. PMID:25399965

  5. Novel hederagenin-triazolyl derivatives as potential anti-cancer agents.

    PubMed

    Rodríguez-Hernández, Diego; Demuner, Antonio J; Barbosa, Luiz C A; Heller, Lucie; Csuk, René

    2016-06-10

    A series of novel aryl-1H-1,2,3-triazol-4-yl methylester and amide derivatives of the natural product hederagenin was synthesized aiming to develop new antitumor agents, using Huisgen 1,3-dipolar cycloaddition reactions, with yields between 35% and 95%. The structures of all derivatives (2-31) were confirmed by MS, IR, (1)H NMR and (13)C NMR spectroscopic data. The cytotoxic activities of all compounds were screened against a panel of six human cancer cell lines using SRB assay. It was found that most of the compounds displayed higher levels of antitumor activities as compared to parent hederagenin. Compounds 4, 8 and 15 were the most potent against all human cancer cell lines. Furthermore, compound 11 was the most cytotoxic against cell HT29 showing EC50 = 1.6 μM and a selectivity index of 5.4. PMID:27017553

  6. Synthesis and biological evaluation of 12-N-p-chlorobenzyl sophoridinol derivatives as a novel family of anticancer agents

    PubMed Central

    Bi, Chongwen; Ye, Cheng; Li, Yinghong; Zhao, Wuli; Shao, Rongguang; Song, Danqing

    2016-01-01

    Taking 12-N-p-chlorobenzyl sophoridinol 2 as a lead, a series of novel sophoridinic derivatives with various 3′-substituents at the 11–side chain were synthesized and evaluated for their anticancer activity from sophoridine (1), a natural antitumor medicine. Among them, the sophoridinic ketones 5a–b, alkenes 7a–b and sophoridinic amines 14a–b displayed reasonable antiproliferative activity with IC50 values ranging from 3.8 to 5.4 μmol/L. Especially, compounds 5a and 7b exhibited an equipotency in both adriamycin (AMD)-susceptible and resistant MCF-7 breast carcinoma cells, indicating a different mechanism from AMD. The primary mechanism of action of 5a was to arrest the cell cycle at the G0/G1 phase, consistent with that of parent compound 1. Thus, we consider 12-chlorobenzyl sophoridinic derivatives with a tricyclic scaffold to be a new class of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells. PMID:27175333

  7. 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-1α 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

  8. Synthesis and evaluation of glycopolymeric decorated gold nanoparticles functionalized with gold-triphenyl phosphine as anti-cancer agents.

    PubMed

    Adokoh, Christian K; Quan, Stephen; Hitt, Mary; Darkwa, James; Kumar, Piyush; Narain, Ravin

    2014-10-13

    In this study, statistical glyco-dithiocarbamate (DTC) copolymers were synthesized by reversible addition-fragmentation chain transfer polymerization (RAFT) and subsequently used to prepare glyconanoparticles and conjugated glyconanoparticles with the anticancer drug, gold(I) triphenylphosphine. These glyconanoparticles and the corresponding conjugates were then tested for their in vitro cytotoxicity in both normal and cancer cell lines using Neutral Red assay. The glyconanoparticles and their Au(I)PPh3 conjugates were all active against MCF7 and HepG2 cells, but galactose-functionalized glyconanoparticles {P(GMA-EDAdtc(AuPPh3)-st-LAEMA)AuNP} were found to be the most cytotoxic to HepG2 cells (IC50 ∼ 4.13 ± 0.73 μg/mL). The p(GMA-EDAdtc(AuPPh3)-st-LAEMA)AuNP was found to be a 4-fold more potent antitumor agent in HepG2 cells, and the overexpressed asialoglycoprotein (ASGPR) receptors revealed to play an important role in the cytotoxicity, presumably by the enhanced uptake. In addition, the glyconanoparticles Au(I) conjugates are found to be significantly more toxic as compared to the standard chemotherapeutic reagents such as cisplatin and cytarabine. PMID:25162942

  9. In vivo and ex vivo magnetic resonance spectroscopy as applied to pharmacokinetic studies with anticancer agents: a review.

    PubMed

    Newell, D R; Maxwell, R J; Golding, B T

    1992-01-01

    The potential role of MRS in studying the pharmacokinetics of anticancer drugs is reviewed. In vivo and ex vivo MRS has been used extensively in studies with fluoropyrimidines. Results from preclinical models have demonstrated that biochemical modulation of 5-fluorouracil metabolism can be demonstrated by MRS. The more general potential of MRS is illustrated by studies with the antifolate CB3988 (C2-desamino-C2-methyl-N10-propargyl-2'-trifluoromethyl-5,8-dideazafolic acid). Studies in mice and rats have shown that hepatobiliary clearance and renal elimination can be measured non-invasively by MRS. Comparison of half-lives derived from MRS and high performance liquid chromatography data gave reasonable agreement. In addition, MRI was used to localize drug-derived material within the abdominal cavity. The application of ex vivo MRS is illustrated by studies on the urinary excretion of platinum complexes. 1H-MRS has been used to demonstrate the presence of the cyclobutanedicarboxylate leaving group, both free and platinum bound, in the urine of patients treated with carboplatin. With iproplatin 195Pt NMR has been used to demonstrate in vivo reduction of this Pt(IV) complex to Pt(II) complexes. Finally, the application of MRS to the study of the molecular pharmacology of alkylating agents (a nitrogen mustard and N-methyl-N-nitrosourea) is discussed. PMID:1449968

  10. Synthesis and biological evaluation of 12-N-p-chlorobenzyl sophoridinol derivatives as a novel family of anticancer agents.

    PubMed

    Bi, Chongwen; Ye, Cheng; Li, Yinghong; Zhao, Wuli; Shao, Rongguang; Song, Danqing

    2016-05-01

    Taking 12-N-p-chlorobenzyl sophoridinol 2 as a lead, a series of novel sophoridinic derivatives with various 3'-substituents at the 11-side chain were synthesized and evaluated for their anticancer activity from sophoridine (1), a natural antitumor medicine. Among them, the sophoridinic ketones 5a-b, alkenes 7a-b and sophoridinic amines 14a-b displayed reasonable antiproliferative activity with IC50 values ranging from 3.8 to 5.4 μmol/L. Especially, compounds 5a and 7b exhibited an equipotency in both adriamycin (AMD)-susceptible and resistant MCF-7 breast carcinoma cells, indicating a different mechanism from AMD. The primary mechanism of action of 5a was to arrest the cell cycle at the G0/G1 phase, consistent with that of parent compound 1. Thus, we consider 12-chlorobenzyl sophoridinic derivatives with a tricyclic scaffold to be a new class of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells. PMID:27175333

  11. Poor oral bioavailability of a promising anticancer agent andrographolide is due to extensive metabolism and efflux by P-glycoprotein.

    PubMed

    Ye, Ling; Wang, Tao; Tang, Lan; Liu, Wei; Yang, Zhen; Zhou, Juan; Zheng, Zhijie; Cai, Zheng; Hu, Ming; Liu, Zhongqiu

    2011-11-01

    Andrographolide (AP), isolated from Andrographis paniculata (Burm. F.) Nees, is an anticancer agent with significant clinical potential. This study determined its oral bioavailability and how intestinal disposition affects its bioavailability. Pharmacokinetics was evaluated in rats. Intestinal disposition was determined using a single-pass rat intestinal perfusion model and the cultured Caco-2 cells and Madin-Darby canine kidney II cells over expressing human P-gp (MDR1-MDCKII). Absolute bioavailability of AP was 2.67%. In the duodenum and jejunum, AP was rapidly metabolized to a sulfonate, identified as 14-deoxy-12-sulfo- andrographolide. AP was also rapidly metabolized by liver S9 fraction and in blank perfusates collected from duodenum and jejunum. The apparent permeability (P(app) ) of AP from basolateral (B) to apical (A) (4.94 × 10 cm/s) in the Caco-2 model was four times higher than the P(app) from A to B (1.14 × 10(-5) cm/s). Moreover, AP was significantly more permeable in the B to A direction than the opposite direction in MDR1-MDCKII cells. In the perfusion model, the effective permeability (P*(eff) ) for AP was highest in the duodenum, followed by jejunum, and then ileum and colon. In the ileum and colon, the P*(eff) for AP was significantly increased by verapamil, a P-glycoprotein (P-gp) inhibitor. AP has poor oral bioavailability because of its rapid biotransformation and efflux by P-gp. PMID:21721007

  12. 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

  13. 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 tubulinPTX 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 5060% 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 PTXtubulin complex. PMID:25052294

  14. Characterisation of mesothelioma-initiating cells and their susceptibility to anti-cancer agents.

    PubMed

    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

  15. Radiation recall reaction: two case studies illustrating an uncommon phenomenon secondary to anti-cancer agents.

    PubMed

    Zhu, Su-Yu; Yuan, Yuan; Xi, Zhen

    2012-09-01

    Radiation recall phenomenon is a tissue reaction that develops throughout a previously irradiated area, precipitated by the administration of certain drugs. Radiation recall is uncommon and easily neglected by physicians; hence, this phenomenon is underreported in literature. This manuscript reports two cases of radiation recall. First, a 44-year-old man with nasopharyngeal carcinoma was treated with radiotherapy in 2010 and subsequently developed multi-site bone metastases. A few days after the docetaxel-based chemotherapy, erythema and papules manifested dermatitis, as well as swallowing pain due to pharyngeal mucositis, developed on the head and neck that strictly corresponded to the previously irradiated areas. Second, a 19-year-old man with recurrent nasal NK/T cell lymphoma initially underwent radiotherapy followed by chemotherapy after five weeks. Erythema and edema appeared only at the irradiated skin. Both cases were considered chemotherapeutic agents that incurred radiation recall reactions. Clinicians should be knowledgeable of and pay attention to such rare phenomenon. PMID:23691480

  16. 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 μg/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

  17. Bacterial biosynthesis and maturation of the didemnin anti-cancer agents.

    PubMed

    Xu, Ying; Kersten, Roland D; Nam, Sang-Jip; Lu, Liang; Al-Suwailem, Abdulaziz M; Zheng, Huajun; Fenical, William; Dorrestein, Pieter C; Moore, Bradley S; Qian, Pei-Yuan

    2012-05-23

    The anti-neoplastic 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 α-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 non-ribosomal peptide synthetase-polyketide synthase enzyme complex organized in a collinear 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

  18. Design, Synthesis and Biological Evaluation of A Novel Class of Anticancer Agents: Anthracenylisoxazole Lexitropsin Conjugates

    PubMed Central

    Han, Xiaochun; Li, Chun; Mosher, Michael D.; Rider, Kevin C.; Zhou, Peiwen; Crawford, Ronald L.; Fusco, William; Paszczynski, Andrzej; Natale, Nicholas R.

    2009-01-01

    The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (2233) is described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinrebs amide formation technique, using SmCl3 as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institutes (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA, and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented. PMID:19167892

  19. 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

  20. The zebrafish embryo as a tool for screening and characterizing pleurocidin host-defense peptides as anti-cancer agents

    PubMed Central

    Morash, Michael G.; Douglas, Susan E.; Robotham, Anna; Ridley, Christina M.; Gallant, Jeffrey W.; Soanes, Kelly H.

    2011-01-01

    SUMMARY The emergence of multidrug-resistant cancers and the lack of targeted therapies for many cancers underscore an unmet need for new therapeutics with novel modes of action towards cancer cells. Host-defense peptides often exhibit selective cytotoxicity towards cancer cells and show potential as anti-cancer therapeutics. Here, we screen 26 naturally occurring variants of the peptide pleurocidin for cytotoxic and anti-cancer activities, and investigate the underlying mechanism of action. Cytotoxicities were assessed in vitro using cell-based assays and in vivo using zebrafish embryos. Morphological changes were assessed by both transmission and scanning electron microscopy, and functional assays were performed on zebrafish embryos to investigate the mechanism of cell death. A total of 14 peptides were virtually inactive against HL60 human leukemia cells, whereas 12 caused >50% death at ≤32 μg/ml. Morphological changes characteristic of oncosis were evident by electron microscopy after only 1 minute of treatment with 32 μg/ml of variant NRC-03. Only two peptides were hemolytic. Four peptides showed no toxicity towards zebrafish embryos at the highest concentration tested (25 μM; ∼64 μg/ml) and one peptide was highly toxic, killing 4-hour-post-fertilization (hpf) embryos immediately after exposure to 1 μM peptide. Four other peptides killed embryos after 24 hours of exposure at 1 μM. Most peptides caused mortality at one or more developmental stages only after continuous exposure (24 hours) with higher lethal doses (≥5 μM). Pleurocidin NRC-03 bound to embryos and induced the release of superoxide, caused an increase in the number of TUNEL-positive nuclei, and caused membrane damage and the loss of embryonic epithelial integrity, marked by the exclusion of cells from the outer epithelium and the appearance of F-actin within the circumferential cells of the repair site. Our results indicate that specific pleurocidin variants are attractive cancer-selective agents that selectively induce cell death in target cells but leave non-target cells such as erythrocytes and non-transformed cells unaffected. PMID:21729875

  1. Design, synthesis and biological evaluation of novel pyrenyl derivatives as anticancer agents.

    PubMed

    Bandyopadhyay, Debasish; Sanchez, Jorge L; Guerrero, Adrian M; Chang, Fang-Mei; Granados, Jose C; Short, John D; Banik, Bimal K

    2015-01-01

    Polycyclic aromatic hydrocarbons are widespread in nature with a toxicity range from non-toxic to extremely toxic. A series of pyrenyl derivatives has been synthesized following a four-step strategy where the pyrene nucleus is attached with a basic heterocyclic moiety through a carbon linker. Virtual screening of the physicochemical properties and druggability has been carried out. The cytotoxicity of the compounds (1-8) have been evaluated in vitro against a small panel of human cancer cell lines which includes two liver cancer (HepG2 and Hepa 1-6), two colon cancer (HT-29 and Caco-2) and one each for cervical (HeLa) and breast (MCF-7) cancer cell lines. The IC50 data indicate that compound 6 and 8 are the most effective cytotoxic agents in the present set of pyrenyl derivatives, suggesting that having a 4-carbon linker is more effective than a 5-carbon linker and the presence of amide carbonyl groups in the linker severely reduces the efficacy of the compound. The compounds showed selectivity toward cancer cells at lower doses (<5 μM) when compared with the normal hepatocytes. The mechanism of action supports the cell death through apoptosis in a caspase-independent manner without cleavage of poly (ADP-ribose) polymerase (PARP), even though the compounds cause plasma membrane morphological changes. The compounds, whether highly cytotoxic or mildly cytotoxic, localize to the membrane of cells. The compounds with either a piperidine ring (6) or an N-methyl piperazine (8) in the side chain were both capable of circumventing the drug resistance in SKOV3-MDR1-M6/6 ovarian cancer cells overexpressing P-glycoprotein. Qualitative structure-activity relationship has also been studied. PMID:25462285

  2. Cytotoxic podophyllotoxin type-lignans from the steam bark of Bursera fagaroides var. fagaroides.

    PubMed

    Rojas-Sepúlveda, Andrés M; Mendieta-Serrano, Mario; Mojica, Mayra Y Antúnez; Salas-Vidal, Enrique; Marquina, Silvia; Villarreal, María Luisa; Puebla, Ana María; Delgado, Jorge I; Alvarez, Laura

    2012-01-01

    The hydroalcoholic extract of the steam bark of B. fagaroides var. fagaroides displayed potent cytotoxic activity against four cancer cell lines, namely KB (ED50 = 9.6 × 10(-2) μg/mL), PC-3 (ED50 = 2.5 × 10(-1) μg/mL), MCF-7 (ED50 = 6.6 μg/mL), and HF-6 (ED50 = 7.1 × 10(-3) μg/mL). This extract also showed anti-tumour activity when assayed on mice inoculated with L5178Y lymphoma cells. Bioactivity-directed isolation of this extract, afforded seven podophyllotoxin-type lignans identified as podophyllotoxin (1), β-peltatin-A-methylether (2), 5'-desmethoxy-β-peltatin-A-methylether (3), desmethoxy-yatein (4), desoxypodophyllotoxin (5), burseranin (6), and acetyl podophyllotoxin (7) by 1D and 2DNMR and FAB-MS analyses, and comparison with reported values. All the isolated compounds showed potent cytotoxic activity in the cell lines tested, especially compound 3, which exhibited greater activity than camptothecin and podophyllotoxin against PC-3 (ED50= 1.0 × 10(-5) μg/mL), and KB (ED50 = 1.0 × 10(-5) μg/mL). This is the first report of the isolation of podophyllotoxin and its acetate in a Bursera species. PMID:22878225

  3. Adherence to oral anticancer agents: Healthcare providers' perceptions, beliefs and shared decision making in Belgium and the Netherlands.

    PubMed

    Verbrugghe, Mathieu; Timmers, Lonneke; Boons, Christel C L M; Van Den Bemt, Bart J F; Hugtenburg, Jacqueline G; Van Hecke, Ann

    2016-04-01

    Background Little is known about healthcare providers' (HCPs) perceptions of adherence management of oral anticancer agents (OACA). The study aims to explore HCPs perceptions of OACA and adherence. Methods A cross-sectional, multi-center observational study among HCPs in hemato-oncology settings in Belgium and the Netherlands was conducted. Physicians, nurse practitioners, nurses and pharmacists were asked to complete questionnaires on their perception of patient adherence and its management (PAMQ) and their beliefs about OACA (BMQ-Specific). Physicians were also asked to complete a questionnaire on their perception of shared decision making (SDM-Q-Doc). Results The sample consisted of 254 HCPs. Variations were found between HCPs on the PAMQ: 56%, 50%, 28% and 23% of, respectively, physicians, nurse practitioners, nurses and pharmacists reported to know the level of adherence of their patients and 59%, 53%, 43% and 10% of, respectively, physicians, nurse practitioners, nurses and pharmacists think that patients discuss adherence with them. 70%, 82%, 63% and 62% of, respectively, physicians, nurse practitioners, nurses and pharmacists reported to have knowledge of causes of non-adherence, while 78%, 87%, 76% and 80% of them reported to have knowledge of consequences of non-adherence. 81%, 92%, 83% and 67% of, respectively, physicians, nurse practitioners, nurses and pharmacists felt able to influence adherence. Lower concerns beliefs were associated with a higher total score on the PAMQ [β (SE)=-0.85 (0.24); CI -1.33--0.38]. Physicians scored a mean of 75 on the SDM-scale. Conclusions A considerable part of the HCPs states they do not know the adherence of their patients, nor do they think patients discuss adherence with them. However, they feel to have knowledge of adherence and perceive to be able to influence adherence of their patients. PMID:26959410

  4. 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

  5. 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

  6. Synthesis and in vitro evaluation of novel triazine analogues as anticancer agents and their interaction studies with bovine serum albumin.

    PubMed

    Singla, Prinka; Luxami, Vijay; Paul, Kamaldeep

    2016-07-19

    A novel series of triazine-benzimidazole analogs has been designed and synthesized for their in vitro anticancer activities. Four compounds (6, 16, 17 and 20) were identified as highly potent anticancer agents against 60 human cancer cell lines with GI50 in the nanomolar range. To improve the drug applications toward cancer cells, there is a need to couple these compounds to some carrier macromolecules. Following this approach, the interaction between triazine-benzimidazole analogues and bovine serum albumin (BSA) has been investigated with UV-Visible and fluorescence spectroscopic methods under physiological conditions. The observed fluorescence quenching indicates that these compounds could efficiently bind with BSA and be transported to the target site. PMID:27089212

  7. Metabolism and biliary excretion of the novel anticancer agent 10-hydroxycamptothecin in the isolated perfused rat liver.

    PubMed

    Platzer, P; Thalhammer, T; Reznicek, G; Hamilton, G; Zhang, R; Jäger, W

    2001-12-01

    10-hydroxycamptothecin (HCPT), a natural analog of the alkaloid camptothecin (CPT), is a promising anticancer agent currently undergoing preclinical trials. Though HCPT is less toxic and more active in various human cancer cell lines and in animal tumor models than the clinically approved CPT-analog topotecan, little is known about its biotransformation products and their route of elimination. To investigate the metabolism and biliary excretion, livers of male Wistar rats were perfused with HCPT (5 microM). Bile and perfusate samples were collected for 60 min and quantified by reversed-phase high-performance liquid chromatography (HPLC). Besides HCPT, three metabolites, namely HCPT glucuronide (M1), hydroxyHCPT glucuronide (M2), and hydroxyHCPT (M3) could be identified by enzymatic hydrolysis with beta-glucuronidase and mass spectroscopy. Biliary secretion of HCPT and M1-M3 reached a peak secretion of 1532+/-124, 75+/-16, 5.8+/-1.6 and 2.1+/-0.5 pmoles/g liver.min, respectively, after 25 min. The total amount of HCPT and M1-M3 excreted into bile during the time of perfusion (60 min) was low and represented a mean of 9.9+/-3.2%, 0.44+/-0.17%, 0.041+/-0.010%, and 0.022+/-0.004% of the initial HCPT dose, respectively. In the perfusate, besides HCPT M1 and M2 but not M3 could be detected (maximum concentrations after about 20 min: 3248+/-210, 16.8+/-2.8 and 1.0+/-0.4 pmoles/g liver.min, respectively). The cumulative efflux of HCPT and M1 and M2 into the perfusate was 21.1+/-3.9%, 0.145+/-0.036% and 0.018+/-0.004% of the initial dose, respectively, indicating a preferable non-biliary secretion for HCPT and a predominant biliary elimination for conjugated HCPT biotransformation products. In conclusion, HCPT is biotransformed in a rat liver model to three metabolites, mainly excreted into bile, which may be of clinical relevance during cancer therapy. PMID:11713602

  8. Synthesis and biological evaluation of 9α- and 9β-hydroxyamino-parthenolides as novel anticancer agents.

    PubMed

    Moumou, Mohamed; El Bouakher, Abderrahman; Allouchi, Hassan; El Hakmaoui, Ahmed; Benharref, Ahmed; Mathieu, Véronique; Guillaumet, Gérald; Akssira, Mohamed

    2014-08-15

    A series of 9α-hydroxyamino-parthenolides 3-10, 9β-hydroxyamino-parthenolides 11-13 and 9α-hydroxy-1β,10α-epoxyamino-parthenolides 15-19 were efficiently synthesized starting from 9α-hydroxyparthenolide 1 and 9β-hydroxyparthenolide 2, which were isolated from Anvillea radiata. Compounds 1-13 and 15-19 were evaluated for their in vitro anticancer activity by the MTT colorimetric assay against one murine and six human cancer cell lines. This work provides new details about the structural requisites for anticancer activity. PMID:24998377

  9. Alleviation of Podophyllotoxin Toxicity Using Coexisting Flavonoids from Dysosma versipellis

    PubMed Central

    Li, Juan; Sun, Hua; Jin, Lu; Cao, Wei; Zhang, Jin; Guo, Chong-Yi; Ding, Ke; Luo, Cheng; Ye, Wen-Cai; Jiang, Ren-Wang

    2013-01-01

    Podophyllotoxin (POD) is a lignan-type toxin existing in many herbs used in folk medicine. Until now, no effective strategy is available for the management of POD intoxication. This study aims to determine the protective effects of flavonoids (quercetin and kaempferol) on POD-induced toxicity. In Vero cells, both flavonoids protected POD-induced cytotoxicity by recovering alleviating G2/M arrest, decreasing ROS generation and changes of membrane potential, and recovering microtubule structure. In Swiss mice, the group given both POD and flavonoids group had significantly lower mortality rate and showed less damages in the liver and kidney than the group given POD alone. As compared to the POD group, the POD plus flavonoids group exhibited decreases in plasma transaminases, alkaline phosphatase, lactate dehydrogenase, plasma urea, creatinine and malondialdehyde levels, and increases in superoxide dismutase and glutathione levels. Histological examination of the liver and kidney showed less pathological changes in the treatment of POD plus flavonoids group. The protective mechanisms were due to the antioxidant activity of flavonoids against the oxidative stress induced by POD and the competitive binding of flavonoids against POD for the same colchicines-binding sites. The latter binding was confirmed by the tubulin assembly assay in combination with molecular docking analyses. In conclusion, this study for the first time demonstrated that the coexisting flavonoids have great protective effects against the POD toxicity, and results of this study highlighted the great potential of searching for effective antidotes against toxins based on the pharmacological clues. PMID:23991049

  10. Anticancer chemotherapy

    SciTech Connect

    Weller, R.E.

    1988-10-01

    Despite troubled beginnings, anticancer chemotherapy has made significant contribution to the control of cancer in man, particularly within the last two decades. Early conceptual observations awakened the scientific community to the potentials of cancer chemotherapy. There are now more than 50 agents that are active in causing regression of clinical cancer. Chemotherapy's major conceptual contributions are two-fold. First, there is now proof that patients with overt metastatic disease can be cured, and second, to provide a strategy for control of occult metastases. In man, chemotherapy has resulted in normal life expectancy for some patients who have several types of metastatic cancers, including choriocarcinoma, Burkitt's lymphomas, Wilm's tumor, acute lymphocytic leukemia, Hodgkins disease, diffuse histiocytic lymphoma and others. Anticancer chemotherapy in Veterinary medicine has evolved from the use of single agents, which produce only limited remissions, to the concept of combination chemotherapy. Three basic principles underline the design of combination chemotherapy protocols; the fraction of tumor cell killed by one drug is independent of the fraction killed by another drug; drugs with different mechanisms of action should be chosen so that the antitumor effects will be additive; and since different classes of drugs have different toxicities the toxic effects will not be additive.

  11. 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...

  12. 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.

  13. Kinetics and thermochemistry of hydrolysis mechanism of a novel anticancer agent trans-[PtCl2(dimethylamine)(isopropylamine)]: A DFT study

    NASA Astrophysics Data System (ADS)

    Hussain, Iftikar; Gour, N. K.; Deka, Ramesh Ch.

    2016-05-01

    Theoretical investigation has been made on the hydrolysis mechanism of a novel transplatin anticancer agent trans-[PtCl2(dimethylamine)(isopropylamine)] in gas as well as aqueous phases using DFT method. The transition state geometries along with other stationary points on potential energy surface are optimized and characterized. The calculated activation barrier and the predicted relative free energies for the two successive steps are in good agreement with the experimental data reported in the literature. The rate constants are calculated using Eyring equation and results show that the second step is the rate-limiting process having higher activation energy compared to that of the first step.

