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1

Synthesis and anticancer activities of fatty acid analogs of podophyllotoxin  

Microsoft Academic Search

Derivatives of podophyllotoxin were prepared by coupling 10 FA with the C4-?-hydroxy function of podophyllotoxin. The coupling reactions between FA and podophyllotoxin were carried out by dicyclohexylcarbodiimide\\u000a in the presence of a catalytic amount of dimethylaminopyridine to produce quantitative yields of desired products. FA incorporated\\u000a were the following: 10-hydroxydecanoic, 12-hydroxydodecanoic, 15-hydroxypentadecanoic, 16-hydroxyhexadecanoic, 12-hydroxyoctadec-Z-9-enoic, eicosa-Z-5,8,11,14-tetraenoic, eicosa-Z-8,11, 14-trienoic, eicosa-Z-11,14-dienoic, eicosa-Z-11-enoic, and eicosanoic

Jamal Mustafa; Shabana I. Khan; Guoyi Ma; Larry A. Walker; Ikhlas A. Khan

2004-01-01

2

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

PubMed Central

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.

Magedov, Igor V.; Frolova, Liliya; Manpadi, Madhuri; Bhoga, Uma devi; Tang, Hong; Evdokimov, Nikolai M.; George, Olivia; Georgiou, Kathy Hadje; Renner, Steffen; Getlic, Matthaus; 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

3

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

PubMed Central

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

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

2013-01-01

4

Synthetic and Application Perspectives of Azapodophyllotoxins: Alternative Scaffolds of Podophyllotoxin  

PubMed Central

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.

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

2012-01-01

5

Arsenic compounds as anticancer agents  

Microsoft Academic Search

In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion

Zhen-Yi Wang

2001-01-01

6

Subcutaneous administration of anticancer agents.  

PubMed

In recent years, much has been discussed on the development of oral anticancer treatment in terms of practical aspects and convenience for the patient. Less has been devoted to the potential of subcutaneous administration as a parenteral alternative. However, recent approvals (bortezomib, omacetaxine, trastuzumab) seem to show a renewed interest in this route of administration. All anticancer agents given subcutaneously display a very high bioavailability (>80%) and are rapidly absorbed (except the monoclonal antibodies trastuzumab and alemtuzumab). Subcutaneous delivery does not impact on the rate of elimination when compared to the intravenous route (azacitidine, cladribine, bortezomib, trastuzumab). Some formulations may be self-administered in educated patients (methotrexate, cladribine) but others require hospitalization (omacetaxine). When available, comparative studies with intravenous administration showed comparable clinical issues with an advantage for subcutaneous bortezomib with regard to the occurrence of peripheral neurotoxicity. Subcutaneous formulations of trastuzumab and, in the future rituximab, may allow for ambulatory treatment and self-administration. From an economic point of view, subcutaneous formulations of monoclonal antibodies may lead to lower healthcare costs but will have to face the arrival of less expensive intravenous biologically similar agents ('biosimilars') that will reduce the cost of hospitalization. PMID:24692685

Leveque, Dominique

2014-04-01

7

Heterocyclic chalcone analogues as potential anticancer agents.  

PubMed

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 ?,?-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

Sharma, Vikas; Kumar, Vipin; Kumar, Pradeep

2013-03-01

8

Arsenic compounds as anticancer agents.  

PubMed

In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution. Patients exhibit a response in 28-42 days. CR rates after administration of Composite Indigo Naturalis tablets containing arsenic sulfide and of pure tetraarsenic tetrasulfide reached 98% and 84.9%, respectively. At higher concentrations (1-2 microM), arsenic induced apoptosis, while at lower concentrations (0.1-0.5 microM), it triggered cell differentiation in vitro. As2O3-induced apoptosis has been observed in many cancer cell lines, including esophageal carcinoma, gastric cancer, neuroblastoma, lymphoid malignancies, and multiple myeloma. Its effectiveness was confirmed in the treatment of multiple myeloma. Arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation. PMID:11587371

Wang, Z Y

2001-08-01

9

Anticancer agents against malaria: time to revisit?  

PubMed

The emergence of artemisinin resistance could adversely impact the current strategy for malaria treatment; thus, new drugs are urgently needed. A possible approach to developing new antimalarials is to find new uses for old drugs. Some anticancer agents such as methotrexate and trimetrexate are active against malaria. However, they are commonly perceived to be toxic and thus not suitable for malaria treatment. In this opinion article, we examine how the toxicity of anticancer agents is just a matter of dose or 'only dose makes the poison', as coined in Paracelsus' law. Thus, the opportunity exists to discover new antimalarials using the anticancer pharmacopoeia. PMID:20056487

Nzila, Alexis; Okombo, John; Becker, Ruy Perez; Chilengi, Roma; Lang, Trudie; Niehues, Tim

2010-03-01

10

Agents from amphibians with anticancer properties.  

PubMed

Amphibians have been found to be a source of agents with anticancer properties. Bufalin, for example, is an anticancer agent that may induce apoptosis by its interaction with other genes and cellular components. Certain peptides with anticancer activities have been found in amphibian skin; they include magainins, aureins, citropin 1.1 and gaegurins. These peptides may exert a cytotoxic effect on human cancer cells through various mechanisms. Onconase, amphinase, cSBL (sialic acid-binding lectin purified from Rana catesbeiana eggs) and jSBL (sialic acid-binding lectin purified from Rana japonica eggs), which belong to the RNase A family, were purified from the oocyte cells and eggs of three amphibians, and they induce cytotoxicity by degrading cellular RNA. This paper discusses the medical and pharmaceutical significance of products derived from amphibians. PMID:18827558

Lu, Chuang-Xin; Nan, Ke-Jun; Lei, Yan

2008-11-01

11

Mitochondrially targeted anti-cancer agents  

Microsoft Academic Search

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

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

2010-01-01

12

Current development of podophyllotoxins  

Microsoft Academic Search

The unique biological properties and therapeutic efficacy of the podophyllotoxin derivatives, Vumon (VM26, teniposide) and Vepesid (VP16-213, etoposide), are stimulating the interest of both laboratory and clinical researchers. Investigations on new pharmaceutical formulations, pharmacokinetics and metabolism are providing more appropriate information on drug administration; experimental chemotherapy indicates that, among others, cytosine arabinoside and cisplatin are highly synergistic with podophyllotoxins; single

Renzo Canetta; Peter Hilgard; Sylvia Florentine; Paolo Bedogni; Luigi Lenaz

1982-01-01

13

Benzothiazoles: search for anticancer agents.  

PubMed

Novel derivatives of 2-amino benzothiazoles 4(a-j) have been synthesized and tested for their antitumor activity using National Cancer Institute (NCI) disease oriented antitumor screen protocol against nine panel of cancer cell lines. Among the synthesized compounds, two compounds were granted NSC code and screened at National Cancer Institute (NCI)-USA for anticancer activity at a single high dose (10(-5) M) and five dose in full NCI 60 cell panel. Among the selected compounds, 7-chloro-N-(2,6-dichlorophenyl)benzo[d]thiazol-2-amine (4i) with GI(50) values of 7.18 × 10(-8) M against Non-Small Cell HOP-92 Lung Cancer cell line proved to be the most active members in this study. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors. PMID:22703845

Noolvi, Malleshappa N; Patel, Harun M; Kaur, Manpreet

2012-08-01

14

Mitochondrially targeted anti-cancer agents.  

PubMed

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

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

2010-11-01

15

Cytotoxic assays for screening anticancer agents.  

PubMed

In the process of identifying potential anticancer agents, the ability of a new agent is tested for cytotoxic activity against a panel of standard cancer cell lines. The National Cancer Institute (NCI) present the cytotoxic profile for each agent as a set of estimates of the dose required to inhibit the growth of each cell line. The NCI estimates are obtained from a linear interpolation method applied to the dose-response curves. In this paper non-linear fits are proposed as an alternative to interpolation. This is illustrated with data from two agents recently submitted to NCI for potential anticancer activity. Fitting of individual non-linear curves proved difficult, but a non-linear mixed model applied to the full set of cell lines overcame most of the problems. Two non-linear functional forms were fitted using random effect models by both maximum likelihood and a full Bayesian approach. Model-based toxicity estimates have some advantages over those obtained from interpolation. They provide standard errors for toxicity estimates and other derived quantities, allow model comparisons. Examples of each are illustrated. PMID:16013035

Baharith, Lamya A; Al-Khouli, Abeer; Raab, Gillian M

2006-07-15

16

Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents  

PubMed Central

Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while discussing the safety and efficacy of these compounds in clinical studies to date.

Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

2013-01-01

17

Organoiridium complexes: anticancer agents and catalysts.  

PubMed

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 ?-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 ?, 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

Liu, Zhe; Sadler, Peter J

2014-04-15

18

Organoiridium Complexes: Anticancer Agents and Catalysts  

PubMed Central

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 ?-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 ?, 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.

2014-01-01

19

Designed TPR Modules as Novel Anticancer Agents  

SciTech Connect

Molecules specifically designed to modulate protein-protein interactions have tremendous potential as novel therapeutic agents. One important anticancer target is the chaperone Hsp90, whose activity is essential for the folding of many oncogenic proteins, including HER2, IGFIR, AKT, RAF-1, and FLT-3. Here we report the design and characterization of new tetratricopeptide repeat modules, which bind to the C-terminus of Hsp90 with higher affinity and with greater specificity than natural Hsp90-binding co-chaperones. Thus, when these modules are introduced into the cell, they out-compete endogenous co-chaperones for binding, thereby inhibiting Hsp90 function. The effect of Hsp90 inhibition in this fashion is dramatic; HER2 levels are substantially decreased and BT474 HER2 positive breast cancer cells are killed. Our designs thus provide new tools with which to dissect the mechanism of Hsp90-mediated protein folding and also open the door to the development of an entirely new class of anticancer agents.

Cortajarena,A.; Yi, F.; Regan, L.

2008-01-01

20

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

PubMed

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

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

2011-02-15

21

Quantitative measure of cytotoxicity of anticancer drugs and other agents  

Microsoft Academic Search

Many anticancer drugs act on cancer cells to promote apoptosis, which includes impairment of cellular respiration (mitochondrial O2 consumption). Other agents also inhibit cellular respiration, sometimes irreversibly. To investigate the sensitivity of cancer cells to cytotoxins, including anticancer drugs, we compare the profiles of cellular O2 consumption in the absence and presence of these agents. Oxygen measurements are made at

Zhimin Tao; Eyone Jones; Jerry Goodisman; Abdul-Kader Souid

2008-01-01

22

Vitamin D as a promising anticancer agent  

PubMed Central

Presence of vitamin D receptors in noncalcemic tissues and subsequent identification of its involvement in growth factor(s)-mediated cellular function suggested its probable beneficial role in genesis, progression and survival of cancerous growths. Data collected from both in vitro and in vivo studies are highly optimistic regarding its potential in prevention and regression of colorectal, prostate and breast cancers. The vitamin has been found to interfere with the transduction pathways of various growth factor(s)-activated receptors (receptor tyrosine kinases) thereby modulating transcription and alteration of genomic functions resulting in inhibition of cell proliferation and angiogenesis and facilitation of cell differentiation and apoptosis. It also increases the level of an endogenous protein - cystatin D, which possesses antitumor and antimetastatic property, by facilitation of the expression of the gene coding for it. Though not as a primary anticancer agent, this vitamin may be used for the prevention of cancer and included as an adjuvant in combination chemotherapy for the treatment of cancer.

Chakraborti, Chandra Kanti

2011-01-01

23

Production of Podophyllotoxin in Juniperus Chinensis Callus Cultures Treated with Oligosaccharides and a Biogenetic Precursor in Honour of Professor G. H. Neil Towers 75th Birthday  

Microsoft Academic Search

Calli were induced from the leaves of young trees of Juniperus chinensis on Schenk and Hildebrandt medium supplemented with napthalenacetic acid and kinetin and subcultured on the same medium. Podophyllotoxin, a strong anti-tumor agent, was isolated from the extractives of calli and found that calli produced podophyllotoxin. The podophyllotoxin in the calli derived from the leaves constituted 0.005% of dry

Toshio Muranaka; Masaru Miyata; Kazutaka Ito; Sanro Tachibana

1998-01-01

24

Efficient synthesis of benzamide riboside, a potential anticancer agent.  

PubMed

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

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

2007-01-01

25

Indenoindolone derivatives as topoisomerase II-inhibiting anticancer agents.  

PubMed

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 TopoII? 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

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

26

Isoxazoline containing natural products as anticancer agents: a review.  

PubMed

Isoxazolines are an important class of nitrogen and oxygen containing heterocycles that belong to the azoles family which have gained much importance in the field of medicinal chemistry as the anticancer agents. Moreover, natural products are always expectedly regarded as an important hoard of a large number of potential chemotherapeutic candidates. Therefore, this review mainly focuses on the existence of isoxazoline derivatives in natural sources, their isolation and uses there of as anticancer agents besides highlighting the synthetic pathways to achieve these compounds. Structural-activity relationship and the influence of stereochemical aspects on anticancer activity of such compounds have also been discussed. It covers the literature upto 2014 and would certainly provide a great insight to scientific community to accelerate further research for the development of some novel anticancer drugs. PMID:24631731

Kaur, Kamalneet; Kumar, Vinod; Sharma, Anil Kumar; Gupta, Girish Kumar

2014-04-22

27

Monitoring of occupational exposure to cytostatic anticancer agents  

Microsoft Academic Search

Many anticancer agents have been shown to be carcinogenic, mutagenic and teratogenic in experimental animals and in in vitro test systems. Epidemiological data on the association of second neoplasms with a specific chemotherapy treatment is available on some 30 agents, and in the case of 10 compounds the overall evidence on human carcinogenicity has been evaluated to be conclusive (Group

Marja Sorsa; Diana Anderson

1996-01-01

28

Nanovectors for anticancer agents based on superparamagnetic iron oxide nanoparticles  

PubMed Central

During the last decade, the application of nanotechnologies for anticancer drug delivery has been extensively explored, hoping to improve the efficacy and to reduce side effects of chemotherapy. The present review is dedicated to a certain kind of anticancer drug nanovectors developed to target tumors with the help of an external magnetic field. More particularly, this work treats anticancer drug nanoformulations based on superparamagnetic iron oxide nanoparticles coated with biocompatible polymers. The major purpose is to focus on the specific requirements and technological difficulties related to controlled delivery of antitumoral agents. We attempt to state the problem and its possible perspectives by considering the three major constituents of the magnetic therapeutic vectors: iron oxide nanoparticles, polymeric coating and anticancer drug.

Douziech-Eyrolles, Laurence; Marchais, Herve; Herve, Katel; Munnier, Emilie; Souce, Martin; Linassier, Claude; Dubois, Pierre; Chourpa, Igor

2007-01-01

29

Resistance mechanisms associated with altered intracellular distribution of anticancer agents  

Microsoft Academic Search

The resistance of tumor cells to anticancer agents remains a major cause of treatment failure in cancer patients. The term multidrug resistance (MDR) is used to define a resistance phenotype where cells are resistant to multiple drugs with no obvious structural resemblance and with different molecular targets. It is now clear that MDR is always multifactorial. The intracellular drug distribution

Annette K. Larsen; Alexandre E. Escargueil; Andrzej Skladanowski

2000-01-01

30

coral Software: QSAR for Anticancer Agents.  

PubMed

CORrelations And Logic (coral at http://www.insilico.eu/coral) is freeware aimed at establishing a quantitative structure - property/activity relationships (QSPR/QSAR). Simplified molecular input line entry system (SMILES) is used to represent the molecular structure. In fact, symbols in SMILES nomenclatures are indicators of the presence of defined molecular fragments. By means of the calculation with Monte Carlo optimization of the so called correlation weights (contributions) for the above-mentioned molecular fragments, one can define optimal SMILES-based descriptors, which are correlated with an endpoint for the training set. The predictability of these descriptors for an external validation set can be estimated. A collection of SMILES-based models of anticancer activity of 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines for different splits into training and validation set which are calculated with the coral are examined and discussed. Good performance has been obtained for three splits: the r(2) ranged between 0.778 and 0.829 for the sub-training set, between 0.828 and 0.933 for the calibration set, and between 0.807 and 0.931 for the validation set. PMID:21435183

Benfenati, Emilio; Toropov, Andrey A; Toropova, Alla P; Manganaro, Alberto; Gonella Diaza, Rodolfo

2011-06-01

31

Design and synthesis of fluoroacylshikonin as an anticancer agent.  

PubMed

A series of shikonin derivatives, selectively acylated by various fluorinated carboxylic acids at the side chain of shikonin, were synthesized and their anticancer activity evaluated, in which eight compounds are reported for the first time. Among all the compounds tested, compound showed the most potent anticancer activity against B16-F10 (malignant melanoma cells), MG63 (human osteosarcoma cells), and A549 (lung cancer cells) with IC50 0.39 ± 0.01, 0.72 ± 0.04 and 0.58 ± 0.02 µmol/L. Docking simulation of compound was carried out to position into a tubulin active site to determine the probable binding conformation. All the results suggested that compound may be a potential anticancer agent. PMID:23908135

Kong, Wen-Yao; Chen, Xiao-Feng; Shi, Jing; Baloch, Shahla Karim; Qi, Jin-Liang; Zhu, Hai-Liang; Wang, Xiao-Ming; Yang, Yong-Hua

2013-11-01

32

Alkaloids isolated from natural herbs as the anticancer agents.  

PubMed

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

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

2012-01-01

33

Alkaloids Isolated from Natural Herbs as the Anticancer Agents  

PubMed Central

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.

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

2012-01-01

34

Fucoidan as a Marine Anticancer Agent in Preclinical Development  

PubMed Central

Fucoidan is a fucose-containing sulfated polysaccharide derived from brown seaweeds, crude extracts of which are commercially available as nutritional supplements. Recent studies have demonstrated antiproliferative, antiangiogenic, and anticancer properties of fucoidan in vitro. Accordingly, the anticancer effects of fucoidan have been shown to vary depending on its structure, while it can target multiple receptors or signaling molecules in various cell types, including tumor cells and immune cells. Low toxicity and the in vitro effects of fucoidan mentioned above make it a suitable agent for cancer prevention or treatment. However, preclinical development of natural marine products requires in vivo examination of purified compounds in animal tumor models. This review discusses the effects of systemic and local administration of fucoidan on tumor growth, angiogenesis, and immune reaction and whether in vivo and in vitro results are likely applicable to the development of fucoidan as a marine anticancer drug.

Kwak, Jong-Young

2014-01-01

35

Targeting Mitochondrial DNA with a Platinum-Based Anticancer Agent  

PubMed Central

Summary An analogue of the anticancer drug cisplatin (mtPt) was delivered to mitochondria of human cells using a peptide specifically targeting this organelle. mtPt induces apoptosis without damaging nuclear DNA, indicating that mtDNA damage is sufficient to mediate the activity of a platinum-based chemotherapeutic. This study is the first to demonstrate specific delivery of a platinum drug to mitochondria and to investigate the effects of directing this agent outside the nucleus.

Wisnovsky, Simon P.; Wilson, Justin J.; Radford, Robert J.; Pereira, Mark P.; Chan, Maria R.; Laposa, Rebecca R.; Lippard, Stephen J.; Kelley, Shana O.

2014-01-01

36

Current development of mTOR inhibitors as anticancer agents  

Microsoft Academic Search

Mammalian target of rapamycin (mTOR) is a kinase that functions as a master switch between catabolic and anabolic metabolism and as such is a target for the design of anticancer agents. The most established mTOR inhibitors — rapamycin and its derivatives — showed long-lasting objective tumour responses in clinical trials, with CCI-779 being a first-in-class mTOR inhibitor that improved the

Sandrine Faivre; Guido Kroemer; Eric Raymond

2006-01-01

37

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

PubMed Central

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

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

2013-01-01

38

Development of Computer-Assisted Biohazard Safety Cabinet for Preparation and Verification of Injectable Anticancer Agents  

Microsoft Academic Search

Background: Medication errors associated with anticancer agents may cause fatal events. Therefore, exact verification of the prescription order and accurate preparation of the mixture of anticancer injections are required for safe management in cancer chemotherapy. Methods: A computer-assisted biohazard safety cabinet was newly developed for verification and preparation of anticancer agents. Using a barcode reader, information on prescription orders was

Shinji Okayasu; Mitsuhiro Nakamura; Tadashi Sugiyama; Koichi Chigusa; Kiyoshi Sakurai; Katsuhiko Matsuura; Mayumi Yamamoto; Yasutomi Kinosada; Yoshinori Itoh

2009-01-01

39

Thioredoxin Increases Redox-Cycling of Anticancer Agents Thereby Sensitizes Cancer Cells to Apoptosis.  

National Technical Information Service (NTIS)

The present invention provides for treatment of cancer by enhancing the effectiveness of anticancer agents. The present invention therefore provides methods of increasing the apoptotic potential of anticancer drugs by increasing the expression of the cell...

R. Dashnamoorthy K. C. Das

2004-01-01

40

Discovery of new anticancer agents from higher plants  

PubMed Central

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.

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

2012-01-01

41

Furanylazaindoles: potent anticancer agents in vitro and in vivo.  

PubMed

Preliminary biological data on 7-anilino-6-azaindoles (8-11) suggested that hydrophobic substituents at C7 contribute to enhancement of antiproliferative activity. A novel series of 7-aryl-6-azaindole-1-benzenesulfonamides (12-22) were developed and showed improved cytotoxicity compared to ABT751 (5). The conversion of C7 phenyl rings into C7 heterocycles led to a remarkable improvement of antiproliferative activity. Among all the synthetic products, 7-(2-furanyl)-1-(4-methoxybenzenesulfonyl)-6-azaindole (21) exhibited the most potent anticancer activity against KB, HT29, MKN45, and H460 cancer cell lines with IC50 values of 21.1, 32.0, 27.5, and 40.0 nM, respectively. Bioassays indicated that 21 not only inhibits tubulin polymerization by binding to tubulin at the colchicine binding site but also arrests the cell cycle at the G2/M phase with slight arrest at the sub-G1 phase. Compound 21 also functions as a vascular disrupting agent and dose-dependently inhibits tumor growth without significant change of body weight in an HT29 xenograft mouse model. Taken together, compound 21 has potential for further development as a novel class of anticancer agents. PMID:24106982

Lee, Hsueh-Yun; Pan, Shiow-Lin; Su, Min-Chieh; Liu, Yi-Min; Kuo, Ching-Chuan; Chang, Yi-Ting; Wu, Jian-Sung; Nien, Chih-Ying; Mehndiratta, Samir; Chang, Chi-Yen; Wu, Su-Ying; Lai, Mei-Jung; Chang, Jang-Yang; Liou, Jing-Ping

2013-10-24

42

Podophyllotoxin and 6-methoxy podophyllotoxin Production in Hairy Root Cultures of Liunm mucronatum ssp. mucronatum  

PubMed Central

Aim: Two bacterial strains of Agrobacterium rhizogenes, A13 and 9534 were evaluated for induction of transformed hairy roots in Linum mucronatum ssp. mucronatum, a high value medicinal plant. Materials and Methods: The hairy roots were successfully initiated, through infecting the hypocotyl and root explants and the A13 strain performed a high transformation frequency for hairy roots induction. Transgenic status of hairy roots was confirmed by polymerase chain reaction (PCR) analysis of the rol genes. Growth kinetics of transgenic roots induced by two strains indicated a similar pattern of growth, with maximum growth occurring between 42 to 56 days. The lignan contents in hairy roots were analyzed using high-performance liquid chromatography (HPLC) method. Results: Transformed cultures showed significant differences (P < 0.05) in lignan content. The highest amount of Podophyllotoxin (PTOX, 5.78 mg/g DW) and 6-methoxy podophyllotoxin (MPTOX, 49.19 mg/g DW) was found in transformed lines induced by strain A13, which was four times higher than those of non-transformed roots. The results showed that hairy root cultures of L. mucronatum are rich sources of MPTOX. Conclusion: hairy root cultures from L. mucronatum can be used as a useful system for scale-up producing MPTOX and precursors for the production of antitumor agents in substitution with PTOX by considering the appropriate optimizations in future studies.

Samadi, Afsaneh; Jafari, Morad; Nejhad, Nasim Mohammad; Hossenian, Farah

2014-01-01

43

Current status on development of steroids as anticancer agents.  

PubMed

Steroids are important biodynamic agents. Their affinities for various nuclear receptors have been an interesting feature to utilize them for drug development particularly for receptor mediated diseases. Steroid biochemistry and its crucial role in human physiology, has attained importance among the researchers. Recent years have seen an extensive focus on modification of steroids. The rational modifications of perhydrocyclopentanophenanthrene nucleus of steroids have yielded several important anticancer lead molecules. Exemestane, SR16157, fulvestrant and 2-methoxyestradiol are some of the successful leads emerged on steroidal pharmacophores. The present review is an update on some of the steroidal leads obtained during past 25 years. Various steroid based enzyme inhibitors, antiestrogens, cytotoxic conjugates and steroidal cytotoxic molecules of natural as well as synthetic origin have been highlighted. This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors". PMID:23727548

Gupta, Atul; Kumar, B Sathish; Negi, Arvind S

2013-09-01

44

Small mitochondria-targeting molecules as anti-cancer agents  

PubMed Central

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.

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

2009-01-01

45

Inhibitors of histone deacetylase as new anticancer agents.  

PubMed

Inhibitors of histone deacetylase (HDAC) are an emerging class of anticancer agents. They induce hyperacetylation in chromatin usually resulting in activation of certain genes. They induce terminal cell differentiation and/or apoptosis in cancer cells. Histone deacetylase activity is recruited by co-repressor proteins to certain regions of the chromatin and aberrant histone acetylation caused by that recruitment is responsible for the pathogenesis of certain cancers on a molecular level. Inhibitors of HDAC have been identified in natural sources and also synthetic inhibitors are available. The best studied inhibitor is trichostatin A, a hydroxamic acid that exerts its activity by complexation of a zinc ion that is supposed to mediate the acetamide cleavage at the catalytic site. There are several synthetic hydroxamic acids that bear resemblance to trichostatin. Another class of potent inhibitors are naturally occurring and synthetic cyclotetrapeptides that all contain an unusual amino acid with an epoxyketone, ketone or hydroxamic acid function in the side chain. Phenylacetate, phenylbutyrate, butyrate and similar short chain fatty acids are also weak inhibitors. Further inhibitors from natural sources are the epoxide depudecin and depsipeptide FR 901228. The benzamide MS-275 belongs to a new class of synthetic HDAC inhibitors and displays oral activity in animal models. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer is possible. Thus, inhibitors of HDAC are one of the most promising class of new anticancer agents. New screening assays are useful tools that will facilitate identification of further inhibitors. PMID:11562279

Jung, M

2001-10-01

46

T-oligo as an anticancer agent in colorectal cancer.  