  14. Endophytic fungi: novel sources of anticancer lead molecules.

    PubMed

    Chandra, Sheela

    2012-07-01

    Cancer is a major killer disease all over the world and more than six million new cases are reported every year. Nature is an attractive source of new therapeutic compounds, as a tremendous chemical diversity is found in millions of species of plants, animals, and microorganisms. Plant-derived compounds have played an important role in the development of several clinically useful anti-cancer agents. These include vinblastine, vincristine, camptothecin, podophyllotoxin, and taxol. Production of a plant-based natural drug is always not up to the desired level. It is produced at a specific developmental stage or under specific environmental condition, stress, or nutrient availability; the plants may be very slow growing taking several years to attain a suitable growth phase for product accumulation and extraction. Considering the limitations associated with the productivity and vulnerability of plant species as sources of novel metabolites, microorganisms serve as the ultimate, readily renewable, and inexhaustible source of novel structures bearing pharmaceutical potential. Endophytes, the microorganisms that reside in the tissues of living plants, are relatively unstudied and offer potential sources of novel natural products for exploitation in medicine, agriculture and the pharmaceutical industry. They develop special mechanisms to penetrate inside the host tissue, residing in mutualistic association and their biotransformation abilities opens a new platform for synthesis of novel secondary metabolites. They produce metabolites to compete with the epiphytes and also with the plant pathogens to maintain a critical balance between fungal virulence and plant defense. It is therefore necessary that the relationship between the plants and endophytes during the accumulation of these secondary metabolites is studied. Insights from such research would provide alternative methods of natural product drug discovery which could be reliable, economical, and environmentally safe. PMID:22622838

  15. 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

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

    PubMed Central

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

    2014-01-01

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

  17. Monofunctional Platinum (PtII) Compounds - Shifting the Paradigm in Designing New Pt-based Anticancer Agents.

    PubMed

    Chong, Shu Xian; Au-Yeung, Steve Chik Fun; To, Kenneth Kin Wah

    2016-01-01

    Platinum (Pt)-based anticancer drugs, exemplified by cisplatin, are key components in combination chemotherapy. However, their effective use is hindered by toxicity and emergence of drug resistance. They bind to DNA and mainly form the Pt-GG diadduct, subsequently leading to apoptosis to mediate cell death. On the other hand, the Pt drug -proteins and -metabolites interactions, which involve the reaction between Pt and sulfur sites located in protein side chains and important bionucleophiles (e.g., glutathione), are responsible for the toxicity and drug resistance problem. Therefore, carefully designed coordinating ligands may provide the means of fine tuning the electronic environment around the core Pt atom and allow the resulting Pt compounds to bind with the DNA in a different manner. This may produce alternative cell death mechanisms in cancer cells, thereby circumventing Pt resistance. This article reviewed the recent development in monofunctional Pt complexes and their prospects in becoming a new generation of anticancer drugs. PMID:26965183

  18. Cobalt-Catalyzed Oxidase C-H/N-H Alkyne Annulation: Mechanistic Insights and Access to Anticancer Agents.

    PubMed

    Mei, Ruhuai; Wang, Hui; Warratz, Svenja; Macgregor, Stuart A; Ackermann, Lutz

    2016-05-10

    Cp*-free cobalt-catalyzed alkyne annulations by C-H/N-H functionalizations were accomplished with molecular O2 as the sole oxidant. The user-friendly oxidase strategy proved viable with various internal and terminal alkynes through kinetically relevant C-H cobaltation, providing among others step-economical access to the anticancer topoisomerase-I inhibitor 21,22-dimethoxyrosettacin. DFT calculations suggest that electronic effects control the regioselectivity of the alkyne insertion step. PMID:26992149

  19. 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 π-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

  20. Discovery of novel heteroarylmethylcarbamodithioates as potent anticancer agents: Synthesis, structure-activity relationship analysis and biological evaluation.

    PubMed

    Li, Ying-Bo; Yan, Xu; Li, Ri-Dong; Liu, Peng; Sun, Shao-Qian; Wang, Xin; Cui, Jing-Rong; Zhou, De-Min; Ge, Ze-Mei; Li, Run-Tao

    2016-04-13

    A series of new analogs based on the structure of lead compound 10 were designed, synthesized and evaluated for their in vitro anti-cancer activities against four selected human cancer cell lines (HL-60, Bel-7402, SK-BR-3 and MDA-MB-468). Several synthesized compounds exhibited improved anti-cancer activities comparing with lead compound 10. Among them, 1,3,4-oxadiazole analogs 17o showed highest bioactivity with IC50 values of 1.23, 0.58 and 4.29 μM against Bel-7402, SK-BR-3 and MDA-MB-468 cells, respectively. It is noteworthy that 17o has potent anti-proliferation activity toward a panel of cancer cells with relatively less cytotoxicity to nonmalignant cells. The further mechanistic study showed that it induced apoptosis and cell cycle arrest through disrupting spindle assembly in mitotic progression, indicating these synthesized dithiocarbamates represented a novel series of anti-cancer compounds targeting mitosis. PMID:26900655

  1. N-Phenyl-2-p-tolylthiazole-4-carboxamide derivatives: Synthesis and cytotoxicity evaluation as anticancer agents

    PubMed Central

    Mohammadi-Farani, Ahmad; Foroumadi, Alireza; Kashani, Monireh Rezvani; Aliabadi, Alireza

    2014-01-01

    Objective(s): According to the prevalence of neoplastic diseases, there is a deep necessity for discovery of novel anticancer drugs in the field of medicinal chemistry. In the current study, a new series of phenylthiazole derivatives (compounds 4a-4f) was synthesized and their anticancer activity was assessed in vitro. Materials and Methods: All synthesized derivatives were evaluated towards three human cancerous cell lines of SKNMC (Neuroblastoma), Hep-G2 (Human hepatocarcinoma) and MCF-7 cell (Breast cancer) using MTT assay and obtained values (IC50 ± SD) were compared with doxorubicin. Results: Unfortunately, none of the synthesized compounds showed superior activity than doxorubicin against cancerous cell lines. MCF-7 cell line was the most resistant cell line against tested compounds. Compounds 4c with para nitro (IC50 = 10.8 ± 0.08 µM) and 4d with meta chlorine (IC50 = 11.6 ± 0.12 µM) moieties exerted the highest cytotoxic effects towards SKNMC and Hep-G2 cell lines respectively. Conclusion: A new series of phenylthiazole derivatives were synthesized and their anticancer activity was assessed against cancerous cell lines. More structural modifications and derivatization is necessary to achieve to the more potent compounds. PMID:25429341

  2. Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic.

    PubMed

    Au, Kin Man; Satterlee, Andrew; Min, Yuanzeng; Tian, Xi; Kim, Young Seok; Caster, Joseph M; Zhang, Longzhen; Zhang, Tian; Huang, Leaf; Wang, Andrew Z

    2016-03-01

    Zoledronate (Zol) is a third-generation bisphosphonate that is widely used as an anti-resorptive agent for the treatment of cancer bone metastasis. While there is preclinical data indicating that bisphosphonates such as Zol have direct cytotoxic effects on cancer cells, such effect has not been firmly established in the clinical setting. This is likely due to the rapid absorption of bisphosphonates by the skeleton after intravenous (i.v.) administration. Herein, we report the reformulation of Zol using nanotechnology and evaluation of this novel nanoscale metal-organic frameworks (nMOFs) formulation of Zol as an anticancer agent. The nMOF formulation is comprised of a calcium zoledronate (CaZol) core and a polyethylene glycol (PEG) surface. To preferentially deliver CaZol nMOFs to tumors as well as facilitate cellular uptake of Zol, we incorporated folate (Fol)-targeted ligands on the nMOFs. The folate receptor (FR) is known to be overexpressed in several tumor types, including head-and-neck, prostate, and non-small cell lung cancers. We demonstrated that these targeted CaZol nMOFs possess excellent chemical and colloidal stability in physiological conditions. The release of encapsulated Zol from the nMOFs occurs in the mid-endosomes during nMOF endocytosis. In vitro toxicity studies demonstrated that Fol-targeted CaZol nMOFs are more efficient than small molecule Zol in inhibiting cell proliferation and inducing apoptosis in FR-overexpressing H460 non-small cell lung and PC3 prostate cancer cells. Our findings were further validated in vivo using mouse xenograft models of H460 and PC3. We demonstrated that Fol-targeted CaZol nMOFs are effective anticancer agents and increase the direct antitumor activity of Zol by 80-85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis. PMID:26763733

  3. 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 posesas 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

  4. Complete genome sequence of antibiotic and anticancer agent violacein producing Massilia sp. strain NR 4-1.

    PubMed

    Myeong, Nu Ri; Seong, Hoon Je; Kim, Hye-Jin; Sul, Woo Jun

    2016-04-10

    Massilia sp. NR 4-1 was a violacein producing strain newly isolated from topsoil under nutmeg tree, Torreya nucifera in Korean national monument Bijarim Forest. Violacein is a novel class of drug exhibiting anticancer and antibiotic activities originated from l-tryptophan. Here, we present the complete genome of Massilia sp. strain NR 4-1 of 6,361,416bp and total 5285 coding sequences (CDSs) including a complete violacein biosynthesis pathway, vioABCDE. The genome sequence of Massilia sp. NR 4-1 will provide stable and efficient biotechnological applications of violacein production. PMID:26916415

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

    PubMed

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

    2012-01-01

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

  6. Evaluation of a curcumin analog as an anti-cancer agent inducing ER stress-mediated apoptosis in non-small cell lung cancer cells

    PubMed Central

    2013-01-01

    Background Recent advances have highlighted the importance of the endoplasmic reticulum (ER) in cell death processes. Pharmacological interventions that effectively enhance tumor cell death through activating ER stress have attracted a great deal of attention for anti-cancer therapy. Methods A bio-evaluation on 113 curcumin analogs against four cancer cell lines was performed through MTT assay. Furthermore, real time cell assay and flow cytometer were used to evaluate the apoptotic induction of (1E,4E)-1,5-bis(5-bromo-2-ethoxyphenyl)penta-1,4-dien-3-one (B82). Western blot, RT-qPCR, and siRNA were then utilized to confirm whether B82-induced apoptosis is mediated through activating ER stress pathway. Finally, the in vivo anti-tumor effect of B82 was evaluated. Results B82 exhibited strong anti-tumor activity in non-small cell lung cancer (NSCLC) H460 cells. Treatment with B82 significantly induced apoptosis in H460 cells in vitro and inhibited H460 tumor growth in vivo. Further studies demonstrated that the B82-induced apoptosis is mediated by activating ER stress both in vitro and in vivo. Conclusions A new monocarbonyl analog of curcumin, B82, exhibited anti-tumor effects on H460 cells via an ER stress-mediated mechanism. B82 could be further explored as a potential anticancer agent for the treatment of NSCLC. PMID:24156374

  7. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives.

    PubMed

    Asati, Vivek; Mahapatra, Debarshi Kar; Bharti, Sanjay Kumar

    2016-02-15

    The protein kinases regulate cellular functions such as transcription, translation, proliferation, growth and survival by the process of phosphorylation. Over activation of signaling pathways play a major role in oncogenesis. The PI3K signaling pathway is dysregulated almost in all cancers due to the amplification, genetic mutation of PI3K gene and the components of the PI3K pathway themselves. Stimulation of the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK pathways enhances growth, survival, and metabolism of cancer cells. Recently, the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways have been identified as promising therapeutic targets for cancer therapy. The kinase inhibitors with enhanced specificity and improved pharmacokinetics have been considered for design and development of anticancer agents. This review focuses primarily on the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways as therapeutic targets of anticancer drugs, their specific and dual inhibitors, structure activity relationships (SARs) and inhibitors under clinical trials. PMID:26807863

  8. Absolute configuration of podophyllotoxin related lignans from Bursera fagaroides using vibrational circular dichroism.

    PubMed

    Velázquez-Jiménez, René; Torres-Valencia, J Martín; Cerda-García-Rojas, Carlos M; Hernández-Hernández, Juan D; Román-Marín, Luisa U; Manríquez-Torres, J Jesús; Gómez-Hurtado, Mario A; Valdez-Calderón, Alejandro; Motilva, Virginia; García-Mauriño, Sofía; Talero, Elena; Avila, Javier; Joseph-Nathan, Pedro

    2011-12-01

    The ethanol extract from the dried exudate of Bursera fagaroides (Burseraceae) showed significant cytotoxic activity in the HT-29 (human colon adenocarcinoma) test system. The extract provided four podophyllotoxin related lignans, identified as (7'R,8R,8'R)-(-)-deoxypodophyllotoxin (3), (7'R,8R,8'R)-(-)-morelensin (4), (8R,8'R)-(-)-yatein (5), and (8R,8'R)-(-)-5'-desmethoxyyatein (6), whose spectroscopic and chiroptical properties were compared with those of (7R,7'R,8R,8'R)-(-)-podophyllotoxin (1) and its acetyl derivative (2). Their absolute configurations were assigned by comparison of the vibrational circular dichroism spectra of 1 and 3 with those obtained by density functional theory calculations. PMID:21840559

  9. Optimization of culture parameters for production of podophyllotoxin in suspension culture of Podophyllum hexandrum.

    PubMed

    Chattopadhyay, Saurabh; Srivastava, A K; Bisaria, V S

    2002-01-01

    The root explants of the germinated seedlings of Podophyllum hexandrum were grown in MS medium supplemented with indole acetic acid (IAA) (2 mg/L) and activated charcoal (0.5%), and healthy callus culture was obtained after incubation for 3 wk at 20 degrees C. The cultivation of plant cells in shake flask was associated with problems such as clumping of cells and browning of media, which were solved by the addition of pectinase and polyvinylpyrrolidone. The effect of major media components and carbon source was studied on the growth and podophyllotoxin production in suspension culture. It was found that glucose was a better carbon source than sucrose and that NH4+:NO3- ratio (total nitrogen concentration of 60 mM) and PO4(3-) did not have much effect on the growth and product formation. The relative effect of culture parameters (inoculum level, pH, IAA, glucose, NH4+:NO3- ratio, and PO4(3-)) on the overall growth and product response of the plant cell suspension culture was further investigated by Plackett-Burman design. This indicated that inoculum level, glucose, IAA, and pH had significant effects on growth and production of podophyllotoxin. To identify the exact optimum concentrations of these parameters on culture growth and podophyllotoxin production, central composite design experiments were formulated. The overall response equations with respect to growth and podophyllotoxin production as a function of these culture parameters were developed and used to determine the optimum concentrations of these parameters, which were pH 6.0, 1.25 mg/L of IAA, 72 g/L of glucose, and inoculum level of 8 g/L. PMID:12396139

  10. Design, Synthesis and Evaluation of Dibenzo[c,h][1,6]naphthyridines as Topoisomerase I Inhibitors and Potential Anticancer Agents

    PubMed Central

    Kiselev, Evgeny; Dexheimer, Thomas; Pommier, Yves; Cushman, Mark

    2010-01-01

    Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents. Modifications of the indenoisoquinoline A, B and D rings have been extensively studied in order to optimize Top1 inhibitory activity and cytotoxicity. To improve understanding of the forces that stabilize drug-Top1-DNA ternary complexes, the five-membered cyclopentadienone C-ring of the indenoisoquinoline system was replaced by six-membered nitrogen heterocyclic rings, resulting in dibenzo[c,h][1,6]naphthyridines that were synthesized by a novel route and tested for Top1 inhibition. This resulted in several compounds that have unique DNA cleavage site selectivities and potent antitumor activities in a number of cancer cell lines. PMID:21090809

  11. Synthesis and Biological Evaluation of New Carbohydrate-Substituted Indenoisoquinoline Topoisomerase I Inhibitors and Improved Syntheses of the Experimental Anticancer Agents Indotecan (LMP400) and Indimitecan (LMP776)

    PubMed Central

    2015-01-01

    Carbohydrate moieties were strategically transported from the indolocarbazole topoisomerase I (Top1) inhibitor class to the indenoisoquinoline system in search of structurally novel and potent Top1 inhibitors. The syntheses and biological evaluation of 20 new indenoisoquinolines glycosylated with linear and cyclic sugar moieties are reported. Aromatic ring substitution with 2,3-dimethoxy-8,9-methylenedioxy or 3-nitro groups exerted strong effects on antiproliferative and Top1 inhibitory activities. While the length of the carbohydrate side chain clearly correlated with antiproliferative activity, the relationship between stereochemistry and biological activity was less clearly defined. Twelve of the new indenoisoquinolines exhibit Top1 inhibitory activity equal to or better than that of camptothecin. An advanced synthetic intermediate from this study was also used to efficiently prepare indotecan (LMP400) and indimitecan (LMP776), two anticancer agents currently under investigation in a Phase I clinical trial at the National Institutes of Health. PMID:24517248

  12. 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.

  13. [Effect of topographical factors on podophyllotoxin content in Sinopodophyllum hexandrum and study on ecological suitability].

    PubMed

    Wu, Ao-lin; Li, Min; Zhang, Shou-wen; Zhao, Ji-feng; Liu, Xiang; Wang, Chang-hua; Wang, Xiao-yun; Zhong, Guo-yue

    2015-06-01

    In order to find the optimal topographical factor for regionslization, the content of cimetidine in 116 Sinopodophyllum hexandrum sample collected from Sichuan, Qinghai, Gansu, Tibet, Yunnan and Shaanxi provinces, was determined. Using mathematical statistics and geographical spatial analysis of GIS analysis, the relationship between content of podophyllotoxin and influencing factors including altitude gradient and gradient position was analyzed. It is found that the optimal altitude was 2 800 m to 3 600 m, the aspect of slope north or northeast and northwest and the slope 12 degrees to 65 degrees with a high suitability degree. Considering the artificial planting, the suitable planting area for S. hexandrum is comfirmed. The topographical factor is important for S. hexandrum regionalization, but has hardly effect on podophyllotoxin content. The results of the study provide an important scientific basis for S. hexandrum production development. But there are many factors which affect suitability index and podophyllotoxin content of S. hexandrum, it is necessary to consider other factors like climate and soil while exploitation and protection of S. hexandrum. PMID:26591513

  14. 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

  15. Synthesis, biological evaluation, drug-likeness, and in silico screening of novel benzylidene-hydrazone analogues as small molecule anticancer agents.

    PubMed

    Alam, Mohammad Sayed; Lee, Dong-Ung

    2016-02-01

    A series of fifteen benzylidene-hydrazone analogues (3a-o), including eight new compounds, were synthesized and evaluated for their cytotoxic activities in four human cancer cell lines and for their antioxidant activities using DPPH. Of the tested compounds 3e, which possesses two methoxy substituents in its benzylidene phenyl ring, was found to be potently cytotoxic to all cancer cell lines tested with IC50 values of 0.12 (lung), 0.024 (ovarian), 0.097 (melanoma), and 0.05?M (colon), and these IC50 values were comparable to those of the doxorubicin standard (IC50=0.021, 0.074, 0.001, and 0.872?M, respectively). DPPH assay showed compounds 3f, 3i, and 3g had IC50 values of 0.60, 0.99, and 1.30?M, respectively, which were comparable to that of ascorbic acid (IC50=0.87?M). Computational parameters such as, drug-likeness, ADME properties, toxicity effects, and drug scores were evaluated, and none of the fifteen compounds violated Lipinski's rule of five or Veber's rule, and thus they demonstrated good drug-likeness properties. In addition, all fifteen compounds had a higher drug score than the doxorubicin and BIBR1532. In silico screening was also conducted by docking of the active compounds on the active site of telomerase reverse transcriptase catalytic subunit, an important therapeutic target of anticancer agents, to determine the probable binding properties. The total binding energies of docked compounds are correlated well with cytotoxic potencies (pIC50) against lung, ovarian, melanoma, and colon cancer cell lines indicating that the benzylidene-hydrazones could use for the development of new anticancer agents as a telomerase inhibitor. PMID:26694484

  16. Indole-based hydrazide-hydrazones and 4-thiazolidinones: synthesis and evaluation as antitubercular and anticancer agents.

    PubMed

    Cihan-Üstündağ, Gökçe; Şatana, Dilek; Özhan, Gül; Çapan, Gültaze

    2016-06-01

    A new series of indolylhydrazones (6) and indole-based 4-thiazolidinones (7, 8) have been designed, synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. 4-Thiazolidinone derivatives 7g-7j, 8g, 8h and 8j displayed notable antituberculosis (anti-TB) activity showing 99% inhibition at MIC values ranging from 6.25 to 25.0 µg/ml. Compounds 7g, 7h, 7i, 8h and 8j demonstrated anti-TB activity at concentrations 10-fold lower than those cytotoxic for the mammalian cell lines. The indolylhydrazone derivative 6b has also been evaluated for antiproliferative activity against human cancer cell lines at the National Cancer Institute (USA). Compound 6b showed an interesting anticancer profile against different human tumor-derived cell lines at sub-micromolar concentrations with obvious selectivity toward colon cancer cell line COLO 205. PMID:25910087

  17. New imidazo[1,2-b]pyrazoles as anticancer agents: synthesis, biological evaluation and structure activity relationship analysis.

    PubMed

    Grosse, Sandrine; Mathieu, Véronique; Pillard, Christelle; Massip, Stéphane; Marchivie, Mathieu; Jarry, Christian; Bernard, Philippe; Kiss, Robert; Guillaumet, Gérald

    2014-09-12

    Synthesis and functionalization strategies of the imidazo[1,2-b]pyrazole core were developed giving a rapid access to three series of novel imidazo[1,2-b]pyrazole type derivatives: C-2/C-6/C-7 trisubstituted, C-2/C-3/C-6 tri(hetero)arylated and C-2/C-3/C-6/C-7 tetrasubstituted imidazo[1,2-b]pyrazoles. 39 of the synthetized products were evaluated for in vitro anticancer activity using the MTT colorimetric assay against 5 human and 1 murine cancer cell lines. Promising in vitro growth inhibitory activities were exhibited by some of the target compounds. Of the 39 evaluated products, 4 displayed an IC50 ≤ 10 μM in the 6 cell lines analyzed (compounds 4d, 4g, 9a, 11a). A structure activity relationship analysis is also reported in this paper. PMID:25064349

  18. 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

  19. 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.

  20. Synthesis and biological evaluation of some 2,4,5-trisubstituted thiazole derivatives as potential antimicrobial and anticancer agents.

    PubMed

    Al-Saadi, Mohammed S; Faidallah, Hassan M; Rostom, Sherif A F

    2008-07-01

    We report on the synthesis and biological evaluation of two series of 2,4,5-polysubstituted thiazoles comprising the acid hydrazide functionality and some derived pharmacophores known to contribute to various chemotherapeutic activities. All newly synthesized compounds were subjected to in-vitro antibacterial and antifungal screening. Of the compounds tested, 13 derivatives displayed inhibitory effect on the growth of three Gram-positive strains while they lack activity against Gram-negative bacteria. Moreover, four compounds were able to exert antifungal activity against C. albicans. Potential antibacterial and antifungal activities were linked to the thiosemicarbazide function 6a-f and those substituted with both the thioureido and thiosemicarbazide moieties 12a-f. Compounds 6f and 12f (R = 4-F-C(6)H(4)) could be considered as the most active members in this investigation with a broad spectrum of antibacterial activity against three types of Gram-positive bacteria, together with an appreciable antifungal activity against C. albicans. Compounds 6d, 6f, and 12f were twice as active as ampicillin against B. subtilis. The best antifungal activity was shown by compound 6d 50% less active than clotrimazole. 17 compounds were selected and tested for their preliminary in-vitro anticancer activity according to the current one-dose protocol of the NCI. Three cell lines, non-small cell lung cancer Hop-92, ovarian cancer IGROV1, and melanoma SK-MEL-2, exhibited some sensitivity against most of the tested compounds. Compound 12f proved to be the most active anticancer member with a broad spectrum of activity against most of the tested subpanel tumor cell lines. Consequently, 12f was carried over to be tested in the five-dose assay. PMID:18574850

  1. Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents

    PubMed Central

    Penthala, Narsimha Reddy; Zong, Hongliang; Ketkar, Amit; Madadi, Nikhil Reddy; Janganati, Venumadav; Eoff, Robert L.; Guzman, Monica L.; Crooks, Peter A.

    2015-01-01

    A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of <10 nM against 74% and 70%, respectively, of the human cancer cell lines in the 60-cell panel. Compounds 8, and 12 and two previously reported compounds in the same structural class, i.e. 29 and 31, also showed potent anti-leukemic activity against leukemia MV4-11 cell lines with LD50 values = 44 nM, 47 nM, 18 nM, and 180 nM, respectively. From the NCI anti-cancer screening results and the data from the in vitro toxicity screening on cultured AML cells, seven compounds: 8, 12, 21, 23, 25, 29 and 31 were screened for their in vitro inhibitory activity on tubulin polymerization in MV4-11 AML cells; at 50 nM, 8 and 29 inhibited polymerization of tubulin by >50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine, and were stablized by van der Waals’ interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs. PMID:25557492

  2. Investigation of the mechanism and apoptotic pathway induced by 4β cinnamido linked podophyllotoxins against human lung cancer cells A549.

    PubMed

    Kamal, Ahmed; Nayak, V Lakshma; Bagul, Chandrakant; Vishnuvardhan, M V P S; Mallareddy, Adla

    2015-11-01

    Apoptosis is essential for normal development and the maintenance of homeostasis. It plays a necessary role to protect against carcinogenesis by eliminating damaged cells. Many studies have demonstrated that the dysregulation of apoptosis results in cancer and this provides an approach to develop therapeutic agents via inducing apoptosis. In our previous studies 4β-cinnamido linked podophyllotoxin conjugates were synthesized and evaluated for their cytotoxic activity in a panel of five human cancer cell lines and the new molecules like 17a and 17f were considered as potential leads. The cytotoxic activity was comparable to etoposide. These observations prompted us to investigate the mechanism underplaying the cytotoxic activity and apoptotic pathway induced by these compounds in human lung cancer cells A459. The results of the present study revealed that these compounds exhibited DNA topoisomerase IIα inhibition and induced mitochondrial mediated apoptosis. It was further confirmed by Mitochondrial membrane potential, Cytochrome c release, cleavage of poly (ADP-ribose) polymerase (PARP), Reactive oxygen species (ROS) generation, regulation of antiapoptotic protein Bcl-2 and pro apoptotic protein Bax studied by Western blot analysis. Annexin V-FITC assay also suggested that these compounds induced cell death by apoptosis. Pretreatment with N-acetyl-L-cysteine (NAC) prevented the generation of ROS. Further, pretreatment with NAC significantly inhibited 17a and 17f induced apoptosis, suggesting that ROS are the key mediators for 17a and 17f induced apoptosis. These data indicate that these compounds might induce apoptosis in A549 cells through a ROS mediated mitochondrial dysfunction pathway. Moreover, these compounds did not significantly inhibit the noncancerous human embryonic kidney cells, HEK-293. Docking studies also elucidate the potential of these molecules to bind to the DNA topoisomerase II. Podophyllotoxin analogs were investigated for their mechanism and apoptotic pathway against lung cancer cell line, A549. These podophyllotoxin analogs inhibited DNA topoisomerase IIα and induced mitochondrial mediated apoptosis in lung cancer cell line, A549. Western blot analysis suggested that these compounds inhibited the DNA topoisomerase IIα. Studies like, Measurement of mitochondrial membrane potential (∆Ψm), Generation of intracellular reactive oxygen species (ROS) and Annexin V-FITC assay suggested that these compounds induced mitochondrial mediated apoptosis. Pretreatment with N-acetyl-L-cysteine (NAC) suggested that ROS plays a role in 17a and 17f induced apoptosis. Further the apoptotic effect of these compounds was confirmed by western blot analysis of pro apoptotic protein Bax and antiapoptotic protein Bcl-2, Cytochrome c release and cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, these compounds did not significantly inhibit the noncancerous human embryonic kidney cells, HEK-293. PMID:26386574

  3. 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

  4. 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

  5. Skeletal metastases and impact of anticancer and bone-targeted agents in patients with castration-resistant prostate cancer.