PubMed

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

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

2014-04-01

47

Immunomodulating tellurium compounds as anti-cancer agents.  

PubMed

Tellurium is a rare element, which has been regarded as a toxic, non-essential trace element; its biological role, if any, has not been clearly established to date. The investigation of therapeutic activities of tellurium compounds is rather limited in the literature, despite the relative abundance of tellurium in the human body. Nevertheless, the varied activities of tellurium agents in both malignant and normal cells are extremely exciting, though very complex. Not surprisingly, an increased interest in tellurium among biological chemists and pharmacists has fuelled the search for more and more diverse tellurium compounds. The present review will focus on two small inorganic tellurium complexes, ammonium trichloro(dioxoethylene-O,O')tellurate (AS101) and Octa-O-bis-(R,R)-tartarate ditellurane (SAS), thoroughly investigated by us, converging at their anti-cancer properties, and elucidating their mechanism of action. AS101 is probably the most extensively studied synthetic tellurium compound from the standpoint of its biological activity. It is a potent immunomodulator (both in vitro and in vivo) with a variety of potential therapeutic applications. It is probably the only tellurium compound to be tested in phase I/II clinical studies in cancer patients. The effects of AS101 and SAS are primarily caused by their specific Te(IV) redox-modulating activities enabling the inactivation of cysteine proteases such as cathepsin B, inhibition of specific tumor survival proteins like survivin, or obstruction of tumor IL-10 production. All of these have profound consequences regarding anti-tumor activity or sensitization of tumors to chemotherapy. These properties, coupled with the excellent safety profile of the compounds, suggest promising anti-cancer therapeutic potential for tellurium compounds such as AS101 or SAS. PMID:22202556

Sredni, Benjamin

2012-02-01

48

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

PubMed Central

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.

JI, CHEN-FENG; JI, YU-BIN

2014-01-01

49

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

PubMed

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

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

2013-03-01

50

Podophyllotoxin Analogues Active versus Trypanosoma brucei  

PubMed Central

In an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (NSAIDs) has been synthesized and evaluated for activity versus Trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. It was discovered that coupling of NSAIDs to podophyllotoxin increased the potencies of both compounds over 1300-fold. The compounds were shown to be cytostatic in nature and seem to act via depolymerization of tubulin in a manner consistent with the known activities of podophyllotoxin. The potencies against T. brucei correlated directly with LogP values of the compounds, suggesting that the conjugates are acting as hydrophobic tags allowing podophyllotoxin to enter the cell.

Uddin, Md. Jashim; Smithson, David C.; Brown, Kristin M.; Crews, Brenda C.; Connelly, Michele; Zhu, Fangyi; Marnett, Lawrence J.; Guy, R. Kiplin

2010-01-01

51

Potential drug–drug interactions between anti-cancer agents and community pharmacy dispensed drugs  

Microsoft Academic Search

Objective of the study To identify the prevalence of potential drug–drug interactions between hospital pharmacy dispensed anti-cancer agents and\\u000a community pharmacy dispensed drugs. Setting A retrospective cohort study was conducted on the haematology\\/oncology department of the internal medicine ward in a large\\u000a teaching hospital in Amsterdam, the Netherlands. Method Prescription data from the last 100 patients treated with anti-cancer agents

Marsha L. VollKim; Kim D. Yap; Wim E. Terpstra; Mirjam Crul

2010-01-01

52

A Genome-Wide Screening in Saccharomyces cerevisiae for Genes That Confer Resistance to the Anticancer Agent Cisplatin  

Microsoft Academic Search

Cisplatin is a potent DNA-damaging agent that has demonstrated anticancer activities against several tumors. However, manifestation of cellular resistance is a major obstacle in anticancer therapy that severely limits the curative potential of cisplatin. Therefore, understanding the molecular basis of cisplatin resistance could significantly improve the clinical efficacy of this anticancer agent. Here, we employed Saccharomyces cerevisiae as a model

Herman Burger; Astrid Capello; Paul W Schenk; Gerrit Stoter; Jaap Brouwer; Kees Nooter

2000-01-01

53

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

PubMed Central

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.

Vickers, Andrew J.

2008-01-01

54

Synthesis and Evaluation of Flavanones as Anticancer Agents  

PubMed Central

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.

Murti, Y.; Mishra, P.

2014-01-01

55

PCL/PEG copolymeric nanoparticles: potential nanoplatforms for anticancer agent delivery.  

PubMed

Nanotechnology provides researchers with new tools for cancer treatment. Biodegradable polymeric nanoparticles, as an advanced drug delivery system, have promising applications in cancer treatment. Poly(?-caprolactone)/poly(ethylene glycol) (PCL/PEG) copolymers are biodegradable and amphiphilic, and show potential application in drug delivery. In recent years, PCL/PEG copolymeric nanoparticles, as a potential nanoplatform for anticancer agent delivery, received increasing attention. This paper reviews PCL/PEG copolymer nanoparticles for anticancer agent delivery, including overcoming water insolubility of hydrophobic drug, targeting chemotherapeutic drug to tumor, and delivering genes, vaccines, and diagnostic agents. PMID:21443476

Gou, MaLing; Wei, XiaWei; Men, Ke; Wang, BiLan; Luo, Feng; Zhao, Xia; Wei, YuQuan; Qian, ZhiYong

2011-07-01

56

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

PubMed Central

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.

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

2014-01-01

57

Potential role of garcinol as an anticancer agent.  

PubMed

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

Saadat, Nadia; Gupta, Smiti V

2012-01-01

58

Discovery of anticancer agents of diverse natural origin*  

PubMed Central

A collaborative multidisciplinary research project is described in which new natural product anticancer drug leads are obtained from a diverse group of organisms, constituted by tropical plants, aquatic cyanobacteria, and filamentous fungi. Information is provided on how these organisms are collected and processed. The types of bioassays are indicated in which crude extracts of these acquisitions are tested. Progress made in the isolation of lead bioactive secondary metabolites from three tropical plants is discussed.

Kinghorn, A. Douglas; Carcache de Blanco, Esperanza J.; Chai, Hee-Byung; Orjala, Jimmy; Farnsworth, Norman R.; Soejarto, D. Doel; Oberlies, Nicholas H.; Wani, Mansukh C.; Kroll, David J.; Pearce, Cedric J.; Swanson, Steven M.; Kramer, Robert A.; Rose, William C.; Fairchild, Craig R.; Vite, Gregory D.; Emanuel, Stuart; Jarjoura, David; Cope, Frederick O.

2009-01-01

59

A novel podophyllotoxin lignan from Justicia heterocarpa.  

PubMed

Chromatographic separation of the extract of Justicia heterocarpa T. ANDERS. afforded, in addition to known fatty acids, terpenoids and steroids, a new podophyllotoxin lignan. Structures were elucidated by spectroscopic methods, and the structure of the new lignan was confirmed by single crystal X-ray diffraction studies, which have shown that there is a H-bonding stabilized dimer. PMID:15133198

Al-Juaid, Salih Salem; Abdel-Mogib, Mamdouh

2004-05-01

60

Biotransformation of podophyllotoxin to picropodophyllin by microbes.  

PubMed

Biotransformation of podophyllotoxin (PT) by several microbial species has been investigated. Among the fungi tested, it was found that Penicillium strains can isomerize PT to picropodophyllin (PPT) in 8% yield and other strains also transform the substrate into the same product but with lower yield. PMID:11261220

Guo, H Z; Guo, D A; Fei, X Y; Cui, Y J; Zheng, J H

1998-01-01

61

Mitochondrial voltage-dependent anion channels (VDACs) as novel pharmacological targets for anti-cancer agents  

Microsoft Academic Search

Recently, it was demonstrated that some anti-cancer agents used mitochondrial voltage-dependent anion channels (VDAC1–3 isoforms)\\u000a as their pharmacological target. VDACs are expressed more highly in cancer cells than normal cells; thus the VDAC-dependent\\u000a cytotoxic agents can have cancer-selectivity. Furanonaphthoquinones (FNQs) induced caspase-dependent apoptosis via the production\\u000a of NADH-dependent reactive oxygen species (ROS) by VDAC1. The ROS production and the anti-cancer

Eriko Simamura; Hiroki Shimada; Toshihisa Hatta; Kei-Ichi Hirai

2008-01-01

62

Design and synthesis of harzialactone analogues: promising anticancer agents.  

PubMed

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

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

2010-12-15

63

Adverse effects of anticancer agents that target the VEGF pathway  

Microsoft Academic Search

Antiangiogenesis agents that target the VEGF\\/VEGF receptor pathway have become an important part of standard therapy in multiple cancer indications. With expanded clinical experience with this class of agents has come the increasing recognition of the diverse adverse effects related to disturbance of VEGF-dependent physiological functions and homeostasis in the cardiovascular and renal systems, as well as wound healing and

Jessica N. Cleck; Helen X. Chen

2009-01-01

64

Novel N-substituted sophoridinol derivatives as anticancer agents.  

PubMed

Using sophoridine (1) as the lead compound, a series of new N-substituted sophoridinic acid derivatives were designed, synthesized and evaluated for their cytotoxicity. SAR analysis indicated that introduction of a chlorobenzyl on the 12-nitrogen atom of sophoridinol might significantly enhance the antiproliferative activity. Of the newly synthesized compounds, sophoridinol analogue 9k exhibited a potent effect against six human tumor cell lines (liver, colon, breast, lung, glioma and nasopharyngeal). The mode of action of 9k was to inhibit the DNA topoisomerase I activity, followed by the G0/G1 phase arrest. It also showed a moderate oral bioavailability and good safety in vivo. Therefore, compound 9k has been selected as a novel-scaffold lead for further structural optimizations or as a chemical probe for exploring anticancer pathways of this kinds of compounds. PMID:24826818

Bi, Chong-Wen; Zhang, Cai-Xia; Li, Ying-Hong; Tang, Sheng; Deng, Hong-Bin; Zhao, Wu-Li; Wang, Zhen; Shao, Rong-Guang; Song, Dan-Qing

2014-06-23

65

[Effects of anti-cancer agents on cultured rat Sertoli cells].  

PubMed

We performed primary immature Sertoli cell culture to investigate whether or not anti-cancer agents would have a direct effect on rat Sertoli cells. Sertoli cells, isolated from testes of 18-day-old rats, were cultured in pellets with medium for 5 days. The concentration of transferrin in cultured medium were measured as the function of Sertoli cells. The anti-cancer agents cis-diamminedichloroplatinum (CDDP), adriamycin and vinblastine were selected for this study, and added to the culture medium. CDDP decreased the level of transferrin concentration in cultured medium, namely 0.5 microgram/ml of CDDP resulted in 54.9% of the transferrin concentration in the medium compared with that without any anti-cancer agents (p < 0.05), and 1.0 micrograms/ml of CDDP produced transferrin concentrations of 57.5% and 46.2% (p < 0.05), respectively. Adriamycin (0.4 microgram/ml) and vinblastine (0.5 microgram/ml) produced transferrin concentrations of 35.2% and 31.3% in cultured medium (p < 0.05), respectively. These findings revealed that anti-cancer agents have direct damaging effects on rat Sertoli cells. PMID:7609355

Nambu, A; Kumamoto, Y; Mikuma, N

1995-06-01

66

Sustainable bioproduction of phytochemicals by plant in vitro cultures: anticancer agents  

Microsoft Academic Search

Due to their complex structure with several chiral centres important anticancer agents are still extracted from plants and not synthesized chemically on a commercial scale. Sustainable biopro- duction of the compounds of interest may be achieved by plant in vitro cultures. Undifferen- tiated callus and suspension cultures, which can be cultivated in large bioreactors easily, very often fail to accumulate

Michael Wink; A. Wilhelm Alfermann; Rochus Franke; Bernhard Wetterauer; Melanie Distl; Oliver Krohn; Elisabeth Fuss; Hermann Garden; Abdolali Mohagheghzadeh; Eckart Wildi; Peter Ripplinger

2005-01-01

67

Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents  

Microsoft Academic Search

Efforts to discover new cancer drugs and predict their clinical activity are limited by the fact that laboratory models to test drug efficacy do not faithfully recapitulate this complex disease. One important model system for evaluating candidate anticancer agents is human tumour-derived cell lines. Although cultured cancer cells can exhibit distinct properties compared with their naturally growing counterparts, recent technologies

Sreenath V. Sharma; Daniel A. Haber; Jeff Settleman

2010-01-01

68

Plant-Derived Anticancer Agents Used in Western and Oriental Medicine  

Microsoft Academic Search

\\u000a Cancer chemotherapeutic agents derived from higher plants are used in Western medicine. Secondary metabolites from plants\\u000a are used in oriental medicine are utilized in anticancer therapy. Immunomodulatory small organic molecules from plant species\\u000a are employed in Chinese traditional medicine are renewed.

Ah-Reum Han; Ye Deng; Yulin Ren; Li Pan; A. Douglas Kinghorn

69

[Chronopharmacologic approach to the administration of anticancer agents in pancreatic adenocarcinoma. Pilot experience].  

PubMed

The authors first analyzed the potential interest of the delivery of anticancer agents according to chronobiological concepts for human pancreatic cancer. They report their experience on 41 patients treated in adjuvant (12 cases) or palliative (29 cases) situations. The excellent therapeutic index observed warrants further evaluations of this concept in randomized trials. PMID:10823003

Focan, C; Kreutz, F; Focan-Henrard, D; Moeneclaey, N; Gillard, V; Delforge, M; Dallemagne, B; Weerts, J; Closon, M T; Honoré, P

2000-03-01

70

Combination of 2-methoxy-3-phenylsulfonylaminobenzamide and 2-aminobenzothiazole to discover novel anticancer agents.  

PubMed

The fragment of 2-substituted-3-sulfonylaminobenzamide has been proposed to replace the fragment of 2-substituted-3-sulfonylaminopyridine in PI3K and mTOR dual inhibitors to design novel anticancer agents based on bioisostere. The combination of the fragment of 2-substituted-3-sulfonylaminobenzamide with the fragment of 2-aminobenzothiazole or 2-aminothiazolo[5,4-b]pyridine, or 2-amino[1,2,4]triazolo[1,5-a]pyridine produced the novel structures of anticancer agents. As a result, nineteen target compounds were synthesized and characterized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines including HCT-116, A549, MCF-7 and U-87 MG. The SAR of target compounds was preliminarily discussed. Compound 1g with potent antiproliferative activity was examined for its effect on the AKT and p-AKT(473). The anticancer effect of 1g was evaluated in established nude mice HCT-116 xenograft model. The results suggested that compound 1g can block PI3K/AKT/mTOR pathway and significantly inhibit tumor growth. These findings strongly support our assumption that the fragment of benzamide can replace the pyridine ring in some PI3K and mTOR dual inhibitor to design novel anticancer agents. PMID:24878359

Li, Huan; Wang, Xiao-Meng; Wang, Juan; Shao, Teng; Li, Yi-Ping; Mei, Qi-Bing; Lu, She-Min; Zhang, San-Qi

2014-07-15

71

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

PubMed

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

Riaz, Ufana; Ashraf, S M

2013-04-01

72

The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity  

Microsoft Academic Search

Summary  The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) has been shown to synergize doxorubicin\\u000a (Dox) anticancer activity while attenuating its cardiotoxicity. In this study we further explored the selectivity of AN-7’s\\u000a action in several cancer and normal cells treated with anticancer agents. The cells studied were murine mammary 4T1, human\\u000a breast T47D and glioblastoma U251 cancer cell lines, neonatal rat

Nataly Tarasenko; Gania Kessler-Icekson; Pnina Boer; Aida Inbal; Hadassa Schlesinger; Don R. Phillips; Suzanne M. Cutts; Abraham Nudelman; Ada Rephaeli

73

Fenugreek: a naturally occurring edible spice as an anticancer agent  

PubMed Central

In recent years, various dietary components that can potentially be used for the prevention and treatment of cancer have been identified. In this study, we demonstrate that extract (FE) from the seeds of the plant Trigonella foenum graecum, commonly called fenugreek, are cytotoxic in vitro to a panel of cancer but not normal cells. Treatment with 10-15 ug/mL of FE for 72h was growth inhibitory to breast, pancreatic and prostate cancer cell lines (PCa). When tested at higher doses (15-20 ug/mL), FE continued to be growth inhibitory to PCa cell lines but not to either primary prostate or htert-immortalized prostate cells. At least part of the growth inhibition is due to induction of cell death, as seen by incorporation of Ethidium Bromide III into cancer cells exposed to FE. Molecular changes induced in PCa cells are: in DU-145 cells: down regulation of mutant p53, and in PC-3 cells up regulation of p21 and inhibition of TGF-? induced phosphorylation of Akt. The surprising finding of our studies is that death of cancer cells occurs despite growth stimulatory pathways being simultaneously up regulated (phosphorylated) by FE. Thus, these studies add another biologically active agent to our armamentarium of naturally occurring agents with therapeutic potential.

Shabbeer, Shabana; Sobolewski, Michelle; Kachhap, Sushant; Davidson, Nancy; Carducci, Michael A.; Khan, Saeed

2011-01-01

74

Determining the optimal dose in the development of anticancer agents.  

PubMed

Identification of the optimal dose remains a key challenge in drug development. For cytotoxic drugs, the standard approach is based on identifying the maximum tolerated dose (MTD) in phase I trials and incorporating this to subsequent trials. However, this strategy does not take into account important aspects of clinical pharmacology. For targeted agents, the dose-effect relationships from preclinical studies are less obvious, and it is important to change the way these agents are developed to avoid recommending drug doses for different populations without evidence of differential antitumour effects in different diseases. The use of expanded cohorts in phase I trials to better define MTD and refine dose optimization should be further explored together with a focus on efficacy rather than toxicity-based predictions. Another key consideration in dose optimization is related to interindividual pharmacokinetic variability. High variability in intra-individual pharmacokinetics has been observed for many orally-administered drugs, especially those with low bioavailability, which might complicate identification of dose-effect relationships. End-organ dysfunction, interactions with other prescription drugs, herbal supplements, adherence, and food intake can influence pharmacokinetics. It is important these variables are identified during early clinical trials and considered in the development of further phase II and subsequent large-scale phase III studies. PMID:24663127

Mathijssen, Ron H J; Sparreboom, Alex; Verweij, Jaap

2014-05-01

75

Curcumin and its formulations: potential anti-cancer agents.  

PubMed

Curcumin, one of the most studied chemopreventive agents, is a natural compound extracted from Curcuma longa L. Extensive research over the last half century has revealed that curcumin can inhibit the proliferation of various tumor cells in culture, prevent carcinogen induced cancers in rodents and inhibit the growth of human tumors in xenotransplant or orthotransplant animal models. Several phase I and phase II clinical trials indicated that curcumin is quite safe and may exhibit therapeutic efficacy. The utility of curcumin is limited by its lack of water solubility and relatively low in vivo bioavailability. Multiple approaches including nanoparticles, liposomes, micelles and phospholipid complexes are being sought to overcome these limitations. This review describes the general properties of curcumin and its potential effect against cancer including evidences of its antitumor action in vitro, in vivo, clinically and the strategies to overcome its low bioavailability. PMID:22044005

Ji, Jun-Ling; Huang, Xian-Feng; Zhu, Hai-Liang

2012-03-01

76

Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts  

Microsoft Academic Search

Objectives: To evaluate the efficacy and cost effectiveness of self applied podophyllotoxin 0.5% solu- tion and podophyllotoxin 0.15% cream, compared to clinic applied 25% podophyllin in the treatment of genital warts over 4 weeks. Methods: We conducted a randomised controlled trial in 358 immunocompetent men and women with genital warts of 3 months' duration or less. Results: In the principal

C J N Lacey; R L Goodall; G Ragnarson Tennvall; R Maw; G R Kinghorn; P G Fisk; S Barton; I Byren

2005-01-01

77

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

PubMed

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

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

2006-01-01

78

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

PubMed Central

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.

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

2006-01-01

79

Anticancer drug-layered hydroxide nanohybrids as potent cancer chemotherapy agents  

Microsoft Academic Search

Methotrexate-layered double hydroxide (MTX-LDH) nanohybrid showed considerably enhanced cellular uptake and drug efficacy compared to free MTX. To evaluate the potential of drug-LDH nanohybrids as cancer chemotherapy agents, the present study was extended to encapsulate another anticancer drug, 5-fluorouracil (5-Fu) into LDH through coprecipitation method. The powder X-ray pattern of 5-Fu-LDH nanohybrid showed interlayer distance of 5.8Å, which well corresponds

Soo-Jin Choi; Jae-Min Oh; Jin-Ho Choy

2008-01-01

80

Bacterial biosynthesis and maturation of the didemnin anticancer agents  

PubMed Central

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

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

2012-01-01

81

New hopes from old drugs: revisiting DNA-binding small molecules as anticancer agents  

PubMed Central

Most of the anticancer chemotherapeutic drugs that are broadly and successfully used today are DNA-damaging agents. Targeting of DNA has been proven to cause relatively potent and selective destruction of tumor cells. However, the clinical potential of DNA-damaging agents is limited by the adverse side effects and increased risk of secondary cancers that are consequences of the agents' genotoxicity. In this review, we present evidence that those agents capable of targeting DNA without inducing DNA damage would not be limited in these ways, and may be as potent as DNA-damaging agents in the killing of tumor cells. We use as an example literature data and our own research of the well-known antimalarial drug quinacrine, which binds to DNA without inducing DNA damage, yet modulates a number of cellular pathways that impact tumor cell survival.

Gurova, Katerina

2010-01-01

82

Lysosomotropic Properties of Weakly Basic Anticancer Agents Promote Cancer Cell Selectivity In Vitro  

PubMed Central

Drug distribution in cells is a fundamentally important, yet often overlooked, variable in drug efficacy. Many weakly basic anticancer agents accumulate extensively in the acidic lysosomes of normal cells through ion trapping. Lysosomal trapping reduces the activity of anticancer drugs, since anticancer drug targets are often localized in the cell cytosol or nucleus. Some cancer cells have defective acidification of lysosomes, which causes a redistribution of trapped drugs from the lysosomes to the cytosol. We have previously established that such differences in drug localization between normal and cancer cells can contribute to the apparent selectivity of weakly basic drugs to cancer cells in vitro. In this work, we tested whether this intracellular distribution-based drug selectivity could be optimized based on the acid dissociation constant (pKa) of the drug, which is one of the determinants of lysosomal sequestration capacity. We synthesized seven weakly basic structural analogs of the Hsp90 inhibitor geldanamycin (GDA) with pKa values ranging from 5 to 12. The selectivity of each analog was expressed by taking ratios of anti-proliferative IC50 values of the inhibitors in normal fibroblasts to the IC50 values in human leukemic HL-60 cells. Similar selectivity assessments were performed in a pair of cancer cell lines that differed in lysosomal pH as a result of siRNA-mediated alteration of vacuolar proton ATPase subunit expression. Optimal selectivity was observed for analogs with pKa values near 8. Similar trends were observed with commercial anticancer agents with varying weakly basic pKa values. These evaluations advance our understanding of how weakly basic properties can be optimized to achieve maximum anticancer drug selectivity towards cancer cells with defective lysosomal acidification in vitro. Additional in vivo studies are needed to examine the utility of this approach for enhancing selectivity.

Ndolo, Rosemary A.; Luan, Yepeng; Duan, Shaofeng; Forrest, M. Laird; Krise, Jeffrey P.

2012-01-01

83

Spectral and electrochemical detection of protonated triplex formation by a small-molecule anticancer agent  

NASA Astrophysics Data System (ADS)

Triplex helical formation has been the focus of considerable interest because of possible applications in developing new molecular biology tools as well as therapeutic agents and the possible relevance of H-DNA structures in biology system. We report here that a small-molecule anticancer agent, coralyne, has binding preference to the less stable protonated triplex d(C +-T) 6:d(A-G) 6·d(C-T) 6 over duplex d(A-G) 6·d(C-T) 6 and shows different spectral and electrochemical characteristics when binding to triplex and duplex DNA, indicating that electrochemical technique can detect the less stable protonated triplex formation.

Feng, Lingyan; Li, Xi; Peng, Yinghua; Geng, Jie; Ren, Jinsong; Qu, Xiaogang

2009-10-01

84

Amino Acid esters substituted phosphorylated emtricitabine and Didanosine derivatives as antiviral and anticancer agents.  

PubMed

Owing to the promising antiviral activity of amino acid ester-substituted phosphorylated nucleosides in the present study, a series of phosphorylated derivatives of emtricitabine and didanosine substituted with bioactive amino acid esters at P-atom were synthesized. Initially, molecular docking studies were screened to predict their molecular interactions with hemagglutinin-neuraminidase protein of Newcastle disease virus and E2 protein of human papillomavirus. The title compounds were screened for their antiviral ability against Newcastle disease virus (NDV) by their in ovo study in embryonated chicken eggs. Compounds 5g and 9c exposed well mode of interactions with HN protein and also exhibited potential growth of NDV inhibition. The remaining compounds exhibited better growth of NDV inhibition than their parent molecules, i.e., emtricitabine (FTC) and didanosine (ddI). In addition, the in vitro anticancer activity of all the title compounds were screenedagainst HeLa cell lines at 10 and 100 ?g/mL concentrations. The compounds 5g and 9c showed an effective anticancer activity than that of the remaining title compounds with IC50 values of 40 and 60 ?g/mL, respectively. The present in silico and in ovo antiviral and in vitro anticancer results of the title compounds are suggesting that the amino acid ester-substituted phosphorylated FTC and ddI derivatives, especially 5g and 9c, can be used as NDV inhibitors and anticancer agents for the control and management of viral diseases with cancerous condition. PMID:24789416

Sekhar, Kuruva Chandra; Janardhan, Avilala; Kumar, Yellapu Nanda; Narasimha, Golla; Raju, Chamarthi Naga; Ghosh, S K

2014-07-01

85

Exploring DNA Topoisomerase I Ligand Space in Search of Novel Anticancer Agents  

PubMed Central

DNA topoisomerase I (Top1) is over-expressed in tumour cells and is an important target in cancer chemotherapy. It relaxes DNA torsional strain generated during DNA processing by introducing transient single-strand breaks and allowing the broken strand to rotate around the intermediate Top1 – DNA covalent complex. This complex can be trapped by a group of anticancer agents interacting with the DNA bases and the enzyme at the cleavage site, preventing further topoisomerase activity. Here we have identified novel Top1 inhibitors as potential anticancer agents by using a combination of structure- and ligand-based molecular modelling methods. Pharmacophore models have been developed based on the molecular characteristics of derivatives of the alkaloid camptothecin (CPT), which represent potent antitumour agents and the main group of Top1 inhibitors. The models generated were used for in silico screening of the National Cancer Institute (NCI, USA) compound database, leading to the identification of a set of structurally diverse molecules. The strategy is validated by the observation that amongst these molecules are several known Top1 inhibitors and agents cytotoxic against human tumour cell lines. The potential of the untested hits to inhibit Top1 activity was further evaluated by docking into the binding site of a Top1 – DNA complex, resulting in a selection of 10 compounds for biological testing. Limited by the compound availability, 7 compounds have been tested in vitro for their Top1 inhibitory activity, 5 of which display mild to moderate Top1 inhibition. A further compound, found by similarity search to the active compounds, also shows mild activity. Although the tested compounds display only low in vitro antitumour activity, our approach has been successful in the identification of structurally novel Top1 inhibitors worthy of further investigation as potential anticancer agents.

Drwal, Malgorzata N.; Agama, Keli; Wakelin, Laurence P. G.; Pommier, Yves; Griffith, Renate

2011-01-01

86

Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property  

PubMed Central

“ Let food be thy medicine and medicine be thy food” was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating) behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents.

Azmi, Asfar S

2013-01-01

87

Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property.  

PubMed

" Let food be thy medicine and medicine be thy food" was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating) behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents. PMID:24358870

Azmi, Asfar S; Sarkar, Fazlul H; Hadi, S M

2013-01-01

88

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

PubMed Central

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

Mantha, Anil K.

2014-01-01

89

Carnosol: A promising anti-cancer and anti-inflammatory agent  

PubMed Central

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 medicincal 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 (NF?B), 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.

Johnson, Jeremy J.

2011-01-01

90

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

PubMed

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 (NF?B), 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

Johnson, Jeremy J

2011-06-01

91

A single-blind study of podophyllotoxin cream 0.5% and podophyllotoxin solution 0.5% in male patients with genital warts  

Microsoft Academic Search

OBJECTIVE--To evaluate the efficacy-safety ratio of a new topical podophyllotoxin cream 0.5% compared with podophyllotoxin solution 0.5% (Condyline) in male patients with genital warts. METHODS--In an observer-blinded controlled study a total of 136 and 133 wart lesions were treated with podophyllotoxin cream 0.5% and podophyllotoxin solution 0.5%, respectively. The preparations were applied twice daily for 3 days, repeated with 4

C S Petersen; T Agner; V Ottevanger; J Larsen; L Ravnborg

1995-01-01

92

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

PubMed

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

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

2014-05-01

93

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

NASA Astrophysics Data System (ADS)

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.

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

94

Anticancer Agent Shikonin Is an Incompetent Inducer of Cancer Drug Resistance  

PubMed Central

Purpose Cancer drug resistance is a major obstacle for the success of chemotherapy. Since most clinical anticancer drugs could induce drug resistance, it is desired to develop candidate drugs that are highly efficacious but incompetent to induce drug resistance. Numerous previous studies have proven that shikonin and its analogs not only are highly tumoricidal but also can bypass drug-transporter and apoptotic defect mediated drug resistance. The purpose of this study is to investigate if or not shikonin is a weak inducer of cancer drug resistance. Experimental Design Different cell lines (K562, MCF-7, and a MDR cell line K562/Adr), after repeatedly treated with shikonin for 18 months, were assayed for drug resistance and gene expression profiling. Results After 18-month treatment, cells only developed a mere 2-fold resistance to shikonin and a marginal resistance to cisplatin and paclitaxel, without cross resistance to shikonin analogs and other anticancer agents. Gene expression profiles demonstrated that cancer cells did strongly respond to shikonin treatment but failed to effectively mobilize drug resistant machineries. Shikonin-induced weak resistance was associated with the up-regulation of ?II-tubulin, which physically interacted with shikonin. Conclusion Taken together, apart from potent anticancer activity, shikonin and its analogs are weak inducers of cancer drug resistance and can circumvent cancer drug resistance. These merits make shikonin and its analogs potential candidates for cancer therapy with advantages of avoiding induction of drug resistance and bypassing existing drug resistance.

Wu, Hao; Xie, Jiansheng; Pan, Qiangrong; Wang, Beibei; Hu, Danqing; Hu, Xun

2013-01-01

95

Screening of anti-cancer agent using zebrafish: comparison with the MTT assay.  

PubMed

The MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide) assay is a classical method for screening cytotoxic anti-cancer agents. Candidate drugs from the MTT assay need in vivo models to test their efficiency and to assess the absorption, distribution, metabolism, excretion, and toxicity of the drugs. An in vivo screening model could increase the rate of development of anti-cancer drugs. Here, we used zebrafish to screen a library of 502 natural compounds and compared the results with those from an MTT assay of the MCF7 breast cancer cell line. We identified 59 toxic compounds in the zebrafish screen, 21 of which were also identified by the MTT assay, and 28 of which were already known for their anti-cancer and apoptosis-inducing effects. These compounds induced apoptosis and activated the p53 pathway in zebrafish within 3h treatment. Our results indicate that zebrafish is a simple, reliable and highly efficient in vivo tool for cancer drug screening, and could complement the MTT assay. PMID:22560901

Li, Yigen; Huang, Wenjin; Huang, Shenyuan; Du, Jiulin; Huang, Cheng

2012-05-25

96

Systemic use of tumor necrosis factor alpha as an anticancer agent  

PubMed Central

Tumor necrosis factor-? (TNF-?) has been discussed as a potential anticancer agent for many years, however initial enthusiasm about its clinical use as a systemic agent was curbed due to significant toxicities and lack of efficacy. Combination of TNF-? with chemotherapy in the setting of hyperthermic isolated limb perfusion (ILP), has provided new insights into a potential therapeutic role of this agent. The therapeutic benefit from TNF-? in ILP is thought to be not only due to its direct anti-proliferative effect, but also due to its ability to increase penetration of the chemotherapeutic agents into the tumor tissue. New concepts for the use of TNF-? as a facilitator rather than as a direct actor are currently being explored with the goal to exploit the ability of this agent to increase drug delivery and to simultaneously reduce systemic toxicity. This review article provides a comprehensive overview on the published previous experience with systemic TNF-?. Data from 18 phase I and 10 phase II single agent as well as 18 combination therapy studies illustrate previously used treatment and dose schedules, response data as well as the most prominently observed adverse effects. Also discussed, based on recent preclinical data, is a potential future role of systemic TNF-? in combination with liposomal chemotherapy to facilitate increased drug uptake into tumors.

Roberts, Nicholas J.; Zhou, Shibin; Diaz, Luis A.; Holdhoff, Matthias

2011-01-01

97

Design, synthesis, and evaluation of novel 6-chloro-/fluorochromone derivatives as potential topoisomerase inhibitor anticancer agents.  

PubMed

6-Chloro-2-pyrrolidino-/morpholino-/piperidino-/N-methylpiperazino-3-formyl-chromones (13-16) and 6-fluoro-2,7-di-morpholino-/piperidino-/N-methylpiperazino-3-formylchromones (17-19) have been synthesized as potential topoisomerase inhibitor anticancer agents, and evaluated, in vitro, against Ehrlich ascites carcinoma (EAC) cells, and also in vivo on EAC bearing mice. The compounds displayed promising anticancer activity under these test systems and shall serve as useful 'leads' for further design. PMID:16332438

Ishar, M P S; Singh, Gurpinder; Singh, Satyajit; Sreenivasan, K K; Singh, Gurmit

2006-03-01

98

Physico chemical characterization of a novel anti-cancer agent and its comparison to Taxol(®).  

PubMed

Every year several thousand compounds are screened for their anti-cancer activity by a general test procedure amongst which only few selected move past the in vitro screening process. This may be due to the intrinsic property of the drug substance. Therefore, a complete physicochemical characterization of a New Chemical Entity (NCE) is essential to understand the effect of these properties on the in vitro and possibly in vivo behavior of these compounds. Various physicochemical properties such as dissociation constant, octanol-water partition co-efficient, pH solubility, stability, thermal characterization and membrane permeability were evaluated for a novel tubulin-binding agent JCA112 and were compared to that of Taxol(®). The drug exhibited a pKa value of 10.9, log P value of 2.3, pH dependent solubility, and low artificial membrane permeability. Stability of the drug substance in the in vitro screening media suggested a significant degradation during the 48-hour study duration. The results demonstrate that due to low aqueous solubility, limited membrane permeability and due to insufficient stability of JCA112 in the in vitro screening media, the drug exhibited limited anti-cancer activity. Along with challenging physicochemical characteristics, a generalization of the in vitro testing procedure may also result in loss of important anti-cancer agents. As a result, a complete understanding of the physico-chemical properties of the drug leading to prototype formulation with acceptable physico-chemical properties may be required for successful in vitro screening. PMID:22339150

Shah, Amit K; Wyandt, Christy M; Stodghill, Steven P

2013-01-01

99

Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents.  

PubMed

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

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

2014-07-01

100

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

PubMed Central

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)-?B 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.

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

2014-01-01

101

PEG conjugates in clinical development or use as anticancer agents: an overview.  

PubMed

During the almost forty years of PEGylation, several antitumour agents, either proteins, peptides or low molecular weight drugs, have been considered for polymer conjugation but only few entered clinical phase studies. The results from the first clinical trials have shared and improved the knowledge on biodistribution, clearance, mechanism of action and stability of a polymer conjugate in vivo. This has helped to design conjugates with improved features. So far, most of the PEG conjugates comprise of a protein, which in the native form has serious shortcomings that limit the full exploitation of its therapeutic action. The main issues can be short in vivo half-life, instability towards degrading enzymes or immunogenicity. PEGylation proved to be effective in shielding sensitive sites at the protein surface, such as antigenic epitopes and enzymatic degradable sequences, as well as in prolonging the drug half-life by decreasing the kidney clearance. In this review PEG conjugates of proteins or low molecular weight drugs, in clinical development or use as anticancer agents, will be taken into consideration. In the case of PEG-protein derivatives the most represented are depleting enzymes, which act by degrading amino acids essential for cancer cells. Interestingly, PEGylated conjugates have been also considered as adjuvant therapy in many standard anticancer protocols, in this regard the case of PEG-G-CSF and PEG-interferons will be presented. PMID:19671438

Pasut, Gianfranco; Veronese, Francesco M

2009-11-12

102

Immuno-Chemotherapeutic Platinum(IV) Prodrugs of Cisplatin as Multimodal Anticancer Agents.  

PubMed

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

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

2014-06-23

103

Effects of Ape1 overexpression on cellular resistance to DNA-damaging and anticancer agents.  

PubMed

In vitro biochemical studies indicate that Ape1 is the major mammalian enzyme responsible for repairing abasic lesions in DNA and a significant factor in the processing of specific 3'-replication-blocking termini. Toward addressing the role of Ape1 in cellular resistance to specific DNA-damaging and anticancer agents, we constructed a chinese hamster ovary (CHO) cell line, AA8-Ape1, that exhibits a 7-fold higher Ape1-dependent nuclease activity; this overexpression is abolished upon exposure to tetracycline (Tc). In comparison to the AA8 parental control, our data indicates that Ape1 activity is not rate-limiting for the repair of cytotoxic damages induced by the alkylating agent methyl methanesulfonate (MMS), the oxidizing agent hydrogen peroxide (H2O2), or ionizing radiation (IR). AA8-Ape1 cells did exhibit increased resistance to bleomycin following a chronic 3-day exposure, but not to more acute challenges of 1 h. Most notably, the AA8-Ape1 line displayed approximately 1.7-fold elevated resistance to the replication-blocking nucleoside analog dioxolane cytidine (L-OddC); this improved resistance was abrogated by the addition of Tc to the medium. These studies demonstrate that Ape1 is not rate-limiting in the repair of MMS- or H2O2-induced DNA damage, that Ape1 may dictate the sensitivity of bleomycin, depending on dosing scheme, and for the first time, that Ape1 can influence cellular resistance to the anticancer/antiviral antimetabolite L-OddC. PMID:15328905

Schild, L J; Brookman, K W; Thompson, L H; Wilson, D M

1999-11-01

104

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

PubMed

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

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

2014-06-23

105

Attenuation of telomerase activity does not increase sensitivity of human melanoma cells to anticancer agents.  

PubMed

In tumour cells, replicative immortality is attained through stabilisation of telomeres by telomerase. Recent evidence suggests that telomerase plays an anti-apoptotic role. Since apoptosis is the primary mode of cell death induced by several drugs, telomerase could be involved in determining the chemosensitivity profile of tumour cells. We investigated whether inhibition of telomerase activity through a hammerhead ribozyme targeting the RNA template of telomerase influences the susceptibility of human melanoma cells to a variety of anticancer agents (platinum compounds, taxanes, topoisomerase I inhibitors). The ribozyme sequence was inserted into an expression vector and the JR8 human melanoma cell line was transfected with it. The cell clones obtained showed a reduced telomerase activity. Growth inhibition curves generated after exposure of ribozyme-transfectant clones to individual drugs were superimposable to those obtained from parental cells. Moreover, telomerase inhibition did not promote apoptosis as a cellular response to drug treatment. Overall, our results indicate that downregulation of telomerase activity does not increase the sensitivity of melanoma cells to anticancer drugs. PMID:11044653

Folini, M; De Marco, C; Orlandi, L; Daidone, M G; Zaffaroni, N

2000-10-01

106

Gold(III)-dithiocarbamato anticancer agents: activity, toxicology and histopathological studies in rodents.  

PubMed

Gold(III)-dithiocarbamato complexes have recently gained increasing attention as potential anticancer agents because of their strong tumor cell growth--inhibitory effects, generally achieved by exploiting non-cisplatin-like mechanisms of action. The rationale of our research work is to combine the antitumor properties of the gold(III) metal center with the potential chemoprotective function of coordinated dithiocarbamates in order to reduce toxic side effects (in particular nephrotoxicity) induced by clinically established platinum-based drugs. In this context, [Au(III) Br(2) (ESDT)] (AUL12) was proved to exert promising and outstanding antitumor activity in vitro and to overcome both acquired and intrinsic resistance showed by some types of tumors toward cisplatin. As a subsequent extension of our previous work, we here report on detailed in vivo studies in rodents, including antitumor activity toward three transplantable murine tumor models, toxicity, nephrotoxicity and histopathological investigations. Remarkably, the gold(III) complex AUL12 stands out for higher anticancer activity than cisplatin toward all the murine tumor models examined, inducing up to 80% inhibition of tumor growth. In addition, it shows low acute toxicity levels (lethal dose, LD(50) = 30 mg kg(-1) ) and reduced nephrotoxicity. Altogether, these results confirm the reliability of our drug design strategy and support the validation of this gold(III)-dithiocarbamato derivative as a suitable candidate for clinical trials. PMID:20853318

Marzano, Cristina; Ronconi, Luca; Chiara, Federica; Giron, Maria Cecilia; Faustinelli, Ivo; Cristofori, Patrizia; Trevisan, Andrea; Fregona, Dolores

2011-07-15

107

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

PubMed

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

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

2010-02-15

108

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

SciTech Connect

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.

Ghani, S. M.; Mohamed, M. S. W.; Yahya, A. F.; Noorsal, K. [Advanced Materials Research Centre (AMREC), SIRIM Berhad, Lot 34, Jalan Hi-Tech 2/3, Kulim Hi-Tech Park, 09000 Kulim Kedah (Malaysia)

2010-03-11

109

A screen to identify drug resistant variants to target-directed anti-cancer agents  

PubMed Central

The discovery of oncogenes and signal transduction pathways important for mitogenesis has triggered the development of target-specific small molecule anti-cancer compounds. As exemplified by imatinib (Gleevec), a specific inhibitor of the Chronic Myeloid Leukemia (CML)-associated Bcr-Abl kinase, these agents promise impressive activity in clinical trials, with low levels of clinical toxicity. However, such therapy is susceptible to the emergence of drug resistance due to amino acid substitutions in the target protein. Defining the spectrum of such mutations is important for patient monitoring and the design of next-generation inhibitors. Using imatinib and BCR/ABL as a paradigm for a drug-target pair, we recently reported a retroviral vector-based screening strategy to identify the spectrum of resistance-conferring mutations. Here we provide a detailed methodology for the screen, which can be generally applied to any drug-target pair.

Azam, Mohammad; Raz, Tal; Nardi, Valentina; Opitz, Sarah L.

2003-01-01

110

A versatile synthesis of "tafuramycin A": a potent anticancer and parasite attenuating agent.  

PubMed

An improved and versatile synthesis of tafuramycin A, a potent anticancer and parasite-attenuating agent, is reported. The three major improvements that optimized yield, simplified purification and allowed the synthesis of more versatile duocarmycin analogues are: a first-time reported regioselective bromination using DMAP as catalyst; the control of the aryl radical alkene cyclization step to prevent the dechlorination side reaction; and the design of a new protection/deprotection method to avoid furan double bond reduction during the classical O-benzyl deprotection in the final step. This alternative protection/deprotection strategy provides ready access to duocarmycin seco-analogues that carry labile functionalities under reducing reaction conditions. Tafuramycin A () was prepared in either 8 steps from intermediate or 7 steps from intermediate in 52% or 37% yield respectively. Our strategy provides a significant improvement on the original procedure (11% overall yield) and greater versatility for analogue development. PMID:24838868

El-Deeb, Ibrahim M; Rose, Faith J; Healy, Peter C; von Itzstein, Mark

2014-05-28

111

Design, synthesis, molecular modeling, and biological evaluation of sulfanilamide-imines derivatives as potential anticancer agents.  

PubMed

A series of sulfanilamide Schiff base derivatives (1 to 15) have been designed as potential antitubulin agents depending on the chemical structures of combretastatine A-4 and isoquinoline sulfamate (antimitotic agents under investigation). The designed compounds were synthesized by microwave chemical synthesis, their purity was confirmed by melting point and HPLC and chemical structures were determined by FT-IR, UV, and 1H and 13C-NMR spectroscopic techniques. The synthesized compounds have been docked in the colchicine binding site of ?-tubulin using molecular modeling programs and the antitumor activities were screened on human breast and lung cancer cells by cell counting assay. Some tested compounds showed potent and selective activity against breast cancer (MCF-7) with IC50 range of 90 to 166 ?M. With regarding broad-spectrum activity, compounds 4, 8, and 13 have shown potent antitumor activity against human breast and human lung cells with IC50 range of 96 to 140 ?M. The obtained results suggest that the sulfanilamide Schiff base derivatives might potentially constitute an interesting novel class of anticancer agents, which deserve further studies. PMID:23708566

Mohamed, Sofian S; Tamer, Abdalkarem R; Bensaber, Salah M; Jaeda, Mousa I; Ermeli, Nouri B; Allafi, Aemen Ali; Mrema, Ibrahim A; Erhuma, Mabrouk; Hermann, Anton; Gbaj, Abdul M

2013-09-01

112

An in vitro model system that can differentiate the stages of DNA replication affected by anticancer agents  

Microsoft Academic Search

We have previously reported on the potential use of a novel in vitro human cell-derived model system to investigate the mechanism of action of anticancer agents that directly affect the process of DNA replication. Our cell-free system uses a multiprotein DNA replication complex (designated the DNA synthesome) that has been isolated, characterized, and extensively purified from a wide variety of

Waleed Abdel-Aziz; Robert J Hickey; Linda H Malkas

2004-01-01

113

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

SciTech Connect

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.

Li, Juan; Dai, Cai-Xia; Sun, Hua [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China)] [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China); Jin, Lu [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China) [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China); State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203 (China); Guo, Chong-Yi; Cao, Wei; Wu, Jie; Tian, Hai-Yan [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China)] [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China); Luo, Cheng [State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203 (China)] [State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203 (China); Ye, Wen-Cai [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China)] [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China); Jiang, Ren-Wang, E-mail: trwjiang@jnu.edu.cn [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China)] [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China)

2012-12-01

114

Pharmaceutical development of a parenteral lyophilised dosage form for the novel anticancer agent C1311.  

PubMed

C1311 (5-[[2-(diethylamino)ethyl]amino]-8-hydroxyimidazo [4,5,1-de]-acridin-6-one-dihydrochloride trihydrate) is the lead compound from the group of imidazoacridinones, a novel group of rationally designed anticancer agents. C1311 shows significant cytotoxic activity in vitro and in vivo toward a range of colon tumours. The aim of the present study is to develop a sterile and stable, injectable pharmaceutical product for C1311 to be used in phase I clinical trials. C1311 drug substance was structurally and analytically characterised by chromatographic, spectrometric, and diffraction techniques. C1311 was freely soluble in water, and its stability was investigated in several liquid and lyophilised formulations with or without the use of buffering, tonicity, and bulking agents. The final product, containing 100 mg/vial C1311 (as anhydrous free base), was stable for at least 3 months under accelerated storage conditions and at the designated long-term storage condition of 5 +/- 3 degrees C in the dark. The drug is currently used in phase I clinical trials. PMID:16316064

Den Brok, Monique W J; Nuijen, Bastiaan; Kettenes-Van Den Bosch, J Jantina; Van Steenbergen, M J; Buluran, Josie N; Harvey, Michael D; Grieshaber, Charles K; Beijnen, Jos H

2005-01-01

115

Association of creatine kinase and skin toxicity in phase I trials of anticancer agents  

PubMed Central

Background: We investigated the association between skin rash and plasma creatine kinase (CK) levels in oncology phase I trials. Methods: We analysed data from 295 patients treated at our institution within 25 phase I trials which included CK measurements in the protocol. Trials involved drugs targeting EGFR/HER2, m-TOR, VEGFR, SRC/ABL, aurora kinase, BRAF/MEK, PARP, CDK, A5B1 integrin, as well as oncolytic viruses and vascular disrupting agents. Results: Creatine kinase measurements were available for 278 patients. The highest levels of plasma CK during the trial were seen among patients with Grade (G) 2/3 rash (median 249?U?l?1) compared with G1 (median 81?U?l?1) and no rash (median 55?U?l?1) (P<0.001). There was a significant reduction in CK after the rash resolved (mean 264.2 vs 100.1; P=0.012) in 25 patients, where serial CK values were available. In vitro exposure of human keratinocytes to EGFR, MEK and a PI3Kinase/m-TOR inhibitor led to the increased expression of CK-brain and not CK-muscle or mitochondrial-CK. Conclusion: Plasma CK elevation is associated with development of skin rash caused by novel anticancer agents. This should be studied further to characterise different isoforms as this will change the way we report adverse events in oncology phase I clinical trials.

Moreno Garcia, V; Thavasu, P; Blanco Codesido, M; Molife, L R; Vitfell Pedersen, J; Puglisi, M; Basu, B; Shah, K; Iqbal, J; de Bono, J S; Kaye, S B; Banerji, U

2012-01-01

116

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

PubMed Central

Callophycin A was originally isolated from the red algae Callophycus oppositifolius and shown to mediate anticancer and cytotoxic effects. In our collaborative effort to identify potential chemopreventive and anticancer agents with enhanced potency and selectivity, we employed a tetrahydro-?-carboline-based template inspired by callophycin A for production of a chemical library. Utilizing a parallel synthetic approach, 50 various functionalized tetrahydro-?-carboline derivatives were prepared and assessed for activities related to cancer chemoprevention and cancer treatment: induction of quinone reductase 1 (QR1) and inhibition of aromatase, nitric oxide (NO) production, tumor necrosis factor (TNF)-?-induced NF?B activity, and MCF7 breast cancer cell proliferation. Biological results showed that the n-pentyl urea S-isomer 6a was the strongest inducer of QR1 with an induction ratio (IR) value of 4.9 at 50 ?M [the concentration to double the activity (CD) = 3.8 ?M] and its corresponding R-isomer 6f had an IR value of 4.3 (CD = 0.2 ?M). The isobutyl carbamate derivative 3d with R stereochemistry demonstrated the most potent inhibitory activity of NF?B, with the half maximal inhibitory concentration (IC50) value of 4.8 ?M, and also showed over 60% inhibition at 50 ?M of NO production (IC50 = 2.8 ?M). The R-isomer urea derivative 6j, having an appended adamantyl group, exhibited the most potent MCF7 cell proliferation inhibitory activity (IC50 = 14.7 ?M). The S-isomer 12a of callophycin A showed the most potent activity in aromatase inhibition (IC50 = 10.5 ?M).

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

2011-01-01

117

Microbioassay system for an anti-cancer agent test using animal cells on a microfluidic gradient mixer.  

PubMed

We developed a novel microbioassay system equipped with a gradient mixer of two solutions, and we applied the microfluidic system to an anti-cancer agent test using living animal cells on a microchip. A microchannel for the gradient mixing of two solutions and eight other microchannels for cell assay were fabricated on a poly(dimethylsiloxane) substrate using a soft-lithography method. The functions necessary for this bioassay, i.e., cell culturing, chemical stimulation, cell staining, and fluorescence determination, were integrated into the microfluidic chip. Eight gradient concentrations of the fluorescein solution, ranging from 1 to 98 microg/ml, were archived at 0.1 microl/min on a microchip. A stomach cancer cell line was cultured, and a cell viability assay was conducted using 5-Fluorouracil as an anti-cancer agent on the microchip. Cell viability changed according to the estimated concentration of the agent solution. With the microbioassay system, an anti-cancer agent test was conducted using living cells simultaneously in eight individual channels with the gradient concentration of the agent on a microchip. PMID:16429779

Fujii, Shin-ichiro; Uematsu, Munehisa; Yabuki, Soichi; Abo, Mitsuru; Yoshimura, Etsuro; Sato, Kiichi

2006-01-01

118

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

PubMed Central

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.