    PubMed

    Vignani, Francesca; Bertaglia, Valentina; Buttigliero, Consuelo; Tucci, Marcello; Scagliotti, Giorgio V; Di Maio, Massimo

    2016-03-01

    Incidence of bone metastases is very high in advanced prostate cancer patients. Bone metastases likely have a significant impact on functional status and quality of life, not only related to pain, but also to the relevant risk of skeletal-related events. A better understanding of mechanisms associated with bone metastatic disease secondary to prostate cancer and more specifically to the cross-talk between tumor cells and bone microenvironment in metastatic progression represented the background for the development of new effective bone-targeted therapies. Furthermore, a better knowledge of biological mechanisms driving disease progression led to significant advances in the treatment of castration-resistant prostate cancer, with the development and approval of new effective drugs. Aim of this review is to outline the physiopathology of bone metastases in prostate cancer and summarize the main results of clinical trials conducted with different drugs to control morbidity induced by skeletal metastases and bone disease progression. For each agent, therapeutic effect on bone metastases has been measured in terms of pain control and/or incidence of skeletal-related events, usually defined as a composite endpoint, including the need for local treatment (radiation therapy or surgery), spinal cord compression, pathological bone fractures. In details, data obtained with chemotherapy (mitoxantrone, docetaxel, cabazitaxel), new generation hormonal agents (abiraterone, enzalutamide), radium-223, bone-targeted agents (zoledronic acid, denosumab) and with several experimental agents (cabozantinib, dasatinib, anti-endothelin and other agents) in patients with castration-resistant prostate cancer are reviewed. PMID:26907461

  6. Gallic acid as a selective anticancer agent that induces apoptosis in SMMC-7721 human hepatocellular carcinoma cells

    PubMed Central

    SUN, GUOJUN; ZHANG, SHUQIN; XIE, YANRU; ZHANG, ZIYU; ZHAO, WENJING

    2016-01-01

    Gallic acid (3,4,5-trihydroxybenzoic acid; GA) is a naturally occurring plant polyphenol, isolated from water caltrop, which has been reported to exert anticancer effects. The present study investigated the antiproliferative effects of GA on the HepG2 and SMMC-7721 human hepatocellular carcinoma (HCC) cell lines using MTT and colony formation assays. In particular, the underlying mechanism of GA-induced apoptosis in SMMC-7721 cells was studied in vitro by flow cytometry and western blotting. The results of the present study indicated that GA was capable of inhibiting the proliferation of HepG2 and SMMC-7721 cells in a time- and dose-dependent manner, as well as inducing the apoptosis of SMMC-7721 cells. GA induced caspase-3, caspase-9 and reactive oxygen species activity, elevated the expression of apoptosis regulator Bcl-2-like protein 4 and reduced the mitochondrial membrane potential in SMMC-7721 cells. When compared with HL-7702 normal human hepatocytes, GA demonstrated selective toxicity for HCC cells. In conclusion, GA is able to induce apoptosis in SMMC-7721 cells in vitro via mitochondrial-mediated pathways, and may possess the potential to be a novel therapeutic compound for use in the treatment of HCC. PMID:26870182

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

    PubMed

    Dörsam, Bastian; Fahrer, Jörg

    2016-02-01

    The endogenous disulfide α-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

  8. Magnetic nanoscale metal organic frameworks for potential targeted anticancer drug delivery, imaging and as an MRI contrast agent.

    PubMed

    Ray Chowdhuri, Angshuman; Bhattacharya, Dipsikha; Sahu, Sumanta Kumar

    2016-02-21

    The development of a novel multifunctional porous nanoplatform for targeted anticancer drug delivery with cell imaging and magnetic resonance imaging has been realised in the current work. Here we have developed a magnetic nanoscale metal organic frameworks (NMOF) for potential targeted drug delivery. These magnetic NMOFs were fabricated by incorporation of Fe3O4 nanoparticles into porous isoreticular metal organic frameworks (IRMOF-3). To achieve targeted drug delivery towards cancer cells specifically, folic acid was conjugated to the NMOF surface. Then, the fluorescent molecule rhodamine B isothiocyanate (RITC) was conjugated to the NMOFs for biological imaging applications. The synthesized magnetic NMOFs were fully characterised by FTIR, powder XRD, XPS, SQUID, TGA, TEM, FESEM, and DLS. The synthesized magnetic NMOFs were observed to be smaller than 100 nm and were found to be nontoxic towards human cervix adenocarcinoma (HeLa) and murine fibroblast (NIH3T3) cells according to cell viability assays. The cancer chemotherapy drug paclitaxel was conjugated to the magnetic NMOFs through hydrophobic interactions with a relatively high loading capacity. Moreover, these folic acid-conjugated magnetic NMOFs showed stronger T2-weighted MRI contrast towards the cancer cells, justifying their possible significance in imaging. PMID:26754449

  9. Gold(I) NHC-based homo- and heterobimetallic complexes: synthesis, characterization and evaluation as potential anticancer agents.

    PubMed

    Bertrand, Benoît; Citta, Anna; Franken, Inge L; Picquet, Michel; Folda, Alessandra; Scalcon, Valeria; Rigobello, Maria Pia; Le Gendre, Pierre; Casini, Angela; Bodio, Ewen

    2015-09-01

    While N-heterocyclic carbenes (NHC) are ubiquitous ligands in catalysis for organic or industrial syntheses, their potential to form transition metal complexes for medicinal applications has still to be exploited. Within this frame, we synthesized new homo- and heterobimetallic complexes based on the Au(I)-NHC scaffold. The compounds were synthesized via a microwave-assisted method developed in our laboratories using Au(I)-NHC complexes carrying a pentafluorophenol ester moiety and another Au(I) phosphane complex or a bipyridine ligand bearing a pendant amine function. Thus, we developed two different methods to prepare homo- and heterobimetallic complexes (Au(I)/Au(I) or Au(I)/Cu(II), Au(I)/Ru(II), respectively). All the compounds were fully characterized by several spectroscopic techniques including far infrared, and were tested for their antiproliferative effects in a series of human cancer cells. They showed moderate anticancer properties. Their toxic effects were also studied ex vivo using the precision-cut tissue slices (PCTS) technique and initial results concerning their reactivity with the seleno-enzyme thioredoxin reductase were obtained. PMID:26202908

  10. Utilizing hydrogen sulfide as a novel anti-cancer agent by targeting cancer glycolysis and pH imbalance

    PubMed Central

    Lee, Z-W; Teo, X-Y; Tay, E Y-W; Tan, C-H; Hagen, T; Moore, P K; Deng, L-W

    2014-01-01

    Background and Purpose Many disparate studies have reported the ambiguous role of hydrogen sulfide (H2S) in cell survival. The present study investigated the effect of H2S on the viability of cancer and non-cancer cells. Experimental Approach Cancer and non-cancer cells were exposed to H2S [using sodium hydrosulfide (NaHS) and GYY4137] and cell viability was examined by crystal violet assay. We then examined cancer cellular glycolysis by in vitro enzymatic assays and pH regulator activity. Lastly, intracellular pH (pHi) was determined by ratiometric pHi measurement using BCECF staining. Key Results Continuous, but not a single, exposure to H2S decreased cell survival more effectively in cancer cells, as compared to non-cancer cells. Slow H2S-releasing donor, GYY4137, significantly increased glycolysis, leading to overproduction of lactate. H2S also decreased anion exchanger and sodium/proton exchanger activity. The combination of increased metabolic acid production and defective pH regulation resulted in an uncontrolled intracellular acidification, leading to cancer cell death. In contrast, no significant intracellular acidification or cell death was observed in non-cancer cells. Conclusions and Implications Low and continuous exposure to H2S targets metabolic processes and pH homeostasis in cancer cells, potentially serving as a novel and selective anti-cancer strategy. PMID:24827113

  11. Benzene-Poly-Carboxylic Acid Complex, a Novel Anti-Cancer Agent Induces Apoptosis in Human Breast Cancer Cells

    PubMed Central

    Fares, Fuad; Azzam, Naiel; Fares, Basem; Larsen, Stig; Lindkaer-Jensen, Steen

    2014-01-01

    Some cases of breast cancer are composed of clones of hormonal-independent growing cells, which do not respond to therapy. In the present study, the effect of Benzene-Poly-Carboxylic Acid Complex (BP-C1) on growth of human breast-cancer cells was tested. BP-C1 is a novel anti-cancer complex of benzene-poly-carboxylic acids with a very low concentration of cis-diammineplatinum (II) dichloride. Human breast cancer cells, MCF-7 and T47D, were used. Cell viability was detected by XTT assay and apoptosis was detected by Flow Cytometry and by annexin V/FITC/PI assay. Caspases were detected by western blot analysis and gene expression was measured by using the Applied Biosystems® TaqMan® Array Plates. The results showed that exposure of the cells to BP-C1 for 48 h, significantly (P<0.001) reduced cell viability, induced apoptosis and activated caspase 8 and caspace 9. Moreover, gene expression experiments indicated that BP-C1 increased the expression of pro-apoptotic genes (CASP8AP1, TNFRSF21, NFkB2, FADD, BCL10 and CASP8) and lowered the level of mRNA transcripts of inhibitory apoptotic genes (BCL2L11, BCL2L2 and XIAP. These findings may lead to the development of new therapeutic strategies for treatment of human cancer using BP-C1 analog. PMID:24523856

  12. The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: ensuing energetic and oxidative stress implications.

    PubMed

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

    2011-06-15

    Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 ?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? efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP+ transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds. PMID:21549140

  13. Utilization of microbial iron assimilation processes for the development of new antibiotics and inspiration for the design of new anticancer agents

    PubMed Central

    Zhu, Helen; Xu, Yanping; Wu, Chunrui; Walz, Andrew J.; Vergne, Anne; Roosenberg, John M.; Moraski, Garrett; Minnick, Albert A.; McKee-Dolence, Julia; Hu, Jingdan; Fennell, Kelley; Dolence, E. Kurt; Dong, Li; Franzblau, Scott; Malouin, Francois; Möllmann, Ute

    2014-01-01

    Pathogenic microbes rapidly develop resistance to antibiotics. To keep ahead in the “microbial war”, extensive interdisciplinary research is needed. A primary cause of drug resistance is the overuse of antibiotics that can result in alteration of microbial permeability, alteration of drug target binding sites, induction of enzymes that destroy antibiotics (ie., beta-lactamase) and even induction of efflux mechanisms. A combination of chemical syntheses, microbiological and biochemical studies demonstrate that the known critical dependence of iron assimilation by microbes for growth and virulence can be exploited for the development of new approaches to antibiotic therapy. Iron recognition and active transport relies on the biosyntheses and use of microbe-selective iron-chelating compounds called siderophores. Our studies, and those of others, demonstrate that siderophores and analogs can be used for iron transport-mediated drug delivery (“Trojan Horse” antibiotics) and induction of iron limitation/starvation (Development of new agents to block iron assimilation). Recent extensions of the use of siderophores for the development of novel potent and selective anticancer agents are also described. PMID:19130268

  14. Tumor microenvironment in focus: LA-ICP-MS bioimaging of a preclinical tumor model upon treatment with platinum(IV)-based anticancer agents.

    PubMed

    Theiner, Sarah; Kornauth, Christoph; Varbanov, Hristo P; Galanski, Markus; Van Schoonhoven, Sushilla; Heffeter, Petra; Berger, Walter; Egger, Alexander E; Keppler, Bernhard K

    2015-08-01

    The selection of drug candidates for entering clinical development relies on in vivo testing in (solid) tumor animal models. However, the heterogeneity of tumor tissue (e.g. in terms of drug uptake or tissue composition) is rarely considered when testing novel drug candidates. Therefore, we used the murine colon cancer CT-26 tumor model to study the spatially-resolved drug distribution in tumor tissue upon repetitive treatment of animals over two weeks with three investigational platinum(IV)-based anticancer agents, oxaliplatin or satraplatin. A quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging method revealed a heterogeneous platinum distribution, which correlated well with the histologic features of the tumor and surrounding tissue at the microscopic level. In most of the cases, higher amounts of intratumoral platinum were found in the surrounding tissue than in the malignant parts of the sample. This indicates that determination of average platinum amounts (e.g. by microwave-assisted digestion of the sample followed by analysis with ICP-MS) might overestimate the drug uptake in tumor tissue causing misleading conclusions. In addition, we studied the platinum distribution in the kidneys of treated animals to probe if accumulation in the cortex and medulla predict potential nephrotoxicity. A 10-fold increase of platinum in the cortex of the kidney over the medulla was observed for oxaliplatin and satraplatin. Although these findings are similar to those in the platinum distribution of the nephrotoxic anticancer drug cisplatin, treatment with the compounds of our study did not show signs of nephrotoxicity in clinical use or clinical trials (oxaliplatin, satraplatin) and did not result in the alteration of renal structures. Thus, predicting the side effects based on bioimaging data by LA-ICP-MS should be considered with caution. To the best of our knowledge, this is the first LA-ICP-MS study on spatially-resolved platinum accumulation in tissues after repetitive platinum-based anticancer drug treatment of mice bearing a preclinical tumor model. PMID:25856224

  15. Influence of serum protein on polycarbonate-based copolymer micelles as a delivery system for a hydrophobic anti-cancer agent.

    PubMed

    Liu, Jubo; Zeng, Faquan; Allen, Christine

    2005-03-21

    A new micelle system formed from methoxy (polyethylene glycol)-b-poly (5-benzyloxy-trimethylene carbonate; MePEG-b-PBTMC 5000-b-4800) was investigated as a delivery system for the hydrophobic anti-cancer agent, ellipticine. The ellipticine was loaded into the MePEG-b-PBTMC micelles with a loading efficiency of 95% using a high-pressure extrusion technique. The ellipticine-loaded micelles have a spherical morphology and an average diameter of 96 nm. The anti-cancer activity of ellipticine was confirmed to be retained following formulation in the MePEG-b-PBTMC micelles. The extent of protein adsorption to the MePEG-b-PBTMC micelles was investigated by transmission electron microscopy, dynamic light scattering and gel filtration chromatography. Overall, the amount of protein both loosely and tightly associated with the micelles was found to be minimal and insignificant. The partitioning properties of ellipticine between an aqueous medium containing protein and the MePEG-b-PBTMC micelles were examined over a range of protein concentrations. Under physiologically relevant conditions, it was found that 61% of the drug remained within the micelle fraction while 39% was in the protein-containing aqueous phase. In addition, the in vitro drug release profile of ellipticine from the micelles was fit using a modified Higuchi model and found to be accelerated in the presence of protein. These studies demonstrate that although there are no significant interactions between micelle and protein, the properties of the micelle as a delivery vehicle may be strongly influenced by protein-drug interactions. PMID:15763628

  16. Comparing the suitability of autodock, gold and glide for the docking and predicting the possible targets of Ru(II)-based complexes as anticancer agents.

    PubMed

    Adeniyi, Adebayo A; Ajibade, Peter A

    2013-01-01

    In cancer chemotherapy, metal-based complexes have been recognized as the most promising means of inhibiting cancer growth due to the successful application of cis-platin and its derivatives above many of the existing organic anticancer agents. The limitations in their rational design can be traced to the complexity of the mechanism of their operations, lack of proper knowledge of their targets and lack of force fields in docking packages to appropriately define the metal centre of the organometallic complexes. In this paper, some of the promising anticancer complexes of Ru(II) such as the rapta-based complexes formulated as [Ru(η6-p-cymene)L2(pta)] and those with unusual ligands are considered. CatB and kinases which have been experimentally confirmed as possible targets of the complexes are also predicted by the three methods as one of the most targeted receptors while TopII and HDAC7 are predicted by two and one of the methods as best targets. The interesting features of the binding of the complexes show that some of the complexes preferentially target specific macromolecules than the others, which is an indication of their specificity and possibility of their therapeutic combination without severe side effects that may come from competition for the same target. Also, introduction of unusual ligands is found to significantly improve the activities of most of the complexes studied. Strong correlations are observed for the predicted binding sites and the orientation of the complexes within the binding site by the three methods of docking. However there are disparities in the ranking of the complexes by the three method of docking, especially that of Glide. PMID:23529035

  17. Mode of action and resistance studies unveil new roles for tropodithietic acid as an anticancer agent and the γ-glutamyl cycle as a proton sink.

    PubMed

    Wilson, Maxwell Z; Wang, Rurun; Gitai, Zemer; Seyedsayamdost, Mohammad R

    2016-02-01

    While we have come to appreciate the architectural complexity of microbially synthesized secondary metabolites, far less attention has been paid to linking their structural features with possible modes of action. This is certainly the case with tropodithietic acid (TDA), a broad-spectrum antibiotic generated by marine bacteria that engage in dynamic symbioses with microscopic algae. TDA promotes algal health by killing unwanted marine pathogens; however, its mode of action (MoA) and significance for the survival of an algal-bacterial miniecosystem remains unknown. Using cytological profiling, we herein determine the MoA of TDA and surprisingly find that it acts by a mechanism similar to polyether antibiotics, which are structurally highly divergent. We show that like polyether drugs, TDA collapses the proton motive force by a proton antiport mechanism, in which extracellular protons are exchanged for cytoplasmic cations. The α-carboxy-tropone substructure is ideal for this purpose as the proton can be carried on the carboxyl group, whereas the basicity of the tropylium ion facilitates cation export. Based on similarities to polyether anticancer agents we have further examined TDA's cytotoxicity and find it to exhibit potent, broad-spectrum anticancer activities. These results highlight the power of MoA-profiling technologies in repurposing old drugs for new targets. In addition, we identify an operon that confers TDA resistance to the producing marine bacteria. Bioinformatic and biochemical analyses of these genes lead to a previously unknown metabolic link between TDA/acid resistance and the γ-glutamyl cycle. The implications of this resistance mechanism in the context of the algal-bacterial symbiosis are discussed. PMID:26802120

  18. Analysis of the antiproliferative effects of 3-deazaneoplanocin A in combination with standard anticancer agents in rhabdoid tumor cell lines.

    PubMed

    Unland, Rebekka; Borchardt, Christiane; Clemens, Dagmar; Kool, Marcel; Dirksen, Uta; Frühwald, Michael C

    2015-03-01

    Rhabdoid tumors (RTs) are highly aggressive pediatric malignancies with a rather poor prognosis. New therapeutic approaches and optimization of already established treatment protocols are urgently needed. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is highly overexpressed in RTs and associated strongly with epigenetic silencing in cancer. EZH2 is involved in aggressive cell growth and stem cell maintenance. Thus, EZH2 is an attractive therapeutic target in RTs. The aim of the study presented here was to analyze the effects of a pharmacological inhibition of EZH2 alone and in combination with other anticancer drugs on RTs cells in vitro. The antitumor activity of the S-adenosyl-homocysteine-hydrolase inhibitor 3-deazaneplanocin A (DZNep) alone and in combination with conventional cytostatic drugs (doxorubicin, etoposide) or epigenetic active compounds [5-Aza-CdR, suberoylanilide hydroxamic acid (SAHA)] was assessed by MTT cell proliferation assays on three RT cell lines (A204, BT16, G401). Combinatorial treatment with DZNep synergistically and significantly enhanced the antiproliferative activity of etoposide, 5-Aza-CdR, and SAHA. In functional analyses, pretreatment with DZNep significantly increased the effects of 5-Aza-CdR and SAHA on apoptosis, cell cycle progression, and clonogenicity. Microarray analyses following sequential treatment with DZNep and 5-Aza-CdR or SAHA showed changes in global gene expression affecting apoptosis, neuronal development, and metabolic processes. In-vitro analyses presented here show that pharmacological inhibition of EZH2 synergistically affects the antitumor activity of the epigenetic active compounds 5-Aza-CdR and SAHA. Sequential treatment with these drugs combined with DZNep may represent a new therapeutic approach in RTs. PMID:25415657

  19. In vivo genotoxicity evaluation of a plant based antiarthritic and anticancer therapeutic agent Boswelic acids in rodents.

    PubMed

    Sharma, R; Singh, S; Singh, G D; Khajuria, A; Sidiq, T; Singh, S K; Chashoo, G; Pagoch, S S; Kaul, A; Saxena, A K; Johri, R K; Taneja, S C

    2009-12-01

    The genotoxic potential of anti-inflammatory/anti-arthritic and anticancer plant based drug molecule Boswelic acids (BA) was studied by in vivo system. Systematic literature survey revealed that studies on the genotoxicity of BA are not available. Although reports on genotoxicity of Boswellia serrata dry extract and modified 3-O-acetyl-11-keto-beta-boswelic acid are available and these studies were conducted in in vitro systems. The earlier general toxicity study of BA has been conducted by us, revealed it to be non toxic. The genotoxicity was carried out in Wistar rats using different cytogenetic assay system-abnormalities viz. chromosomal aberrations; sperm morphology, micronuclei and comet assays. Six groups of animals, each comprised of five rats, were taken for each study. Group1-4 received BA at 125, 250, 500 and 1000 mg/kg p.o., respectively prepared as 2% gum acacia suspension, fifth group received a positive control cyclophosphamide (CP) 40 mg/kg p.o. or metronedazole (MTZ) 130 mg/kg p.o. or mercuric chloride (HgCl(2)) 0.864 mg/kg p.o. (as per the experiment requirement) whereas the sixth group kept as vehicle control. The results on the bases of the data obtained revealed that BA is quite safe as it did not show any genotoxicity at any dose level up to 1000 mg/kg. The positive controls used in different experiments showed highly significant abnormal cytogenetic changes in comparison to the control group. PMID:19679457

  20. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90.

    PubMed

    Sydor, Jens R; Normant, Emmanuel; Pien, Christine S; Porter, James R; Ge, Jie; Grenier, Louis; Pak, Roger H; Ali, Janid A; Dembski, Marlene S; Hudak, Jebecka; Patterson, Jon; Penders, Courtney; Pink, Melissa; Read, Margaret A; Sang, Jim; Woodward, Caroline; Zhang, Yilong; Grayzel, David S; Wright, Jim; Barrett, John A; Palombella, Vito J; Adams, Julian; Tong, Jeffrey K

    2006-11-14

    Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90. PMID:17090671

  1. 1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: Anti-cancer agents that target nucleophosmin 1 (NPM1).

    PubMed

    Penthala, Narsimha Reddy; Ketkar, Amit; Sekhar, Konjeti R; Freeman, Michael L; Eoff, Robert L; Balusu, Ramesh; Crooks, Peter A

    2015-11-15

    In the present study, we have designed and synthesized a series of 1-benzyl-2-methyl-3-indolylmethylene barbituric acid analogs (7a-7h) and 1-benzyl-2-methyl-3-indolylmethylene thiobarbituric acid analogs (7 i-7 l) as nucleophosmin 1 (NPM1) inhibitors and have evaluated them for their anti-cancer activity against a panel of 60 different human cancer cell lines. Among these analogs 7 i, 7 j, and 7 k demonstrated potent growth inhibitory effects in various cancer cell types with GI50 values <2 μM. Compound 7 k exhibited growth inhibitory effects on a sub-panel of six leukemia cell lines with GI50 values in the range 0.22-0.35 μM. Analog 7 i also exhibited GI50 values <0.35 μM against three of the leukemia cell lines in the sub-panel. Analogs 7 i, 7 j, 7 k and 7 l were also evaluated against the mutant NPM1 expressing OCI-AML3 cell line and compounds 7 k and 7 l were found to cause dose-dependent apoptosis (AP50 = 1.75 μM and 3.3 μM, respectively). Compound 7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: that is, A498 renal cancer (GI50 = 0.19 μM), HOP-92 and NCI-H522 lung cancer (GI50 = 0.25 μM), COLO 205 and HCT-116 colon cancer (GI50 = 0.20 and 0.26 μM, respectively), CNS cancer SF-539 (GI50 = 0.22 μM), melanoma MDA-MB-435 (GI50 = 0.22 μM), and breast cancer HS 578T (GI50 = 0.22 μM) cell lines. Molecular docking studies suggest that compounds 7 k and 7 l exert their anti-leukemic activity by binding to a pocket in the central channel of the NPM1 pentameric structure. These results indicate that the small molecule inhibitors 7 i, 7 j, 7 k, and 7 l could be potentially developed into anti-NPM1 drugs for the treatment of a variety of hematologic malignancies and solid tumors. PMID:26602084

  2. Synthesis of new secretory phospholipase A2-inhibitory indole containing isoxazole derivatives as anti-inflammatory and anticancer agents.