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

2012-01-01

119

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

PubMed

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

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

2012-04-01

120

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

PubMed Central

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

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

1995-01-01

121

Synthesis and insecticidal activity of novel hydrazone compounds derived from a naturally occurring lignan podophyllotoxin against Mythimna separata (Walker).  

PubMed

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, a series of novel hydrazone derivatives of podophyllotoxin, which is a naturally occurring aryltetralin lignan and isolated as the main secondary metabolite from the roots and rhizomes of Podophyllum species, were synthesized and evaluated as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. Especially compounds 8i, 8j, 8t, and 8u showed the more potent insecticidal activity with the final mortality rates greater than 60%. PMID:24810569

Wang, Yi; Yu, Xiang; Zhi, Xiaoyan; Xiao, Xiao; Yang, Chun; Xu, Hui

2014-06-15

122

The anticancer agent prodigiosin is not a multidrug resistance protein substrate.  

PubMed

The brilliant red pigments prodiginines are natural secondary metabolites that are produced by select species of Gram-negative and Gram-positive bacteria. These molecules have received significant attention due to their reported antibacterial, antifungal, immunosuppressive, and anticancer activities. In this study, a Serratia marcescens SER1 strain was isolated and verified using 16s rDNA. The prodigiosin was purified using silica chromatography and was analyzed by (1)H-NMR spectroscopy. The cell cytotoxic effects of the purified prodigiosin on multiple drug resistant cell lines that overexpress MDR1, BCRP, or MRP2 pumps were analyzed. Prodigiosin had nearly identical cytotoxic effects on the resistant cells in comparison to their parental lines. In agreement with the same prodigiosin cytotoxicity, FACS analysis of prodigiosin accumulation and efflux in MDR overexpressing cell lines also indicated that this pro-apoptotic agent operates independently of the presence of the MDR1, BCRP, or MRP transporter and may be a potential treatment for malignant cancer cells that overexpress multidrug resistance transporters. PMID:23373476

Elahian, Fatemeh; Moghimi, Bahareh; Dinmohammadi, Farideh; Ghamghami, Mahsa; Hamidi, Mehrdad; Mirzaei, Seyed Abbas

2013-03-01

123

The Anticancer Agent Prodigiosin Is Not a Multidrug Resistance Protein Substrate  

PubMed Central

The brilliant red pigments prodiginines are natural secondary metabolites that are produced by select species of Gram-negative and Gram-positive bacteria. These molecules have received significant attention due to their reported antibacterial, antifungal, immunosuppressive, and anticancer activities. In this study, a Serratia marcescens SER1 strain was isolated and verified using 16s rDNA. The prodigiosin was purified using silica chromatography and was analyzed by 1H-NMR spectroscopy. The cell cytotoxic effects of the purified prodigiosin on multiple drug resistant cell lines that overexpress MDR1, BCRP, or MRP2 pumps were analyzed. Prodigiosin had nearly identical cytotoxic effects on the resistant cells in comparison to their parental lines. In agreement with the same prodigiosin cytotoxicity, FACS analysis of prodigiosin accumulation and efflux in MDR overexpressing cell lines also indicated that this pro-apoptotic agent operates independently of the presence of the MDR1, BCRP, or MRP transporter and may be a potential treatment for malignant cancer cells that overexpress multidrug resistance transporters.

Elahian, Fatemeh; Moghimi, Bahareh; Dinmohammadi, Farideh; Ghamghami, Mahsa; Hamidi, Mehrdad

2013-01-01

124

Comparison of the pharmacokinetics of S-1, an oral anticancer agent, in Western and Japanese patients  

PubMed Central

Objective S-1 is an oral anticancer agent combining tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with potassium oxonate (oteracil) and gimeracil (CDHP) respectively to mitigate gastrointestinal toxicity and increase the half-life of 5-FU. This article presents a population pharmacokinetic analysis of these four compounds in Western cancer patients. The second objective was to compare the pharmacokinetics of S-1 in Western and Japanese patients. Methods A single dose (25–45mg/m2) of S-1 was administered to 60 patients. In each patient, 6 concentrations of FT, 5-FU, oteracil and CDHP were measured over 24hr. Using NONMEM, oteracil and CDHP were analysed separately, and the individual estimates of CDHP parameters were included in the joint analysis of FT and 5-FU. We used validation techniques to assess differences between the two populations, and finally we compared the exposures in Western and Japanese patients using simulations. Results A compartmental model describing the PK of the 4 compounds was developed. The influence of CDHP on the elimination of 5-FU was well described by an enzymatic inhibition model. The model provided a good fit for all compounds. The pharmacokinetics for 5-FU and oteracil were similar between Western and Japanese patients, but apparent differences in exposure to 5-FU resulted from different total doses due to different body sizes.

Comets, Emmanuelle; Ikeda, Kazumasa; Hoff, Paulo; Fumoleau, Pierre; Wanders, Jantien; Tanigawara, Yusuke

2003-01-01

125

NAD-analogues as potential anticancer agents: conformational restrictions as basis for selectivity.  

PubMed

Cofactor type inhibitors (NAD-analogues) of IMP-dehydrogenase (IMPDH) were synthesized and their application as potential anticancer agents are discussed. C-nucleoside isosteres of NAD, C-NAD and C-PAD, showed an effective competitive inhibition of IMPDH, C-NAD but not C-PAD caused extremely potent inhibition of alcohol dehydrogenase. We also synthesized compounds in which nicotinamide riboside was replaced with tiazofurin (TAD-analogues) and the 2' and 3'-positions of adenosine part were fluorinated. The ribose ring of 2'-deoxy-2'-fluoroadenosine is in the C3'-endo conformation whereas 3'-deoxy-3'-fluoroadenosine favors the C2'-endo sugar pucker. These derivatives are good inhibitors of IMPDH type II, the isoenzyme dominant in neoplastic cells. In contrast, all these analogues showed rather week inhibitory activity against alcohol dehydrogenase. Nicotinamide riboside derivatives in which the base and the sugar are linked through an oxygen or a methylene bridge were synthesized. NAD-analogues containing such conformationally restricted nicotinamide nucleoside moiety (syn or anti) are expected to be selective inhibitors of B-specific (IMPDH) or A-specific dehydrogenases, respectively. PMID:8790723

Pankiewicz, K W; Zatorski, A; Watanabe, K A

1996-01-01

126

3D-QSAR of Benzothiazole Derivatives as Potent Anticancer Agents  

NASA Astrophysics Data System (ADS)

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.

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

2007-04-01

127

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

PubMed Central

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

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

2013-01-01

128

Synergistic activity of ixabepilone plus other anticancer agents: preclinical and clinical evidence.  

PubMed

Ixabepilone demonstrates marked synergistic activity in combination with capecitabine, which served as the rationale for the evaluation of this combination in the clinic. Ixabepilone plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer (MBC) progressing after treatment with an anthracycline and a taxane; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy. An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab, bevacizumab, brivanib, and cetuximab; with immune-modulating agents such as anti-CTLA-4 antibody; and with other chemotherapy drugs such as irinotecan and epirubicin. Notably, experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab-paclitaxel combined with bevacizumab. These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in HER2-positive breast cancer; with bevacizumab in breast cancer, endometrial cancer, renal cancer, and non-small cell lung cancer (NSCLC); with cetuximab in breast cancer, NSCLC, and pancreatic cancer; and with brivanib, dasatinib, sorafinib, sunitinib, or vorinostat in MBC. Preliminary results from several of these trials suggest that ixabepilone-based combinations have promising anticancer activity. PMID:21789152

Lee, Francis; Jure-Kunkel, Maria N; Salvati, Mark E

2011-01-01

129

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

PubMed

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

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

2014-08-01

130

Anticancer agent E7070 inhibits amino acid and uracil transport in fission yeast.  

PubMed

E7070 is a novel sulfonamide anticancer agent that inhibits cell cycle progression in G1 in mammalian cells, but its action targets are not known. We recently employed the genetically amenable fission yeast Schizosaccharomyces pombe as a model organism to search for its targets. Here, we show that E7070 inhibits imports of amino acid and uracil into S. pombe cells. Unlike their prototrophic counterparts, leucine- and uracil-auxotrophic strains are sensitive to E7070 and are unable to proliferate with a delayed G1-S transition in low-glucose yeast extract-polypeptone medium containing this drug because this chemical markedly inhibits the uptake of leucine and uracil in low glucose medium. Furthermore, addition of leucine or uracil to the culture medium or overexpression of genes encoding an amino acid or uracil transporter suppresses the E7070-imposed growth inhibition of these auxotrophic strains. Thus, some of the molecular targets for E7070 action in S. pombe are likely to be leucine and uracil transporters. PMID:11723232

Tsukahara, K; Watanabe, T; Hata-Sugi, N; Yoshimatsu, K; Okayama, H; Nagasu, T

2001-12-01

131

Biosynthetic characterization and chemoenzymatic assembly of the cryptophycins. Potent anticancer agents from cyanobionts.  

PubMed

The lichen cyanobacterial symbiont Nostoc sp. ATCC 53789 and its close relative Nostoc sp. GSV 224 are prolific producers of natural products, generating >25 derivatives of the cryptophycin class of secondary metabolites. Cryptophycin 1, the prototypic member of the class, is a potent tubulin-depolymerizing agent, and several semisynthetic derivatives are being developed as anticancer therapeutics. Here we provide a detailed characterization of the cryptophycin metabolic pathway by stable-isotope labeling experiments and through cloning, sequencing, and annotating the cryptophycin biosynthetic gene cluster. A comparative secondary metabolomic analysis based on polyketide (PK)/non-ribosomal peptide gene clusters from the phylogenetically related, non-cryptophycin producing cycad symbiont, Nostoc punctiforme ATCC 29133, was used to identify the cryptophycin biosynthetic genes that encompass approximately 40 kb within the lichen symbiont Nostoc sp. ATCC 53789 genome. The pathway encodes a collinear set of enzymes, including three modular PK synthases, two non-ribosomal peptide synthetase modules, and an integrated adenylation/ketoreductase didomain for elaboration of the leucic acid subunit. In addition, genes encoding key tailoring steps, including a FAD-dependent halogenase and CYP450 epoxidase, were identified. The inherent flexibility of the cryptophycin biosynthetic enzymes was harnessed to generate a suite of new analogues by altering the pool of PK starter units and selected amino acid extender groups. Characterization of the cryptophycin CYP450 enabled development of the first stereospecific synthesis of cryptophycin 2, through a tandem chemoenzymatic synthesis from the natural seco-cryptophycin 4 chain elongation intermediate. PMID:17240975

Magarvey, Nathan A; Beck, Zachary Q; Golakoti, Trimurtulu; Ding, Yousong; Huber, Udo; Hemscheidt, Thomas K; Abelson, Dafna; Moore, Richard E; Sherman, David H

2006-12-15

132

Assessment of micronucleus induction in murine SCCVII cells treated with various anticancer agents.  

PubMed

The possibility of using the cytokinesis-block micronucleus (MN) assay as a rapid test of chemosensitivity was investigated. SCCVII murine carcinoma cells growing exponentially in vitro were treated for 1 h under aerobic conditions with various concentrations of 11 anticancer agents: mitomycin C, doxorubicin, epirubicin, cisplatin, carboplatin, etoposide, vincristine, 5-fluorouracil, methotrexate, nimustine and dacarbazine. After removing the drugs, cytochalasin B (1.5 micrograms/ml) was added to block cytoplasmic but not nuclear division. At various times during culture, the proportions of binucleate cells (BNC) and multinucleate cells in the total cell population, and the mean number of micronuclei per single BNC were determined. Cell survival was also determined using the standard colony formation assay and was compared with the MN frequency. Maximal percentage of BNC was usually reached at 24-30 h of culture, except for cells treated with doxorubicin and epirubicin, in which it was reached at 30-72 h. All drugs induced formation of micronuclei and dose-response curves for MN frequency were obtained using the data at peak percentage of BNC times. For all drugs, MN frequency increased with concentration, but at the highest concentrations used (which are considered to be overly toxic) the MN frequency was rather lower. This decrease in MN frequency was largely attributable to the decrease in percent BNC. When the data at the highest concentrations of all drugs were excluded, a correlation was found between MN frequency and surviving fraction (r = 0.85). Therefore, it was concluded that the cytokinesis-block MN assay can be used to assess sensitivity of at least some tumor cells to appropriate concentrations of various chemotherapeutic agents. PMID:8804794

Jeremic, B; Shibamoto, Y; Abe, M

1996-01-01

133

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

PubMed Central

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

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

2014-01-01

134

Anticancer agent ukrain and bortezomib combination is synergistic in 4T1 breast cancer cells.  

PubMed

The identification and in-depth understanding of intracellular signalling pathways led to the synthesis and discovery of many agents targeting cancer cells. In this study, we investigated for the first time the effect of anticancer agent ukrain as a single agent or in combination with cisplatin, etoposide, 5-fluorouracil, quercetin and bortezomib in 4T1 breast cancer and B16F10 melanoma cells. It was found that ukrain is cytotoxic and apoptotic in 4T1 breast carcinoma and B16F10 melanoma cells when given alone. The IC50 value of ukrain in 4T1 cells was found as 40 ± 6.8 ?M and that in B16F10 cells as 76 ± 10 ?M. It was then found that apoptosis can be induced in 4T1 breast cancer cells in a dose-dependent manner in response to ukrain treatment, based on DNA fragmentation evidence. The induction of apoptosis was corroborated by the analysis of cleavage products of caspase-3 in 4T1 cells using Western blot technique. When ukrain was tested in combination with cisplatin and etoposide, no significant enhancement of cytotoxicity was detected as compared with single agent treatments. Similarly, 5-fluorouracil and quercetin also did not potentiate the cytotoxic effects of ukrain in 4T1 cells. Finally, we examined the effect of various concentrations of ukrain in combination with 10 nM bortezomib in 4T1 cells. Determination of combination index values showed that bortezomib potentiated the effect of ukrain. And the combination was found to cause synergistic cell death. The lowest combination index detected was 0.57 which was obtained when the cells were treated with 10 nM bortezomib + 100 ?M ukrain. Likewise, when cells were treated with different doses of bortezomib in the presence of 25 ?M ukrain, synergism was similarly detected between the two drugs in a dose-dependent manner. Altogether, the results presented here suggest that the combination of ukrain + bortezomib may be further evaluated and tested in clinical settings. PMID:23919744

Savran, Bircan; Yerlikaya, Azmi; Erdo?an, Elif; Genç, Osman

2014-03-01

135

The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity.  

PubMed

The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) has been shown to synergize doxorubicin (Dox) anticancer activity while attenuating its cardiotoxicity. In this study we further explored the selectivity of AN-7's action in several cancer and normal cells treated with anticancer agents. The cells studied were murine mammary 4T1, human breast T47D and glioblastoma U251 cancer cell lines, neonatal rat cardiomyocytes, cardiofibroblasts and astrocytes, and immortalized cardiomyocyte H9C2 cells. Cell death, ROS production and changes in protein expression were measured and in vivo effects were evaluated in Balb-c mice. AN-7 synergized Dox and anti-HER2 cytotoxicity against mammary carcinoma cells with combination indices of 0.74 and 0.79, respectively, while it protected cardiomyocytes against their toxicity. Additionally AN-7 protected astrocytes from Dox-cytoxicity. Cell-type specific changes in the expression of proteins controlling survival, angiogenesis and inflammation by AN-7 or AN-7+Dox were observed. In mice, the protective effect of AN-7 against Dox cardiotoxicity was associated with a reduction in inflammatory factors. In summary, AN-7 augmented the anticancer activity of Dox and anti-HER2 and attenuated their toxicity against normal cells. AN-7 modulation of c-Myc, thrombospondin-1, lo-FGF-2 and other proteins were cell type specific. The effects of AN-7, Dox and their combination were preserved in vivo indicating the potential benefit of combining AN-7 and Dox for clinical use. PMID:20862515

Tarasenko, Nataly; Kessler-Icekson, Gania; Boer, Pnina; Inbal, Aida; Schlesinger, Hadassa; Phillips, Don R; Cutts, Suzanne M; Nudelman, Abraham; Rephaeli, Ada

2012-02-01

136

Urokinase-targeted recombinant bacterial protein toxins — a rationally designed and engineered anticancer agent for cancer therapy  

Microsoft Academic Search

Urokinase-targeted recombinant bacterial protein toxins are a sort of rationally designed and engineered anticancer recombinant\\u000a fusion proteins representing a novel class of agents for cancer therapy. Bacterial protein toxins have long been known as\\u000a the primary virulence factor(s) for a variety of pathogenic bacteria and are the most powerful human poisons. On the other\\u000a hand, it has been well documented

Yizhen Liu; Shi-Yan Li

2009-01-01

137

Development History and Concept of an Oral Anticancer Agent S-1 (TS1w): Its Clinical Usefulness and Future Vistas  

Microsoft Academic Search

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-1w). 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

Tetsuhiko Shirasaka

2008-01-01

138

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

PubMed Central

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.

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

2009-01-01

139

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

PubMed Central

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.

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

2012-01-01

140

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

Cancer.gov

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

141

Novel Anticancer Agents that Block Dissociation of Hsp90 from Estrogen Receptors in Breast Cancers.  

National Technical Information Service (NTIS)

Heat shock protein 90 (Hsp90) is a chaparone protein that facilitates the folding of estrogen receptors (ERs) and other proteins involved in breast cancer proliferation. This protein is under investigation as a target of anticancer drugs because breast ca...

B. R. Peterson

2006-01-01

142

A genome-wide screening in Saccharomyces cerevisiae for genes that confer resistance to the anticancer agent cisplatin.  

PubMed

Cisplatin is a potent DNA-damaging agent that has demonstrated anticancer activities against several tumors. However, manifestation of cellular resistance is a major obstacle in anticancer therapy that severely limits the curative potential of cisplatin. Therefore, understanding the molecular basis of cisplatin resistance could significantly improve the clinical efficacy of this anticancer agent. Here, we employed Saccharomyces cerevisiae as a model organism to study cisplatin resistance mechanisms and describe a one-step cisplatin selection to identify and characterize novel cisplatin resistance genes. Screening a multicopy yeast genomic library enabled us to isolate several yeast clones for which we could confirm that the cisplatin resistance phenotype was linked to the introduced fragment. In a first attempt, a number of open reading frames could be identified. Among these genes, PDE2 and ZDS2 were repeatedly identified as genes whose overexpression confers cellular resistance to cisplatin. PDE2, encoding cAMP-phosphodiesterase 2, is of particular interest because the overexpression of this yeast gene is known to induce cisplatin resistance in mammalian cells as well, providing proof of the principle of our experimental approach. In addition, the identification of PDE2 shows that our yeast screening system can directly be informative for drug resistance in mammalian cells. PMID:10720490

Burger, H; Capello, A; Schenk, P W; Stoter, G; Brouwer, J; Nooter, K

2000-03-24

143

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

PubMed

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 ?B (NF-?B 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-?B. 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

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

144

Timely recognition of cardiovascular toxicity by anticancer agents: a common objective of the pharmacologist, oncologist and cardiologist.  

PubMed

Both conventional and new anticancer drugs can frequently cause adverse cardiovascular effects, which can span from subclinical abnormalities to serious life-threatening and sometimes fatal events. This review examines the principal basic and clinical elements that may be of profit to identify, prevent and treat such toxicities. Clearly, the accomplishment of such objectives requires the strong commitment and cooperation of different professional figures including, but not limited to, pharmacologists, oncologists and cardiologists. The aspect of anticancer drug cardiotoxicity seems to be somehow underestimated, mainly due to inadequate reporting of adverse reactions from oncology drugs in the post-marketing setting. Thus, the implementation of pharmacovigilance is indispensable to rapidly and fully assess the safety of newer agents in real-life patients. PMID:21894547

Bonura, Francesca; Di Lisi, Daniela; Novo, Salvatore; D'Alessandro, Natale

2012-06-01

145

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

PubMed Central

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

Carreira, Monica; Calvo-Sanjuan, Ruben; Sanau, Mercedes; Marzo, Isabel; Contel, Maria

2012-01-01

146

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

PubMed

Mitoxantrone (MH(2)X), an anthraquinone-type anti-cancer agent used clinically in the treatment of human malignancies, is oxidatively activated by the peroxidase/H(2)O(2) enzyme system. In contrast to the enzymatic mechanisms of drug oxidation, the chemical transformations of MH(2)X are not well described. In this study, MH(2)X metabolites, produced by the horseradish, lacto- or lignin peroxidase (respectively HRP, LPO and LIP)/H(2)O(2) system, were investigated by steady-state spectrokinetic and HPLC-MS methods. At an equimolar mitoxantrone/H(2)O(2) ratio, the efficacy of the enzyme-catalyzed oxidation of mitoxantrone decreased in the following order: LPO > HRP > LIP, which accorded with the decreasing size of the substrate access channel in the enzyme panel examined. In all cases, the central drug oxidation product was the redox-active cyclic metabolite, hexahydronaphtho-[2,3-f]-quinoxaline-7,12-dione (MH(2)), previously identified in the urine of mitoxantrone-treated patients. As the reaction progressed, data gathered in this study suggests that further oxidation of the MH(2) side-chains occurred, yielding the mono- and dicarboxylic acid derivatives respectively. Based on the available data a further MH(2) derivative is proposed, in which the amino-alkyl side-chain(s) are cyclised. With increasing H(2)O(2) concentrations, these novel MH(2) derivatives were oxidised to additional metabolites, whose spectral properties and MS data indicated a stepwise destruction of the MH(2) chromophore due to an oxidative cleavage of the 9,10-anthracenedione moiety. The novel metabolites extend the known sequence of peroxidase-induced mitoxantrone metabolism, and may contribute to the cytotoxic effects of the drug in vivo. Based on the structural features of the proposed MH(2) oxidation products we elaborate on various biochemical mechanisms, which extend the understanding of mitoxantrone's pharmaceutical action and its clinical effectiveness with a particular focus on peroxidase-expressing solid tumors, such as breast carcinoma. PMID:20887767

Brück, Thomas B; Brück, Dieter W

2011-02-01

147

Pharmacokinetic drug-drug interaction of the novel anticancer agent E7070 and acenocoumarol.  

PubMed

E7070 is a novel sulfonamide anticancer agent that arrests cancer cells at the G1/S boundary of the cell cycle. Three patients receiving chronic therapy with the oral anticoagulant acenocoumarol experienced bleeding and/or a prolonged prothrombin time after treatment with E7070 at a dose of 700 mg/m2 given as a 1-h infusion. In vitro studies have shown that E7070 has the potential to inhibit several cytochrome P450 (CYP)-enzymes, including CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The major enzyme involved in the metabolism of acenocoumarol in man is CYP2C9. This study was performed to investigate the interaction between E7070 and acenocoumarol. Blood samples were obtained from two patients receiving daily oral maintenance treatment with acenocoumarol both prior to and following treatment with E7070. In addition, we incubated acenocoumarol enantiomers with pooled human microsomes with and without E7070 and measured the in vitro plasma protein binding of acenocoumarol after incubation with E7070. Pharmacokinetic parameters of acenocoumarol were calculated by noncompartmental analysis and revealed that in both patients the area under the concentration-time curve up to 24 h after the acenocoumarol administration was higher following E7070 (2.56 and 1.58 h*micromol/L) compared to the systemic exposure in the absence of E7070 (1.87 and 1.23 h*micromol/l). The formation of acenocoumarol metabolites was retarded by E7070 at already low concentrations (2.1 microM). The plasma protein binding of acenocoumarol was reduced at higher concentrations of E7070 (259 microM). These results indicate that E7070 may primarily interact with acenocoumarol by reducing its systemic clearance. Displacement of acenocoumarol's plasma protein binding by E7070 may also occur but to a minor extent. In the absence of careful monitoring this drug-drug interaction may result in hypoprothrombinemia and a hemorrhagic tendency. PMID:14739663

van den Bongard, H J G Desirée; Sparidans, Rolf W; Critchley, David J P; Beijnen, Jos H; Schellens, Jan H M

2004-04-01

148

An excretion balance and pharmacokinetic study of the novel anticancer agent E7070 in cancer patients.  

PubMed

E7070 is a novel sulfonamide anticancer agent that arrests the G /S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics of the drug. The objective of this study was to quantify the excretion of E7070 and the metabolite 1,4-benzene-sulfonamide (M1) in cancer patients. E7070 (1,000 mg) radiolabeled by (14)C in the benzene disulfonamide moiety (cohort 1, n = 6) or in the indole moiety (cohort 2, n = 7) was i.v. infused over 1 h. The levels of radioactivity in plasma, red blood cells, urine and feces were determined by liquid scintillation counting, and the E7070 and M1 concentrations in plasma, urine and feces were determined by coupled liquid chromatography-tandem mass spectrometry (LC/ESI-MS/MS). In plasma, the mean area under the concentration-time curve (AUC) based on radio-activity measurements (32.5 and 28.9 h. mM in cohorts 1 and 2, respectively) was substantially higher than the mean AUC of E7070 (3.8 h x mmol/l) and M1 (0.1 h x mmol/l) in all patients. The excretion of radioactivity (mean +/- SD) as a percentage of administered radioactivity was higher in urine [63.7 +/- 9.8% (cohort 1) and 61.5 +/- 5.5% (cohort 2)] than in feces [22.7 +/- 2.6% (1) and 21.1 +/- 3.1% (2)] during a mean collection period of 11 days. In both cohorts, the contribution of urinary and fecal recovery of E7070 (2.3 and 2.7%, respectively) and M1 (5.3 and 5.1%, respectively) was low. Subsequent HPLC analysis with online radioisotope detection of urine showed that the high radioactivity levels are caused by compounds other than E7070 and M1. The major metabolite is formed by glucuronidation of a hydroxylated metabolite of E7070. In conclusion, the excretion of the benzene sulfonamide and the indole moieties of E7070 was the same with a higher renal than gastrointestinal excretion. E7070 is extensively converted into currently unidentified metabolites. Glucuronidation is a major metabolic pathway. PMID:12394264

van sen Bongard, H J G Desirée; Pluim, Dick; Rosing, Hilde; Nan-Offeringa, Lianda; Schot, Margaret; Ravic, Miroslav; Schellens, Jan H M; Beijnen, Jos H

2002-09-01

149

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

PubMed

The synthesis and characterization of a new water-soluble iminophosphorane ligand TPA=N-C(O)-2BrC(6)H(4) (C,N-IM; TPA = 1,3,5-triaza-7-phosphaadamantane) 1 is reported. Oxidative addition of 1 to Pd(2)(dba)(3) affords the orthopalladated dimer [Pd(?-Br){C(6)H(4)(C(O)N=TPA-kC,N)-2}](2) (2) as a mixture of cis and trans isomers (1:1 molar ratio) where the iminophosphorane moeity behaves as a C,N-pincer ligand. By addition of different neutral or monoanionic ligands to 2, the bridging bromide can be cleaved and a variety of hydrophilic or water-soluble mononuclear organometallic palladium(II) complexes of the type [Pd{C(6)H(4)(C(O)N=TPA-kC,N)-2}(L-L)] (L-L = acac (3); S(2)CNMe(2) (4); 4,7-Diphenyl-1,10-phenanthrolinedisulfonic acid disodium salt C(12)H(6)N(2)(C(6)H(4)SO(3)Na)(2) (5)); [Pd{C(6)H(4)(C(O)N=TPA-kC,N)-2}(L)Br] (L = P(mC(6)H(4)SO(3)Na)(3) (6); P(3-Pyridyl)(3) (7)) and, [Pd(C(6)H(4)(C(O)N=TPA)-2}(TPA)(2)Br] (8) are obtained as single isomers. All new complexes were tested as potential anticancer agents and their cytotoxicity properties were evaluated in vitro against human Jurkat-T acute lymphoblastic leukemia cells, normal T-lymphocytes (PBMC) and DU-145 human prostate cancer cells. Compounds [Pd(?-Br){C(6)H(4)(C(O)N=TPA-kC,N)-2}](2) (2) and [Pd{C(6)H(4)(C(O)N=TPA-kC,N)-2}(acac)] 3 (which has been crystallographically characterized) display the higher cytotoxicity against the above mentioned cancer cell lines while being less toxic to normal T-lymphocytes (peripheral blood mononuclear cells: PBMC). In addition, 3 is very toxic to cisplatin resistant Jurkat shBak indicating a cell death pathway that may be different to that of cisplatin. The interaction of 2 and 3 with plasmid (pBR322) DNA is much weaker than that of cisplatin pointing to an alternative biomolecular target for these cytotoxic compounds. All the compounds show an interaction with human serum albumin (HSA) faster than that of cisplatin. PMID:23066172

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

2012-08-27

150

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

PubMed Central

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.

Tan, Chalet; Wang, Yingzhe; Fan, Wei

2013-01-01

151

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

PubMed Central

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.

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

2014-01-01

152

Bidirectional Functions of Arsenic as a Carcinogen and an Anti-Cancer Agent in Human Squamous Cell Carcinoma  

PubMed Central

Bidirectional cancer-promoting and anti-cancer effects of arsenic for cancer cells have been revealed in previous studies. However, each of these effects (cancer-promoting or anti-cancer) was found in different cells at different treated-concentration of arsenic. In this study, we for the first time indicated that arsenic at concentration of 3 µM, equal to average concentration in drinking water in cancer-prone areas in Bangladesh, simultaneously expressed its bidirectional effects on human squamous cell carcinoma HSC5 cells with distinct pathways. Treatment with 3 µM of arsenic promoted cell invasion via upregulation of expression of MT1-MMP and downregulation of expression of p14ARF and simultaneously induced cell apoptosis through inhibition of expression of N-cadherin and increase of expression of p21(WAF1/CIP1) at both transcript and protein levels in HSC5 cells. We also showed that inhibition of MT1-MMP expression by NSC405020 resulted in decrease of arsenic-mediated invasion of HSC5 cells involving decrease in phosphorylated extracellular signal-regulated kinases (pERK). Taken together, our biological and biochemical findings suggested that arsenic expressed bidirectional effects as a carcinogen and an anti-cancer agent in human squamous cell carcinoma HSC5 cells with distinct pathways. Our results might play an important scientific evident for further studies to find out a better way in treatment of arsenic-induced cancers, especially in squamous cell carcinoma.

Thang, Nguyen Dinh; Yajima, Ichiro; Kumasaka, Mayuko Y.; Kato, Masashi

2014-01-01

153

Discovery of 4-Substituted Methoxybenzoyl-Aryl-Thiazole as Novel Anticancer Agents: Synthesis, Biological Evaluation and Structure-Activity Relationships  

PubMed Central

A series of 4-substituted methoxylbenzoyl-aryl-thiazoles (SMART) have been discovered and synthesized as a result of structural modifications of the lead compound 2-arylthiazolidine-4-carboxylic acid amides (ATCAA). The antiproliferative activity of the SMART agents against melanoma and prostate cancer cells was improved from ?M to low nM range compared with ATCAA series. The structure-activity relationship was discussed from modifications of “A”, “B” “C” rings and the linker. Preliminary mechanism of action studies indicated that these compounds exert their anticancer activity through inhibition of tubulin polymerization.

Lu, Yan; Li, Chien-Ming; Wang, Zhao; Ross, Charles R.; Chen, Jianjun; Dalton, James; Li, Wei; Miller, Duane.D.

2009-01-01

154

Molecular designing and in silico evaluation of darunavir derivatives as anticancer agents  

PubMed Central

Darunavir is a synthetic nonpeptidic protease inhibitor which has been tested for anticancer properties. To deduce and enhance the anticancer activity of the Darunavir, we have modified its reactive moiety in an effective way. We designed 9 analogues in ChemBioOffice 2010 and minimized using the LigPrep tool of Schrödinger 2011. These analogues can obstruct the activity of other signalling pathways which are implicated in many tumors. Results of the QikProp showed that all the analogues lied in the specified range of all the pharmacokinetic (ADMET) properties required to become the successful drug. Docking study was performed to test its anticancer activity against the biomarkers of the five main types of cancers i.e. bone, brain, breast, colon and skin cancer. Grid was generated for each oncoproteins by specifying the active site amino acids. The binding model of best scoring analogue with each protein was assessed from their G-scores and disclosed by docking analysis using the XP visualizer tool. An analysis of the receptor-ligand interaction studies revealed that these nine Darunavir analogues are active against all cancer biomarkers and have the features to prove themselves as anticancer drugs, further to be synthesized and tested against the cell lines.

Mahto, Manoj kumar; Yellapu, Nanda Kumar; Kilaru, Ravendra Babu; Chamarthi, Naga Raju; Bhaskar, Matcha

2014-01-01

155

In vitro evaluation of dichloro-bis(pyrazole)palladium(II) and dichloro-bis(pyrazole)platinum(II) complexes as anticancer agents  

Microsoft Academic Search

Introduction  Cisplatin (cis-diamminedichloroplatinum) was first identified for its anti-bacterial activity, and was later also shown to be an efficient\\u000a anticancer agent. However, the therapeutic use of this anticancer drug is somewhat limited by its toxic side effects, which\\u000a include nephrotoxicity, nausea, and vomiting. Furthermore the development of drug-resistant tumours is commonly observed following\\u000a therapy with cisplatin. Hence there is a need

Frankline K. Keter; Stonard Kanyanda; Sylvester S. L. Lyantagaye; James Darkwa; D. Jasper G. Rees; Mervin Meyer

2008-01-01

156

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

PubMed

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

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

2014-08-18

157

Synthesis and evaluation of novel marine bromopyrrole alkaloid-based hybrids as anticancer agents.  

PubMed

A series of twenty three novel hybrids of marine bromopyrrole alkaloids with chalcone, isoxazole and flavone structural features were synthesized and evaluated for in vitro anticancer activity by MTT assay against five human cancer cell lines. Among the synthesized chalcones, hybrids 4a and 4h (IC50 range: 0.18 ?M-12.00 ?M) showed anticancer activity against all the tested cancer cell lines. Promising cytotoxic activities were exhibited by flavones derivatives, 5a and 5b (0.41 ?M-1.28 ?M) against cell lines PA1 and KB403. Isoxazole hybrids, 6b-6e selectively inhibited oral and mouth cancer cell line KB403, among which 6c (IC50 = 2.45 ?M) was found to be most active. PMID:23584542

Rane, Rajesh A; Sahu, Niteshkumar U; Gutte, Shweta D; Mahajan, Anand A; Shah, Chetan P; Bangalore, Pavankumar

2013-05-01

158

Honokiol analogs: a novel class of anticancer agents targeting cell signaling pathways and other bioactivities.  

PubMed

Honokiol (3,5-di-(2-propenyl)-1,1-biphenyl-2,2-diol) is a natural bioactive neolignan isolated from the genus Magnolia. In recent studies, honokiol has been observed to have anti-angiogenic, anticancer, anti-inflammatory, neuroprotective and GABA-modulating properties in vitro and in preclinical models. Honokiol and its analogs target multiple signaling pathways including NF-?B, STAT3, EGFR, mTOR and caspase-mediated common pathway, which regulate cancer initiation and progression. Honokiol and its targets of action may be helpful in the development of effective analogs and targeted cancer therapy. In this review, recent data describing the molecular targets of honokiol and its analogs with anticancer and some other bioactivities are discussed. PMID:23651094

Kumar, Ankit; Kumar Singh, Umesh; Chaudhary, Anurag

2013-05-01

159

Design, synthesis and biological activity of piperlongumine derivatives as selective anticancer agents.  

PubMed

In an effort to expand the structure-activity relationship of the natural anticancer compound piperlongumine, we have prepared sixteen novel piperlongumine derivatives with halogen or morpholine substituents at C2 and alkyl substituents at C7. Most of 2-halogenated piperlongumines showed potent in vitro activity against four cancer cells and modest selectivity for lung normal cells. The highly active anticancer compound 11h exhibited obvious ROS elevation and excellent in vivo antitumor potency with suppressed tumor growth by 48.58% at the dose of 2 mg/kg. The results indicated that halogen substituents as electrophilic group at C2 played an important role in increasing cytotoxicity. PMID:24937186

Wu, Yuelin; Min, Xiao; Zhuang, Chunlin; Li, Jin; Yu, Zhiliang; Dong, Guoqiang; Yao, Jiangzhong; Wang, Shengzheng; Liu, Yang; Wu, Shanchao; Zhu, Shiping; Sheng, Chunquan; Wei, Yunyang; Zhang, Huojun; Zhang, Wannian; Miao, Zhenyuan

2014-07-23

160

Alginate-based microfluidic system for tumor spheroid formation and anticancer agent screening  

Microsoft Academic Search

We demonstrate a microfluidic system for long-term tumor cell culture and drug testing. Three-dimensional cell culture is\\u000a critical in characterizing anticancer treatments since it may provide a better model than monolayer culture of tumor cells.\\u000a Breast tumor cells were encapsulated within alginate which was gelled in situ within the microchannels. Tumor spheroid formation was observed several days after cell seeding,

Michael C. W. Chen; Madhuja Gupta; Karen C. Cheung

2010-01-01

161

Toward discovering new anti-cancer agents targeting topoisomerase II?: a facile screening strategy adaptable to high throughput platform.  

PubMed

Topoisomerases are a family of vital enzymes capable of resolving topological problems in DNA during various genetic processes. Topoisomerase poisons, blocking reunion of cleaved DNA strands and stabilizing enzyme-mediated DNA cleavage complex, are clinically important antineoplastic and anti-microbial agents. However, the rapid rise of drug resistance that impedes the therapeutic efficacy of these life-saving drugs makes the discovering of new lead compounds ever more urgent. We report here a facile high throughput screening system for agents targeting human topoisomerase II? (Top2?). The assay is based on the measurement of fluorescence anisotropy of a 29 bp fluorophore-labeled oligonucleotide duplex. Since drug-stabilized Top2?-bound DNA has a higher anisotropy compared with free DNA, this assay can work if one can use a dissociating agent to specifically disrupt the enzyme/DNA binary complexes but not the drug-stabilized ternary complexes. Here we demonstrate that NaClO4, a chaotropic agent, serves a critical role in our screening method to differentiate the drug-stabilized enzyme/DNA complexes from those that are not. With this strategy we screened a chemical library of 100,000 compounds and obtained 54 positive hits. We characterized three of them on this list and demonstrated their effects on the Top2?-mediated reactions. Our results suggest that this new screening strategy can be useful in discovering additional candidates of anti-cancer agents. PMID:24809695

Lin, Yu-Shih; Huang, Wan-Chen; Chen, Mei-Shya; Hsieh, Tao-Shih

2014-01-01

162

Toward Discovering New Anti-Cancer Agents Targeting Topoisomerase II?: A Facile Screening Strategy Adaptable to High Throughput Platform  

PubMed Central

Topoisomerases are a family of vital enzymes capable of resolving topological problems in DNA during various genetic processes. Topoisomerase poisons, blocking reunion of cleaved DNA strands and stabilizing enzyme-mediated DNA cleavage complex, are clinically important antineoplastic and anti-microbial agents. However, the rapid rise of drug resistance that impedes the therapeutic efficacy of these life-saving drugs makes the discovering of new lead compounds ever more urgent. We report here a facile high throughput screening system for agents targeting human topoisomerase II? (Top2?). The assay is based on the measurement of fluorescence anisotropy of a 29 bp fluorophore-labeled oligonucleotide duplex. Since drug-stabilized Top2?-bound DNA has a higher anisotropy compared with free DNA, this assay can work if one can use a dissociating agent to specifically disrupt the enzyme/DNA binary complexes but not the drug-stabilized ternary complexes. Here we demonstrate that NaClO4, a chaotropic agent, serves a critical role in our screening method to differentiate the drug-stabilized enzyme/DNA complexes from those that are not. With this strategy we screened a chemical library of 100,000 compounds and obtained 54 positive hits. We characterized three of them on this list and demonstrated their effects on the Top2?–mediated reactions. Our results suggest that this new screening strategy can be useful in discovering additional candidates of anti-cancer agents.

Lin, Yu-Shih; Huang, Wan-Chen; Chen, Mei-Shya; Hsieh, Tao-shih

2014-01-01

163

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

PubMed Central

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

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

164

Surface engineered dendrimers as antiangiogenic agent and carrier for anticancer drug: dual attack on cancer.  

PubMed

The present research work describes the formulation of arginine conjugated 3.0G Poly(propylene) imine (PPI) dendrimers, mimicking the surface structure of an endogenous angiogenesis-inhibitor endostatin; for tumor specific delivery of a model anticancer drug, doxorubicin hydrochloride (Dox). Synthesis of PPI dendrimers and conjugation of arginine to surface groups was confirmed by FTIR, NMR, TEM and mass spectrometry. Drug was loaded by equilibrium dialysis method and developed formulation was evaluated for entrapment efficiency, hemolytic toxicity, in vitro drug release, stability, anti-angiogenic activity via in vivo chick embryo chorioallantoic membrane (CAM) assay, and anticancer activity and cell uptake using MCF-7 cancer cell lines. The system exhibited the initial rapid release followed by sustained release of Dox with significant antiangiogenic activity in the CAM assay. Further, the arginine conjugated dendrimers was found to inhibit growth of cancer cells in ex vivo studies with MCF-7 cell lines. Cell uptake studies suggested that in comparison to free drug the formulation was preferably taken up by the tumor cells. Thus the two pronged attack on cancerous tissue i.e., inhibition of angiogenesis and killing of cancer cells by anticancer drug, might prove to be a promising approach in the treatment of fatal disease, cancer. PMID:24757983

Jain, K; Jain, N K

2014-07-01

165

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

PubMed

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

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

166

Ferns and lycopods-a potential treasury of anticancer agents but also a carcinogenic hazard.  

PubMed

Many species of seedless vascular plants-ferns and lycopods-have been used as food and folk medicine since ancient times. Some of them have become the focus of intensive research concerning their anticancer properties. Studies on the anticancer effect of crude extracts are being increasingly replaced by bioactivity-guided fractionation, as well as detailed assessment of the mechanism of action. Numerous compounds-especially flavonoids such as amentoflavone and protoapigenone, and also simpler phenolic compounds, steroids, alkaloids and terpenoids-were isolated and found to be cytotoxic, particularly pro-apoptotic, or to induce cell cycle arrest in cancer cell lines in vitro. In in vivo experiments, some fern-derived compounds inhibited tumour growth with little toxicity. On the other hand, many ferns-not only the well-known Bracken (Pteridium)-may pose a significant hazard to human health due to the fact that they contain carcinogenic sesquiterpenoids and their analogues. The objective of this review is to summarise the recent state of research on the anticancer properties of ferns and lycopods, with a focus on their characteristic bioactive constituents. The carcinogenic hazard posed by ferns is also mentioned. Copyright © 2013 John Wiley & Sons, Ltd. PMID:24123573

Tomšík, Pavel

2014-06-01

167

Recent developments of DNA poisons--human DNA topoisomerase II? inhibitors--as anticancer agents.  

PubMed

DNA topoisomerases are an important family of enzymes that catalyze the induction of topological changes in the DNA molecule. Their ability to modulate the topology of the DNA makes DNA topoisomerases a key player in several vital cell processes such as replication, transcription, chromosome separation and segregation. Consequently, they already represent an important collection of macromolecular targets for some of the established anticancer drugs on the market as well as serve as templates in the development of novel anticancer drugs especially supported by recent structural advances in the field. The aim of this review is to provide an overview of the recent developments in the field of DNA poisons - a major class of human topoisomerase II? inhibitors - of which several are already in clinical use. Due to frequently experienced occurrence of serious side effects of these molecules during therapy, especially cardiotoxicity issues, further drug design efforts were initiated already yielding novel promising compounds that have overcome this issue and already entered into clinical studies. Some of the presented and discussed chemical classes include intercalators, non-intercalators and redox-dependent poisons of human topoisomerase II?. In particular, this review focuses on the currently available structure-based standpoint of molecular design and on the medicinal chemist's perspective of this field of anticancer drug design. PMID:23363399

Pogorel?nik, Barbara; Perdih, Andrej; Solmajer, Tom

2013-01-01

168

Wip1 promotes RUNX2-dependent apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents.  

PubMed

The inactivation of the p53 tumor suppressor pathway in many cancers often increases their resistance to anticancer therapy. Here we show that a previously proposed strategy directed to Wip1 inhibition could be ineffective in tumors lacking p53. On the contrary, Wip1 overexpression sensitized these tumors to chemotherapeutic agents. This effect was mediated through interaction between Wip1 and RUNX2 that resulted, in response to anticancer treatment, in RUNX2-dependent transcriptional induction of the proapoptotic Bax protein. The potentiating effects of Wip1 overexpression on chemotherapeutic agents were directed only to tumor cells lacking p53. The overexpression of Wip1 in normal tissues provided protection from cisplatin-induced apoptosis through decreased strength of upstream signaling to p53. Thus, Wip1 phosphatase promotes apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents. PMID:22065775

Goloudina, Anastasia R; Tanoue, Kan; Hammann, Arlette; Fourmaux, Eric; Le Guezennec, Xavier; Bulavin, Dmitry V; Mazur, Sharlyn J; Appella, Ettore; Garrido, Carmen; Demidov, Oleg N

2012-01-10

169

Small-molecule inhibitors of acetyltransferase p300 identified by high-throughput screening are potent anticancer agents.  

PubMed

Acetyltransferase p300 (KAT3B) plays key roles in signaling cascades that support cancer cell survival and sustained proliferation. Thus, p300 represents a potential anticancer therapeutic target. To discover novel anticancer agents that target p300, we conducted a high-throughput screening campaign. A library of 622,079 compounds was assayed for cytotoxicity to the triple-negative breast cancer (TNBC) cell line MDA-MB-231 but not to the human mammary epithelial cells. The resulting compounds were tested in a biochemical assay for inhibiting the enzymatic activity of p300. One compound (L002, NSC764414) displayed an IC50 of 1.98 ?mol/L against p300 in vitro, inhibited acetylation of histones and p53, and suppressed STAT3 activation in cell-based assays. L002 could be docked to the active site of the p300 catalytic domain. Biochemical tests of a series of related compounds revealed functional groups that may impact inhibitory potency of L002 against p300. Interestingly, these analogs showed inhibitory activities against the cellular paralog of p300 (CBP), p300/CBP-associated factor, and GCN5, but not to other acetyltransferases (KAT5, KAT6B, and KAT7), histone deacetylases, and histone methyltransferases. Among the NCI-60 panel of cancer cell lines, leukemia and lymphoma cell lines were extremely sensitive to L002, whereas it is toxic to only a limited number of cell lines derived from solid tumors. Notably, breast cancer cell lines, especially those derived from TNBC, were highly susceptible to L002. In vivo, it potently suppressed tumor growth and histone acetylation of MDA-MB-468 xenografts. Thus, these new acetyltransferase inhibitors are potential anticancer therapeutics. PMID:23625935

Yang, Heng; Pinello, Christie E; Luo, Jian; Li, Dawei; Wang, Yunfei; Zhao, Lisa Y; Jahn, Stephan C; Saldanha, Sanjay Adrian; Chase, Peter; Planck, Jamie; Geary, Kyla R; Ma, Haiching; Law, Brian K; Roush, William R; Hodder, Peter; Liao, Daiqing

2013-05-01

170

Benzylidine pregnenolones and their oximes as potential anticancer agents: Synthesis and biological evaluation.  

PubMed

The present study reveals the anticancer activity of benzylidine pregnenolones and their oxime derivatives. The synthesis of the analogs of both series is very simple and involves aldol condensation in the first step followed by nucleophillic addition of hydroxylamine across carbonyl in the second step. Quantitative yields of more than 80% are obtained in both the steps. All the compounds were tested for their cytotoxic activities against a panel of six human cancer cell lines. Amongst all the compounds of both the series screened for their cytotoxic activity, compound 3e, 3f and 4e are very potent especially against HCT-15 and MCF-7 cancer cell lines. PMID:24699163

Banday, Abid H; Akram, S M M; Shameem, Shameem A

2014-06-01

171

Recent advances in the development of catalytic inhibitors of human DNA topoisomerase II? as novel anticancer agents.  

PubMed

DNA topoisomerases comprise an important family of enzymes that catalyse the induction of topological changes (e.g. relaxation/ supercoiling, catenation/decatenation and knotting/unknotting) in the DNA molecule. These enzymes perform their functions by creating transient either single-stranded or double-stranded breaks in the DNA molecule. Due to their ability to modulate the topology of the DNA molecule, DNA topoisomerases play vital roles in replication, transcription, chromosome separation and segregation, and thus represent an important collection of design targets for novel anticancer drugs. The aim of this review is to provide an overview of the development of catalytic inhibitors of the human topoisomerase II? enzyme--an important member of the DNA topoisomerase family--as potential novel anticancer agents. The group of catalytic topoII inhibitors is classified into four types according to their molecular mechanism of action: inhibitors that bind to the ATP binding site, inhibitors that prevent the ATP hydrolysis step and trap the enzyme in a closed clamp, inhibitors that block the DNA cleavage and inhibitors that prevent the enzyme binding to the DNA. One of the important considerations highlighted throughout this review is the structure-based perspective of inhibitor design, giving the reader a medicinal chemist's perspective on this vibrant and active field of drug design research. PMID:23210851

Pogorel?nik, B; Perdih, A; Solmajer, T

2013-01-01

172

Phenylpropiophenone derivatives as potential anticancer agents: synthesis, biological evaluation and quantitative structure-activity relationship study.  

PubMed

Series of twelve chalcone and propafenone derivatives has been synthesized and evaluated for anticancer activities against HeLa, Fem-X, PC-3, MCF-7, LS174 and K562 cell lines. The 2D-QSAR and 3D-QSAR studies were performed for all compounds with cytotoxic activities against each cancer cell line. Partial least squares (PLS) regression has been applied for selection of the most relevant molecular descriptors and QSAR models building. Predictive potentials of the created 2D-QSAR and 3D-QSAR models for each cell line were compared, by use of leave-one-out cross-validation and external validation, and optimal QSAR models for each cancer cell line were selected. The QSAR studies have selected the most significant molecular descriptors and pharmacophores of the chalcone and propafenone derivatives and proposed structures of novel chalcone and propafenone derivatives with enhanced anticancer activity on the HeLa, Fem-X, PC-3, MCF-7, LS174 and K562 cells. PMID:23501110

Ivkovi?, Branka M; Nikolic, Katarina; Ili?, Bojana B; Žižak, Željko S; Novakovi?, Radmila B; ?udina, Olivera A; Vladimirov, Sote M

2013-05-01

173

Advances in the molecular design of potential anticancer agents via targeting of human telomeric DNA.  

PubMed

Telomerases are an attractive drug target to develop new generation drugs against cancer. A telomere appears from the chromosomal termini and protects it from double-stranded DNA degradation. A short telomere promotes genomic instability, like end-to-end fusion and regulates the over-expression of the telomere repairing enzyme, telomerase. The telomerase maintains the telomere length, which may lead to genetically abnormal situations, leading to cancer. Thus, the design and synthesis of an efficient telomerase inhibitor is a viable strategy toward anticancer drugs development. Accordingly, small molecule induced stabilization of the G-quadruplex structure, formed by the human telomeric DNA, is an area of contemporary scientific art. Several such compounds efficiently stabilize the G-quadruplex forms of nucleic acids, which often leads to telomerase inhibition. This Feature article presents the discovery and development of the telomere structure, function and evolution in telomere targeted anticancer drug design and incorporates the recent advances in this area, in addition to discussing the advantages and disadvantages in the methods, and prospects for the future. PMID:24695755

Maji, Basudeb; Bhattacharya, Santanu

2014-06-21

174

Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents.  