    PubMed

    Pedada, Srinivasa Rao; Yarla, Nagendra Sastry; Tambade, Pawan J; Dhananjaya, Bhadrapura Lakkappa; Bishayee, Anuapam; Arunasree, Kalle M; Philip, Gundala Harold; Dharmapuri, Gangappa; Aliev, Gjumrach; Putta, Swathi; Rangaiah, Gururaja

    2016-04-13

    Secretory phospholipase A2 (sPLA2) is an important enzyme that plays a key role in various inflammatory diseases including cancer and its inhibitors have been developed as preventive or therapeutic agents. In the present study, a series of new indole containing isoxazole derivatives (10a-10o) is synthesized and evaluated for their sPLA2 inhibitory activities. All compounds (10a-10o) showed significant sPLA2 inhibition activities both in vitro and in vivo studies which is substantiated in in silico studies. Among all the tested compounds, 10o showed potent sPLA2 inhibition activity, that is comparable or more to ursolic acid (positive control). Further studies demonstrated that 10o showed in vitro antiproliferative activity when tested against MCF-7 breast and DU145 prostate cancer cells. Furthermore, compounds 10a-10o obeyed lipinsky's rule of 5 and suggesting druggable properties. The in vitro, in vivo and in silico results are encouraging and warrant pre-clinical studies to develop sPLA2-inhibitory compound 10o as novel therapeutic agent for various inflammatory disorders and several malignancies. PMID:26907155

  3. 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

  4. Design, Synthesis, and SAR Studies of 4-Substituted Methoxylbenzoyl-aryl-thiazoles Analogues as Potent and Orally Bioavailable Anticancer Agents

    PubMed Central

    Lu, Yan; Li, Chien-Ming; Wang, Zhao; Chen, Jianjun; Mohler, Michael L.; Li, Wei; Dalton, James T.; Miller, Duane D.

    2016-01-01

    In a continued effort to improve upon the previously published 4-substituted methoxybenzoyl-arylthiazole (SMART) template, we explored chemodiverse B rings and B to C ring linkage. Further, to overcome the poor aqueous solubility of this series of agents, we introduced polar and ionizable hydrophilic groups to obtain water-soluble compounds. For instance, based on in vivo pharmacokinetic (PK) studies, an orally bioavailable phenyl-aminothiazole (PAT) template was designed and synthesized in which an amino linkage was inserted between A and B rings of compound 1. The PAT template maintained nanomolar (nM) range potency against cancer cell lines via inhibiting tubulin polymerization and was not susceptible to P-glycoprotein mediated multidrug resistance in vitro, and markedly improved solubility and bioavailability compared with the SMART template (45ac (PAT) vs 1 (SMART)). PMID:21557538

  5. PT-ACRAMTU, a platinum-acridine anticancer agent, lengthens and aggregates, but does not stiffen or soften DNA.

    PubMed

    Dutta, Samrat; Snyder, Matthew J; Rosile, David; Binz, Kristen L; Roll, Eric H; Suryadi, Jimmy; Bierbach, Ulrich; Guthold, Martin

    2013-01-01

    We used atomic force microscopy (AFM) to study the dose-dependent change in conformational and mechanical properties of DNA treated with PT-ACRAMTU ([PtCl(en)(ACRAMTU-S)](NO3)2, (en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea. PT-ACRAMTU is the parent drug of a family of non-classical platinum-based agents that show potent activity in non-small cell lung cancer in vitro and in vivo. Its acridine moiety intercalates between DNA bases, while the platinum group forms mono-adducts with DNA bases. AFM images show that PT-ACRAMTU causes some DNA looping and aggregation at drug-to-base pair ratio (r b) of 0.1 and higher. Very significant lengthening of the DNA was observed with increasing doses of PT-ACRAMTU, and reached saturation at an r b of 0.15. At r b of 0.1, lengthening was 0.6 nm per drug molecule, which is more than one fully stretched base pair stack can accommodate, indicating that ACRAMTU also disturbs the stacking of neighboring base pair stacks. Analysis of the AFM images based on the worm-like chain (WLC) model showed that PT-ACRAMTU did not change the flexibility of (non-aggregated) DNA, despite the extreme lengthening. The persistence length of untreated DNA and DNA treated with PT-ACRAMTU was in the range of 49-65 nm. Potential consequences of the perturbations caused by this agent for the recognition and processing of the DNA adducts it forms are discussed. PMID:23636685

  6. Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate.

    PubMed

    Lis, Paweł; Jurkiewicz, Paweł; Cal-Bąkowska, Magdalena; Ko, Young H; Pedersen, Peter L; Goffeau, Andre; Ułaszewski, Stanisław

    2016-03-01

    In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of yeast cells to 3-BP, possibly due to the non-functional system of mitophagy of damaged mitochondria through the Ras-cAMP-PKA pathway. Single deletions of genes encoding glycolytic enzymes, the TCA cycle enzymes and mitochondrial carriers result in multiple effects after 3-BP treatment. However, it can be concluded that activity of the pentose phosphate pathway is necessary to prevent the toxicity of 3-BP, probably due to the fact that large amounts of NADPH are produced by this pathway, ensuring the reducing force needed for glutathione reduction, crucial to cope with the oxidative stress. Moreover, single deletions of genes encoding the TCA cycle enzymes and mitochondrial carriers generally cause sensitivity to 3-BP, while totally inactive mitochondrial respiration in the rho0 mutant resulted in increased resistance to 3-BP. PMID:26862728

  7. One-Pot Three-Component Synthesis of Novel Diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(arylamino)methyl)phosphonate as Potential Anticancer Agents

    PubMed Central

    Fang, Yi-Lin; Wu, Zhi-Lin; Xiao, Meng-Wu; Tang, Yu-Ting; Li, Kang-Ming; Ye, Jiao; Xiang, Jian-Nan; Hu, Ai-Xi

    2016-01-01

    With the aim of discovering new anticancer agents, we have designed and synthesized novel α-aminophosphonate derivatives containing a 2-oxoquinoline structure using a convenient one-pot three-component method. The newly synthesized compounds were evaluated for antitumor activities against the A549 (human lung adenocarcinoma cell), HeLa (human cervical carcinoma cell), MCF-7 (human breast cancer cell), and U2OS (human osteosarcoma cell) cancer cell lines in vitro, employing a standard 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The results of pharmacological screening indicated that many compounds exhibited moderate to high levels of antitumor activities against the tested cancer cell lines and that most compounds showed more potent inhibitory activities comparable to 5-fluorouracil (5-FU) which was used as a positive control. The mechanism of representative compound 4u (diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(phenyl-amino)methyl)phosphonate) indicated that the compound mainly arrested HeLa cells in S and G2 stages and was accompanied by apoptosis in HeLa cells. This action was confirmed by acridine orange/ethidium bromide staining, Hoechst 33342 staining, and flow cytometry. PMID:27136538

  8. Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline).

    PubMed

    Jiang, Hongchao; Taggart, Jori E; Zhang, Xiaoxi; Benbrook, Doris M; Lind, Stuart E; Ding, Wei-Qun

    2011-12-15

    Clioquinol has been shown to have anticancer activity both in vitro and in vivo. The present study compared the cytotoxicity of clioquinol with six analogues using human cancer cell lines. Of the analogues tested, 8-hydroxy-5-nitroquinoline (NQ) was the most toxic, with an IC(50) that was five to ten fold lower than that of other congeners. Its activity was enhanced by copper, but not zinc, and the use of a zinc-sensitive fluorophore showed that unlike clioquinol, NQ is not a zinc ionophore. NQ increased intracellular reactive oxygen species generation, an effect that was significantly enhanced by the addition of copper at levels approximately the same as those found in human plasma. NQ has been used in humans for the treatment of urinary infections. NQ is an 8-hydroxyquinoline derivative that is more potent than the halogenated 8-hydroxyquinolines, and it may be less neurotoxic because it lacks zinc ionophore activity. NQ is another clinically used anti-microbial agent whose properties suggest that it may be useful in treating cancer. PMID:21899946

  9. Nitroxoline (5-amino-8-hydroxyquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline)

    PubMed Central

    Jiang, Hongchao; Taggart, Jori E.; Zhang, Xiaoxi; Benbrook, Doris M.; Lind, Stuart E.; Ding, Wei-Qun

    2012-01-01

    Clioquinol has been shown to have anticancer activity both in vitro and in vivo. The present study compared the cytotoxicity of clioquinol with six analogues, using human cancer cell lines. Of the analogues tested, 8-hydroxy-5-nitroquinoline (NQ) was the most toxic, with an IC50 that was 5-10 fold lower than other congeners. Its activity was enhanced by copper, but not zinc, and the use of a zinc-sensitive fluorophore showed that unlike clioquinol, NQ is not a zinc ionophore. NQ increased intracellular reactive oxygen species generation, an effect that was significantly enhanced by the addition of copper at levels that approximate those found in human plasma. NQ has been used in humans for the treatment of urinary infections. NQ is an 8-hydroxyquinoline derivative that is more potent than the halogenated 8-hydroxyquinolines, and may be less neurotoxic because it lacks zinc ionophore activity. NQ is another clinical used anti-microbial agent whose properties suggest that it may be useful in treating cancer. PMID:21899946

  10. Synthesis, characterization and biological evaluation of bile acid-aromatic/heteroaromatic amides linked via amino acids as anti-cancer agents.

    PubMed

    Agarwal, Devesh S; Anantaraju, Hasitha Shilpa; Sriram, Dharmarajan; Yogeeswari, Perumal; Nanjegowda, Shankara H; Mallu, P; Sakhuja, Rajeev

    2016-03-01

    A series of bile acid (Cholic acid and Deoxycholic acid) aryl/heteroaryl amides linked via α-amino acid were synthesized and tested against 3 human cancer cell-lines (HT29, MDAMB231, U87MG) and 1 human normal cell line (HEK293T). Some of the conjugates showed promising results to be new anticancer agents with good in vitro results. More specifically, Cholic acid derivatives 6a (1.35μM), 6c (1.41μM) and 6m (4.52μM) possessing phenyl, benzothiazole and 4-methylphenyl groups showed fairly good activity against the breast cancer cell line with respect to Cisplatin (7.21μM) and comparable with respect to Doxorubicin (1μM), while 6e (2.49μM), 6i (2.46μM) and 6m (1.62μM) showed better activity against glioblastoma cancer cell line with respect to both Cisplatin (2.60μM) and Doxorubicin (3.78μM) drugs used as standards. Greater than 65% of the compounds were found to be safer on human normal cell line. PMID:26748355

  11. Synthesis and biological evaluation of novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases as potential anticancer agents.

    PubMed

    Chazin, Eliza de Lucas; Sanches, Paola de Souza; Lindgren, Eric Brazil; Vellasco Júnior, Walcimar Trindade; Pinto, Laine Celestino; Burbano, Rommel Mario Rodríguez; Yoneda, Julliane Diniz; Leal, Kátia Zaccur; Gomes, Claudia Regina Brandão; Wardell, James Lewis; Wardell, Solange Maria Silva Veloso; Montenegro, Raquel Carvalho; Vasconcelos, Thatyana Rocha Alves

    2015-01-01

    With the aim of discovering new anticancer agents, we have designed and synthesized novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases. The synthesis started with the selective nitration at 5-position of 6-hydroxybenzo[d][1,3]oxathiol-2-one (1) leading to the nitro derivative 2. The nitro group of 2 was reduced to give the amino intermediate 3. Schiff bases 4a-r were obtained from coupling reactions between 3 and various benzaldehydes and heteroaromatic aldehydes. All the new compounds were fully identified and characterized by NMR (1H and 13C) and specifically for 4q by X-ray crystallography. The in vitro cytotoxicity of the compounds was evaluated against cancer cell lines (ACP-03, SKMEL-19 and HCT-116) by using MTT assay. Schiff bases 4b and 4o exhibited promising cytotoxicity against ACP-03 and SKMEL-19, respectively, with IC50 values lower than 5 μM. This class of compounds can be considered as a good starting point for the development of new lead molecules in the fight against cancer. PMID:25633329

  12. 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

  13. Synthesis and evaluation of 1,7-diheteroarylhepta-1,4,6-trien-3-ones as curcumin-based anticancer agents.

    PubMed

    Wang, Rubing; Zhang, Xiaojie; Chen, Chengsheng; Chen, Guanglin; Zhong, Qiu; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong

    2016-03-01

    Thirty (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones, featuring a central linear trienone linker and two identical nitrogen-containing heteroaromatic rings, were designed and synthesized as curcumin-based anticancer agents on the basis of their structural similarity to the enol-tautomer of curcumin, in addition to taking advantage of the possibly enhanced pharmacokinetic profiles contributed by the basic nitrogen-containing heteroaromatic rings. Their cytotoxicity and antiproliferative activity were evaluated towards both androgen-dependent and androgen-independent prostate cancer cell lines, as well as HeLa human cervical cancer cells. Among them, the ten most potent analogues are 5- to 36-fold more potent than curcumin in inhibiting cancer cell proliferation. The acquired structure-activity relationship data indicate (i) that (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones represent a potential scaffold for development of curcumin-based agents with substantially improved cytotoxicity and anti-proliferative effect; and (ii) 1-alkyl-1H-imidazol-2-yl and 1-alkyl-1H-benzo[d]imidazole-2-yl serve as optimal heteroaromatic rings for increased in vitro potency of this scaffold. Two of most potent compounds displayed no apparent cytotoxicity toward MCF-10A normal mammary epithelial cells at 1 μM concentration. Treatment of PC-3 prostate cancer cells with the most potent compound led to appreciable cell cycle arrest at a G1/G0 phase and cell apoptosis induction. PMID:26827161

  14. 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

  15. Caffeine-based gold(I) N-heterocyclic carbenes as possible anticancer agents: synthesis and biological properties.

    PubMed

    Bertrand, Benoît; Stefan, Loic; Pirrotta, Marc; Monchaud, David; Bodio, Ewen; Richard, Philippe; Le Gendre, Pierre; Warmerdam, Elena; de Jager, Marina H; Groothuis, Geny M M; Picquet, Michel; Casini, Angela

    2014-02-17

    A new series of gold(I) N-heterocyclic carbene (NHC) complexes based on xanthine ligands have been synthesized and characterized by mass spectrometry, NMR, and X-ray diffraction. The compounds have been tested for their antiproliferative properties in human cancer cells and nontumorigenic cells in vitro, as well as for their toxicity in healthy tissues ex vivo. The bis-carbene complex [Au(caffein-2-ylidene)2][BF4] (complex 4) appeared to be selective for human ovarian cancer cell lines and poorly toxic in healthy organs. To gain preliminary insights into their actual mechanism of action, two biologically relevant in cellulo targets were studied, namely, DNA (more precisely a higher-order DNA structure termed G-quadruplex DNA that plays key roles in oncogenetic regulation) and a pivotal enzyme of the DNA damage response (DDR) machinery (poly-(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-1), strongly involved in the cancer resistance mechanism). Our results indicate that complex 4 acts as an efficient and selective G-quadruplex ligand while being a modest PARP-1 inhibitor (i.e., poor DDR impairing agent) and thus provide preliminary insights into the molecular mechanism that underlies its antiproliferative behavior. PMID:24499428

  16. Synthesis and biological evaluation of non-glucose glycoconjugated N-hydroyxindole class LDH inhibitors as anticancer agents

    PubMed Central

    Di Bussolo, Valeria; Calvaresi, Emilia C.; Granchi, Carlotta; Del Bino, Linda; Frau, Ileana; Lang, Maria Chiara Dasso; Tuccinardi, Tiziano; Macchia, Marco; Martinelli, Adriano

    2015-01-01

    Inhibitors of human lactate dehydrogenase A (LDH-A) are promising therapeutic agents against cancer. The development of LDH-A inhibitors that possess cellular activities has so far proved to be particularly challenging, since the enzyme’s active site is narrow and highly polar. In the recent past, we were able to develop a glucose-conjugated N-hydroxyindole-based LDH-A inhibitor designed to exploit the sugar avidity expressed by cancer cells (the Warburg effect). Herein we describe a structural modulation of the sugar moiety of this class of inhibitors, with the insertion of α-D-mannose, β-D-gulose, or β-N-acetyl-D-glucosamine portions in their structures. Their stereospecific chemical synthesis, which involves a substrate-dependent stereospecific glycosylation step, and their biological activity in reducing lactate production and proliferation in cancer cells are reported. Interestingly, the α-D-mannose conjugate displayed the best properties in the cellular assays, demonstrating an efficient antiglycolytic and antiproliferative activity in cancer cells. PMID:26167277

  17. 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.

  18. Inhibitory effects of trehalose on malignant melanoma cell growth: implications for a novel topical anticancer agent on the ocular surface.

    PubMed

    Kudo, Takashi; Takeuchi, Kimio; Ebina, Yu-Ichi; Nakazawa, Mitsuru

    2012-01-01

    Purpose. To investigate the inhibitory effects of trehalose on malignant melanoma cell growth. Methods. We cultured human malignant melanoma cells in a medium containing trehalose (control/2.5%/5.0%/7.5%/10.0%) and used the MTT assay to evaluate the growth activities. Subsequently, trehalose was topically instilled on subconjunctivally inoculated melanoma cells in F334/NJcl-rmu/rmu rats, followed by a histopathological evaluation of tumor growth. Using flow cytometry, we compared the distribution of the cell cycle, rate of apoptotic cells, and intracellular factors related to the cell cycle in cultured melanoma cells after trehalose treatment. Results. The MTT study showed that proliferation of melanoma cells was significantly inhibited by ≧ 5% of trehalose concentrations in the culture media. Subconjunctivally inoculated melanoma cell masses were significantly smaller in eyes administered trehalose as compared to controls. Flow cytometry analyses demonstrated that the trehalose groups had increased rates of G2/M phase cells and apoptotic cells in the cell culture. These cells also exhibited increased expressions of cell-cycle inhibitory factors. Conclusions. The current results show trehalose inhibits malignant melanoma cell growth by inducing G2/M cell cycle arrest and apoptosis, suggesting trehalose as a potential candidate for a topical agent to inhibit proliferation of malignant tumor cells of the ocular surface. PMID:24558596

  19. Design, synthesis and structural studies of meta-xylyl linked bis-benzimidazolium salts: potential anticancer agents against ‘human colon cancer’

    PubMed Central

    2012-01-01

    Background Benzimidazole derivatives are structurally bioisosteres of naturally occurring nucleotides, which makes them compatible with biopolymers of living systems. This property gives benzimidazole a biological and clinical importance. In the last decade, this class of compounds has been reported to possess anti-allergic, anti-diabatic, anti-HIV, anti-hypertensive, anti-inflammatory, anti-mycobacterial, anti-oxidant, anti-protozoal, and anti-viral properties. The researchers are now interested to explore their potential as anti-cancer agents. In the present study, an effort was made to further explore this area of research. Furthermore, in order to increase the solubility and efficacy of these heterocycles, the interest is now shifted to the salts of these compounds. With this background, we planned to synthesize a series of meta-xylyl linked bis-benzimidazolium salts to assess their anti-proliferation efficacy on human colon cancer cell line (HCT 116). Results A number of N-alkylbenzimidazoles were synthesized by reactions of benzimidazole with alkyl halides (i-PrBr, PrBr, EthBr, Pent-2-ylBr, BuBr, BenzCl, HeptBr). The subsequent treatment of the resulting N-alkylbenzimidazoles with 1,3-(bromomethylene)benzene afforded corresponding bis-benzimidazolium salts. All synthesized compounds were characterized by spectroscopic techniques (Additional file 1: NMR & FT-IR) and microanalysis. Molecular structures of selected compounds were established through single crystal x-ray diffraction studies. All the compounds were assessed for their anti-proliferation test on human colorectal cancer cell line (HCT 116). Results showed that the compounds exhibited dose dependent cytotoxicity towards the colon cancer cells with IC50 ranges between 0.1 to 17.6 μM. The anti-proliferation activity of all compounds was more pronounced than that of standard reference drug 5-flourouracil (IC50 =19.2 μM). Conclusions All the synthesized bis-benzimidazolium salts showed potential anticancer activity. Out of them, some of these salts showed IC50 value as low as 0.1–0.2 μM. Based on the results it can be concluded that, the bis-benzimidazolium salts could probably be the potential source of chemotherapeutic drugs. PMID:22809051

  20. Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent

    SciTech Connect

    Li, Jason Z.; Ke, Yuebin; Misra, Hara P.; Trush, Michael A.; Li, Y. Robert; Zhu, Hong; Jia, Zhenquan

    2014-12-15

    Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16–F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone, a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16–F10 cells. In HepG2 cells ES936 inhibited beta-Lp-mediated oxygen radical formation by ∼ 80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16–F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells. - Highlights: • Both isolated mitochondria and purified NQO1 are able to generate ROS by beta-Lp. • The differential roles of mitochondria and NQO1 in mediating redox activation of beta-Lp • In cancer cells with low NQO1 expression, mitochondria play a critical role in beta-Lp redox activation. • In cancer cells with high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1.

  1. 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±6μM, 44±6μM, 26±3μM, and 21±1μM 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

  2. 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 μg/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

  3. Anti-cancer effects of ursane triterpenoid as a single agent and in combination with cisplatin in bladder cancer.

    PubMed

    Lin, Kai-Wei; Huang, A-Mei; Lin, Chi-Chen; Chang, Chia-Che; Hsu, Wei-Chi; Hour, Tzyh-Chyuan; Pu, Yeong-Shiau; Lin, Chun-Nan

    2014-10-01

    Ursolic acid and most of its derivatives are cytotoxic to bladder cancer cells. An ursolic acid derivative, isopropyl 3β-hydroxyurs-12-en-28-oat (UA17), previously reported that it exhibited potent cytotoxicity against bladder cancer cells, NTUB1 cells. In this study, we further investigated the underlying mechanism of UA17 and evaluated its potential clinical use. UA17 may exert the onset of a p53-mediated p38 MAPK activation to up-regulate GADD153. GADD153, in turn, down-regulated Bcl-2 protein to cause mitochondrial membrane potential loss and apoptosis through intracellular ROS generation. In addition, UA17 markedly decreased the levels of cyclins (D1 and E), cyclin-dependent kinases (CDK2 and CDK4), and caused increase of p21 and p27 levels. To assess the suitability of UA17 as a chemotherapeutic agent against NTUB1 cells, its cytotoxic effects have been further evaluated in the combination with cisplatin. The addition of UA17 to cisplatin induces possibly additive cell growth inhibition which correlated to the accumulation of S phase cells and a corresponding decrease in accumulation of G1 phase cells, accompanied an increased accumulation of sub-G1 phase cells. Furthermore, UA17/cisplatin combination exhibited increase of p21, cyclin E, and p-p53 level, and decrease of p27 and cyclin D1 proteins, and slightly diminishing the level of CDK2. P-p38 up-regulation induced by UA17/cisplatin combination through generation of ROS and Bcl-2 down-regulation induced by UA17/cisplatin combination increased cell death. Finally, the antitumorigenic effects of UA17 or UA17/cisplatin combination were further supported by their inhibition on growth of bladder tumor cells in a therapeutic murine MBT-2 bladder tumor model. PMID:24933647

  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 11β (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 11β 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 11β; flow cytometry studies showed that 11β exposure rapidly induced oxidative stress, mitochondria being an important source of reactive oxygen species (ROS). Additionally, 11β inhibited oxygen consumption both in intact HeLa cells and in isolated mitochondria. Specifically, 11β 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, 11β 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 11β, 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 11β, which supplements conventional DNA adduct formation to promote cancer cell death. PMID:21832047

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

    PubMed

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

    2012-03-15

    Vicrostatin (VCN) is a chimeric recombinant disintegrin generated in Origami B (DE3) Escherichia 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 200 mg 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. Biological evaluation of morin and its new oxovanadium(IV) complex as antioxidant and specific anti-cancer agents.

    PubMed

    Naso, Luciana G; Lezama, Luis; Rojo, Teófilo; Etcheverry, Susana B; Valcarcel, María; Roura, Meritxell; Salado, Clarisa; Ferrer, Evelina G; Williams, Patricia A M

    2013-11-25

    It is known that flavonoids possess, among others, antioxidant and antitumoral properties that depend on their molecular structure. The central objective if this study was to investigate the potential antioxidant and antiproliferative properties of the flavonol morin and its new oxovanadium(IV) complex (VOmor) that was synthesized in order to modify the morin chemical structure. Two osteoblast (UMR106 and MC3T3E1), two breast tumor (T47D and SKBR3) and breast epithelial cell lines in culture were used for the antitumoral determinations. Additionally, a comparative study of their antioxidant capacities using different radicals (DPPH, ABTS(+), OH, O2(-), ROO) was performed. Selected mechanisms of action were studied using the breast cancer cell lines. Results obtained show that morin and its complex behaved as good antioxidant agents for some of the radicals and that the complexation improved the behavior with respect to OH and O2(-) radicals being morin more effective as ROO scavenger. A considerable variation in sensitivity was observed in the breast cancer cells but non-specificity was found for the treatment of osteosarcoma. Moreover, the compounds did not affect the normal proliferation of the breast epithelial mammal cells. The mechanistic studies demonstrated that the complex did not generate reactive oxygen species in the cells (confirming the in vitro studies) and did not produce any damage of DNA. The plasmatic membrane was observed to be damaged only in the SKBR3 cell line. In contrast, the perturbation of the mitochondrial membrane potential and the activation of caspase 3/7 for the breast tumor cells revealed an apoptotic cell death process. All these results collectively suggested that VOmor complex could serve as promising pharmacologically active substance against breast cancer treatment. PMID:24125835

  7. Preparation, characterization, and anti-tumor property of podophyllotoxin-loaded solid lipid nanoparticles

    NASA Astrophysics Data System (ADS)

    Zhu, R. R.; Qin, L. L.; Wang, M.; Wu, S. M.; Wang, S. L.; Zhang, R.; Liu, Z. X.; Sun, X. Y.; Yao, S. D.

    2009-02-01

    In an effort to develop an alternative formulation of podophyllotoxin suitable for drug release and delivery, podophyllotoxin-loaded solid lipid nanoparticles (PPT-SLNs) were constructed, characterized and examined for in vitro cytotoxicity and tumor inhibition. The SLNs were prepared by using a solvent emulsification-evaporation method, and their size was around 50 nm. TEM detection showed that the SLNs were homogeneous and spherical in shape, and differential scanning calorimetry (DSC) measurement revealed a new conformation of PPT-SLNs. An in vitro drug release study showed that PPT was released from the SLNs in a slow but time-dependent manner. Furthermore, the treatment of 293T and HeLa cells with PPT-SLNs demonstrated that PPT-SLNs were less toxic to normal cells and more effective in anti-tumor potency compared with unconjugated PPT. A colony forming efficiency assay showed an effective long-term cancer growth suppression of PPT-SLNs; in addition, they can also enhance the apoptotic and cellular uptake processes on tumor cells compared with PPT. These results collectively demonstrated that this SLN formulation has a potential application as an alternative delivery system for anti-tumor drugs.

  8. Preparation, characterization, and anti-tumor property of podophyllotoxin-loaded solid lipid nanoparticles.

    PubMed

    Zhu, R R; Qin, L L; Wang, M; Wu, S M; Wang, S L; Zhang, R; Liu, Z X; Sun, X Y; Yao, S D

    2009-02-01

    In an effort to develop an alternative formulation of podophyllotoxin suitable for drug release and delivery, podophyllotoxin-loaded solid lipid nanoparticles (PPT-SLNs) were constructed, characterized and examined for in vitro cytotoxicity and tumor inhibition. The SLNs were prepared by using a solvent emulsification-evaporation method, and their size was around 50 nm. TEM detection showed that the SLNs were homogeneous and spherical in shape, and differential scanning calorimetry (DSC) measurement revealed a new conformation of PPT-SLNs. An in vitro drug release study showed that PPT was released from the SLNs in a slow but time-dependent manner. Furthermore, the treatment of 293T and HeLa cells with PPT-SLNs demonstrated that PPT-SLNs were less toxic to normal cells and more effective in anti-tumor potency compared with unconjugated PPT. A colony forming efficiency assay showed an effective long-term cancer growth suppression of PPT-SLNs; in addition, they can also enhance the apoptotic and cellular uptake processes on tumor cells compared with PPT. These results collectively demonstrated that this SLN formulation has a potential application as an alternative delivery system for anti-tumor drugs. PMID:19417361

  9. NF-κB-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-κB) 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-κB 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-κB-dependent and -independent manner. DMAPT-mediated NF-κB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of NF-κB 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-κB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive NF-κB activity. Overexpression of a constitutively active p65 subunit of NF-κB 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-κB inhibition. These results add KMT5C to the list NF-κB-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-κB-dependent and -independent cancer-specific epigenetic abnormalities. PMID:25611383

  10. NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT.

    PubMed

    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-κB) 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-κB 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-κB-dependent and -independent manner. DMAPT-mediated NF-κB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of NF-κB 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-κB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive NF-κB activity. Overexpression of a constitutively active p65 subunit of NF-κB 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-κB inhibition. These results add KMT5C to the list NF-κB-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-κB-dependent and -independent cancer-specific epigenetic abnormalities. PMID:25611383

  11. 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.

  12. The Anticancer Agent Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Prosurvival Autophagy by Two Mechanisms

    PubMed Central

    Gutierrez, Elaine; Richardson, Des R.; Jansson, Patric J.

    2014-01-01

    Autophagy functions as a survival mechanism during cellular stress and contributes to resistance against anticancer agents. The selective antitumor and antimetastatic chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) causes lysosomal membrane permeabilization and cell death. Considering the integral role of lysosomes in autophagy and cell death, it was important to assess the effect of Dp44mT on autophagy to further understand its mechanism of action. Notably, Dp44mT affected autophagy by two mechanisms. First, concurrent with its antiproliferative activity, Dp44mT increased the expression of the classical autophagic marker LC3-II as a result of induced autophagosome synthesis. Second, this effect was supplemented by a reduction in autophagosome degradation as shown by the accumulation of the autophagic substrate and receptor p62. Conversely, the classical iron chelator desferrioxamine induced autophagosome accumulation only by inhibiting autophagosome degradation. The formation of redox-active iron or copper Dp44mT complexes was critical for its dual effect on autophagy. The cytoprotective antioxidant N-acetylcysteine inhibited Dp44mT-induced autophagosome synthesis and p62 accumulation. Importantly, Dp44mT inhibited autophagosome degradation via lysosomal disruption. This effect prevented the fusion of lysosomes with autophagosomes to form autolysosomes, which is crucial for the completion of the autophagic process. The antiproliferative activity of Dp44mT was suppressed by Beclin1 and ATG5 silencing, indicating the role of persistent autophagosome synthesis in Dp44mT-induced cell death. These studies demonstrate that Dp44mT can overcome the prosurvival activity of autophagy in cancer cells by utilizing this process to potentiate cell death. PMID:25301941

  13. Genome-wide functional genetic screen with the anticancer agent AMPI-109 identifies PRL-3 as an oncogenic driver in triple-negative breast cancers.

    PubMed

    Gari, Hamid H; Gearheart, Christy M; Fosmire, Susan; DeGala, Gregory D; Fan, Zeying; Torkko, Kathleen C; Edgerton, Susan M; Lucia, M Scott; Ray, Rahul; Thor, Ann D; Porter, Christopher C; Lambert, James R

    2016-03-29

    Triple-negative breast cancers (TNBC) are among the most aggressive and heterogeneous cancers with a high propensity to invade, metastasize and relapse. Here, we demonstrate that the anticancer compound, AMPI-109, is selectively efficacious in inhibiting proliferation and inducing apoptosis of multiple TNBC subtype cell lines as assessed by activation of pro-apoptotic caspases-3 and 7, PARP cleavage and nucleosomal DNA fragmentation. AMPI-109 had little to no effect on growth in the majority of non-TNBC cell lines examined. We therefore utilized AMPI-109 in a genome-wide shRNA screen in the TNBC cell line, BT-20, to investigate the utility of AMPI-109 as a tool in helping to identify molecular alterations unique to TNBC. Our screen identified the oncogenic phosphatase, PRL-3, as a potentially important driver of TNBC growth, migration and invasion. Through stable lentiviral knock downs and transfection with catalytically impaired PRL-3 in TNBC cells, loss of PRL-3 expression, or functionality, led to substantial growth inhibition. Moreover, AMPI-109 treatment, downregulation of PRL-3 expression or impairment of PRL-3 activity reduced TNBC cell migration and invasion. Histological evaluation of human breast cancers revealed PRL-3 was significantly, though not exclusively, associated with the TNBC subtype and correlated positively with regional and distant metastases, as well as 1 and 3 year relapse free survival. Collectively, our study is proof-of-concept that AMPI-109, a selectively active agent against TNBC cell lines, can be used as a molecular tool to uncover unique drivers of disease progression, such as PRL-3, which we show promotes oncogenic phenotypes in TNBC cells. PMID:26909599

  14. Synthesis and structure-activity relationship study of 2-(substituted benzylidene)-7-(4-fluorophenyl)-5-(furan-2-yl)-2H-thiazolo[3,2-a]pyrimidin-3(7H)-one derivatives as anticancer agents.

    PubMed

    Selvam, T P; Karthick, V; Kumar, P V; Ali, M A

    2012-08-01

    The synthesis and structure-activity relationship (SAR) study of a series of 2-(substituted benzylidene)-7-(4-fluorophenyl)-5-(furan-2-yl)-2H-thiazolo[3,2-a]pyrimidin-3(7H)-one (4a-4j) derivatives as anticancer agents are described. This series of thiazolopyrimidines were synthesized by the reaction of 7-(4-fluoro phenyl)-5-(furan-2-yl)-2H-thiazolo[3,2-a] pyrimidin-3(7H)-one (3) with appropriate substituted aldehydes in the presence of anhydrous sodium acetate and glacial acetic acid. Their structures were confirmed by IR, (1)H-NMR, mass, and elemental analyses. These novel thiazolopyrimidine derivatives were screened for their anticancer activity on the U937 human histocytic lymphoma cell line by 3-(4,5-dimethyl thiazole-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. The comparison of anticancer activity of thiazolopyrimidine was performed considering their structures. This study was done using 2-(substituted benzylidene)-7-(4-fluorophenyl)-5-(furan-2-yl)-2H-thiazolo[3,2-a]pyrimidin-3(7H)-one (4a-4j) as a basic model, showing that i) presence of a hydrogen donor/acceptor domain [thiazolo[3,2-a]pyrimidin-3(7H)-one] on the thiazolopyrimidine ring; ii) presence of a hydrophobic [(4-fluorophenyl)] aryl ring system on the thiazolopyrimidine ring; iii) presence of an electron donor moiety [5-(furan-2-yl)] on the thiazolopyrimidine ring; iv) ortho and para substitution of the distal aryl ring [2-(substituted benzylidene)] function strongly influenced anticancer activity. Among these compounds (4a-4j) para substituted derivatives 4c, 4e, 4f, 4g, 4h, and 4j showed significant anticancer activity. PMID:23006990

  15. Synthesis and biological evaluation of novel 2,3-dihydrochromeno[3,4-d]imidazol-4(1H)-one derivatives as potent anticancer cell proliferation and migration agents.

    PubMed

    Han, Xuan; Luo, Jiang; Wu, Feng; Hou, XueYan; Yan, Guoyi; Zhou, Meng; Zhang, Mengqi; Pu, Chunlan; Li, Rui

    2016-05-23

    In this study, a series of novel molecules containing chromeno [3,4-d] imidazol-4(1H)-one was synthesized and their biological activities were evaluated. Among them, compound 35 showed a dramatic anticancer activity against HCT116 and MCF-7, and the flow cytometry assays demonstrated that it could arrest G0/G1 cell-cycle and induce apoptosis of SW620 cells in a dose-dependent manner. Besides, it also blocked MCF-7 cancer cell migration. Moreover, it inhibited tumor growth in HCT116 subcutaneously implanted xenografted mice. Taken together, compound 35 may be a promising candidate for anti-cancer agent as well as metastatic one. PMID:26994691

  16. 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

    Pawłowska, 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 β-galactosidase (SA-β-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

  17. Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL

    PubMed Central

    2011-01-01

    Introduction It is postulated that breast cancer stem cells (bCSCs) mediate disease recurrence and drive formation of distant metastases - the principal cause of mortality in breast cancer patients. Therapeutic targeting of bCSCs, however, is hampered by their heterogeneity and resistance to existing therapeutics. In order to identify strategies to selectively remove bCSCs from breast cancers, irrespective of their clinical subtype, we sought an apoptosis mechanism that would target bCSCs yet would not kill normal cells. Suppression of the apoptosis inhibitor cellular FLICE-Like Inhibitory Protein (c-FLIP) partially sensitizes breast cancer cells to the anti-cancer agent Tumour Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL). Here we demonstrate in breast cancer cell lines that bCSCs are exquisitely sensitive to the de-repression of this pro-apoptotic pathway, resulting in a dramatic reduction in experimental metastases and the loss of bCSC self-renewal. Methods Suppression c-FLIP was performed by siRNA (FLIPi) in four breast cancer cell lines and by conditional gene-knockout in murine mammary glands. Sensitivity of these cells to TRAIL was determined by complementary cell apoptosis assays, including a novel heterotypic cell assay, while tumour-initiating potential of cancer stem cell subpopulations was determined by mammosphere cultures, aldefluor assay and in vivo transplantation. Results Genetic suppression of c-FLIP resulted in the partial sensitization of TRAIL-resistant cancer lines to the pro-apoptotic effects of TRAIL, irrespective of their cellular phenotype, yet normal mammary epithelial cells remained refractory to killing. While 10% to 30% of the cancer cell populations remained viable after TRAIL/FLIPi treatment, subsequent mammosphere and aldefluor assays demonstrated that this pro-apoptotic stimulus selectively targeted the functional bCSC pool, eliminating stem cell renewal. This culminated in an 80% reduction in primary tumours and a 98% reduction in metastases following transplantation. The recurrence of residual tumour initiating capacity was consistent with the observation that post-treated adherent cultures re-acquired bCSC-like properties in vitro. Importantly however this recurrent bCSC activity was attenuated following repeated TRAIL/FLIPi treatment. Conclusions We describe an apoptotic mechanism that selectively and repeatedly removes bCSC activity from breast cancer cell lines and suggest that a combined TRAIL/FLIPi therapy could prevent metastatic disease progression in a broad range of breast cancer subtypes. PMID:21914219

  18. Design and Evaluation of Novel Antimicrobial and Anticancer Agents Among Tetrazolo[1,5-c]quinazoline-5-thione S-Derivatives

    PubMed Central

    Antypenko, Lyudmyla M.; Kovalenko, Sergey I.; Antypenko, Olexii M.; Katsev, Andrey M.; Achkasova, Olena M.

    2013-01-01

    The novel heterocyclization of 5-(2-aminophenyl)-1H-tetrazole with potassium ethylxanthogenate or carbon disulfide was proposed. The potassium salt of the tetrazolo[1,5-c]quinazoline-5-thione was subsequently modified by alkylation with proper halogen derivatives to (tetrazolo[1,5-c]quinazolin-5-ylthio)alkyls, N,N-dialkylethylamines, 1-aryl-2-ethanones, 1-(alkyl)aryl-2-ethanols, carboxylic acids, and esters. The structures of all newly synthesized compounds were confirmed by FT-IR, UV-vis, LC-MS, 1H, 13C NMR, and elemental analysis data. The substances were screened for antibacterial and antifungal activities (100 μg) against Escherichia coli, Staphylococcus aureus, Enterobacter aerogenes, Entrococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans. Preliminary bioluminescence inhibition tests against Photobacterium leiognathi Sh1 showed that substances 5.2–5.4, 6.1, 7.1 with ethanone or carboxylic acid substituents showed toxicity against bacteria cells. The substances chosen by the US National Cancer Institute (NCI) were screened for their ability to inhibit 60 different human tumor cell lines, where 2-(tetrazolo[1,5-c]quinazolin-5-ylthio)-1-(4-tolyl)ethanone (5.2), 3-(tetrazolo[1,5-c]quinazolin-5-ylthio)propanoic and related 3-metyl-butanoic acids (6.2, 6.3), and ethyl tetrazolo[1,5-c]quinazolin-5-ylthio)acetate (7.2) showed lethal antitumor activity (1.0 μM) against the acute lymphoblastic leukemia cell line (CCRF-CEM), and substances 5.2 and 6.3 exhibited moderate anticancer properties inhibiting growth of the leukemia MOLT-4 and HL06-(TB) cell lines. The moderate antitumor activity was demonstrated in 1-(2,5-dimethoxyphenyl)-2-(tetrazolo[1,5-c]quinazolin-5-ylthio)ethanone (5.4) against the CNS cancer cell line SNB-75. Comparing the docking mode of the Gefitinib and synthesised substances on the ATP binding site of EGFR, it could be assumed that these compounds might act in the same way. The results of the investigation could be considered as a useful base for future development of potent antimicrobials and antitumor agents among tetrazolo[1,5-c]quinazoline-5-thione S-derivatives. PMID:23641327

  19. 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

  20. 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

  1. 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

  2. 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

  3. Anticancer Studies of Aqueous Extract of Roots and Leaves of Pandanus Odoratissimus f. ferreus (Y. Kimura) Hatus: An In Vitro Approach.

    PubMed

    Raj, Gunti Gowtham; Varghese, Hyma Sara; Kotagiri, Sarita; Vrushabendra Swamy, B M; Swamy, Archana; Pathan, Rafi Khan

    2014-10-01

    A number of medicinal plant extracts are being used against various diseases in different systems of medicine such as Ayurveda, Unani, and Siddha, but only a few of them have been scientifically explored. The objective of the present study was to explore the dose-dependent in vitro anticancer effects of the extracts of Pandanus odoratissimus whose scientific documentation as an anticancer agent is lacking despite being used traditionally. The dried parts of roots and leaves were extracted with methanol (MEPO) and water (AEPO). The extracts were then subjected to in vitro cytotoxic and antimitotic screening by brine shrimp lethality assay and onion root tip method, respectively. Further, the behavior of the extracts on calu-6 (non-small cell lung cancer cell lines), PBMC (peripheral blood mononuclear cells) and WI (lung fibroblast cell lines) was studied using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay followed by flow cytometric analysis on calu-6 cell lines. AEPO showed significant cytotoxic and antimitotic activities. It showed 100% lethality of brine shrimps at 80 μg/ml and an LC50 of 33.33 μg/ml, which was eightfold higher than that of synthetic standard podophyllotoxin (4.16 μg/ml). AEPO at 10 mg/ml concentration showed significant antimitotic activity by showing 3% mitotic index. which was more than that of standard cyclophosphamide with 4% mitotic index in comparison to control. There was a significant reduction in cell proliferation of calu-6 cells, ranging from 56 to 35%, after 24-48 h of treatment with 200 μg/ml (P < 0.001) of AEPO, while AEPO remained unaffected on PBMC and WI-38 cel lines. Cell cycle analysis revealed that AEPO at 50 μg/ml and 100 μg/ml significantly increased the number of cells in sub G0-G1 phase, indicating the cells entering in to apoptotic phase. These results suggest that aqueous extract of P. odoratissimus possesses better anticancer activity. The plant has the potential to be used in anticancer therapy, and this study scientifically validated the folklore use of this plant. PMID:25379472

  4. Hydrothiolation of benzyl mercaptan to arylacetylene: application to the synthesis of (E) and (Z)-isomers of ON 01910Na (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 01910Na, a phase III clinical stage anti-cancer agent and its inactive geometrical isomer (Z)-ON 01910Na. 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

  5. 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

  6. Countering effects of a combination of podophyllotoxin, podophyllotoxin β-D-glucoside and rutin hydrate in minimizing radiation induced chromosomal damage, ROS and apoptosis in human blood lymphocytes.

    PubMed

    Dutta, Sangeeta; Yashavarddhan, M H; Srivastava, Nitya Nand; Ranjan, Rajiv; Bajaj, Sania; Kalita, Bhargab; Singh, Abhinav; Flora, Swaran J S; Gupta, Manju Lata

    2016-05-01

    The present study was conceptualized with the aim of developing a safe radioprotector for human application against radiation induced toxicity. For this study, a formulation (G-002M) prepared by combining three active principles isolated from rhizomes of Podophyllum hexandrum, was evaluated for its potential to protect genomic DNA of human blood cells exposed to different doses of radiation (5,7&10Gy). Blood samples were pretreated (-1hr to exposure) with G-002M. Parameters of Premature Chromosome Condensation (PCC) assay like PCC-index, PCC-rings and PCC-fragments were used to estimate radiation induced chromosomal aberrations. Radiation (7Gy) induce ROS generation and its modulation by G-002M was determined by flow-cytometry and fluorescent microscopy while apoptosis (0,2,24&48 hr) was analyzed using TUNEL assay. Effect on spindle organization in G2/M arrested cells by all the three compounds individually was studied using immunofluorescence microscopy. Irradiation caused dose dependent linear increase in PCC-rings and fragments, while decline in PCC index. G-002M pretreatment significantly decreased these chromosomal aberrations at all the radiation doses and assisted cell survival as indicated by increased PCC index compared with radiation only group. Significant decrease in radiation induced intracellular ROS (45 ± 3%) and apoptosis (49.9%) was also exhibited by the formulation. On podophyllotoxin treatment, most of the cells have shown blocked spindles however, depicted normal arrangement. G-002M also demonstrated a highly significant Dose Modifying Factor or DMF (PCC-rings: 2.27 and PCC-fragments: 1.60). Present study based on many parameters along with DMF study, strongly suggests that G-002M is an effective formulation with a potential to minimize chromosomal damage even at very high radiation doses. PMID:26993954

  7. A promising anti-cancer and anti-oxidant agents based on the pyrrole and fused pyrrole: synthesis, docking studies and biological evaluation.

    PubMed

    Fatahala, Samar Said; Shalaby, Emad Ahmed; Kassab, Shaymaa Emam; Mohamed, Mossad Said

    2015-01-01

    A series of N-aryl derivatives of pyrrole and its related derivatives of fused form (namely; tetrahydroindole and dihydroindenopyrroles) were prepared in fair to good yields. The newly synthesized compounds were confirmed using IR, (1)H NMR, Mass spectral and elemental analysis. Tetrahydrobenzo[b] pyrroles Ia-d, 1,4-dihydroindeno[1,2-b]pyrroles IIa,b and pyrroles IIIa-c,e were evaluated for anticancer activity, coinciding with the antioxidant activity; using Di-Phenyl Picryl Hydrazyl (DPPH) tests. The cytotoxicity of the tested compounds (at a concentration of 100 and 200 μg /mL) was performed against HepG-2 and EACC cell lines. Compounds Ib, d and IIa showed promising antioxidant activity beside their anticancer activity. Docking studies were employed to justify the promising anticancer activity of Ib,d and IIa. Protein kinase (PKase)-PDB entry 1FCQ was chosen as target enzyme for this purpose using the MOLSOFT ICM 3.4-8C program. The docking results of the tested compounds went aligned with the respective anticancer assay results. PMID:25929576

  8. Synthesis, structure-activity relationship of iodinated-4-aryloxymethyl-coumarins as potential anti-cancer and anti-mycobacterial agents.

    PubMed

    Basanagouda, Mahantesha; Jambagi, Vishwanath B; Barigidad, Nivedita N; Laxmeshwar, Sandeep S; Devaru, Venkatesh; Narayanachar

    2014-03-01

    A series of new iodinated-4-aryloxymethylcoumarins 6, 8 and 10 have been obtained from the reaction of various 4-bromomethylcoumarins 4 with 2-iodophenol 5, 3-iodophenol 7 and 4-iodophenol 9 respectively. All the title compounds were screened for anticancer activity against two cancer cell lines (MDA-MB human adenocarcinoma mammary gland and A-549 human lung carcinoma) and two mycobacterial strains (Mycobacterium tuberculosis H₃₇ RV and Mycobacterium phlei). The SAR results indicate that nine compounds are potent, among these 10h and 10i having chlorine are most effective. This is the first report assigning in vitro anti-mycobacterial, anticancer and structure-activity relationship for this new class of iodinated-4-aryloxymethyl-coumarins. PMID:24463645

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

    PubMed

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

    2016-05-01

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

  10. 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 (ΔG =−9.2 kcal/mol) when compared with other PIs: this is in a reasonable accordance with the experimental data (IC50 3.1 μM). Indinavir, saquinavir, and ritonavir have close binding affinity to NFV (ΔG =−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

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

    PubMed

    Arodola, Olayide A; Soliman, Mahmoud E S

    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 (ΔG =-9.2 kcal/mol) when compared with other PIs: this is in a reasonable accordance with the experimental data (IC50 3.1 μM). Indinavir, saquinavir, and ritonavir have close binding affinity to NFV (ΔG =-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

  12. 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)

  13. Anticancer mechanisms of cannabinoids

    PubMed Central

    Velasco, G.; Sánchez, C.; Guzmán, M.

    2016-01-01

    In addition to the well-known palliative effects of cannabinoids on some cancer-associated symptoms, a large body of evidence shows that these molecules can decrease tumour growth in animal models of cancer. They do so by modulating key cell signalling pathways involved in the control of cancer cell proliferation and survival. In addition, cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals. In this review, we discuss the current understanding of cannabinoids as antitumour agents, focusing on recent discoveries about their molecular mechanisms of action, including resistance mechanisms and opportunities for their use in combination therapy. Those observations have already contributed to the foundation for the development of the first clinical studies that will analyze the safety and potential clinical benefit of cannabinoids as anticancer agents. PMID:27022311

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

    PubMed

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

    2016-01-20

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

  15. 4H-Chromene-based anticancer agents towards multi-drug resistant HL60/MX2 human leukemia: SAR at the 4th and 6th positions.

    PubMed

    Puppala, Manohar; Zhao, Xinghua; Casemore, Denise; Zhou, Bo; Aridoss, Gopalakrishnan; Narayanapillai, Sreekanth; Xing, Chengguo

    2016-03-15

    4H-Chromene-based compounds, for example, CXL017, CXL035, and CXL055, have a unique anticancer potential that they selectively kill multi-drug resistant cancer cells. Reported herein is the extended structure-activity relationship (SAR) study, focusing on the ester functional group at the 4th position and the conformation at the 6th position. Sharp SARs were observed at both positions with respect to cellular cytotoxic potency and selectivity between the parental HL60 and the multi-drug resistant HL60/MX2 cells. These results provide critical guidance for future medicinal optimization. PMID:26867486

  16. Synthesis and biological screening of a combinatorial library of beta-chlorovinyl chalcones as anticancer, anti-inflammatory and antimicrobial agents.

    PubMed

    Bandgar, Babasaheb P; Gawande, Shrikant S

    2010-03-01

    A combinatorial library of beta-chlorovinyl chalcones (4) were synthesized by Claisen-Schmidt condensation reaction. Catalytic reaction of substituted 3-chloro-3-phenyl-propenal (2) and 1-(2,4-dimethoxy-phenyl)-ethanone or 1-(4-methoxy-phenyl)-ethanone (3) in alkaline conditions furnished the target compound 5-chloro-1-(2,4-dimethoxy-phenyl)-5-phenyl-penta-2,4-dien-1-one (4). The synthesized compounds were screened for their biological activity viz. anticancer, anti-inflammatory and antimicrobial activities. Synthesized compounds 4g and 4h revealed promising anti-inflammatory activity (66-67% TNF-alpha and 95-97% IL-6 inhibitory activity at 10 microM). Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Furthermore, the anticancer activity (30-40%) was shown by compounds 4d, 4e, 4h and 4b at 10 microM concentrations against ACHN followed by Calu 1, Panc1, HCT116 and H460 cell lines. Some of the compounds 4d, 4e, 4a, 4i and 4b revealed promising antimicrobial activity at MIC 50-100 microg/mL against selected pathogenic bacteria and fungi. PMID:20138527

  17. Cinnamomum verum Component 2-Methoxycinnamaldehyde: A Novel Anticancer Agent with Both Anti-Topoisomerase I and II Activities in Human Lung Adenocarcinoma A549 Cells In Vitro and In Vivo.

    PubMed

    Wong, Ho-Yiu; Tsai, Kuen-Daw; Liu, Yi-Heng; Yang, Shu-Mei; Chen, Ta-Wei; Cherng, Jonathan; Chou, Kuo-Shen; Chang, Chen-Mei; Yao, Belen T; Cherng, Jaw-Ming

    2016-02-01

    Cinnamomum verum is used to make the spice cinnamon and has been used as a traditional Chinese herbal medicine. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the bark of the plant, and its underlying molecular biomarkers associated with carcinogenesis in human lung adenocarcinoma A549 cells. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by an upregulation of pro-apoptotic Bax and Bak genes and downregulation of anti-apoptotic Bcl-2 and Bcl-XL genes, mitochondrial membrane potential loss, cytochrome c release, activation of caspase-3 and -9, and morphological characteristics of apoptosis, including plasma membrane blebbing and long comet tail. In addition, 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartment (VAC) and suppressions of nuclear transcription factors nuclear factor-κB (NF-κB) and both topoisomerase I and II activities. Further study reveals that the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against A549 cells is accompanied by downregulations of NF-κB binding activity and proliferative control involving apoptosis and both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and VAC. Our data suggest that 2-MCA could be a potential agent for anticancer therapy. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26676220

  18. 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

  19. Discovery of a novel anti-cancer agent targeting both topoisomerase I and II in hepatocellular carcinoma Hep 3B cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde.