PubMed

A simple and efficient synthesis of 6-fluoro-4-oxopyrido[2,3-a]carbazole-3-carboxylic acids (13a-e) and a structurally related 6-fluoro-4-oxothieno[2',3':4,5]pyrrolo[3,2-h]quinoline (13f) was achieved via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. The ability of 13a-f to inhibit the activity of DNA gyrase and topoisomerase IV was also investigated. The thieno isostere (13f) emerged as the most active antibacterial, while the 9-fluoro derivative (13e) was the most potent against multidrug-resistant staphylococci. Compounds 13a, 13c-f displayed growth inhibition against MCF-7 breast tumor and A549 non-small cell lung cancer cells coupled with an absence of cytotoxicity toward normal human-derm fibroblasts (HuDe). Compound 13e was the most active anticancer against MCF-7 cells, with greater potency than ellipticine (IC(50) 0.8 and 1.6muM, respectively). The most active compounds in this series show promise as dual acting anticancer and antibacterial chemotherapeutics. PMID:20667744

Al-Trawneh, Salah A; Zahra, Jalal A; Kamal, Marwan R; El-Abadelah, Mustafa M; Zani, Franca; Incerti, Matteo; Cavazzoni, Andrea; Alfieri, Roberta R; Petronini, Pier G; Vicini, Paola

2010-08-15

175

Preclinical Pharmacology of BA-TPQ, a Novel Synthetic Iminoquinone Anticancer Agent  

PubMed Central

Marine natural products and their synthetic derivatives represent a major source of novel candidate anti-cancer compounds. We have recently tested the anti-cancer activity of more than forty novel compounds based on an iminoquinone makaluvamine scaffold, and have found that many of the compounds exert potent cytotoxic activity against human cancer cell lines. One of the most potent compounds, BA-TPQ [(11,12),7-(benzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one], was active against a variety of human cancer cell lines, and inhibited the growth of breast and prostate xenograft tumors in mice. However, there was some toxicity noted in the mice following administration of the compound. In order to further the development of BA-TPQ, and in a search for potential sites of accumulation that might underlie the observed toxicity of the compound, we accomplished preclinical pharmacological studies of the compound. We herein report the in vitro and in vivo pharmacological properties of BA-TPQ, including its stability in plasma, plasma protein binding, metabolism by S9 enzymes, and plasma and tissue distribution. We believe these studies will be useful for further investigations, and may be useful for other investigators examining the use of similar compounds for cancer therapy.

Ezell, Scharri J.; Li, Haibo; Xu, Hongxia; Zhang, Xiangrong; Gurpinar, Evrim; Zhang, Xu; Rayburn, Elizabeth R.; Sommers, Charnell I.; Yang, Xinyi; Velu, Sadanandan E.; Wang, Wei; Zhang, Ruiwen

2010-01-01

176

Non-peptidic substrate-mimetic inhibitors of Akt as potential anti-cancer agents  

PubMed Central

Akt has emerged as a critical target for the development of anti-cancer therapies. It has been found to be amplified, overexpressed, or constitutively activated in numerous human malignancies with oncogenesis derived from the simultaneous promotion of cell survival and suppression of apoptosis. A valuable alternative to the more common ATP-mimetic based chemotherapies is a substrate-mimetic approach, which has the potential advantage of inherent specificity of the substrate-binding pocket. In this paper we present the development of high affinity non-peptidic, substrate-mimetic inhibitors based on the minimum GSK3? substrate sequence. Optimization of initial peptidic leads resulted in the development of several classes of small molecule inhibitors, which have comparable potency to the initial peptidomimetics, while eliminating the remaining amino acid residues. We have identified the first non-peptidic substrate-mimetic lead inhibitors of Akt 29a–b, which have affinities of 17 and 12 ?M, respectively. This strategy has potential to provide a useful set of molecular probes to assist in the validation of Akt as a potential target for anti-cancer drug design.

Kayser-Bricker, Katherine J.; Glenn, Matthew P.; Lee, Sang Hoon; Sebti, Said M.; Cheng, Jin Q.; Hamilton, Andrew D.

2014-01-01

177

The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1  

PubMed Central

Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukaemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from resveratrol by having an additional aromatic hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumours and catalyses aromatic hydroxylation reactions. We report here that the cancer preventative agent resveratrol undergoes metabolism by the cytochrome P450 enzyme CYP1B1 to give a metabolite which has been identified as the known antileukaemic agent piceatannol. The metabolite was identified by high performance liquid chromatography analysis using fluorescence detection and the identity of the metabolite was further confirmed by derivatisation followed by gas chromatography–mass spectrometry studies using authentic piceatannol for comparison. This observation provides a novel explanation for the cancer preventative properties of resveratrol. It demonstrates that a natural dietary cancer preventative agent can be converted to a compound with known anticancer activity by an enzyme that is found in human tumours. Importantly this result gives insight into the functional role of CYP1B1 and provides evidence for the concept that CYP1B1 in tumours may be functioning as a growth suppressor enzyme. British Journal of Cancer (2002) 86, 774–778. DOI: 10.1038/sj/bjc/6600197 www.bjcancer.com © 2002 Cancer Research UK

Potter, G A; Patterson, L H; Wanogho, E; Perry, P J; Butler, P C; Ijaz, T; Ruparelia, K C; Lamb, J H; Farmer, P B; Stanley, L A; Burke, M D

2002-01-01

178

Polyvalent Saccharide-Functionalized Generation 3 Poly (amidoamine) Dendrimer-Methotrexate Conjugate as a Potential Anticancer Agent  

PubMed Central

A saccharide-terminated Generation 3 (G3) polyamidoamine (PAMAM) dendrimer was synthesized as a drug carrier. Utilizing this dendritic platform, we have successfully synthesized polyvalent conjugates (G3-MTX) containing the drug methotrexate (MTX). Surface plasmon resonance (SPR) results showed that G3-MTX presented 3 orders of magnitude enhancement in binding avidity to folate-binding protein (FBP) as compared to the free folic acid (FA). Flow cytometric and confocal microscopic analysis showed that conjugate (G3-MTX-FI) containing imaging agent fluorescein-5(6)-carboxamidohexanoic acid (FI) was internalized into folate receptor (FR)-expressing KB cells in dose-dependent and receptor-mediated fashion. The G3-MTX induced a dose-dependent cytotoxicity in the KB cells. Therefore, the polyvalent G3-MTX may have potential as an anti-cancer nanodevice for the specific targeting and killing of FR-expressing tumor cells.

Zhang, Yuehua; Thomas, Thommey P.; Lee, Kyung-Hoon; Li, Minghsin; Zong, Hong; Desai, Ankur M.; Kotlyar, Alina; Huang, Baohua; Banaszak Holl, Mark M.; Baker, James R.

2011-01-01

179

The Anticancer Agent Adriamycin Can be Actively Cytotoxic without Entering Cells  

NASA Astrophysics Data System (ADS)

The antineoplastic agent adriamycin was coupled to an insoluble agarose support. This material was actively cytotoxic to L1210 cells in culture under conditions in which no free adriamycin could enter the cell. It is concluded that an agent whose principal target was previously thought to be DNA can exert its cytotoxic action solely by interaction at the cell surface.

Tritton, Thomas R.; Yee, Gene

1982-07-01

180

Evaluation of the molecular mechanisms of a palladium(II) saccharinate complex with terpyridine as an anticancer agent.  

PubMed

Metal-based compounds represent promising anticancer therapeutic agents. In this study, the mechanism of action of a novel metal-based drug, a palladium(II) (Pd) complex ([PdCl(terpy)](sac)·2H2O, terpy=2,2':6',2''-terpyridine and sac=saccharinate), was elucidated. The tested compound induced cytotoxicity in nine different human cancer cell lines that originated from various organs, suggesting a broad spectrum of activity. The IC50 values were significantly higher for noncancerous cells when compared with cancer cells. We found that cells treated with the Pd(II) complex exhibited increased caspase 3/7 activities and condensed/fragmented nuclei, as demonstrated by nuclear staining and DNA laddering. Morphological features, such as cellular shrinkage and blebbing, were also observed, indicating that apoptosis was the primary mechanism of cell death. Pd(II) treatment induced DNA double-stranded breaks both in vitro and in vivo, potentially accounting for the source of stress in these cells. Although caspase 3/7 activities were elevated after Pd(II) treatment, silencing or using inhibitors of caspase 3 did not block apoptosis. Other molecules that could potentially play a role in Pd(II)-induced apoptosis, such as p53 and Bax, were also tested using silencing technology. However, none of these proteins were essential for cell death, indicating either that these molecules do not participate in Pd(II)-induced apoptosis or that other pathways were activated in their absence. Hence, this new molecule might represent a promising anticancer agent that exhibits cytotoxicity in p53-mutant, Bax-mutant, and/or caspase 3-mutant cancer cells. PMID:24045367

Kacar, Omer; Adiguzel, Zelal; Yilmaz, Veysel T; Cetin, Yuksel; Cevatemre, Buse; Arda, Nazli; Baykal, Ahmet T; Ulukaya, Engin; Acilan, Ceyda

2014-01-01

181

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

PubMed Central

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.

Shirasaka, Tetsuhiko

2009-01-01

182

Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents.  

PubMed

Histone deacetylase 6 (HDAC6) is structurally and functionally unique among the 11 human zinc-dependent histone deacetylases. Here we show that chemical inhibition with the HDAC6-selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan-HDAC inhibitor SAHA (vorinostat) in transformed cells (LNCaP, MCF-7), an effect not observed in normal cells (human foreskin fibroblast cells). The inactive analogue of tubacin, nil-tubacin, does not sensitize transformed cells to these anticancer agents. Further, we show that down-regulation of HDAC6 expression by shRNA in LNCaP cells enhances cell death induced by etoposide, doxorubicin, and SAHA. Tubacin in combination with SAHA or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells, as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan-caspase inhibitor Z-VAD-fmk. HDAC6 inhibition with tubacin induces the accumulation of ?H2AX, an early marker of DNA double-strand breaks. Tubacin enhances DNA damage induced by etoposide or SAHA as indicated by increased accumulation of ?H2AX and activation of the checkpoint kinase Chk2. Tubacin induces the expression of DDIT3 (CHOP/GADD153), a transcription factor up-regulated in response to cellular stress. DDIT3 induction is further increased when tubacin is combined with SAHA. These findings point to mechanisms by which HDAC6-selective inhibition can enhance the efficacy of certain anti-cancer agents in transformed cells. PMID:21037108

Namdar, Mandana; Perez, Gisela; Ngo, Lang; Marks, Paul A

2010-11-16

183

Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents  

PubMed Central

Histone deacetylase 6 (HDAC6) is structurally and functionally unique among the 11 human zinc-dependent histone deacetylases. Here we show that chemical inhibition with the HDAC6-selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan-HDAC inhibitor SAHA (vorinostat) in transformed cells (LNCaP, MCF-7), an effect not observed in normal cells (human foreskin fibroblast cells). The inactive analogue of tubacin, nil-tubacin, does not sensitize transformed cells to these anticancer agents. Further, we show that down-regulation of HDAC6 expression by shRNA in LNCaP cells enhances cell death induced by etoposide, doxorubicin, and SAHA. Tubacin in combination with SAHA or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells, as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan-caspase inhibitor Z-VAD-fmk. HDAC6 inhibition with tubacin induces the accumulation of ?H2AX, an early marker of DNA double-strand breaks. Tubacin enhances DNA damage induced by etoposide or SAHA as indicated by increased accumulation of ?H2AX and activation of the checkpoint kinase Chk2. Tubacin induces the expression of DDIT3 (CHOP/GADD153), a transcription factor up-regulated in response to cellular stress. DDIT3 induction is further increased when tubacin is combined with SAHA. These findings point to mechanisms by which HDAC6-selective inhibition can enhance the efficacy of certain anti-cancer agents in transformed cells.

Namdar, Mandana; Perez, Gisela; Ngo, Lang; Marks, Paul A.

2010-01-01

184

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

PubMed

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

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

2014-03-01

185

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

NASA Astrophysics Data System (ADS)

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.

Ziomkowska, Blanka; Cyrankiewicz, Micha?; Kruszewski, Stefan; Siuda, Ryszard

2005-08-01

186

Fused Thiopyrano[2,3-d]thiazole Derivatives as Potential Anticancer Agents  

PubMed Central

rel-(5aR,11bR)-3,5a,6,11b-tetrahydro-2H,5H-chromeno[4?,3?:4,5]thiopyrano[2,3-d][1,3]thiazol-2-ones formed by the stereoselective Knoevenagel-hetero-Diels-Alder reaction were functionalized at the nitrogen in position 3 via reactions of alkylation, cyanoethylation, and acylation. The synthesized compounds were evaluated for their anticancer activity in NCI60 cell lines. Among the tested compounds, 3f was found to be the most active candidate with the greatest influence on leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, prostate cancer, and breast cancer subpanel cell lines with GI50 values over a range of 0.37–0.67 ?M.

Kryshchyshyn, Anna; Atamanyuk, Dmytro; Lesyk, Roman

2012-01-01

187

Fused Thiopyrano[2,3-d]thiazole Derivatives as Potential Anticancer Agents.  

PubMed

rel-(5aR,11bR)-3,5a,6,11b-tetrahydro-2H,5H-chromeno[4',3':4,5]thiopyrano[2,3-d][1,3]thiazol-2-ones formed by the stereoselective Knoevenagel-hetero-Diels-Alder reaction were functionalized at the nitrogen in position 3 via reactions of alkylation, cyanoethylation, and acylation. The synthesized compounds were evaluated for their anticancer activity in NCI60 cell lines. Among the tested compounds, 3f was found to be the most active candidate with the greatest influence on leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, prostate cancer, and breast cancer subpanel cell lines with GI(50) values over a range of 0.37-0.67 ?M. PMID:23008803

Kryshchyshyn, Anna; Atamanyuk, Dmytro; Lesyk, Roman

2012-09-01

188

Synthesis and cytotoxicity studies of Hedgehog enzyme inhibitors SANT-1 and GANT-61 as anticancer agents.  

PubMed

Cancer-related death is one of the most common causes of mortality in society. Small molecules have the capability to disrupt aberrant signaling pathways in tumors, leading to anticancer activities. Therefore the search for new molecules for cancer treatment continues to draw attention to the scientific research community. Synthesis and biological evaluation of hedgehog (Hh) pathway inhibitors SANT-1 and GANT-61 are disclosed. These molecules have been synthesized from common precursors using simple conversions, our synthesis features Vils-Meier-Haack reaction, imine formation reaction and N-arylation reaction. These drugs were evaluated using a Hh reporter assay to confirm pathway inhibitory activity, and tested for cell viability against pancreatic and prostate cancer cells. These methodologies can be applied to make potent analogs of both inhibitors. PMID:24521409

Chenna, Venugopal; Hu, Chaoxin; Khan, Saeed R

2014-01-01

189

Library construction and biological evaluation of enmein-type diterpenoid analogues as potential anticancer agents.  

PubMed

A library of promising enmein-type 14-O-diterpenoid derivatives was constructed from a commercially available kaurene-type oridonin by practical and efficient synthetic methods. These synthetic derivatives were evaluated for their antiproliferative activities against a set of four human cancer cell lines. The IC50 values are similar to or improved over those of the parent molecule and paclitaxel, the latter of which was used as a positive control. Compound 29 was further investigated for its apoptotic properties against human hepatocarcinoma Bel-7402 cells to better understand its mode of action. Moreover, compound 29 was shown to have potent antitumor activity in?vivo in studies with a murine model of gastric cancer (MGC-803 mice). These results warrant further preclinical investigations of these diterpenoid-based analogues as potential novel anticancer chemotherapeutics. PMID:23520191

Li, Dahong; Xu, Shengtao; Cai, Hao; Pei, Lingling; Wang, Lei; Wu, Xiaoming; Yao, Hequan; Jiang, Jieyun; Sun, Yijun; Xu, Jinyi

2013-05-01

190

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

PubMed

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

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

2014-01-01

191

RasGRPs Are Targets of the Anti-Cancer Agent Ingenol-3-Angelate  

PubMed Central

Ingenol-3–angelate (I3A) is a non-tumor promoting phorbol ester-like compound identified in the sap of Euphoria peplus. Similar to tumor promoting phorbol esters, I3A is a diacylglycerol (DAG) analogue that binds with high affinity to the C1 domains of PKCs, recruits PKCs to cellular membranes and promotes enzyme activation. Numerous anti-cancer activities have been attributed to I3A and ascribed to I3A’s effects on PKCs. We show here that I3A also binds to and activates members of the RasGRP family of Ras activators leading to robust elevation of Ras-GTP and engagement of the Raf-Mek-Erk kinase cascade. In response to I3A, recombinant proteins consisting of GFP fused separately to full-length RasGRP1 and RasGRP3 were rapidly recruited to cell membranes, consistent with direct binding of the compound to RasGRP’s C1 domain. In the case of RasGRP3, IA3 treatment led to positive regulatory phosphorylation on T133 and activation of the candidate regulatory kinase PKC?. I3A treatment of select B non-Hodgkin’s lymphoma cell lines resulted in quantitative and qualitative changes in Bcl-2 family member proteins and induction of apoptosis, as previously demonstrated with the DAG analogue bryostatin 1 and its synthetic analogue pico. Our results offer further insights into the anticancer properties of I3A, support the idea that RasGRPs represent potential cancer therapeutic targets along with PKC, and expand the known range of ligands for RasGRP regulation.

Song, Xiaohua; Lopez-Campistrous, Ana; Sun, Lucy; Dower, Nancy A.; Kedei, Noemi; Yang, Jing; Kelsey, Jessica S.; Lewin, Nancy E.; Esch, Tim E.; Blumberg, Peter M.; Stone, James C.

2013-01-01

192

Podophyllotoxin 0.5% v podophyllin 20% to treat penile warts.  

PubMed Central

The increasing incidence of genital warts has led to more public awareness of this infection and its possible sequelae. Currently available treatment remains unsatisfactory, and there is pressure to develop effective and convenient alternatives. Podophyllotoxin is standardised and stable, whereas podophyllin has a variable composition. In an open comparison of self applied podophyllotoxin 0.5% versus podophyllin 20% applied by a doctor to treat external penile warts, podophyllotoxin was more effective and gave quicker resolution than podophyllin. Side effects were similar for both preparations, and few patients experienced complications severe enough to stop treatment. Podophyllotoxin can therefore be used safely and effectively for home treatment monitored at an outpatient clinic and provides a useful alternative to treatment with podophyllin at overburdened genitourinary medicine clinics.

Edwards, A; Atma-Ram, A; Thin, R N

1988-01-01

193

The potential of acridine carboxamide pt complexes as anti-cancer agents : a review.  

PubMed

There has been a concerted attempt to produce more effective anti-tumour agents based on the widely-used cancer chemotherapeutic agent, cisplatin. One interesting approach is to attach a DNA-affinic chemical group to the cisplatin molecule. This could result in a more efficient binding to the biological target, DNA, and produce a different spectrum of Pt-DNA crosslinks that may permit an agent to overcome cisplatin resistance. Acridine Pt complexes, have activity against cisplatin-resistant cells, have a differing DNA sequence selectivity compared to cisplatin and hence, are strong candidates for development as anti-tumour agents. The properties of acridine Pt analogues, especially 9-aminoacridine carboxamide Pt complexes, are reviewed here and the sequence specific interaction of acridine carboxamide Pt complexes with DNA is explored. The 9-aminoacridine carboxamide Pt complexes have a reduced reaction at runs of consecutive guanine nucleotides compared with cisplatin, and form adducts at novel DNA sequences, especially 5'-CGA. The activity of the 9-aminoacridine Pt complexes against cisplatin-resistant cell lines is due to their ability to escape the DNA repair capacity of the cells, through the production of variant DNA adducts. The future prospects for development of acridine carboxamide Pt complexes as cancer chemotherapeutic agents are discussed. PMID:24102313

Murray, Vincent; Chen, John K; Galea, Anne M

2014-06-01

194

Synthesis and cytotoxicity evaluation of 13-n-alkyl berberine and palmatine analogues as anticancer agents.  

PubMed

By introducing long carbon-chain alkyl groups at the C-13 position of berberine and palmatine, 13-n-hexyl/13-n-octyl berberine and palmatine chloride analogues 4a-d were synthesized and examined by MTT assays for cytotoxic activity in seven human cancer cell lines (7701QGY, SMMC7721, HepG2, CEM, CEM/VCR, KIII, Lewis), yielding IC?? values of 0.02 ± 0.01-13.58 ± 2.84 ?M. 13-n-Octyl palmatine (compound 4d) gave the most potent inhibitor activity, with an IC?? of 0.02 ± 0.01 ?M for SMMC7721. In all cases, the 13-n-alkyl berberine and palmatine analogues 4a-d were more cytotoxic than berberine and palmatine. In addition, compounds 4a-d also exhibited more potent cytotoxicity than berberine and palmatine in mice with S180 sarcoma xenografted in vivo. The primary screening results indicated that the 13-n-hexyl/13-n-octyl berberine and palmatine analogues might be valuable source for new potent anticancer drug candidates. PMID:23011273

Zhang, Lei; Li, Jingjing; Ma, Fei; Yao, Shining; Li, Naisan; Wang, Jing; Wang, Yongbin; Wang, Xiuzhen; Yao, Qizheng

2012-01-01

195

Gd3+-DTPA-DG: novel nanosized dual anticancer and molecular imaging agent  

PubMed Central

Background: Difficulties in the use, preparation, and cost of radioactively-labeled glycosylated compounds led to this research and development study of a new gadolinium-labeled glucose compound that does not have a radioactive half-life or difficulties in its synthesis and utilization. Methods: Based on the structure of the 2-fluoro-2-deoxy-D-glucose molecule (18FDG), a new compound consisting of D-glucose (1.1 nm) conjugated to a well-known chelator, diethylenetriamine penta-acetic acid (DTPA), was synthesized, labeled with Gd3+, and examined in vitro and in vivo. Results: This novel compound not only demonstrated excellent and less costly imaging capability, but also showed anticancer effects on treated cells. Our results demonstrated that the new Gd3+-DTPA-DG compound (GDD, with GDD conjugate aggregation of about 8 nm at 0.02 mg/mL concentration) significantly decreased HT1080 and HT29 tumor cell numbers. Application of GDD to cancer cells also increased levels of tumor necrosis factor alpha, but did not alter blood glucose levels. Interestingly, no toxicological findings were seen in normal human kidney cells. Conclusion: Dual application of GDD for both imaging and treatment of tumor cells could be remarkably advantageous in both the diagnosis and treatment of cancer.

Amanlou, Massoud; Siadat, Seyed Davar; Ebrahimi, Seyed Esmaeil Sadat; Alavi, Abass; Aghasadeghi, Mohammad Reza; Ardestani, Mehdi Shafiee; Shanehsaz, Saeed; Ghorbani, Masoud; Mehravi, Bita; Shafiee Alavidjeh, Mohammad; Jabbari-Arabzadeh, Ali; Abbasi, Mehdi

2011-01-01

196

A new paradigm for the development of anticancer agents from natural products  

PubMed Central

A novel pharmacology paradigm has been developed which quickly and efficiently moves prospective anticancer drugs from the discovery phase through pharmacology testing and into therapeutic trial assessment. Following discovery, the drug is first assessed in a clonogenic assay which determines the cytotoxic effect of different concentrations of the drug at 3 different exposure durations: 2h, 24h and continuous (168 h). Second, pharmacokinetic information is obtained in both plasma and tumor for the drug administered at the maximum tolerated dose given intravenously. The first study defines the time-concentration profile required to obtain a specific cell survival for the tumor cells; the second study determines the concentration-time profile that can be obtained in both plasma and tumor at the maximum tolerated dose of the drug. The integration of this information determines whether a successful therapeutic trial is possible. Only when a drug shows therapeutic efficacy is a proteomics-based mechanism of action study initiated. Two drugs have been assessed in this paradigm: salicortin and fascaplysin A.

Subramanian, Balanehru; Nakeff, Alexander; Tenney, Karen; Crews, Phillip; Gunatilaka, Leslie; Valeriote, Fred

2006-01-01

197

Azoles and bis-azoles: synthesis and biological evaluation as antimicrobial and anti-cancer agents.  

PubMed

Novel hydrazonoyl halides 3, 5 and bis-hydrazonoyl halides 7, 9 were synthesized. The synthetic utility of bis-hydrazonoyl halide 7 was explored to prepare novel bis-azole 13 with antipyrine moiety. On the other hand, [1,3,4]thiadiazol-2(3H)-ylidene 17 and thiazol-2(3H)-ylidene 21 derivatives, with antipyrine moiety, were prepared from the reaction of 3-mercapto-3-(phenylamino)acrylamide derivative 10 with N-phenyl benzenecarbohydrazonoyl chloride (14) and 3-(2-bromoacetyl)-2H-chromen-2-one (18), respectively. The structures of the isolated products were confirmed by spectral data (IR, (1)H-NMR, (13)C-NMR, MS) and elemental analyses. The anti-cancer activitiy of the synthesized products against the colon carcinoma (HCT) cell line was determined and the results revealed promising activity of compound 3. In addition, the antimicrobial activity of some selected products was evaluated. The results proclaimed that compounds 9, 17, and 21 have high antibacterial activity against Gram-positive bacteria (SA, BS) and Gram-negative bacteria (PA, EC). PMID:23649193

Kheder, Nabila Abdelshafy; Riyadh, Sayed Mohamed; Asiry, Ahlam Maade

2013-01-01

198

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

PubMed

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

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

199

Four-component synthesis of 1,2-dihydropyridine derivatives and their evaluation as anticancer agents.  

PubMed

Two series of compounds with the general formula of 4,6-diaryl-2-oxo-1,2 dihydropyridine-3-carbonitriles and their isosteric imino derivatives were synthesized through a one pot reaction of acetophenone, aldehyde and ammonium acetate with ethyl cyanoacetate or malononitrile, respectively. The synthesized compounds were evaluated for tumor cell growth inhibitory using the human HT-29 colon and MDA-MB-231 breast tumor cell lines. Compound 4-(2- Ethoxyphenyl)-2-imino-6-(4-fluorophenyl)-1,2-dihydropyridine-3 carbonitrile (6) showed IC50 value of 0.70 ?M versus HT-29. Meanwhile, compound 4-(2-Hydroxyphenyl)-2-imino-6-(4-fluorophenyl)-1,2-dihydropyridine-3-carbonitrile (4) showed IC50 value of 4.6 ?M versus MDA-MB-231. Docking compound 10 to possible molecular targets, survivin and PIM1 kinase showed appreciable interactions with both, which suggest possible targets for the antitumor activity of this novel class of anticancer compounds. PMID:22530887

Abdel-Fattah, Mohamed A O; El-Naggar, Mahmoud A M; Rashied, Rasha M H; Gary, Bernard D; Piazza, Gary A; Abadi, Ashraf H

2012-05-01

200

CRM1 is a direct cellular target of the natural anti-cancer agent plumbagin.  

PubMed

Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, has been shown to exert anti-cancer and anti-proliferative activities in vitro as well as in animal tumor models. However, the mechanism underlying its anti-tumor action still remains unclear. CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors whose function is altered in cancer due to increased expression and overactive transport. We showed that CRM1 is a direct cellular target of plumbagin. The nuclei of cells incubated with plumbagin accumulated tumor-suppressor proteins and inhibited the interactions between CRM1 and these proteins. Particularly, we demonstrated that plumbagin could specifically react with the conserved Cys(528) of CRM1 but not with a Cys(528) mutant peptide through Mass spectrometric analysis. More importantly, cancer cells that are transfected with mutant CRM1 (C528S) are resistant to the inhibitory effects of plumbagin, demonstrating that the inhibition is through direct interaction with Cys(528) of CRM1. The inhibition of nuclear traffic by plumbagin may account for its therapeutic properties in cancer and inflammatory diseases. Our findings could contribute to the development of a new class of CRM1 inhibitors. PMID:24739265

Liu, Xuejiao; Niu, Mingshan; Xu, Xiaoyu; Cai, Wei; Zeng, Lingyu; Zhou, Xiuping; Yu, Rutong; Xu, Kailin

2014-01-01

201

Application of computer assisted combinatorial chemistry in antivirial, antimalarial and anticancer agents design  

NASA Astrophysics Data System (ADS)

Combinatorial chemistry and technologies have been developed to a stage where synthetic schemes are available for generation of a large variety of organic molecules. The innovative concept of combinatorial design assumes that screening of a large and diverse library of compounds will increase the probability of finding an active analogue among the compounds tested. Since the rate at which libraries are screened for activity currently constitutes a limitation to the use of combinatorial technologies, it is important to be selective about the number of compounds to be synthesized. Early experience with combinatorial chemistry indicated that chemical diversity alone did not result in a significant increase in the number of generated lead compounds. Emphasis has therefore been increasingly put on the use of computer assisted combinatorial chemical techniques. Computational methods are valuable in the design of virtual libraries of molecular models. Selection strategies based on computed physicochemical properties of the models or of a target compound are introduced to reduce the time and costs of library synthesis and screening. In addition, computational structure-based library focusing methods can be used to perform in silico screening of the activity of compounds against a target receptor by docking the ligands into the receptor model. Three case studies are discussed dealing with the design of targeted combinatorial libraries of inhibitors of HIV-1 protease, P. falciparum plasmepsin and human urokinase as potential antivirial, antimalarial and anticancer drugs. These illustrate library focusing strategies.

Burello, E.; Bologa, C.; Frecer, V.; Miertus, S.

202

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

PubMed

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

Dinnen, R D; Ebisuzaki, K

1997-01-01

203

Using a build-and-click approach for producing structural and functional diversity in DNA-targeted hybrid anticancer agents.  

PubMed

An efficient screening method was developed for functionalized DNA-targeted platinum-containing hybrid anticancer agents based on metal-mediated amine-to-nitrile addition, a form of "click" chemistry. The goal of the study was to generate platinum-acridine agents for their use as cytotoxic "warheads" in targeted and multifunctional therapies. This was achieved by introducing hydroxyl, carboxylic acid, and azide functionalities in the acridine linker moiety and by varying the nonleaving groups attached to platinum. The assay, which was based on microscale reactions between 6 platinum-nitrile complexes and 10 acridine derivatives, yielded a small library of 60 platinum-acridines. Reactions were monitored, and product mixtures were quantitatively analyzed by automated in-line high-performance liquid chromatography-electrospray mass spectrometry (LC-ESMS) analysis and subjected to cell viability screening using a nonradioactive cell proliferation assay. The new prescreening methodology proves to be a powerful tool for establishing structure-activity relationships and for identifying target compounds. PMID:23074987

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

2012-11-26

204

Perifosine as a Potential Novel Anti-Cancer Agent Inhibits EGFR/MET-AKT Axis in Malignant Pleural Mesothelioma  

PubMed Central

Background PI3K/AKT signalling pathway is aberrantly active and plays a critical role for cell cycle progression of human malignant pleural mesothelioma (MMe) cells. AKT is one of the important cellular targets of perifosine, a novel bio-available alkylphospholipid that has displayed significant anti-proliferative activity in vitro and in vivo in several human tumour model systems and is currently being tested in clinical trials. Methods We tested Perifosine activity on human mesothelial cells and different mesothelioma cell lines, in order to provide evidence of its efficacy as single agent and combined therapy. Results We demonstrate here that perifosine, currently being evaluated as an anti-cancer agent in phase 1 and 2 clinical trials, caused a dose-dependent reduction of AKT activation, at concentrations causing MMe cell growth arrest. In this study we firstly describe that MMe cells express aside from AKT1 also AKT3 and that either the myristoylated, constitutively active, forms of the two proteins, abrogated perifosine-mediated cell growth inhibition. Moreover, we describe here a novel mechanism of perifosine that interferes, upstream of AKT, affecting EGFR and MET phosphorylation. Finally, we demonstrate a significant increase in cell toxicity when MMe cells were treated with perifosine in combination with cisplatin. Conclusions This study provides a novel mechanism of action of perifosine, directly inhibiting EGFR/MET-AKT1/3 axis, providing a rationale for a novel translational approach to the treatment of MMe.

Pinton, Giulia; Manente, Arcangela Gabriella; Angeli, Giovanni

2012-01-01

205

Using a Build-and-Click Approach for Producing Structural and Functional Diversity in DNA-Targeted Hybrid Anticancer Agents  

PubMed Central

An efficient screening method was developed for functionalized DNA-targeted platinum-containing hybrid anticancer agents based on metal-mediated amine-to-nitrile addition, a form of “click” chemistry. The goal of the study was to generate platinum–acridine agents for their use as cytotoxic “warheads” in targeted and multifunctional therapies. This was achieved by introducing hydroxyl, carboxylic acid, and azide functionalities in the acridine linker moiety and by varying the nonleaving groups attached to platinum. The assay, which was based on microscale reactions between 6 platinum–nitrile complexes and 10 acridine derivatives, yielded a small library of 60 platinum–acridines. Reactions were monitored and product mixtures were quantitatively analyzed by automated in-line high-performance liquid chromatography– electrospray mass spectrometry (LC-ESMS) analysis and subjected to cell viability screening using a non-radioactive cell proliferation assay. The new prescreening methodology proves to be a powerful tool for establishing structure–activity relationships and for identifying target compounds.

Ding, Song; Qiao, Xin; Kucera, Gregory L.; Bierbach, Ulrich

2012-01-01

206

The antiepileptic and anticancer agent, valproic acid, induces P-glycoprotein in human tumour cell lines and in rat liver  

PubMed Central

Background and purpose: The antiepileptic drug valproic acid, a histone deacetylase (HDAC) inhibitor, is currently being tested as an anticancer agent. However, HDAC inhibitors may interact with anticancer drugs through induction of P-glycoprotein (P-gp, MDR1) expression. In this study we assessed whether valproic acid induces P-gp function in tumour cells. We also investigated effects of valproic acid on the mRNA for P-gp and the cytochrome P450, CYP3A, in rat livers. >Experimental approach: Effects of valproic acid on P-gp were assessed in three tumour cell lines, SW620, KG1a and H4IIE. Accumulation of acetylated histone H3 in rats' livers treated for two or seven days with valproic acid was evaluated using a specific antibody. Hepatic expression of the P-gp genes, mdr1a, mdr1b and mdr2, was determined by real-time polymerase chain reaction. The effects of valproic acid on CYP3A were assessed by Northern blot analysis and CYP3A activity assays. Key results: Valproic acid (0.5–2.0?mM) induced P-gp expression and function up to 4-fold in vitro. The effect of a series of valproic acid derivatives on P-gp expression in SW620 and KG1a cells correlated with their HDAC inhibition potencies. Treatment of rats with 1?mmol kg?1 valproic acid for two and seven days increased hepatic histone acetylation (1.3- and 3.5-fold, respectively) and the expression of mdr1a and mdr2 (2.2–4.1-fold). Valpromide (0.5–2.0?mM) did not increase histone acetylation or P-gp expression in rat livers, but induced CYP3A expression. Conclusions: Valproic acid increased P-gp expression and function in human tumour cell lines and in rat liver. The clinical significance of this increase merits further investigation.

Eyal, S; Lamb, J G; Smith-Yockman, M; Yagen, B; Fibach, E; Altschuler, Y; White, H S; Bialer, M

2006-01-01

207

Bcl-2 attenuates anticancer agents-induced apoptosis by sustained activation of Akt/protein kinase B in U937 cells.  

PubMed

Aberrant overexpression of antiapoptotic members of the Bcl-2 protein family contributes to resistance to anticancer therapeutic drugs. Thus, this protein represent attractive target for novel anticancer agents. In the present study, we determined the effect of the anti-apoptosis protein Bcl-2 on caspase-3 activation, PLC-gamma1 degradation and Akt activation during the various anticancer agents-induced apoptosis. Treatment with chrysin for 12 h produced morphological features of apoptosis in U937 cells, which was associated with caspase-3 activation and PLC-gamma1 degradation. Induction of apoptosis was also accompanied by down-regulation of XIAP and inactivation of Akt. Chrysin-induced caspase-3 activation, PLC-gamma1 degradation and apoptosis were significantly attenuated in Bcl-2 overexpressing U937/Bcl-2 cells. Ectopic expression of Bcl-2 appeared to inhibit ceramide-, and Akt specific inhibitor (SH-6)-induced apoptosis by sustained Akt activation. Thus, our findings imply that some of the biological functions of Bcl-2 may be attributed to their ability to inhibit anticancer agents-induced apoptosis through the sustained Akt activation. PMID:16215670

Woo, K J; Yoo, Y H; Park, J-W; Kwon, T K

2005-12-01

208

Compatibility and Stability of the Investigational Polypeptide Marine Anticancer Agent Kahalalide F in Infusion Devices  

Microsoft Academic Search

Kahalalide F is a novel marine-derivedantitumor agent isolated from the marinemollusk Elysia rufescens, an organismliving in the seas near Hawaii. Thecompound has shown highly selective invitro activity against prostate tumors andphase I trials in patients with androgenindependent prostate tumors incorporating adaily times five and weekly schedule have been initiated.Kahalalide F is pharmaceuticallyformulated as a lyophilized productcontaining 150 µg active substance

Bastiaan Nuijen; Marjan Bouma; Consuelo Manada; José M. Jimeno; Luis L. Lazaro; Auke Bult; Jos H. Beijnen

2001-01-01

209

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

DOEpatents

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.

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

2012-10-23

210

PEG conjugates in clinical development or use as anticancer agents: An overview  

Microsoft Academic Search

During the almost forty years of PEGylation, several antitumour agents, either proteins, peptides or low molecular weight drugs, have been considered for polymer conjugation but only few entered clinical phase studies. The results from the first clinical trials have shared and improved the knowledge on biodistribution, clearance, mechanism of action and stability of a polymer conjugate in vivo. This has

Gianfranco Pasut; Francesco M. Veronese

2009-01-01

211

Interaction between novel anticancer agents and radiation in non-small cell lung cancer cell lines  

Microsoft Academic Search

Integration of chemotherapy and radiation is the standard practice in the management of locally advanced inoperable NSCLC. To assess the biological interaction between third generation chemotherapeutic agents and radiation in non-small cell lung cancer (NSCLC) in vitro, we tested a number of different drugs (paclitaxel, docetaxel, gemcitabine, topotecan, SN-38 and cisplatin) combined with radiation, in lung cancer cell lines. Cellular

Maura Loprevite; Roberto E Favoni; Alessandra de Cupis; Paolo Pirani; Gabriella Pietra; Silvia Bruno; Francesco Grossi; Tindaro Scolaro; Andrea Ardizzoni

2001-01-01

212

A modified HSP70 inhibitor shows broad activity as an anticancer agent  

PubMed Central

The stress-induced heat shock protein 70 (HSP70) is an ATP-dependent molecular chaperone that plays a key role in refolding misfolded proteins and promoting cell survival following stress. HSP70 is marginally expressed in non-transformed cells, but is greatly overexpressed in tumor cells. Silencing HSP70 is uniformly cytotoxic to tumor but not normal cells; therefore, there has been great interest in the development of HSP70 inhibitors for cancer therapy. Here we report that the HSP70 inhibitor 2-phenylethynesulfonamide (PES) binds to the substrate-binding domain of HSP70, and requires the C-terminal helical ‘lid’ of this protein (amino acids 573-616) in order to bind. Using molecular modeling and in silico docking, we have identified a candidate binding site for PES in this region of HSP70, and we identify point mutants that fail to interact with PES. A preliminary structure-activity relationship analysis has revealed a derivative of PES, 2-(3-chlorophenyl) ethynesulfonamide (PES-Cl), which shows increased cytotoxicity and ability to inhibit autophagy, along with significantly improved ability to extend the life of mice with pre-B cell lymphoma, compared to the parent compound (p=0.015). Interestingly, we also show that these HSP70 inhibitors impair the activity of the Anaphase Promoting Complex/Cyclosome (APC/C) in cell-free extracts, and induce G2/M arrest and genomic instability in cancer cells. PES-Cl is thus a promising new anti-cancer compound with several notable mechanisms of action.

Balaburski, Gregor M.; Leu, Julia I-Ju; Beeharry, Neil; Hayik, Seth; Andrake, Mark D.; Zhang, Gao; Herlyn, Meenhard; Villanueva, Jessie; Dunbrack, Roland L.; Yen, Tim; George, Donna L.; Murphy, Maureen E.

2013-01-01

213

Semi-physiological model describing the hematological toxicity of the anti-cancer agent indisulam.  

PubMed

Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer drug currently in phase II clinical development for the treatment of solid tumors. Phase I dose-escalation studies were conducted comparing four treatment schedules. Neutropenia and thrombocytopenia were dose limiting in all schedules. The aim of this study was to describe the extent and the time course of the hematological toxicity and its possible schedule dependency using a semi-physiological model. Data from 142 patients were analyzed using NONMEM. The semi-physiological model comprised a progenitor blood cell compartment, linked to the central circulation compartment, through 3 transition compartments representing the maturation chain in the bone marrow. Plasma concentrations of the drug were assumed to reduce the proliferation rate in the progenitor compartment according to a linear function. A feedback mechanism was included in the model representing the rebound effect of endogenous growth factors. The model was validated using a posterior predictive check. The model adequately described the extent and time course of neutropenia and thrombocytopenia. The mean transition time (MTT, i.e. maturation time in bone marrow) of neutrophils was increased by 47% in patients who received indisulam as a weekly dose administered for four out of every six weeks. For platelets, MTT was increased by 33% in patients who received this schedule and also in patients who received a continuous 120-h infusion. The validation procedure indicated that the model adequately predicts the nadir value of neutrophils and platelets and the time to reach this nadir. A semi-physiological model was successfully applied to describe the time course and extent of the neutropenia and thrombocytopenia after indisulam administration for four treatment schedules. PMID:15868378

van Kesteren, Charlotte; Zandvliet, Anthe S; Karlsson, Mats O; Mathôt, Ron A A; Punt, Cornelis J A; Armand, Jean-Pierre; Raymond, Eric; Huitema, Alwin D R; Dittrich, Christian; Dumez, Herlinde; Roché, Henri H; Droz, Jean-Pierre; Ravic, Miroslav; Yule, S Murray; Wanders, Jantien; Beijnen, Jos H; Fumoleau, Pierre; Schellens, Jan H M

2005-06-01

214

Preclinical Predictors of Anticancer Drug Efficacy: Critical Assessment with Emphasis on Whether Nanomolar Potency Should Be Required of Candidate Agents  

PubMed Central

In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses (“the nanomolar rule”). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed.

Wong, C. C.; Cheng, Ka-Wing

2012-01-01

215

Preclinical predictors of anticancer drug efficacy: critical assessment with emphasis on whether nanomolar potency should be required of candidate agents.  

PubMed

In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses ("the nanomolar rule"). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed. PMID:22448039

Wong, C C; Cheng, Ka-Wing; Rigas, Basil

2012-06-01

216

Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy?  

PubMed

A majority of the novel orally administered, molecularly targeted anticancer therapies are weak bases that exhibit pH-dependent solubility, and suppression of gastric acidity with acid-reducing agents could impair their absorption. In addition, a majority of cancer patients frequently take acid-reducing agents to alleviate symptoms of gastroesophageal reflux disease, thereby raising the potential for a common but underappreciated drug-drug interaction (DDI) that could decrease the exposure of anticancer medication and result in subsequent failure of therapy. This article is a review of the available clinical literature describing the extent of the interaction between 15 orally administered, small-molecule targeted anticancer therapies and acid-reducing agents. The currently available clinical data suggest that the magnitude of this DDI is largest for compounds whose in vitro solubility varies over the pH range 1-4. This range represents the normal physiological gastric acidity (pH ~1) and gastric acidity while on an acid-reducing agent (pH ~4). PMID:22739140

Budha, N R; Frymoyer, A; Smelick, G S; Jin, J Y; Yago, M R; Dresser, M J; Holden, S N; Benet, L Z; Ware, J A

2012-08-01

217

The in vitro rabbit whole bladder as a model to investigate the urothelial transport of anticancer agents The ONCOFID-P paradigm.  

PubMed

Intravesical instillation of BCG or anticancer agents after transurethral resection is currently considered a standard of therapy. However, this approach is basically empirical; none of the anticancer agents used in this setting was specifically formulated for intravesical therapy. Moreover, concern is raised by the kinetic features of water soluble drugs, because of poor transport across the mucosal barrier, or of liphophylic compounds, for the increased risks of systemic toxicity. A need exists to improve the pre-clinical and clinical approaches used at present to test anticancer agents undergoing specific development for intravesical use. We used in vitro rabbit whole bladders as a new pre-clinical model to investigate the kinetics of locally administered anticancer agents. In this study, we investigated the rate of urothelial transport of a novel paclitaxel derivative, Oncofid-P. Male New Zealand albino rabbits were used. Bladders were rapidly explanted, filled with vehicle alone or vehicle containing graded concentrations of Oncofid-P, and kept for various times under standardized incubation conditions. At the end of experiments, drug concentrations were assessed by high-pressure-liquid-chromatography technique in the intravesical and external bath solutions, as well as in bladder wall homogenates. We found that less than 1% of the drug additioned to the intravesical solution is recovered within the bladder wall in the form of paclitaxel; experiments carried out collecting different areas from the same bladders showed that Oncofid-P is uniformly distributed over the internal surface of bladder mucosa. Isolated rabbit bladders may be a useful pre-clinical model to investigate the rate of transport of chemotherapeutic agents administered by intravesical route. In this paradigm, Oncofid-P displays a kinetic profile that is predictive of local activity over the whole urothelial surface, and low or absent systemic absorption. PMID:18848989

Tringali, Giuseppe; Lisi, Lucia; Bettella, Fabio; Renier, Davide; Di Stasi, Savino M; Navarra, Pierluigi

2008-01-01

218

Polycyclic aromatic compounds as anticancer agents: structure-activity relationships of chrysene and pyrene derivatives.  

PubMed

A large number of diamides and diamines were synthesized using 6-amino chrysene and 1-amino pyrene as starting materials. A structure activity study with cis-platinum as internal control against animal and human tumor lines was carried out in vitro. This study indicated that the in vitro cytotoxicity toward these lines depends on the functionality present in the molecules. The diamino compounds were found to be more potent than the diamides, and these were equally active irrespective of the end heterocyclic group, whereas the activity of the diamides was strongly dependent on the terminal unit. In general, the diamides containing chrysene as the chromophore were more active than those with a pyrene ring. The size of the end heterocyclic ring, along with the nature of the spacer connecting the polycyclic ring to the heterocyclic ring, seemed to affect the biological activity in certain cell lines. Hemolysis experiments on a lead compound established that it had activities similar to those described for membrane-stabilizing agents. This agent also demonstrated the capacity to produce differentiation in leukemia cell lines. PMID:11310593

Banik, B K; Becker, F F

2001-03-01

219

Effects of 13-hydroxy SM5887 in combination with other anticancer agents on human tumor cell lines.  

PubMed

A new anthracycline derivative, SM5887, in combination with commonly used anticancer agents was evaluated against T-cell leukemia MOLT-3 and human osteosarcoma MG-63 cell lines in culture. MOLT-3 and MG-63 cells were incubated with various concentrations of 13-hydroxy SM5887 (SM5887-OH, the active metabolite of SM5887) and other drugs for 3 and 4 days, respectively. Cell growth inhibition was determined by MTT assay. The antitumor effects of the drug combinations at 80% inhibitory concentration (IC80) were analyzed by the isobologram of Steel and Peckham. In MOLT-3 cells, SM5887-OH had additive effects with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, 4-hydroperoxy ifosfamide, 5-fluorouracil, cytarabine, and vincristine, whereas it had mainly protective (marked antagonistic) effects with methotrexate. In MG-63 cells, SM5887-OH had additive effects with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, 4-hydroperoxy ifosfamide; mainly subadditive (mild antagonistic) effects with 5-fluorouracil and cytarabine; and mainly protective (marked antagonistic) effects with vincristine and methotrexate. These findings suggest that SM5887 is suitable for simultaneous administration with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, or ifosfamide and not suitable for simultaneous administration with methotrexate. The effects of SM5887 in combination with 5-fluorouracil, cytarabine or vincristine may be variable, depending on cell lines. To find optimal combinations, further in vitro and in vivo studies of antitumor activity and toxicity appear to be warranted. PMID:9157070

Takagi, T; Yazawa, Y; Suzuki, K; Yamauchi, Y; Kano, Y

1996-01-01

220

Insights into the reactivity of gold-dithiocarbamato anticancer agents toward model biomolecules by using multinuclear NMR spectroscopy.  

PubMed

Some gold(III)-dithiocarbamato derivatives of either single amino acids or oligopeptides have shown promise as potential anticancer agents, but their capability to interact with biologically relevant macromolecules is still poorly understood. We investigated the affinity of the representative complex [Au(III)Br2(dtc-Sar-OCH3)] (dtc: dithiocarbamate; Sar: sarcosine (N-methylglycine)) with selected model molecules for histidine-, methionine-, and cysteine-rich proteins (that is, 1-methylimidazole, dimethylsulfide, and N-acetyl-L-cysteine, respectively). In particular, detailed mono- and multinuclear NMR studies, in combination with multiple (13)C/(15)N enrichments, allowed interactions to be followed over time and indicated somewhat unexpected reaction pathways. Whereas dimethylsulfide proved to be unreactive, a sudden multistep redox reaction occurred in the presence of the other potential sulfur donor, N-acetyl-L-cysteine (confirmed if glutathione was used instead). On the other hand, 1-methylimidazole underwent an unprecedented acid-base reaction with the gold(III) complex, rather than the expected coordination to the metal center by replacing, for instance, a bromide. Our results are discussed herein and compared with the data available in the literature on related complexes; our findings confirm that the peculiar reactivity of gold(III)-dithiocarbamato complexes can lead to novel reaction pathways and, therefore, to new cytotoxic mechanisms in cancer cells. PMID:24038383

Boscutti, Giulia; Marchiò, Luciano; Ronconi, Luca; Fregona, Dolores

2013-09-27

221

Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo.  

PubMed

We report the analysis of CPI-613, the first member of a large set of analogs of lipoic acid (lipoate) we have investigated as potential anticancer agents. CPI-613 strongly disrupts mitochondrial metabolism, with selectivity for tumor cells in culture. This mitochondrial disruption includes activation of the well-characterized, lipoate-responsive regulatory phosphorylation of the E1? pyruvate dehydrogenase (PDH) subunit. This phosphorylation inactivates flux of glycolysis-derived carbon through this enzyme complex and implicates the PDH regulatory kinases (PDKs) as a possible drug target. Supporting this hypothesis, RNAi knockdown of the PDK protein levels substantially attenuates CPI-613 cancer cell killing. In both cell culture and in vivo tumor environments, the observed strong mitochondrial metabolic disruption is expected to significantly compromise cell survival. Consistent with this prediction, CPI-613 disruption of tumor mitochondrial metabolism is followed by efficient commitment to cell death by multiple, apparently redundant pathways, including apoptosis, in all tested cancer cell lines. Further, CPI-613 shows strong antitumor activity in vivo against human non-small cell lung and pancreatic cancers in xenograft models with low side-effect toxicity. PMID:21769686

Zachar, Zuzana; Marecek, James; Maturo, Claudia; Gupta, Sunita; Stuart, Shawn D; Howell, Katy; Schauble, Alexandra; Lem, Joanna; Piramzadian, Arin; Karnik, Sameer; Lee, King; Rodriguez, Robert; Shorr, Robert; Bingham, Paul M

2011-11-01

222

Synthesis and Evaluation of Some New Aza-B-homocholestane Derivatives as Anticancer Agents  

PubMed Central

Using analogues of some marine steroidal oximes as precursors, a series of aza-B-homocholestane derivatives possessing different substituted groups at the 3-position of the steroidal nucleus were synthesized. Their biological activity against cancer cell proliferation was determined with multiple cancer cell lines. Aza-B-homocholestane derivatives possessing 3-hydroxyl, 3-hydroximino and 3-thiosemicarbazone groups displayed remarkable cytotoxicity to cancer cells via apoptosis inducing mechanism. Compounds 5, 10, 12, 15 and 18 exhibited better potency to inhibit cancer cell proliferation. In addition, compound 15 was further evaluated with three dimensional (3D) multicellular spheroids assay to determine its potency against spheroid growth. The structure-activity relationship (SAR) generated in the studies is valuable for the design of novel chemotherapeutic agents.

Huang, Yanmin; Cui, Jianguo; Chen, Sijing; Lin, Qifu; Song, Huacan; Gan, Chunfang; Su, Bin; Zhou, Aimin

2014-01-01

223

Preclinical evaluation of illudins as anticancer agents: basis for selective cytotoxicity.  