    PubMed

    Perng, Daw-Shyong; Tsai, Yu-Hsin; Cherng, Jonathan; Kuo, Chih-Wei; Shiao, Chih-Chung; Cherng, Jaw-Ming

    2016-08-01

    Cinnamomum verum has been used as a traditional Chinese herbal medicine. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the bark of the plant, in hepatocellular carcinoma Hep 3B cells. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by an up-regulation of pro-apoptotic bax and bak genes and down-regulation of anti-apoptotic bcl-2 and bcl-XL genes, mitochondrial membrane potential loss, cytochrome c release, activation of caspase 3 and 9, increase in the DNA content in sub G1, and morphological characteristics of apoptosis. 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartments (VAC), suppressions of nuclear transcription factors NF-κB, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and both topoisomerase I and II activities in a dose-dependent manner. Further study reveals the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against Hep 3B cells is accompanied by downregulations of NF-κB binding activity, inflammatory responses involving COX-2 and PGE2, and proliferative control involving apoptosis, both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and VAC. Our data suggest that 2-MCA could be a potential agent for anticancer therapy. PMID:26707867

  20. The application of poly(N-isopropylacrylamide)-co-polystyrene nanofibers as an additive agent to facilitate the cellular uptake of an anticancer drug

    NASA Astrophysics Data System (ADS)

    Song, Min; Guo, Dadong; Pan, Chao; Jiang, Hui; Chen, Chen; Zhang, Renyun; Gu, Zhongze; Wang, Xuemei

    2008-04-01

    In this paper, we have fabricated poly(N-isopropylacrylamide)-co-polystyrene (PNIPAM-co-PS) nanofibers by electrospinning and explored the possibility to utilize the PNIPAM-co-PS nanofibers to enhance the permeation and uptake of the anticancer drug daunorubicin in drug-sensitive and drug-resistant leukemia K562 cells. Our MTT assay and electrochemical studies demonstrate that PNIPAM-co-PS nanofibers could play an important role in facilitating the cell track and drug delivery to the cancer cells. Meanwhile, the observations of atomic force microscopy (AFM) and confocal fluorescence microscopy indicate that the relevant interaction of the PNIPAM-co-PS nanofibers with bioactive molecules on the membrane of leukemia cell lines could affect the intracellular drug uptake positively and lead to the efficient accumulation of daunorubicin in drug-sensitive and drug-resistant cancer cells.

  1. 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 μM 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

  2. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists. PMID:12132261

  3. Design, synthesis and molecular modeling studies of few chalcone analogues of benzimidazole for epidermal growth factor receptor inhibitor in search of useful anticancer agent.

    PubMed

    Chhajed, Santosh S; Sonawane, Sandeep S; Upasani, Chandrashekhar D; Kshirsagar, Sanjay J; Gupta, Pramodkumar P

    2016-04-01

    In the present investigation, few 3-(substitutedphenyl)-1-[2-(1-hydroxy-ethyl)]-1H-benzimidazol-1-yl)prop-2-en-1-ones are EGFR antagonist are designed, by molecular docking analysis. The synthesized compounds were tested for their in vitro anticancer activity by propidium iodide fluorescent assay and Trypan blue viability assay against colorectal cancer cell lines (HCT116) and non-small cell lung cancer cell lines (H460). Human Epithelial Kidney cell lines (HEK) are used as normal cell lines for studying effect of drug on non-cancerous cells within human body. Evaluation of cytotoxic studies of synthesized compounds CHL(1-8) reveal that compound CHL1 [IC50=7.31 and 10.16μM against HCT116 and H460 cell lines respectively, by PI assay] and CHL8 [IC50=12.52 and 6.83 against HCT116 and H460μM cell lines respectively] possess promising cytotoxic activity. PMID:26878127

  4. An anticancer agent, pyrvinium pamoate inhibits the NADH-fumarate reductase system--a unique mitochondrial energy metabolism in tumour microenvironments.

    PubMed

    Tomitsuka, Eriko; Kita, Kiyoshi; Esumi, Hiroyasu

    2012-08-01

    Increased glycolysis is the principal explanation for how cancer cells generate energy in the absence of oxygen. However, in actual human tumour microenvironments, hypoxia is often associated with hypoglycemia because of the poor blood supply. Therefore, glycolysis cannot be the sole mechanism for the maintenance of the energy status in cancers. To understand energy metabolism in cancer cells under hypoxia-hypoglycemic conditions mimicking the tumour microenvironments, we examined the NADH-fumarate reductase (NADH-FR) system, which functions in parasites under hypoxic condition, as a candidate mechanism. In human cancer cells (DLD-1, Panc-1 and HepG2) cultured under hypoxic-hypoglycemic conditions, NADH-FR activity, which is composed of the activities of complex I (NADH-ubiquinone reductase) and the reverse reaction of complex II (quinol-FR), increased, whereas NADH-oxidase activity decreased. Pyrvinium pamoate (PP), which is an anthelmintic and has an anti-cancer effect within tumour-mimicking microenvironments, inhibited NADH-FR activities in both parasites and mammalian mitochondria. Moreover, PP increased the activity of complex II (succinate-ubiquinone reductase) in mitochondria from human cancer cells cultured under normoxia-normoglycemic conditions but not under hypoxia-hypoglycemic conditions. These results indicate that the NADH-FR system may be important for maintaining mitochondrial energy production in tumour microenvironments and suggest its potential use as a novel therapeutic target. PMID:22528668

  5. 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

  6. CARBOXYLESTERASE-2 IS A HIGHLY SENSITIVE TARGET OF THE ANTIOBESITY AGENT ORLISTAT WITH PROFOUND IMPLICATIONS IN THE ACTIVATION OF ANTICANCER PRODRUGS

    PubMed Central

    Xiao, Da; Shi, Deshi; Yang, Dongfang; Barthel, Benjamin; Koch, Tad H.; Yan, Bingfang

    2014-01-01

    Orlistat has been the most used anti-obesity drug and the mechanism of its action is to reduce lipid absorption by inhibiting gastrointestinal lipases. These enzymes, like carboxylesterases (CESs), structurally belong to the ?/? hydrolase fold superfamily. Lipases and CESs are functionally related as well. Some CESs (e.g., human CES1) have been shown to hydrolyze lipids. This study was designed to test the hypothesis that orlistat inhibits CESs with higher potency toward CES1 than CES2, a carboxylesterase with little lipase activity. Liver microsomes and recombinant CESs were tested for the inhibition of the hydrolysis of standard substrates and the anticancer prodrugs pentyl carbamate of p-aminobenzyl carbamate of doxazolidine (PPD) and irinotecan. Contrary to the hypothesis, orlistat at 1 nM inhibited CES2 activity by 75% but no inhibition on CES1, placing CES2 one of the most sensitive targets of orlistat. The inhibition varied among some CES2 polymorphic variants. Pretreatment with orlistat reduced the cell killing activity of PPD. Certain mouse but not rat CESs were also highly sensitive. CES2 is responsible for the hydrolysis of many common drugs and abundantly expressed in the gastrointestinal track and liver. Inhibition of this carboxylesterase probably presents a major source for altered therapeutic activity of these medicines if co-administered with orlistat. In addition, orlistat has been linked to various types of organ toxicities, and this study provides an alternative target potentially involved in these toxicological responses. PMID:23228697

  7. Fabrication of hollow and porous structured GdVO4:Dy3+ nanospheres as anticancer drug carrier and MRI contrast agent.

    PubMed

    Kang, Xiaojiao; Yang, Dongmei; Ma, Ping'an; Dai, Yunlu; Shang, Mengmeng; Geng, Dongling; Cheng, Ziyong; Lin, Jun

    2013-01-29

    Hollow and porous structured GdVO(4):Dy(3+) spheres were fabricated via a facile self-sacrificing templated method. The large cavity allows them to be used as potential hosts for therapeutic drugs, and the porous feature of the shell allows guest molecules to easily pass through the void space and surrounding environment. The samples show strong yellow-green emission of Dy(3+) (485 nm, (4)F(9/2) → (6)H(15/2); 575 nm, (4)F(9/2) → (6)H(13/2)) under UV excitation. The emission intensity of GdVO(4):Dy(3+) was weakened after encapsulation of anticancer drug (doxorubicin hydrochloride, DOX) and gradually restored with the cumulative released time of DOX. These hollow spheres were nontoxic to HeLa cells, while DOX-loaded samples led to apparent cytotoxicity as a result of the sustained release of DOX. ICP measurement indicates that free toxic Gd ions can hardly dissolate from the matrix. The endocytosis process of DOX-loaded hollow spheres is observed using confocal laser scanning microscopy (CLSM). Furthermore, GdVO(4):Dy(3+) hollow spheres can be used for T(1)-weighted magnetic resonance (MR) imaging. These results implicate that the luminescent GdVO(4):Dy(3+) spheres with hollow and porous structure are promising platforms for drug storage/release and MR imaging. PMID:23281806

  8. 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 μM (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 μM; little activity was seen against Gram-negative strains. It has been established that all the compounds are catalytic inhibitors of human topoisomerase II.

  9. Discovery of a novel anticancer agent with both anti-topoisomerase I and II activities in hepatocellular carcinoma SK-Hep-1 cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde

    PubMed Central

    Perng, Daw-Shyong; Tsai, Yu-Hsin; Cherng, Jonathan; Wang, Jeng-Shing; Chou, Kuo-Shen; Shih, Chia-Wen; Cherng, Jaw-Ming

    2016-01-01

    Cinnamomum verum is used to make the spice cinnamon and has been used as a traditional Chinese herbal medicine for various applications. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the bark of the plant, and its underlying molecular biomarkers associated with carcinogenesis in human hepatocellular carcinoma SK-Hep-1 cell line. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by mitochondrial membrane potential loss, activation of caspase-3 and caspase-9, increase in the DNA content in sub-G1, and morphological characteristics of apoptosis, including blebbing of plasma membrane, nuclear condensation, fragmentation, apoptotic body formation, and long comet tail. In addition, 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartments, suppressions of nuclear transcription factors NF-κB, cyclooxygenase-2, prostaglandin E2 (PGE2), and both topoisomerase I and II activities in a dose-dependent manner. Further study reveals the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against SK-Hep-1 cells is accompanied by downregulations of NF-κB-binding activity, inflammatory responses involving cyclooxygenase-2 and PGE2, and proliferative control involving apoptosis, both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and volume of acidic compartments. Similar effects (including all of the above-mentioned effects) were found in other tested cell lines, including human hepatocellular carcinoma Hep 3B, lung adenocarcinoma A549, squamous cell carcinoma NCI-H520, colorectal adenocarcinoma COLO 205, and T-lymphoblastic MOLT-3 (results not shown). Our data suggest that 2-MCA could be a potential agent for anticancer therapy. PMID:26792981

  10. Discovery of a novel anticancer agent with both anti-topoisomerase I and II activities in hepatocellular carcinoma SK-Hep-1 cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde.

    PubMed

    Perng, Daw-Shyong; Tsai, Yu-Hsin; Cherng, Jonathan; Wang, Jeng-Shing; Chou, Kuo-Shen; Shih, Chia-Wen; Cherng, Jaw-Ming

    2016-01-01

    Cinnamomum verum is used to make the spice cinnamon and has been used as a traditional Chinese herbal medicine for various applications. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the bark of the plant, and its underlying molecular biomarkers associated with carcinogenesis in human hepatocellular carcinoma SK-Hep-1 cell line. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by mitochondrial membrane potential loss, activation of caspase-3 and caspase-9, increase in the DNA content in sub-G1, and morphological characteristics of apoptosis, including blebbing of plasma membrane, nuclear condensation, fragmentation, apoptotic body formation, and long comet tail. In addition, 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartments, suppressions of nuclear transcription factors NF-κB, cyclooxygenase-2, prostaglandin E2 (PGE2), and both topoisomerase I and II activities in a dose-dependent manner. Further study reveals the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against SK-Hep-1 cells is accompanied by downregulations of NF-κB-binding activity, inflammatory responses involving cyclooxygenase-2 and PGE2, and proliferative control involving apoptosis, both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and volume of acidic compartments. Similar effects (including all of the above-mentioned effects) were found in other tested cell lines, including human hepatocellular carcinoma Hep 3B, lung adenocarcinoma A549, squamous cell carcinoma NCI-H520, colorectal adenocarcinoma COLO 205, and T-lymphoblastic MOLT-3 (results not shown). Our data suggest that 2-MCA could be a potential agent for anticancer therapy. PMID:26792981

  11. 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.

  12. 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-β 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

  13. Structure–activity relationship studies of naphthol AS-E and its derivatives as anticancer agents by inhibiting CREB-mediated gene transcription

    PubMed Central

    Li, Bingbing X.; Yamanaka, Kinrin; Xiao, Xiangshu

    2012-01-01

    CREB (cyclic AMP-response element binding protein) is a downstream transcription factor of a multitude of signaling pathways emanating from receptor tyrosine kinases or G-protein coupled receptors. CREB is not activated until it is phosphorylated at Ser133 and its subsequent binding to CREB-binding protein (CBP) through kinase-inducible domain (KID) in CREB and KID-interacting (KIX) domain in CBP. Tumor tissues from various organs present higher level of expression and activation of CREB. Thus CREB has been proposed as a promising cancer drug target. We previously described naphthol AS-E (1a) as a small molecule inhibitor of CREB-mediated gene transcription in living cells. Here we report the structure–activity relationship (SAR) studies of 1a by modifying the appendant phenyl ring. All the compounds were evaluated for in vitro inhibition of KIX–KID interaction, cellular inhibition of CREB-mediated gene transcription and inhibition of proliferation of four cancer cell lines (A549, MCF-7, MDA-MB-231 and MDA-MB-468). SAR indicated that a small and electron-withdrawing group was preferred at the para-position for KIX–KID interaction inhibition. Compound 1a was selected for further biological characterization and it was found that 1a down-regulated the expression of endogenous CREB target genes. Expression of a constitutively active CREB mutant, VP16-CREB in MCF-7 cells rendered the cells resistant to 1a, suggesting that CREB was critical in mediating its anticancer activity. Furthermore, 1a was not toxic to normal human cells. Collectively, these data support that 1a represents a structural template for further development into potential cancer therapeutics with a novel mechanism of action. PMID:23102993

  14. 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 μg/mL nanoparticles showed good toxicity. The IC50 value of nanoparticles was found to be 4.91 and 8.23 μg/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

  15. Antibody-Drug Conjugates and Small Molecule-Drug Conjugates: Opportunities and Challenges for the Development of Selective Anticancer Cytotoxic Agents.

    PubMed

    Casi, Giulio; Neri, Dario

    2015-11-25

    Conventional cancer chemotherapy heavily relies on the use of cytotoxic agents, which typically do not preferentially localize at the tumor site and cause toxicity to normal organs, preventing dose escalation to therapeutically active regimens. In principle, antibodies and other ligands could be used for the selective pharmacodelivery of cytotoxic agents to the neoplastic mass. For many years, the availability of ligands, capable of selective internalization into tumor cells, has been considered to be an essential requirement for the development of targeted cytotoxics. This assumption, however, has recently been challenged on the basis of therapeutic data obtained with noninternalizing drug conjugates. Moreover, quantitative evaluations of the tumor targeting properties of antibodies and of small organic ligands have provided new insights for the implementation of optimal strategies for the development of targeted cytotoxics. In this article, we highlight opportunities and challenges associated with the clinical and industrial development of antibody-drug conjugates and small molecule-drug conjugates for cancer therapy. PMID:26079148

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

    SciTech Connect

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

    2014-09-15

    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. - Highlights: • We intercalated chlorogenic into Zn/Al-layered double hydroxide by ion-exchange and coprecipitation methods. • The two methods gave nanocomposites with slightly different physico-chemical properties. • Chlorogenate-zinc aluminium layered double hydroxide nanohybrids have the potential to be used as a controlled release formulation. • The thermal stability of chlorogenic acid is markedly enhanced upon the intercalation process. • The inhibition of cancer cell growth is higher for nanohybrids than for free chlorogenic acid.

  17. 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine: An anticancer agent targeting hypoxic cells

    PubMed Central

    Seow, Helen A.; Penketh, Philip G.; Shyam, Krishnamurthy; Rockwell, Sara; Sartorelli, Alan C.

    2005-01-01

    To target malignant cells residing in hypoxic regions of solid tumors, we have designed and synthesized prodrugs generating the cytotoxic alkylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) after bioreductive activation. We postulate that one of these agents, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119), requires enzymatic nitro reduction to produce 90CE, whereas another agent, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-nitrobenzyloxy)carbonyl]hydrazine (PNBC), can also be activated by nucleophilic attack by thiols such as glutathione (GSH)/GST. We demonstrated that these agents selectively kill hypoxic EMT6 mouse mammary carcinoma and CHO cells. In hypoxia, 50 μM KS119 produced 5 logs of kill of EMT6 cells without discernable cytotoxicity in air; similar effects were observed with CHO cells. PNBC was less efficacious against hypoxic tumor cells and also had some toxicity to aerobic cells, presumably because of GST/thiol activation, making PNBC less interesting as a selective hypoxic-cell cytotoxin. BALB/c mice with established EMT6 solid tumors were used to demonstrate that KS119 could reach and kill hypoxic cells in solid tumors. To gain information on bioreductive enzymes involved in the activation of KS119, cytotoxicity was measured in CHO cell lines overexpressing NADH:cytochrome b5 reductase (NBR), NADPH:cytochrome P450 reductase (NPR), or NAD(P)H: quinone oxidoreductase 1 (NQO1). Increased cytotoxicity occurred in cells overexpressing NBR and NPR, whereas overexpressed NQO1 had no effect. These findings were supported by enzymatic studies using purified NPR and xanthine oxidase to activate KS119. KS119 has significant potential as a hypoxia-selective tumor-cell cytotoxin and is unlikely to cause major toxicity to well oxygenated normal tissues. PMID:15964988

  18. A Novel Sensitive Electrochemical Sensor for Podophyllotoxin Assay Based on the Molecularly Imprinted Poly-o-Phenylenediamine Film.

    PubMed

    Bai, Huiping; Wang, Chunqiong; Jun Peng; Wu, Yun; Yang, Yunhui; Cao, Qiue

    2015-03-01

    An electrochemical sensor for podophyllotoxin (PPT) based on the molecular imprinting polymer (MIP) membranes was constructed. The sensor was prepared by electropolymerizing o-phenylenediamine (o-PD) on a glassy carbon electrode (GCE) in the presence of PPT as template, and then removing the template by immersing the modified GCE in ethanol. Experimental parameters such as the types of monomer, scan cycles, concentration of o-PD and extraction condition were optimized. Under optimal conditions, the sensor exhibits a good selectivity and high sensitivity. A good linearity was obtained in the range of 4 x 10-8 mol · L(-1) to 3.2 x 10(-5) mol · L(-1) with an estimated detection limit of 4.8 x 10(-9) mol · L(-1). The sensor was applied to the determination of PPT in podophyllum hexandrum and human serum samples with satisfactory results. PMID:26413687

  19. Transition metal based anticancer drugs.

    PubMed

    Garbutcheon-Singh, K Benjamin; Grant, Maxine P; Harper, Benjamin W; Krause-Heuer, Anwen M; Manohar, Madhura; Orkey, Nikita; Aldrich-Wright, Janice R

    2011-01-01

    With an ageing baby-boomer population in the Western World, cancer is becoming a significant cause of death. The prevalence of cancer and all associated costs, both in human and financial terms, drives the search for new therapeutic drugs and treatments. Platinum anticancer agents, such as cisplatin have been highly successful but there are several disadvantages associated with their use. What is need are new compounds with different mechanisms of action and resistance profiles. What needs to be recognised is that there are many other metal in the periodic table with therapeutic potential. Here we have highlighted metal complexes with activity and have illustrate the different approaches to the design of anticancer complexes. PMID:21189131

  20. Anticancer Molecular Mechanisms of Resveratrol

    PubMed Central

    Varoni, Elena M.; Lo Faro, Alfredo Fabrizio; Sharifi-Rad, Javad; Iriti, Marcello

    2016-01-01

    Resveratrol is a pleiotropic phytochemical belonging to the stilbene family. Though it is only significantly present in grape products, a huge amount of preclinical studies investigated its anticancer properties in a plethora of cellular and animal models. Molecular mechanisms of resveratrol involved signaling pathways related to extracellular growth factors and receptor tyrosine kinases; formation of multiprotein complexes and cell metabolism; cell proliferation and genome instability; cytoplasmic tyrosine kinase signaling (cytokine, integrin, and developmental pathways); signal transduction by the transforming growth factor-β super-family; apoptosis and inflammation; and immune surveillance and hormone signaling. Resveratrol also showed a promising role to counteract multidrug resistance: in adjuvant therapy, associated with 5-fluoruracyl and cisplatin, resveratrol had additive and/or synergistic effects increasing the chemosensitization of cancer cells. Resveratrol, by acting on diverse mechanisms simultaneously, has been emphasized as a promising, multi-target, anticancer agent, relevant in both cancer prevention and treatment. PMID:27148534

  1. In vitro synergistic anticancer activity of the combination of T-type calcium channel blocker and chemotherapeutic agent in A549 cells.

    PubMed

    Byun, Joon Seok; Sohn, Joo Mi; Leem, Dong Gyu; Park, Byeongyeon; Nam, Ji Hye; Shin, Dong Hyun; Shin, Ji Sun; Kim, Hyoung Ja; Lee, Kyung-Tae; Lee, Jae Yeol

    2016-02-01

    As a result of our continuous research, new 3,4-dihydroquinazoline derivative containing ureido group, KCP10043F was synthesized and evaluated for T-type Ca(2+) channel (Cav3.1) blockade, cytotoxicity, and cell cycle arrest against human non-small cell lung (A549) cells. KCP10043F showed both weaker T-type Ca(2+) channel blocking activity and less cytotoxicity against A549 cells than parent compound KYS05090S [4-(benzylcarbamoylmethyl)-3-(4-biphenylyl)-2-(N,N',N'-trimethyl-1,5-pentanediamino)-3,4-dihydroquinazoline 2 hydrochloride], but it exhibited more potent G1-phase arrest than KYS05090S in A549 cells. This was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 2, CDK4, CDK6, cyclin D2, cyclin D3, and cyclin E at the protein levels. However, p27(KIP1) as a CDK inhibitor was gradually upregulated at the protein levels and increased recruitment to CDK2, CDK4 and CDK6 after KCP10043F treatment. Based on the strong G1-phase cell cycle arrest of KCP10043F in A549 cells, the combination of KCP10043F with etoposide (or cisplatin) resulted in a synergistic cell death (combination index=0.2-0.8) via the induction of apoptosis compared with either agent alone. Taken together with these overall results and the favorable in vitro ADME (absorption, distribution, metabolism, and excretion) profiles of KCP10043F, therefore, it could be used as a potential agent for the combination therapy on human lung cancer. PMID:26739776

  2. An estrogen analogue and promising anticancer agent refrains from inducing morphological damage and reactive oxygen species generation in erythrocytes, fibrin and platelets: a pilot study

    PubMed Central

    2014-01-01

    Background 2-Methoxyestradiol is known to have antitumour and antiproliferative action in vitro and in vivo. However, when 2-methoxyestradiol is orally administered, it is rapidly oxidized by the enzyme 17β-hydroxysteriod dehydrogenase in the gastrointestinal tract. Therefore, 2-methoxyestradiol never reaches high enough concentrations in the tissue to be able to exert these antitumour properties. This resulted in the in silico-design of 2-methoxyestradiol analogues in collaboration with the Bioinformatics and Computational Biology Unit (UP) and subsequent synthesis by iThemba Pharmaceuticals (Pty) Ltd (Modderfontein, Midrand, South Africa). One such a novelty-designed analogue is 2-ethyl-3-O-sulphamoyl-estra-1, 3, 5(10)16-tetraene (ESE-16). Methods This pilot study aimed to determine the morphological effect and possible generation of reactive oxygen species by ESE-16 on erythrocytes and platelet samples (with and without added thrombin) by means of scanning electron microscopy, transmission electron microscopy and flow cytometry. Results Erythrocytes and platelets were exposed to ESE-16 at a concentration of 180nM for 24 hours. Scanning- and transmission electron microscopy indicated that ESE-16 did not cause changes to erythrocytes, platelets or fibrin networks. Flow cytometry measurements of hydrogen peroxide and superoxide indicated that ESE-16 does not cause an increase in the generation of reactive oxygen species in these blood samples. Conclusion Further in vivo research is warranted to determine whether this novel in silico-designed analogue may impact on development of future chemotherapeutic agents and whether it could be considered as an antitumour agent. PMID:24932135

  3. Synthesis of α,β-Unsaturated Carbonyl-Based Compounds, Oxime and Oxime Ether Analogs as Potential Anticancer Agents for Overcoming Cancer Multidrug Resistance by Modulation of Efflux Pumps in Tumor Cells.

    PubMed

    Qin, Hua-Li; Leng, Jing; Zhang, Cheng-Pan; Jantan, Ibrahim; Amjad, Muhammad Wahab; Sher, Muhammad; Naeem-Ul-Hassan, Muhammad; Hussain, Muhammad Ajaz; Bukhari, Syed Nasir Abbas

    2016-04-14

    Sixty-nine novel α,β-unsaturated carbonyl based compounds, including cyclohexanone, tetralone, oxime, and oxime ether analogs, were synthesized. The antiproliferative activity determined by using seven different human cancer cell lines provided a structure-activity relationship. Compound 8ag exhibited high antiproliferative activity against Panc-1, PaCa-2, A-549, and PC-3 cell lines, with IC50 value of 0.02 μM, comparable to the positive control Erlotinib. The ten most active antiproliferative compounds were assessed for mechanistic effects on BRAF(V600E), EGFR TK kinases, and tubulin polymerization, and were investigated in vitro to reverse efflux-mediated resistance developed by cancer cells. Compound 8af exhibited the most potent BRAF(V600E) inhibitory activity with an IC50 value of 0.9 μM. Oxime analog 7o displayed the most potent EGFR TK inhibitory activity with an IC50 of 0.07 μM, which was analogous to the positive control. Some analogs including 7f, 8af, and 8ag showed a dual role as anticancer and MDR reversal agents. PMID:27010345

  4. Development and validation of a highly rapid and sensitive LC-MS/MS method for determination of SZ-685C, an investigational marine anticancer agent, in rat plasma--application to a pharmacokinetic study in rats.

    PubMed

    Chen, Jiang-Ying; Wang, Xue-Ding; Zhong, Guo-Ping; Qin, Xiao-Ling; Li, Jia-Li; Huang, Zhi-Ying; Zhu, Xun; Li, Meng-Feng; Huang, Min

    2011-07-15

    A sensitive and rapid method was developed and validated for the quantitative analysis of the novel anticancer agent SZ-685C in rat plasma using high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) in negative ion mode in order to support the following pre-clinical and clinical studies. SZ-685C and the internal standard (IS, emodin) were extracted from rat plasma by a simple liquid-liquid extraction technique using ethyl acetate as extraction solvent. Chromatographic separation was performed on an Elite Hypersil BDS C18 column (100 mm × 2.1 mm i.d., 3 μm). Elution was carried out using methanol/acetonitrile/2mM ammonium formate (pH 4) (80:15:5 (v/v/v)) at a flow-rate of 0.3 mL/min with a run time of 2.5 min. This assay was linear over a concentration range of 50-10,000 ng/mL with a lower limit of quantification of 50 ng/mL. The intra- and inter-batch precision was less than 15% for all quality control samples at concentrations of 100, 1000 and 7500 ng/mL. These results indicate that the method was efficient with a short run time and acceptable accuracy, precision and sensitivity. This method was successfully applied to explore pharmacokinetics of SZ-685C in rats after oral and intravenous administration of this agent. The absolute bioavailability is about 54.8-66.8% and the t(1/2) is 5.7-9.2h, these results provide basic information for further comprehensive pre-clinical research. PMID:21703949

  5. Applying linear interaction energy method for binding affinity calculations of podophyllotoxin analogues with tubulin using continuum solvent model and prediction of cytotoxic activity.

    PubMed

    Alam, Md Afroz; Naik, Pradeep Kumar

    2009-01-01

    Podophyllotoxin and its analogues have important therapeutic value in the treatment of cancer, due to their ability to induce apoptosis in cancer cells in a proliferation-independent manner. These ligands bind to colchicine binding site of tubulin near the alpha- and beta-tubulin interface and interfere with tubulin polymerization. The binding free energies of podophyllotoxin-based inhibitors of tubulin were computed using a linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model. A training set of 76 podophyllotoxin analogues was used to build a binding affinity model for estimating the free energy of binding for 36 inhibitors (test set) with diverse structural modifications. The average root mean square error (RMSE) between the experimental and predicted binding free energy values was 0.56kcal/mol which is comparable to the level of accuracy achieved by the most accurate methods, such as free energy perturbation (FEP) or thermodynamic integration (TI). The squared correlation coefficient between experimental and SGB-LIE estimates for the free energy for the test set compounds is also significant (R(2)=0.733). On the basis of the analysis of the binding energy, we propose that the three-dimensional conformation of the A, B, C and D rings is important for interaction with tubulin. On the basis of this insight, 12 analogues of varying ring modification were taken, tested with LIE methodology and then validated with their experimental potencies of tubulin polymerization inhibition. Low levels of RMSE for the majority of inhibitors establish the structure-based LIE method as an efficient tool for generating more potent and specific inhibitors of tubulin by testing rationally designed lead compounds based on podophyllotoxin derivatization. PMID:19286405

  6. 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 (ΔT = 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 (ΔT = 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 irradiation with the 785 nm laser diode for 30 min (Fig. S2); in vitro cytotoxicity of free DOX against A2780/AD human ovarian cancer cells (Fig. S3); the release profiles of SiNc from SiNc-NP under various conditions (Fig. S4); body weight curves of the mice with or without treatment (Fig. S5). See DOI: 10.1039/c4nr06050d

  7. 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

  8. 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 < 5μM and with virtually no effect in MCF-7 cells. These lead compounds are excellent candidates for further optimization. PMID:26188796

  9. An Improved High Yield Total Synthesis and Cytotoxicity Study of the Marine Alkaloid Neoamphimedine: An ATP-Competitive Inhibitor of Topoisomerase IIα 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 IIα. 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

  10. Discovery and optimization of a series of 2-aryl-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazoles as novel anticancer agents.

    PubMed

    Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Preti, Delia; Aghazadeh Tabrizi, Mojgan; Brancale, Andrea; Fu, Xian-Hua; Li, Jun; Zhang, Su-Zhan; Hamel, Ernest; Bortolozzi, Roberta; Porcù, Elena; Basso, Giuseppe; Viola, Giampietro

    2012-06-14

    A new series of tubulin polymerization inhibitors based on the 2-aryl/heteroaryl-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazole scaffold was synthesized and evaluated for growth inhibition activity on a panel of cancer cell lines, cell cycle effects, and in vivo potency. Structure-activity relationships were elucidated with various substitutions at the 2-position of the thiazole skeleton. Hydrophobic moieties, such as phenyl and 3-thienyl, were well tolerated at this position, and variation of the phenyl substituents had remarkable effects on potency. The most active compound (3b) induced apoptosis through the mitochondrial pathway with activation of caspase-3. We also showed that it has potential antivascular activity since it reduced in vitro endothelial cell migration and disrupted capillary-like tube formation at noncytotoxic concentrations. Furthermore, compound 3b significantly reduced the growth of the HT-29 xenograft in a nude mouse model, suggesting that 3b is a promising new antimitotic agent with clinical potential. PMID:22578111

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

    PubMed Central

    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

    2015-01-01

    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

  12. An in vitro evaluation of the victim and perpetrator potential of the anticancer agent laromustine (VNP40101M), based on reaction phenotyping and inhibition and induction of cytochrome P450 enzymes.

    PubMed

    Nassar, Alaa-Eldin F; King, Ivan; Paris, Brandy L; Haupt, Lois; Ndikum-Moffor, Florence; Campbell, Rebecca; Usuki, Etsuko; Skibbe, Jennifer; Brobst, Dan; Ogilvie, Brian W; Parkinson, Andrew

    2009-09-01

    Laromustine (VNP40101M, also known as Cloretazine) is a novel sulfonylhydrazine alkylating (anticancer) agent. Laromustine generates two types of reactive intermediates: 90CE and methylisocyanate. When incubated with rat, dog, monkey, and human liver microsomes, [(14)C]laromustine was converted to 90CE (C-8) and seven other radioactive components (C-1-C-7). There was little difference in the metabolite profile among the species examined, in part because the formation of most components (C-1-C-6 and 90CE) did not require NADPH but involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Laromustine caused direct inhibition of CYP2B6 and CYP3A4/5 (the two enzymes involved in C-7 formation) as well as of CYP2C19. K(i) values were 125 microM for CYP2B6, 297 muM for CYP3A4/5, and 349 microM for CYP2C19 and were greater than the average clinical plasma C(max) of laromustine (25 microM). There was evidence of time-dependent inhibition of CYP1A2, CYP2B6, and CYP3A4/5. Treatment of primary cultures of human hepatocytes with up to 100 microM laromustine did not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, but the highest concentration of laromustine decreased the activity and levels of immunoreactive CYP3A4. The results of this study suggest the laromustine has 1) negligible victim potential with respect to metabolism by cytochrome P450 enzymes, 2) negligible enzyme-inducing potential, and 3) the potential in some cases to cause inhibition of CYP2B6, CYP3A4, and possibly CYP2C19 during and shortly after the duration of intravenous administration of this anticancer drug, but the clinical effects of such interactions are likely to be insignificant. PMID:19520774

  13. Binding and molecular dynamic studies of sesquiterpenes (2R-acetoxymethyl-1,3,3-trimethyl-4t-(3-methyl-2-buten-1-yl)-1t-cyclohexanol) derived from marine Streptomyces sp. VITJS8 as potential anticancer agent.

    PubMed

    Naine, S Jemimah; Devi, C Subathra; Mohanasrinivasan, V; Doss, C George Priya; Kumar, D Thirumal

    2016-03-01

    The main aim of the current study is to explore the bioactive potential of Streptomyces sp. VITJS8 isolated from the marine saltern. The cultural, biochemical, and morphological studies were performed to acquire the characteristic features of the potent isolate VITJS8. The 16Sr DNA sequencing was performed to investigate the phylogenetic relationship between the Streptomyces genera. The structure of the compound was elucidated by gas chromatography-mass spectrometry (GC-MS), infra-red (IR), and ultra-violet (UV) spectroscopic data analysis. The GC-MS showed the retention time at 22.39 with a single peak indicating the purity of the active compound, and the molecular formula was established as C14H9ONCl2 based on the peak at m/z 277 [M](+). Furthermore, separated by high-performance liquid chromatography (HPLC), their retention time (t r) 2.761 was observed with the absorption maxima at 310 nm. The active compound showed effective inhibitory potential against four clinical pathogens at 500 μg/mL. The antioxidant activity was found effective at the IC50 value of 500 μg/mL with 90 % inhibition. The 3-(4,5-dimethylthiazol-2-yl)-2,5-ditetrazolium bromide (MTT) assay revealed the cytotoxicity against HepG2 cells at IC50 of 250 μg/mL. The progression of apoptosis was evidenced by morphological changes by nuclear staining. The DNA fragmentation pattern was observed at 250 μg/mL concentration. Based on flow cytometric analysis, it was evident that the compound was effective in inhibiting the sub-G0/G1 phase of cell cycle. The in vitro findings were also supported by the binding mode molecular docking studies. The active compound revealed minimum binding energy of -7.84 and showed good affinity towards the active region of topoisomerase-2α that could be considered as a suitable inhibitor. Lastly, we performed 30 ns molecular dynamic simulation analysis using GROMACS to aid in better designing of anticancer drugs. Simulation result of root mean square deviation (RMSD) analysis showed that protein-ligand complex reaches equilibration state around 10 ns that illustrates the docked complex is stable. We propose the possible mechanism of sesquiterpenes to play a significant role in antitumor cascade. Hence, our studies open up a new facet for a potent drug as an anticancer agent. PMID:26590587

  14. 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. α-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 α-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 α-santalol in carcinogenesis. PMID:26026073

  15. Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4.

    PubMed

    Broggini, M; Marchini, S V; Galliera, E; Borsotti, P; Taraboletti, G; Erba, E; Sironi, M; Jimeno, J; Faircloth, G T; Giavazzi, R; D'Incalci, M

    2003-01-01

    The mechanism by which aplidine, a marine natural product in early clinical development as an anticancer agent, induces cell growth inhibition and apoptosis has been investigated in the human leukemia cell line MOLT-4. This cell line is characterized not only by the ability to secrete VEGF, but also for the presence on its surface of the VEGF receptor-1 (VEGFR-1). Previous studies from our laboratory concerned with evaluating early changes in gene expression induced by aplidine in MOLT-4 cells have shown that the drug decreases the expression of VEGFR-1 (Marchini et al. Proc Am Assoc Cancer Res 2000; 41: 833). Here, we report the ability of aplidine to block the VEGF/VEGFR-1 loop. We found that aplidine blocked VEGF secretion that was temporally followed by a decrease in both VEGF and VEGFR-1 production. Aplidine did not directly affect either VEGF transcription or stabilization of its mRNA. Transfection of MOLT-4 cells with an antisense VEGF cDNA construct, resulted in inhibition of colony formations. One clone, transfected with sense VEGF cDNA, secreting 8-10 times more VEGF than parental cells, was less sensitive to aplidine-induced cytotoxicity and apoptosis than control cells. Moreover, addition of VEGF in the medium decreased the activity of aplidine in MOLT-4 cells. These data demonstrate that aplidine inhibits the growth and induces apoptosis in MOLT-4 cells through the inhibition of VEGF secretion which blocks the VEGF/VEGFR-1 autocrine loop necessary for the growth of these cells. PMID:12529660

  16. Anticancer activities of histone deacetylase inhibitors.

    PubMed

    Bolden, Jessica E; Peart, Melissa J; Johnstone, Ricky W

    2006-09-01

    Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs. PMID:16955068

  17. Anticancer potential of animal venoms and toxins.

    PubMed

    Gomes, Antony; Bhattacharjee, Pushpak; Mishra, Roshnara; Biswas, Ajoy K; Dasgupta, Subir Chandra; Giri, Biplab

    2010-02-01

    Anticancer drug development from natural resources are ventured throughout the world. Animal venoms and toxins a potential bio resource and a therapeutic tool were known to man for centuries through folk and traditional knowledge. The biodiversity of venoms and toxins made it a unique source of leads and structural templates from which new therapeutic agents may be developed. Venoms of several animal species (snake, scorpion, toad, frog etc) and their active components (protein and non protein toxins, peptides, enzymes, etc) have shown therapeutic potential against cancer. In the present review, the anticancer potential of venoms and toxins from snakes, scorpions, toads and frogs has been discussed. Some of these molecules are in the clinical trials and may find their way towards anticancer drug development in the near future. The implications of combination therapy of natural products in cancer have been discussed. PMID:20455317

  18. 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.

  19. 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

  20. 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 π-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.

  1. Ligands for cannabinoid receptors, promising anticancer agents.

    PubMed

    Nikan, Marjan; Nabavi, Seyed Mohammad; Manayi, Azadeh

    2016-02-01

    Cannabinoid compounds are unique to cannabis and provide some interesting biological properties. These compounds along with endocannabinoids, a group of neuromodulator compounds in the body especially in brain, express their effects by activation of G-protein-coupled cannabinoid receptors, CB1 and CB2. There are several physiological properties attributed to the endocannabinoids including pain relief, enhancement of appetite, blood pressure lowering during shock, embryonic development, and blocking of working memory. On the other hand, activation of endocannabinoid system may be suppresses evolution and progression of several types of cancer. According to the results of recent studies, CB receptors are over-expressed in cancer cell lines and application of multiple cannabinoid or cannabis-derived compounds reduce tumor size through decrease of cell proliferation or induction of cell cycle arrest and apoptosis along with desirable effect on decrease of tumor-evoked pain. Therefore, modulation of endocannabinoid system by inhibition of fatty acid amide hydrolase (FAAH), the enzyme, which metabolized endocannabinoids, or application of multiple cannabinoid or cannabis-derived compounds, may be appropriate for the treatment of several cancer subtypes. This review focuses on how cannabinoid affect different types of cancers. PMID:26764235

  2. Selective anticancer agents suppress aging in Drosophila

    PubMed Central

    Danilov, Anton; Shaposhnikov, Mikhail; Plyusnina, Ekaterina; Kogan, Valeria; Fedichev, Peter; Moskalev, Alexey

    2013-01-01

    Mutations of the PI3K, TOR, iNOS, and NF-κB genes increase lifespan of model organisms and reduce the risk of some aging-associated diseases. We studied the effects of inhibitors of PI3K (wortmannin), TOR (rapamycin), iNOS (1400W), NF-κB (pyrrolidin dithiocarbamate and QNZ), and the combined effects of inhibitors: PI3K (wortmannin) and TOR (rapamycin), NF-κB (pyrrolidin dithiocarbamates) and PI3K (wortmannin), NF-κB (pyrrolidine dithiocarbamates) and TOR (rapamycin) on Drosophila melanogaster lifespan and quality of life (locomotor activity and fertility). Our data demonstrate that pharmacological inhibition of PI3K, TOR, NF-κB, and iNOS increases lifespan of Drosophila without decreasing quality of life. The greatest lifespan expanding effect was achieved by a combination of rapamycin (5 μM) and wortmannin (5 μM) (by 23.4%). The bioinformatic analysis (KEGG, REACTOME.PATH, DOLite, and GO.BP) showed the greatest aging-suppressor activity of rapamycin, consistent with experimental data. PMID:24096697

  3. 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

  4. Chemosensitizing effect of podophyllotoxin acetate on topoisomerase inhibitors leads to synergistic enhancement of lung cancer cell apoptosis

    PubMed Central

    HONG, WAN GI; CHO, JEONG HYUN; HWANG, SANG-GU; LEE, EUNAH; LEE, JAESEOK; KIM, JONG-IL; UM, HONG-DUCK; PARK, JONG KUK

    2016-01-01

    Podophyllotoxin acetate (PA) acts as a radiosensitizer against non-small cell lung cancer (NSCLC) in vitro and in vivo. In this study, we examined its potential role as a chemosensitizer in conjunction with the topoisomerase inhibitors etoposide (Eto) and camptothecin (Cpt). The effects of combinations of PA and Eto/Cpt were examined with CompuSyn software in two NSCLC cell lines, A549 and NCI-H1299. Combination index (CI) values indicated synergistic effects of PA and the topoisomerase inhibitors. The intracellular mechanism underlying synergism was further determined using propidium iodide uptake, immunoblotting and electrophoretic mobility shift assay (EMSA). Combination of PA with Eto/Cpt promoted disruption of the dynamics of actin filaments, leading to subsequent enhancement of apoptotic cell death via induction of caspase-3, -8, and -9, accompanied by increased phosphorylation of p38. Conversely, suppression of p38 phosphorylation blocked the apoptotic effect of the drug combinations. Notably, CREB-1, a transcription factor, was constitutively activated in both cell types, and synergistically inhibited upon combination treatment. Our results collectively indicate that PA functions as a chemosensitizer by enhancing apoptosis through activation of the p38/caspase axis and suppression of CREB-1. PMID:27035096

  5. Factors affecting podophyllotoxin yield in the ex situ grown Podophyllum hexandrum, an endangered alpine native of the western Himalayas.

    PubMed

    Kushwaha, Rekha; Bhattacharya, Amita; Singh, Bikram; Singh, R D

    2012-01-01

    This study reports an appreciable yield of podophyllotoxin (PDT) in P. hexandrum plants grown ex situ under polyhouse conditions of a temperate locale. The PDT content of below-ground parts was affected by both plant age and growth period. However, only the effect of plant age on PDT content was significant. Thus, the highest amounts of PDT were recorded in the below-ground parts of 2-year-old plants harvested during the late-growth period (LGP). High total soluble sugars in the below-ground parts during the early growth period (EGP) and the highest nitrate and nitrate reductase in the leaves of 2-year-old plants during the peak-growth period (PGP) indicated higher mobilization and assimilation of starch and nitrate. Probably the surplus carbon and nitrogen gained during the PGP were diverted from aerial parts to below-ground parts during the LGP and in turn contributed to the synthesis of higher amounts of PDT. This study shows that commercial cultivation of P. hexandrum is possible under ex situ temperate conditions. PMID:21625946

  6. Chemosensitizing effect of podophyllotoxin acetate on topoisomerase inhibitors leads to synergistic enhancement of lung cancer cell apoptosis.

    PubMed

    Hong, Wan Gi; Cho, Jeong Hyun; Hwang, Sang-Gu; Lee, Eunah; Lee, Jaeseok; Kim, Jong-Il; Um, Hong-Duck; Park, Jong Kuk

    2016-06-01

    Podophyllotoxin acetate (PA) acts as a radiosensitizer against non-small cell lung cancer (NSCLC) in vitro and in vivo. In this study, we examined its potential role as a chemosensitizer in conjunction with the topoisomerase inhibitors etoposide (Eto) and camptothecin (Cpt). The effects of combinations of PA and Eto/Cpt were examined with CompuSyn software in two NSCLC cell lines, A549 and NCI-H1299. Combination index (CI) values indicated synergistic effects of PA and the topoisomerase inhibitors. The intracellular mechanism underlying synergism was further determined using propidium iodide uptake, immunoblotting and electrophoretic mobility shift assay (EMSA). Combination of PA with Eto/Cpt promoted disruption of the dynamics of actin filaments, leading to subsequent enhancement of apoptotic cell death via induction of caspase-3, -8, and -9, accompanied by increased phosphorylation of p38. Conversely, suppression of p38 phosphorylation blocked the apoptotic effect of the drug combinations. Notably, CREB-1, a transcription factor, was constitutively activated in both cell types, and synergistically inhibited upon combination treatment. Our results collectively indicate that PA functions as a chemosensitizer by enhancing apoptosis through activation of the p38/caspase axis and suppression of CREB-1. PMID:27035096

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  9. Development of Synthetic Lethality Anticancer Therapeutics

    PubMed Central

    2015-01-01

    The concept of synthetic lethality (the creation of a lethal phenotype from the combined effects of mutations in two or more genes) has recently been exploited in various efforts to develop new genotype-selective anticancer therapeutics. These efforts include screening for novel anticancer agents, identifying novel therapeutic targets, characterizing mechanisms of resistance to targeted therapy, and improving efficacies through the rational design of combination therapy. This review discusses recent developments in synthetic lethality anticancer therapeutics, including poly ADP-ribose polymerase inhibitors for BRCA1- and BRCA2-mutant cancers, checkpoint inhibitors for p53 mutant cancers, and small molecule agents targeting RAS gene mutant cancers. Because cancers are caused by mutations in multiple genes and abnormalities in multiple signaling pathways, synthetic lethality for a specific tumor suppressor gene or oncogene is likely cell context-dependent. Delineation of the mechanisms underlying synthetic lethality and identification of treatment response biomarkers will be critical for the success of synthetic lethality anticancer therapy. PMID:24893124

  10. 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

  11. Anti-cancer potential of a novel SERM ormeloxifene.

    PubMed

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

    2013-01-01

    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

  12. '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

  13. [Anticancer drugs and pharmacologic actions].

    PubMed

    Ogawa, M

    1997-05-01

    Anticancer drugs are traditionally classified either by their mechanism of action or by their origins. Alkylating agents are reactive to DNA and cellular proteins and the primary mode of action is mostly through cross-linking of DNA strands, inhibiting replication of DNA and transcription of RNA. Some antimetabolites are structural analogs of normal molecular essentials for cell growth. After intaking into cells the analogues change to substances to interfere with DNA or RNA synthesis. Drugs derived from microorganism are called antitumor antibiotics. Some plants alkaloids blind to tublin and inhibit the formation of microtubules causing metaphase arrest, while camptothecins inhibit topoisomelase 1. Other compounds which are not classified to any categories expects characteristic mode for action to induce cell death or differentiation. PMID:9155146

  14. Multidimensional Design of Anticancer Peptides.

    PubMed

    Lin, Yen-Chu; Lim, Yi Fan; Russo, Erica; Schneider, Petra; Bolliger, Lea; Edenharter, Adriana; Altmann, Karl-Heinz; Halin, Cornelia; Hiss, Jan A; Schneider, Gisbert

    2015-08-24

    The computer-assisted design and optimization of peptides with selective cancer cell killing activity was achieved through merging the features of anticancer peptides, cell-penetrating peptides, and tumor-homing peptides. Machine-learning classifiers identified candidate peptides that possess the predicted properties. Starting from a template amino acid sequence, peptide cytotoxicity against a range of cancer cell lines was systematically optimized while minimizing the effects on primary human endothelial cells. The computer-generated sequences featured improved cancer-cell penetration, induced cancer-cell apoptosis, and were enabled a decrease in the cytotoxic concentration of co-administered chemotherapeutic agents in vitro. This study demonstrates the potential of multidimensional machine-learning methods for rapidly obtaining peptides with the desired cellular activities. PMID:26119906

  15. Anticancer effects of chitin and chitosan derivatives.

    PubMed

    Karagozlu, Mustafa Zafer; Kim, Se-Kwon

    2014-01-01

    Despite considerable progress in medical research, cancer is still one of the high-ranking causes of death in the world. It is the second most common cause of death due to disease after heart disease, and according to World Health Organization it will be the cause of death for more than 10 million people in 2020; therefore, one of the main research goals for researchers investigating new anticancer agents. But the major complication for the cancer cure without surgeries is side effects. Especially, cytotoxic anticancer chemotherapeutic agents generally produce severe side effects, while reducing host resistance to cancer and infections. Therefore, it is important to find new, powerful anticancer agents that are highly effective, biodegradable, and biocompatible. Chitin and chitosan are biopolymers which have unique structural possibilities for chemical and mechanical modifications to generate novel properties, functions. These biopolymers are biocompatible, biodegradable, and nontoxic, and their chemical properties allow them to be easily processed into gels, sponges, membranes, beads, and scaffolds forms also. Due to their unique properties, they are excellent candidates for cancer cure or cancer diagnosis. PMID:25081085

  16. Cell Death Signaling and Anticancer Therapy

    PubMed Central

    Galluzzi, Lorenzo; Vitale, Ilio; Vacchelli, Erika; Kroemer, Guido

    2011-01-01

    For a long time, it was commonly believed that efficient anticancer regimens would either trigger the apoptotic demise of tumor cells or induce a permanent arrest in the G1 phase of the cell cycle, i.e., senescence. The recent discovery that necrosis can occur in a regulated fashion and the increasingly more precise characterization of the underlying molecular mechanisms have raised great interest, as non-apoptotic pathways might be instrumental to circumvent the resistance of cancer cells to conventional, pro-apoptotic therapeutic regimens. Moreover, it has been shown that some anticancer regimens engage lethal signaling cascades that can ignite multiple oncosuppressive mechanisms, including apoptosis, necrosis, and senescence. Among these signaling pathways is mitotic catastrophe, whose role as a bona fide cell death mechanism has recently been reconsidered. Thus, anticancer regimens get ever more sophisticated, and often distinct strategies are combined to maximize efficacy and minimize side effects. In this review, we will discuss the importance of apoptosis, necrosis, and mitotic catastrophe in the response of tumor cells to the most common clinically employed and experimental anticancer agents. PMID:22655227

  17. Synthesis and characterization of Cu(II)-based anticancer chemotherapeutic agent targeting topoisomerase Iα: 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](NO₃)₂ (1) and [Zn(phen)L](NO₃)₂ (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 (GI₅₀ values < 10 μg/ml), and to elucidate the mechanism of cancer inhibition, Topo-I enzymatic activity was carried out. PMID:24508781

  18. 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

  19. Anticancer properties of Monascus metabolites.

    PubMed

    Yang, Tao; Liu, Junwen; Luo, Feijun; Lin, Qinlu; Rosol, Thomas J; Deng, Xiyun

    2014-08-01

    This review provides up-to-date information on the anticancer properties of Monascus-fermented products. Topics covered include clinical evidence for the anticancer potential of Monascus metabolites, bioactive Monascus components with anticancer potential, mechanisms of the anticancer effects of Monascus metabolites, and existing problems as well as future perspectives. With the advancement of related fields, the development of novel anticancer Monascus food products and/or pharmaceuticals will be possible with the ultimate goal of decreasing the incidence and mortality of malignancies in humans. PMID:24637578

  20. 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

  1. [Anticancer properties of flagellate protozoan Trypanosoma cruzi Chagas, 1909].

    PubMed

    Kallinikova, V D; Matekin, P V; Ogloblina, T A; Leĭkina, M I; Kononenko, A F; Sokolova, N M; Pogodina, L S

    2001-01-01

    The anticancer activity of Trypanosoma cruzi has been confirmed by the example of seven strains. Five virulent strains induced the infection, which inhibited sarcoma-180 growth 1.5-22.0 times. The parasites featured tumortropism; i.e., the successfully developed in cancer cells and even preferred them to normal cells. This taxis-based phenomenon was particularly pronounced at cocultivation of the normal and cancer cells. Cultures of the seven (avirulent and virulent) strains can produce an anticancer agent that selectively damages human cancer cells in vitro. The long-term anticancer effect of T. cruzi or preparations from it, as well as possible its cancer preventing effect, has been demonstrated. Three problems are discussed on the basis of the obtained and recently published data: (1) the mechanism of T. cruzi anticancer effect; (2) the nature of the anticancer agent; and (3) the distribution of the considered phenomenon among trypanosomatides. The anticancer activity of T. cruzi may be due to a combination of surface cellular antigens and an inhibiting or lysing factor. PMID:11433940

  2. Oncolytic Viruses as Anticancer Vaccines

    PubMed Central

    Woller, Norman; Gürlevik, Engin; Ureche, Cristina-Ileana; Schumacher, Anja; Kühnel, Florian

    2014-01-01

    Oncolytic virotherapy has shown impressive results in preclinical studies and first promising therapeutic outcomes in clinical trials as well. Since viruses are known for a long time as excellent vaccination agents, oncolytic viruses are now designed as novel anticancer agents combining the aspect of lysis-dependent cytoreductive activity with concomitant induction of antitumoral immune responses. Antitumoral immune activation by oncolytic virus infection of tumor tissue comprises both, immediate effects of innate immunity and also adaptive responses for long lasting antitumoral activity, which is regarded as the most prominent challenge in clinical oncology. To date, the complex effects of a viral tumor infection on the tumor microenvironment and the consequences for the tumor-infiltrating immune cell compartment are poorly understood. However, there is more and more evidence that a tumor infection by an oncolytic virus opens up a number of options for further immunomodulating interventions such as systemic chemotherapy, generic immunostimulating strategies, dendritic cell-based vaccines, and antigenic libraries to further support clinical efficacy of oncolytic virotherapy. PMID:25101244

  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. 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

  5. Targets in anticancer research--A review.

    PubMed

    Jayashree, B S; Nigam, Sukriti; Pai, Aravinda; Patel, Harsh K; Reddy, N D; Kumar, Nitesh; Rao, C M

    2015-08-01

    Cancer is a complex disease characterized by a loss in the normal cell regulatory mechanisms that govern cell survival, proliferation, and differentiation. Current chemotherapeutics, as anticancer agents, are developing resistance to single drug and also to treatment therapies involving multiple drugs. Cross resistance associated with the specificity and selectivity of existing drugs has restricted the application of chemotherapy. Alternatively, these limitations have given better insight in understanding the underlying molecular mechanisms responsible for the development of various stages in cancer. In the light of this, continuous efforts are being made in order to identify and validate newer anticancer targets. This review presents some of the important targets that have been already reported, such as aromatase, farnesyl transferase, histone deacetylase, tyrosine kinase and cyclin-dependent kinase. A few molecules designed against these targets have successfully reached clinical trials. However, only limited marketed drugs are available from these classes. Besides, the review also highlights some of the other important targets and strategies that have also drawn considerable attention in the area of anticancer drug development such as, cancer stem cells and monoclonal antibodies. Further, the integration of the tools in molecular biology with the results from preclinical and clinical trials would strengthen the effectiveness of treatment regimens in cancer patients. There lies a much scope for designing promising lead compounds and treatment therapies against these established targets. PMID:26349312

  6. Anticancer effects of fucoidan.

    PubMed

    Senthilkumar, Kalimuthu; Kim, Se-Kwon

    2014-01-01

    Recently, there has been an increased interest in the pharmacologically active natural compounds isolated and used for remedies of various kinds of diseases, including cancer. The great deal of interest has been developed to isolate bioactive compounds from marine resources because of their numerous health beneficial effects. Among marine resources, marine algae are valuable sources of structurally diverse bioactive compounds. Fucoidan is a sulfated polysaccharide derived from brown seaweeds and has been used as an ingredient in some dietary supplement products. Fucoidan has various biological activities including antibacterial, antioxidant, anti-inflammatory, anticoagulant, and antitumor activities. So this chapter deals with anticancer effects of fucoidan. PMID:25081084

  7. 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

  8. Anticancer effects of Ganoderma lucidum: a review of scientific evidence.

    PubMed

    Yuen, John W M; Gohel, Mayur Danny I

    2005-01-01

    "Lingzhi" (Ganoderma lucidum), a popular medicinal mushroom, has been used in China for longevity and health promotion since ancient times. Investigations into the anticancer activity of lingzhi have been performed in both in vitro and in vivo studies, supporting its application for cancer treatment and prevention. The proposed anticancer activity of lingzhi has prompted its usage by cancer patients. It remains debatable as to whether lingzhi is a food supplement for health maintenance or actually a therapeutic "drug" for medical proposes. Thus far there has been no report of human trials using lingzhi as a direct anticancer agent, despite some evidence showing the usage of lingzhi as a potential supplement to cancer patients. Cellular immune responses and mitogenic reactivity of cancer patients have been enhanced by lingzhi, as reported in two randomized and one nonrandomized trials, and the quality of life of 65% of lung cancer patients improved in one study. The direct cytotoxic and anti-angiogenesis mechanisms of lingzhi have been established by in vitro studies; however, clinical studies should not be neglected to define the applicable dosage in vivo. At present, lingzhi is a health food supplement to support cancer patients, yet the evidence supporting the potential of direct in vivo anticancer effects should not be underestimated. Lingzhi or its products can be classified as an anticancer agent when current and more direct scientific evidence becomes available. PMID:16351502

  9. 2-AZETIDINONE DERIVATIVES: SYNTHESIS, ANTIMICROBIAL, ANTICANCER EVALUATION AND QSAR STUDIES.

    PubMed

    Deep, Aakash; Kumar, Pradeep; Narasimhan, Balasubramanian; Lim, Siong Meng; Ramasamy, Kalavathy; Mishra, Rakesh Kumar; Mani, Vasudevan

    2016-01-01

    A series of 2-azetidinone derivatives was synthesized from hippuric acid and evaluated for its in vitro antimicrobial and anticancer activities. Antimicrobial properties of the title compounds were investigated against Gram positive and Gram negative bacterial as well as fungal strains. Anticancer activity was performed against breast cancer (MCF7) cell lines. Antimicrobial activity results revealed that N-{2-[3-chloro-2-(2- chlorophenyl)-4-oxoazetidin-1-ylamino]-2-oxoethyl}benzamide (4) was found to be the most potent antimicrobial agent. Results of anticancer study indicated that the synthesized compounds exhibited average anticancer potential and N-[2-(3-chloro-2-oxo-4-styrylazetidin-1-ylamino)-2-oxoethyl]benzamide (17) was found to be most potent anticancer agent against breast cancer (MCF7) cell lines. QSAR models indicated that the antibacterial, antifungal and the overall antimicrobial activities of the synthesized compounds were governed by topological parameters, Balaban index (J) and valence zero and first order molecular connectivity indices (⁰χv and ¹χv). PMID:27008802

  10. 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

  11. Classification of mitocans, anti-cancer drugs acting on mitochondria.

    PubMed

    Neuzil, Jiri; Dong, Lan-Feng; Rohlena, Jakub; Truksa, Jaroslav; Ralph, Stephen J

    2013-05-01

    Mitochondria have emerged as an intriguing target for anti-cancer drugs, inherent to vast majority if not all types of tumours. Drugs that target mitochondria and exert anti-cancer activity have become a focus of recent research due to their great clinical potential (which has not been harnessed thus far). The exceptional potential of mitochondria as a target for anti-cancer agents has been reinforced by the discouraging finding that even tumours of the same type from individual patients differ in a number of mutations. This is consistent with the idea of personalised therapy, an elusive goal at this stage, in line with the notion that tumours are unlikely to be treated by agents that target only a single gene or a single pathway. This endows mitochondria, an invariant target present in all tumours, with an exceptional momentum. This train of thoughts inspired us to define a class of anti-cancer drugs acting by way of mitochondrial 'destabilisation', termed 'mitocans'. In this communication, we define mitocans (many of which have been known for a long time) and classify them into several classes based on their molecular mode of action. We chose the targets that are of major importance from the point of view of their role in mitochondrial destabilisation by small compounds, some of which are now trialled as anti-cancer agents. The classification starts with targets at the surface of mitochondria and ending up with those in the mitochondrial matrix. The purpose of this review is to present in a concise manner the classification of compounds that hold a considerable promise as potential anti-cancer drugs. PMID:22846431

  12. Fenbendazole as a Potential Anticancer Drug

    PubMed Central

    DUAN, QIWEN; LIU, YANFENG; ROCKWELL, SARA

    2013-01-01

    Background/Aims To evaluate the anticancer activity of fenbendazole, a widely used antihelminth with mechanisms of action that overlap with those of the hypoxia-selective nitroheterocyclic cytotoxins/radiosensitizers and the taxanes. Materials and Methods We used EMT6 mouse mammary tumor cells in cell culture and as solid tumors in mice to examine the cytotoxic and antitumor effects of fenbendazole as a single agent and in combination regimens. Results Intensive treatments with fenbendazole were toxic to EMT6 cells in vitro; toxicity increased with incubation time and under conditions of severe hypoxia. Fenbendazole did not alter the dose-response curves for radiation or docetaxel; instead, the agents produced additive cytotoxicities. Febendazole in maximally-intensive regimens did not alter the growth of EMT6 tumors, or increase the antineoplastic effects of radiation. Conclusion These studies provided no evidence that fenbendazole would have value in cancer therapy, but suggested that this general class of compounds merits further investigation. PMID:23393324

  13. Enediyne compounds - new promises in anticancer therapy.

    PubMed

    Gredicak, Matija; Jerić, Ivanka

    2007-06-01

    Scientists of all kinds have long been intrigued by the nature, action and potential of natural toxins that possess exceptional antibacterial and anticancer activities. These compounds, named enediynes, are among the most effective chemotherapeutic agents known. Often compared with intelligent weapons, due to the unique structure and sophisticated mechanism by which they destroy double-helical DNA, enediyne antibiotics are nowadays the most promising leaders in the anticancer therapy. Apart from their diversity, enediyne compounds share some structural and functional similarities. One fragment of a structure is responsible for the recognition and transport, another part acts as molecular trigger while the third, reactive enediyne unit, undergoes Bergman cycloaromatization and causes DNA breakage. Members of the enediyne family are already in clinical use to treat various cancers, but more general use is limited by their complex structure, which makes them formidable targets for synthetic chemists. There are three main approaches in the design of new enediyne-related compounds: improvement of enediyne >warheads<, increasing the selectivity and control of chemical or photo-induced activation. This paper gives an overview of naturally occurring enediynes, their mode of action and efforts undertaken to design artificial enediyne-related DNA cleaving agents. PMID:17507311

  14. Microbiome and Anticancer Immunosurveillance.

    PubMed

    Zitvogel, Laurence; Ayyoub, Maha; Routy, Bertrand; Kroemer, Guido

    2016-04-01

    Anticancer immune responses can be considered a desirable form of autoimmunity that may be profoundly shaped by the microbiome. Here, we discuss evidence for the microbiome's influence on anti-tumor immunosurveillance, including those that are indirect and can act at a distance, and we put forward hypotheses regarding mechanisms of how these effects are implemented. These may involve cross-reactivity between microbial and tumor antigens shaping T cell repertoires and/or microbial products stimulating pattern recognition receptors that influence the type and intensity of immune responses. Understanding how the microbiome impacts natural cancer immunosurveillance as well as treatment-induced immune responses will pave the way for more effective therapies and prophylactics. PMID:27058662

  15. [Update on anticancer drugs].

    PubMed

    Roila, Fausto; Ballatori, Enzo

    2014-01-01

    Update on anticancer drugs. A thorough review of the clinical trials published over the last two years in major medical and oncological journals on a comprehensive spectrum of oncological conditions aims to provide at the same time (as the authors are well known representatives of the critical and complementary competences of clinical care and research methodology) an interesting double opportunity of update on: a) what is truly (i.e.documented and reliable) innovative and deserves adoption in daily care,vs what is either purely suggestive or clearly misleading; b) what are the methological, concrete, simple rules to observe in a field which is certainly moving fast, but at the same time generates highly controversial behaviors in research as well as in daily practices. The accompanying editorial (pag 60-63) further illustrates the way and the yield of using this material and approach both in the areas of nursing sciences and practice. PMID:25002061

  16. 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 AMPKα 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

  17. 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 Central

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

    2015-01-01

    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 AMPKα 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

  18. Synthesis of (Z)-1-(1,3-diphenyl-1H-pyrazol-4-yl)-3-(phenylamino)prop-2-en-1-one derivatives as potential anticancer and apoptosis inducing agents.

    PubMed

    Srinivasa Reddy, T; Ganga Reddy, V; Kulhari, Hitesh; Shukla, Ravi; Kamal, Ahmed; Bansal, Vipul

    2016-07-19

    A series of (Z)-1-(1,3-diphenyl-1H-pyrazol-4-yl)-3-(phenylamino)prop-2-en-1-one derivatives were synthesized and characterized by (1)H and (13)C NMR, ESI-MS and HRMS. All the synthesized compounds were evaluated for their anticancer activity against HT-29, PC-3, A549 and U87MG human tumor cell lines. Most of the synthesized compounds displayed potent growth inhibition selectively of A549 cancer cells and did not show significant toxicity to the non-cancerous HaCaT cells. Some of the representative compounds, particularly, 16, 22 and 28 exhibited potent growth inhibition with IC50 values in the range of 1.25-3.98 μM, which are comparable or even better than the standard chemotherapeutic drug 5-fluorouracil. Preliminary mechanistic studies revealed that these compounds could effectively inhibit the migration ability of A549 cells. Flow-cytometry analysis revealed that the compounds treatment led to G2/M cell cycle arrest. Moreover, the compounds induced apoptosis in A549 cells through depolarization of mitochondrial membrane potential (DΨm) and increased reactive oxygen species (ROS) production, suggesting their potential to act as promising lead compounds for the development of cancer chemotherapeutics. PMID:27092413

  19. Proteomic profiling predicts drug response to novel targeted anticancer therapeutics.

    PubMed

    Lin, Fan; Li, Zilin; Hua, Yunfen; Lim, Yoon Pin

    2016-04-01

    Most recently approved anti-cancer drugs by the US FDA are targeted therapeutic agents and this represents an important trend for future anticancer therapy. Unlike conventional chemotherapy that rarely considers individual differences, it is crucial for targeted therapies to identify the beneficial subgroup of patients for the treatment. Currently, genomics and transcriptomics are the major 'omic' analytics used in studies of drug response prediction. However, proteomic profiling excels both in its advantages of directly detecting an instantaneous dynamic of the whole proteome, which contains most current diagnostic markers and therapeutic targets. Moreover, proteomic profiling improves understanding of the mechanism for drug resistance and helps finding optimal combination therapy. This article reviews the recent success of applications of proteomic analytics in predicting the response to targeted anticancer therapeutics, and discusses the potential avenues and pitfalls of proteomic platforms and techniques used most in the field. PMID:26954459

  20. Anticancer compounds from cyanobacterium Lyngbya species: a review.

    PubMed

    Swain, Shasank S; Padhy, Rabindra N; Singh, Pawan K

    2015-08-01

    The use of synthetic anticancer drugs and other methods followed in cancer therapy have several side effects; and ineffective methods or drugs give a way to the emergence of drug resistant cancer cells, with the intrinsic metastasis as the aftermath. Anticancer efficacy of many cyanobacterial compounds has been claimed in literature. This review considers 144 compounds isolated and characterized from seven species of the non-nitrogen fixing filamentous cyanobacterium Lyngbya, as the source of antineoplastic agents, which have been screened primarily with cancer cell lines. Structure and information of Lyngbya compounds were retrieved from databases, PubChem, ChemSpider and ChEBI. Information and clinical status of Lyngbya compounds are summarized, and those might be the future anticancer drugs for drug-resistant cancer cells even, as complementary/adduct drugs, if pursued thoroughly in pharmacology and pharmaceutics. PMID:26026796

  1. 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

  2. Anticancer activity, toxicity and pharmacokinetic profile of an indanone derivative.

    PubMed

    Chanda, Debabrata; Bhushan, Shashi; Guru, Santosh K; Shanker, Karuna; Wani, Z A; Rah, B A; Luqman, Suaib; Mondhe, Dilip M; Pal, Anirban; Negi, Arvind S

    2012-12-18

    The present study describes anticancer effect of gallic acid based indanone derivative (1). Indanone 1 exhibited in vivo anticancer activity against Erhlich ascites carcinoma in Swiss albino mice by inhibiting tumor growth by 54.3% at 50 mg/kg b.wt. It showed antitubulin effect by inhibiting tubulin polymerase enzyme. In cell cycle analysis, it inhibited G2/M phase and induced apoptosis. It significantly suppressed VEGF-R1, VEGF-R2 and HIF-α in human breast cancer MCF-7 cells, thus exhibiting antiangiogenic activity. In acute oral toxicity, indanone 1 was well tolerated and was found to be non-toxic up to 1000 mg/kg b.wt. in Swiss albino mice. Pharmacokinetic studies in rabbits revealed rate of absorption, half life, volume of distribution with high plasma and blood clearance after i.v. administration. Indanone 1, is a safe and moderately active anticancer agent. PMID:23017432

  3. Hyaluronic acid for anticancer drug and nucleic acid delivery.

    PubMed

    Dosio, Franco; Arpicco, Silvia; Stella, Barbara; Fattal, Elias

    2016-02-01

    Hyaluronic acid (HA) is widely used in anticancer drug delivery, since it is biocompatible, biodegradable, non-toxic, and non-immunogenic; moreover, HA receptors are overexpressed on many tumor cells. Exploiting this ligand-receptor interaction, the use of HA is now a rapidly-growing platform for targeting CD44-overexpressing cells, to improve anticancer therapies. The rationale underlying approaches, chemical strategies, and recent advances in the use of HA to design drug carriers for delivering anticancer agents, are reviewed. Comprehensive descriptions are given of HA-based drug conjugates, particulate carriers (micelles, liposomes, nanoparticles, microparticles), inorganic nanostructures, and hydrogels, with particular emphasis on reports of preclinical/clinical results. PMID:26592477

  4. Synthesis and anticancer evaluation of furfurylidene 4-piperidone analogs.

    PubMed

    Jadhav, Rahul L; Magdum, Chandrakant S; Patil, Manisha V

    2014-06-01

    Recently different series of compounds have been designed that utilize the 1,5-diaryl-3-oxo-1,4-pentadinenyl pharmacophore for the development of novel cytotoxic and anticancer agents. These compounds interact with cellular thiols and thiols are not part of nucleic acids. Hence, these compounds are free from the problem of mutagenicity and carcinogenicity. The Claisen-Schmidt reaction is used for synthesizing furfurylidene analogs in a basic medium. The title compounds were prepared by reacting furfurylidenes with aryl sulfonyl, benzoyl, acroylyl, or acetyl chloride. The resulting synthesized compounds were screened for their in vitro cytotoxic properties by MTT and SRB assays against leukemic and colon cancer cell lines. Acute toxicity was determined by OECD-423 guidelines. The in vivo anticancer activities were evaluated against Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The MTT assay showed that compounds 2d and 3d have significant cytotoxicity against the Molt-4 human cell line as compared to the standard, 5-fluorouracil. In addition, the SRB assay indicated that the compounds 2, 2a, 2d, and 3d showed equipotent cytotoxicity against human leukemia cell lines as compared to the standard, doxorubicin. Compounds 2a and 2d showed significant anticancer activity against EAC in Swiss albino mice. This study revealed the potential of these molecules for further development as anticancer agents. PMID:24623392

  5. 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

  6. Trial Watch: Peptide-based anticancer vaccines

    PubMed Central

    Pol, Jonathan; Bloy, Norma; Buqué, Aitziber; Eggermont, Alexander; Cremer, Isabelle; Sautès-Fridman, Catherine; Galon, Jérôme; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2015-01-01

    Malignant cells express antigens that can be harnessed to elicit anticancer immune responses. One approach to achieve such goal consists in the administration of tumor-associated antigens (TAAs) or peptides thereof as recombinant proteins in the presence of adequate adjuvants. Throughout the past decade, peptide vaccines have been shown to mediate antineoplastic effects in various murine tumor models, especially when administered in the context of potent immunostimulatory regimens. In spite of multiple limitations, first of all the fact that anticancer vaccines are often employed as therapeutic (rather than prophylactic) agents, this immunotherapeutic paradigm has been intensively investigated in clinical scenarios, with promising results. Currently, both experimentalists and clinicians are focusing their efforts on the identification of so-called tumor rejection antigens, i.e., TAAs that can elicit an immune response leading to disease eradication, as well as to combinatorial immunostimulatory interventions with superior adjuvant activity in patients. Here, we summarize the latest advances in the development of peptide vaccines for cancer therapy. PMID:26137405

  7. Synthesis and anti-cancer activity of 2-alkylaminomethyl-5-(E)-alkylidene cyclopentanone hydrochlorides.

    PubMed

    Chen, H; Ji, Z; Wong, L K; Siuda, J F; Narayanan, V L

    1994-10-01

    A series of 2-alkylaminomethyl-5-(E)-alkylidene cyclopentanone hydrochlorides (2), have been synthesized and evaluated as anti-cancer agents. These compounds were designed as masked alpha-methylenecyclopentanones, which appear in many cytotoxic or anti-cancer natural products. Most of the synthesized compounds were found to be active towards various human cancer cell lines and many showed significant subpanel selectivity. For compounds containing the same alkylidene moiety (from C3 to C9), the dimethylaminomethyl analogs were more active than structures possessing morpholino-, pyrrolidino-, or piperidino-methyl groups. Alteration of the alkylidene moiety had little effect on anti-cancer potency. The mass spectrum of a glutathione adduct of 2h indicated that the mechanism of action for these anti-cancer agents may be related to the attack at the aminomethyl carbon atom by biological nucleophilic thiols. PMID:7773626

  8. 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

  9. 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

  10. CEST theranostics: label-free MR imaging of anticancer drugs

    PubMed Central

    Xu, Jiadi; Yadav, Nirbhay N.; Chan, Kannie W. Y.; Luo, Liangping; McMahon, Michael T.; Vogelstein, Bert; van Zijl, Peter C.M.; Zhou, Shibin; Liu, Guanshu

    2016-01-01

    Image-guided drug delivery is of great clinical interest. Here, we explored a direct way, namely CEST theranostics, to detect diamagnetic anticancer drugs simply through their inherent Chemical Exchange Saturation Transfer (CEST) MRI signal, and demonstrated its application in image-guided drug delivery of nanoparticulate chemotherapeutics. We first screened 22 chemotherapeutic agents and characterized the CEST properties of representative agents and natural analogs in three major categories, i.e., pyrimidine analogs, purine analogs, and antifolates, with respect to chemical structures. Utilizing the inherent CEST MRI signal of gemcitabine, a widely used anticancer drug, the tumor uptake of the i.v.-injected, drug-loaded liposomes was successfully detected in CT26 mouse tumors. Such label-free CEST MRI theranostics provides a new imaging means, potentially with an immediate clinical impact, to monitor the drug delivery in cancer. PMID:26837220

  11. Recent Advances in chemistry and pharmacology of 2-methoxyestradiol: An anticancer investigational drug.

    PubMed

    Kumar, B Sathish; Raghuvanshi, Dushyant Singh; Hasanain, Mohammad; Alam, Sarfaraz; Sarkar, Jayanta; Mitra, Kalyan; Khan, Feroz; Negi, Arvind S

    2016-06-01

    2-Methoxyestradiol (2ME2), an estrogen hormone metabolite is a potential cancer chemotherapeutic agent. Presently, it is an investigational drug under various phases of clinical trials alone or in combination therapy. Its anticancer activity has been attributed to its antitubulin, antiangiogenic, pro-apoptotic and ROS induction properties. This anticancer drug candidate has been explored extensively in last twenty years for its detailed chemistry and pharmacology. Present review is an update of its chemistry and biological activity. It also extends an assessment of potential of 2ME2 and its analogues as possible anticancer drug in future. PMID:27020471

  12. EF24 and RAD001 potentiates the anticancer effect of platinum-based agents in human malignant pleural mesothelioma (MSTO-211H) cells and protects nonmalignant mesothelial (MET-5A) cells.

    PubMed

    Onen, H I; Yilmaz, A; Alp, E; Celik, A; Demiroz, S M; Konac, E; Kurul, I C; Menevse, E S

    2015-02-01

    The most widespread neoplasm of the pleura is malignant pleural mesothelioma (MPM) with low prevalence rate. The mechanistic target of rapamycin signaling pathway, inhibited by RAD001, was shown to be deregulated in MPM development and considered a novel target for the MPM therapy. The EF24, a curcumin analog, also affects several signaling pathways and kills cancer cells as a single agent or in combination with classical drugs. We aimed to evaluate possible effects of RAD001, EF24, cisplatin, and oxaliplatin treatments on both malignant pleural mesothelioma (MSTO-211H) and nonmalignant mesothelial (Met-5A) cell lines. The effects of the agents on MSTO-211H and Met-5A cells were evaluated in terms of cell viability, cytotoxicity, DNA synthesis rate, quantitation of apoptotic DNA fragmentation, and cleaved caspase 3 levels. Moreover, quantitative messenger RNA (mRNA) analysis of apoptotic (CASP9) and antiapoptotic (BCL2L1 and BCL2) genes were also performed. We found that both EF24 and RAD001 alone treatments decreased only MSTO-211H cell viability, but cisplatin and oxaliplatin affected both cell lines. Pretreatment with EF24 or RAD001 followed by cisplatin increased the effects of cisplatin alone application. EF24 and RAD001 pretreatment decreased DNA fragmentation rate when compared with cisplatin alone treatment in Met-5A cells. Sequential treatments resulted in a significant increase of CASP9 mRNA expression in MSTO-211H cells but not in Met-5A cells. Our preliminary results suggest that pretreatment with EF24 or RAD001 may reduce cytotoxic effect of cisplatin on nonmalignant mesothelial cells and increase cell death response of MPM cells. Further analyses using animal models are needed to confirm these findings in vivo. PMID:25028262

  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.; Fučíková, 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. Classification of current anticancer immunotherapies.

    PubMed

    Galluzzi, Lorenzo; Vacchelli, Erika; Bravo-San Pedro, Jos-Manuel; Buqu, 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; Caign