PubMed

Illudins are potent natural products derived from Omphalotus illudens and related fungi. The chemical structure of illudins differs from that of other conventional chemotherapeutic agents. While illudins are toxic to most tumor cells after prolonged exposure (greater than or equal to 48 hr), with shorter exposure times (less than or equal to 2 hr), they show selective toxicity for human myelocytic leukemia and epidermoid, lung, ovarian, and breast carcinoma cells of various species of origin. The apparent histologic specificity of illudin S toxicity is based on an energy-dependent transport mechanism present in sensitive cells, but absent in cells relatively resistant to illudin S. For human myeloid leukemia HL60 cells, the Michaelis constant was 4.2 microM and the maximum velocity was 12.2 pmol/minute per 10 million cells or 730 pmol/hour per 10 million cells. The energy-dependent transport mechanism was detected in other mammalian tumor cells. PMID:2402017

Kelner, M J; McMorris, T C; Taetle, R

1990-10-01

224

Variation of podophyllotoxin in leaves of Eastern Red Cedar (Juniperus virginiana).  

PubMed

Leaves of Eastern red cedar (Juniperus virginiana L. Cupressaceae) have been reported to contain podophyllotoxin, a pharmaceutical compound used to manufacture drugs for treatment of cancer, rheumatoid arthritis, genital warts, psoriasis, and multiple sclerosis. Podophyllotoxin content of leaves of immature, mature male, and mature female plants (approximately 1.45 mg x g -1) was significantly higher than that of leaves of juvenile plants (0.60 mg x g -1). Sampling date also affected podophyllotoxin content. Leaves harvested in January and April exhibited higher podophyllotoxin contents (1.56 and 1.45 mg x g -1, respectively) than leaves harvested in February and June (1.06 and 1.08 mg x g -1, respectively). There was no obvious pattern or trend in the data due to sampling date. There was no significant interaction between plant type and sampling date. These results indicate that foliage of mature Eastern red cedar, a waste product of the lumber industry, could be a low-yielding, but relatively stable, source of podophyllotoxin. PMID:12802737

Cushman, Kent E; Maqbool, Muhammad; Gerard, Patrick D; Bedir, Ebru; Lata, Hemant; Moraes, Rita M

2003-05-01

225

Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer.  

PubMed

Heat shock proteins (HSPs), which are molecular chaperones that stabilize numerous vital proteins, may be attractive targets for cancer therapy. The aim of the present study was to investigate the possible anticancer effect of single or dual targeting of HSP90 and HSP70 and the combination treatment with HSP inhibitors and chemotherapeutic agents in bladder cancer cells. The expression of HSP90 and the anticancer effect of the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) coupled with cisplatin, docetaxel, or gemcitabine were examined using immunohistochemistry, quantitative real-time PCR, cell growth, flow cytometry, immunoblots and caspase-3/7 assays. The expression of HSP70 under HSP90 inhibition and the additive effect of HSP70 inhibitor pifithrin-? (PFT-?) were examined by the same assays and transmission electron microscopy. HSP90 was highly expressed in bladder cancer tissues and cell lines. 17-AAG enhanced the antiproliferative and apoptotic effects of each chemotherapeutic agent. 17-AAG also suppressed Akt activity but induced the upregulation of HSP70. PFT-? enhanced the effect of 17-AAG or chemotherapeutic agents; the triple combination of 17-AAG, PFT-? and a chemotherapeutic agent showed the most significant anticancer effect on the T24 cell line. The combination of 17-AAG and PFT-? markedly suppressed Akt and Bad activities. With HSP90 suppression, HSP70 overexpression possibly contributes to the avoidance of cell death and HSP70 may be a key molecule for overcoming resistance to the HSP90 inhibitor. The dual targeting of these two chaperones and the combination with conventional anticancer drugs could be a promising therapeutic option for patients with advanced bladder cancer. PMID:24718854

Ma, Liang; Sato, Fuminori; Sato, Ryuta; Matsubara, Takanori; Hirai, Kenichi; Yamasaki, Mutsushi; Shin, Toshitaka; Shimada, Tatsuo; Nomura, Takeo; Mori, Kenichi; Sumino, Yasuhiro; Mimata, Hiromitsu

2014-06-01

226

Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer  

PubMed Central

Heat shock proteins (HSPs), which are molecular chaperones that stabilize numerous vital proteins, may be attractive targets for cancer therapy. The aim of the present study was to investigate the possible anticancer effect of single or dual targeting of HSP90 and HSP70 and the combination treatment with HSP inhibitors and chemotherapeutic agents in bladder cancer cells. The expression of HSP90 and the anticancer effect of the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) coupled with cisplatin, docetaxel, or gemcitabine were examined using immunohistochemistry, quantitative real-time PCR, cell growth, flow cytometry, immunoblots and caspase-3/7 assays. The expression of HSP70 under HSP90 inhibition and the additive effect of HSP70 inhibitor pifithrin-? (PFT-?) were examined by the same assays and transmission electron microscopy. HSP90 was highly expressed in bladder cancer tissues and cell lines. 17-AAG enhanced the antiproliferative and apoptotic effects of each chemotherapeutic agent. 17-AAG also suppressed Akt activity but induced the upregulation of HSP70. PFT-? enhanced the effect of 17-AAG or chemotherapeutic agents; the triple combination of 17-AAG, PFT-? and a chemotherapeutic agent showed the most significant anticancer effect on the T24 cell line. The combination of 17-AAG and PFT-? markedly suppressed Akt and Bad activities. With HSP90 suppression, HSP70 overexpression possibly contributes to the avoidance of cell death and HSP70 may be a key molecule for overcoming resistance to the HSP90 inhibitor. The dual targeting of these two chaperones and the combination with conventional anticancer drugs could be a promising therapeutic option for patients with advanced bladder cancer.

MA, LIANG; SATO, FUMINORI; SATO, RYUTA; MATSUBARA, TAKANORI; HIRAI, KENICHI; YAMASAKI, MUTSUSHI; SHIN, TOSHITAKA; SHIMADA, TATSUO; NOMURA, TAKEO; MORI, KENICHI; SUMINO, YASUHIRO; MIMATA, HIROMITSU

2014-01-01

227

Oxazoline chemistry. Part 12: A metal-mediated synthesis of DMU212; X-ray diffraction studies of an important anti-cancer agent  

Microsoft Academic Search

An improved synthesis of the anti-cancer agent DMU-212 (trans-3,4,5,4?-tetramethoxystilbene) is described. The methodology involves the use of a Pd-oxazoline catalyst as a mediator of a regio-selective (Heck) C–C bond formation reaction. A simple isolation step is then used to obtain the title material. The compound has been further characterised in the solid-state by X-ray diffraction methods.

Gordon G. Cross; Charles R. Eisnor; Robert A. Gossage; Hilary A. Jenkins

2006-01-01

228

Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (-)-picropodophyllin.  

PubMed

Described is the first catalytic, asymmetric synthesis of (-)-podophyllotoxin and its C(2)-epimer, (-)-picropodophyllin. Asymmetry is achieved via the enzymatic desymmetrization of advanced meso diacetate 20, through PPL-mediated ester hydrolysis. A second key feature of the synthesis is the strategically late introduction of the highly oxygenated natural ring E through an arylcopper species. The successful implementation of this approach augers well for the introduction of other functionalized rings E for future SAR work. The synthesis begins from piperonal, which is fashioned into isobenzofuran (IBF) precursor 14 in three steps (bromination, acetalization, and halogen-metal exchange/hydroxymethylation). Interestingly, treatment of 14 with HOAc in commerical dimethyl maleate (contains 5% dimethyl fumarate) leads to a nearly equimolar mixture of fumarate- (15) and maleate-IBF Diels-Alder adducts (16 and 17), indicating that IBF 11 reacts about 15 times faster with dimethyl fumarate than with dimethyl maleate. With scrupulously pure dimethyl maleate a 2.8:1 endo:exo mixture of maleate DA adducts is still obtained. On the other hand, the desired meso diester 16 is obtained pure and in nearly quantitative yield by employing neat dimethyl acetylene dicarboxylate as the dienophile, followed by catalytic hydrogenation. Reduction (LiAlH(4)) of 16 provides meso diol 19, which is then treated with Ac(2)O, BzCl, and PhCH(2)COCl to provide the corresponding meso diesters, 20-22. Screening of these meso benzoxabicyclo[2.2.1]heptyl substrate candidates across a battery of acyl transfer enzymes leads to an optimized match of diacetate 20 with PPL. Even on 10-20 g scales, asymmetry is efficiently introduced here, yielding the key chiral intermediate, monoacetate 25 (66% isolated yield, 83% corrected yield, 95% ee). Protecting group manipulation and oxidation (Swern) provide aldehyde 27b, which undergoes efficient retro-Michael ring opening to produce dihydronaphthalene 30, in which the C(3) and C(4) stereocenters are properly set. Following several unsuccessful approaches to the intramolecular delivery of ring E (via Claisen rearrangement, Heck-type cyclization, or radical cyclization), a highly diastereoselective, intermolecular conjugate addition of the arylcopper reagent derived from (3,4,5-trimethoxy)phenylmagnesium bromide and CuCN to acyl oxazolidinone 50 was developed (85% yield, only the required alpha-stereochemistry at C(1) is observed). The conjugate addition product is converted to (-)-picropodophyllin in two steps (lactonization, SEM deprotection) or to (-)-podophyllotoxin, in three steps, through the introduction of a C(2)-epimerization step, under Kende conditions, prior to the final conjugate addition. PMID:10814019

Berkowitz, D B; Choi, S; Maeng, J H

2000-02-11

229

The anticancer agent ellipticine on activation by cytochrome P450 forms covalent DNA adducts.  

PubMed

Ellipticine is a potent antitumor agent whose mechanism of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Using [3H]-labeled ellipticine, we observed substantial microsome (cytochrome P450)-dependent binding of ellipticine to DNA. In rat, rabbit, minipig, and human microsomes, in reconstituted systems with isolated cytochromes P450 and in Supersomes containing recombinantly expressed human cytochromes P450, we could show that ellipticine forms a covalent DNA adduct detected by [32P]-postlabeling. The most potent human enzyme is CYP3A4, followed by CYP1A1, CYP1A2, CYP1B1, and CYP2C9. Another minor adduct is formed independent of enzymatic activation. The [32P]-postlabeling analysis of DNA modified by activated ellipticine confirms the covalent binding to DNA as an important type of DNA modification. The DNA adduct formation we describe is a novel mechanism for the ellipticine action and might in part explain its tumor specificity. PMID:11755121

Stiborová, M; Bieler, C A; Wiessler, M; Frei, E

2001-12-15

230

DNA interaction studies of new nano metal based anticancer agent: validation by spectroscopic methods.  

PubMed

A new nano dimensional heterobimetallic Cu-Sn containing complex as a potential drug candidate was designed, synthesized and characterized by analytical and spectral methods. The electronic absorption and electron paramagnetic resonance parameters of the complex revealed that the Cu(II) ion exhibits a square pyramidal geometry with the two pyrazole nitrogen atoms, the amine nitrogen atom and the carboxylate oxygen of the phenyl glycine chloride ligand located at the equatorial sites and the coordinated chloride ion occupying an apical position. (119)Sn NMR spectral data showed a hexa-coordinated environment around the Sn(IV) metal ion. TEM, AFM and XRD measurements illustrate that the complex could induce the condensation of CT-DNA to a particulate nanostructure. The interaction of the Cu-Sn complex with CT-DNA was investigated by UV-vis absorption and emission spectroscopy, as well as cyclic voltammetric measurements. The results indicated that the complex interacts with DNA through an electrostatic mode of binding with an intrinsic binding constant K(b) = 8.42 x 10(4) M( - 1). The Cu-Sn complex exhibits effective cleavage of pBR322 plasmid DNA by an oxidative cleavage mechanism, monitored at different concentrations both in the absence and in the presence of reducing agents. PMID:20407140

Tabassum, Sartaj; Chandra Sharma, Girish; Arjmand, Farukh; Azam, Ameer

2010-05-14

231

Platinum anticancer agents and antidepressants: desipramine enhances platinum-based cytotoxicity in human colon cancer cells  

PubMed Central

A unique synergistic effect on platinum drug cytotoxicity is noted in the presence of the tricyclic anti-depressant desipramine. Desipramine is used for treating neuropathic pain, particularly in prostate cancer patients. The clinically used drugs cisplatin (cis-[PtCl2(NH3)2]), oxaliplatin [1,2-diaminocyclohexaneoxalatoplatinum(II)], and the cationic trinuclear agent BBR3464 [{trans-PtCl(NH3)2}2-?-(trans-Pt(NH3)2(H2N(CH2)6NH2)2)]4+, which has undergone evaluation in phase II clinical trials for activity in lung and ovarian cancers, were evaluated. Surprisingly, desipramine greatly augments the cytotoxicity of all the platinum-based chemotherapeutics in HCT116 colorectal carcinoma cell lines. Desipramine enhanced cellular accumulation of cisplatin, but had no effect on the accumulation of oxaliplatin or BBR3464, suggesting that enhanced accumulation could not be a consistent means by which desipramine altered the platinum-drug-mediated cytotoxicity. The desipramine/cisplatin combination resulted in increased levels of p53 as well as mitochondrial damage, caspase activation, and poly(ADP ribose) polymerase cleavage, suggesting that desipramine may synergize with cisplatin more than with other platinum chemotherapeutics partly by activating distinct apoptotic pathways. The study argues that desipramine may be a means of enhancing chemoresponsiveness of platinum drugs and the results warrant further investigation. The results emphasize the importance of understanding the differential pharmacological action of adjuvants employed in combinations with cancer chemotherapeutics.

Kabolizadeh, Peyman; Engelmann, Brigitte J.; Pullen, Nicholas; Stewart, Jennifer K.; Ryan, John J.

2011-01-01

232

Platinum anticancer agents and antidepressants: desipramine enhances platinum-based cytotoxicity in human colon cancer cells.  

PubMed

A unique synergistic effect on platinum drug cytotoxicity is noted in the presence of the tricyclic antidepressant desipramine. Desipramine is used for treating neuropathic pain, particularly in prostate cancer patients. The clinically used drugs cisplatin (cis-[PtCl(2)(NH(3))(2)]), oxaliplatin [1,2-diaminocyclohexaneoxalatoplatinum(II)], and the cationic trinuclear agent BBR3464 [{trans-PtCl(NH(3))(2)}(2)-?-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2))](4+), which has undergone evaluation in phase II clinical trials for activity in lung and ovarian cancers, were evaluated. Surprisingly, desipramine greatly augments the cytotoxicity of all the platinum-based chemotherapeutics in HCT116 colorectal carcinoma cell lines. Desipramine enhanced cellular accumulation of cisplatin, but had no effect on the accumulation of oxaliplatin or BBR3464, suggesting that enhanced accumulation could not be a consistent means by which desipramine altered the platinum-drug-mediated cytotoxicity. The desipramine/cisplatin combination resulted in increased levels of p53 as well as mitochondrial damage, caspase activation, and poly(ADP ribose) polymerase cleavage, suggesting that desipramine may synergize with cisplatin more than with other platinum chemotherapeutics partly by activating distinct apoptotic pathways. The study argues that desipramine may be a means of enhancing chemoresponsiveness of platinum drugs and the results warrant further investigation. The results emphasize the importance of understanding the differential pharmacological action of adjuvants employed in combinations with cancer chemotherapeutics. PMID:21918844

Kabolizadeh, Peyman; Engelmann, Brigitte J; Pullen, Nicholas; Stewart, Jennifer K; Ryan, John J; Farrell, Nicholas P

2012-01-01

233

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

PubMed Central

The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs)¥ (22–33) 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 Weinreb’s 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 Institute’s (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.

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

234

Hemi-synthesis and biological activity of new analogues of podophyllotoxin.  

PubMed

Various 4-analogues of podophyllotoxin and epipodophyllotoxin were obtained via the formation of the corresponding 4-keto derivatives. Methyloximation of podophyllotoxone, followed by subsequent catalytic hydrogenation, gave stereoselective access to 4-alpha-amino-4-deoxypodophyllotoxin and from there, to the corresponding acetamido and formamido derivatives. Base-catalyzed isomerisation of 4-alpha-amino-4-deoxypodophyllotoxin led to the corresponding picropodophyllin isomer while the 4-beta-amino afforded a neopodophyllotoxin-like derivative. On the other hand, oxirane and hydroxymethyl-containing analogues were prepared from podophyllotoxin and 4-epi-4'-demethyl-podophyllotoxin, using a Takai olefination strategy. In the latter series, carboxaldehyde- and carboxylic acid-containing derivatives were also synthesized. PMID:12213460

Roulland, Emmanuel; Magiatis, Prokopios; Arimondo, Paola; Bertounesque, Emmanuel; Monneret, Claude

2002-11-01

235

Microtubules and axoplasmic transport. Inhibition of transport by podophyllotoxin: an interaction with microtubule protein.  

PubMed

Pharmacological evidence is presented for the involvement of microtubules in the process of fast axoplasmic transport. A quantitative measure of the inhibition of axoplasmic transport in an in vitro preparation of rat sciatic nerve is described. The alkaloids colchicine, podophyllotoxin, and vinblastine, which are known both to disrupt microtubules and to bind to the protein subunit of microtubules, are inhibitors of axoplasmic transport. Lumicolchine and picropodophyllin, unlike their respective isomers colchicine and podophyllotoxin, are poor inhibitors of axoplasmic transport. The dissociation constants for the binding of colchicine, lumicolchicine, podophyllotoxin, and picropodophyllin to purified microtubule protein from rat brain have been measured. Inhibition of axoplasmic transport by these drugs correlates favorably with their affinities of microtubule protein. PMID:53233

Paulson, J C; McClure, W O

1975-11-01

236

The anticancer agent YC-1 suppresses progestin-stimulated VEGF in breast cancer cells and arrests breast tumor development.  

PubMed

Recent epidemiological studies show that postmenopausal women taking estrogen-progestin hormone replacement therapy (HRT) have a higher risk of breast cancer than women on an HRT regimen lacking progestins. This may be related to the observation that progestin-treated breast cancer cells express and secrete high levels of vascular endothelial growth factor (VEGF), a potent angiogenic factor that promotes breast tumor growth. Anti-progestins such as RU-486 block this effect, indicating that progesterone receptors (PR) are involved in promoting VEGF induction; however antiprogestins cross-react with other steroid receptors which limits their clinical use. Alternative strategies are, therefore, needed to arrest the growth of progestin-dependent tumors. 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), a novel anticancer drug initially developed as an inhibitor of HIF-1?, is currently undergoing preclinical trials against various forms of cancer. Since HIF-1? has recently been implicated in PR-mediated VEGF synthesis, we undertook studies to determine whether YC-1 inhibits progestin-dependent VEGF induction and tumor progression. Surprisingly, we found that YC-1 downregulated PR in human breast cancer cells, both in vivo and in vitro, thereby blocking progestin-dependent induction of VEGF and tumor growth. YC-1 also inhibited progestin-accelerated DMBA-induced mammary tumors in rats, properties which would likely render it effective against progestin-dependent tumors which frequently develop in post-menopausal women. We, therefore, propose that based on our observations, YC-1 warrants further investigation as a novel agent which could prove extremely useful as an anti-angiogenic chemotherapeutic drug. PMID:23123638

Carroll, Candace E; Liang, Yayun; Benakanakere, Indira; Besch-Williford, Cynthia; Hyder, Salman M

2013-01-01

237

Phase-I trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent radiotherapy in patients with unresectable pancreatic cancer  

PubMed Central

In this phase-I trial, we evaluated the safety of S-1, a novel oral fluoropyrimidine anticancer agent, combined with external-beam radiotherapy (EBRT) to determine the maximum-tolerated dose and dose-limiting toxicity (DLT) in unresectable pancreatic cancer patients. Patients had histologically proven unresectable locally advanced or metastatic pancreatic cancer. S-1 was administered orally twice daily. External-beam radiotherapy was delivered in fractions of 1.25?Gy × 2 per day, totalling 50?Gy per 40 fractions for 4 weeks. S-1 was given at five dose levels: 60?mg?m–2?day–1 on days 1–7 and 15–21 (level 1), 1–14 (level 2), and 1–21 (level 3a) and 80?mg?m–2?day–1 on days 1–21 (level 3b) and 1–28 (level 4). We studied 17 patients: dose levels 1 (four patients), 2 (four patients), 3a (three patients), 3b (three patients), and 4 (three patients). One patient in level 1 (grade 3 vomiting) and two patients in level 4 (grade 4 neutropenia and grade 3 anorexia) showed DLT. No DLT was seen for levels 2, 3a, and 3b. Clinical effects by computed tomography included 5 partial responses (35%), 11 cases of stable disease, and one case of progressive disease. CA19–9 levels of less than half the starting values were observed in 8 of 16 (50%) patients. S-1 at a dose of 80?mg?m–2?day–1 given on days 1–21 is safe and recommended for phase-II study in patients with locally advanced and unresectable pancreatic cancer when given with EBRT.

Shinchi, H; Maemura, K; Noma, H; Mataki, Y; Aikou, T; Takao, S

2007-01-01

238

Anticancer chemotherapy  

SciTech Connect

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.

Weller, R.E.

1988-10-01

239

Naphthamides as anticancer agents  

US Patent & Trademark Office Database

A compound (particularly useful for inhibiting cancer) according to formula I: ##STR00001## or a pharmaceutically acceptable salt thereof, wherein: x is 0 or 1; R.sup.1-R.sup.6 are each independently H, --CN, --NO.sub.2, --NO, --OH, halogen, hydroxyalkyl, carboxyl, substituted carboxyl, aminocarbonyl, alkoxy, carbonyl or substituted carbonyl; R.sup.7 is H, alkyl, alkyl amino, aminoacyl, hydroxyacyl, heteroaryl, heterocycloalkyl, alkyl heteroaryl or alkyl heterocycloalkyl; R.sup.8 is H or alkyl; A is O or N; and Ar is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl, provided that if R.sup.7 is H then Ar is aryl substituted with alkyl amino.

2014-02-18

240

Design, synthesis and biological evaluation of N-arylphenyl-2,2-dichloroacetamide analogues as anti-cancer agents.  

PubMed

Our earlier research has shown that N-phenyl-2,2-dichloroacetamide analogues had much higher anti-cancer activity than the lead compound sodium dichloroacetate (DCA). In this current study, a variety of N-arylphenyl-2,2-dichloroacetamide analogues were synthesized via Suzuki coupling reaction and their anti-cancer activity was evaluated. The results showed that N-terphenyl-2,2-dichloroacetamide analogues had satisfactory anti-cancer activity. Among them, N-(3,5-bis(benzo[d][1,3]dioxol-5-yl)phenyl)-2,2-dichloroacetamide (6 k) had an IC(50) of 2.40 ?M against KB-3-1 cells, 1.04 ?M against H460 cells and 1.73 ?M against A549 cells. PMID:23067553

Li, Tianwen; Yang, Yongchong; Cheng, Changmei; Tiwari, Amit K; Sodani, Kamlesh; Zhao, Yufen; Abraham, Ioana; Chen, Zhe-Sheng

2012-12-01

241

A concise stereocontrolled formal total synthesis of (+/-)-podophyllotoxin using sulfoxide chemistry.  

PubMed

A short stereoselective formal total synthesis of (+/-)-podophyllotoxin has been carried out from a sulfoxide, using a one-pot tandem conjugate addition/aldol/electrophilic aromatic substitution reaction to form a tetralin, which was converted into picropodophyllin in two steps. PMID:14737540

Casey, Mike; Keaveney, Claire M

2004-01-21

242

Thymoquinone as an anticancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo.  

PubMed

Phytochemical compounds are emerging as a new generation of anticancer agents with limited toxicity in cancer patients. The purpose of this study was to investigate the potential impact of thymoquinone (TQ), the major constituent of black seed, on survival, invasion of cancer cells in vitro, and tumor growth in vivo. Exposure of cells derived from lung (LNM35), liver (HepG2), colon (HT29), melanoma (MDA-MB-435), and breast (MDA-MB-231 and MCF-7) tumors to increasing TQ concentrations resulted in a significant inhibition of viability through the inhibition of Akt phosphorylation leading to DNA damage and activation of the mitochondrial-signaling proapoptotic pathway. We provide evidence that TQ at non-toxic concentrations inhibited the invasive potential of LNM35, MDA-MB-231, and MDA-MB231-1833 cancer cells. Moreover, we demonstrate that TQ synergizes with DNA-damaging agent cisplatin to inhibit cellular viability. The anticancer activity of thymoquinone was also investigated in athymic mice inoculated with the LNM35 lung cells. Administration of TQ (10 mg/kg/i.p.) for 18 days inhibited the LNM35 tumor growth by 39% (P < 0.05). Tumor growth inhibition was associated with significant increase in the activated caspase-3. The in silico target identification suggests several potential targets of TQ mainly HDAC2 proteins and the 15-hydroxyprostaglandin dehydrogenase. In this context, we demonstrated that TQ treatment resulted in a significant inhibition of HDAC2 proteins. In view of the available experimental findings, we contend that thymoquinone and/or its analogues may have clinical potential as an anticancer agent alone or in combination with chemotherapeutic drugs such as cisplatin. PMID:22788741

Attoub, Samir; Sperandio, Olivier; Raza, Haider; Arafat, Kholoud; Al-Salam, Suhail; Al Sultan, Mahmood Ahmed; Al Safi, Maha; Takahashi, Takashi; Adem, Abdu

2013-10-01

243

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

DOEpatents

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.

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

2013-01-29

244

PEG–Anticancer Drugs  

Microsoft Academic Search

\\u000a The concept of polymer–anticancer conjugates was first proposed in 1975 by Ringsdorf, and the biological rationale for their\\u000a design and current understanding of the mechanism of action is well known. During the past 10 years, there has been a renaissance\\u000a in the field of PEG-conjugated anticancer agents. Benefits which can be achieved through application of PEGylation, i.e. the\\u000a attachment of

Francesca Cateni; Marina Zacchigna

245

Meta-Analysis of 5% Imiquimod and 0.5% Podophyllotoxin in the Treatment of Condylomata Acuminata  

Microsoft Academic Search

Background: Genital warts are a common sexually transmitted disease caused by human papillomaviruses. Podophyllotoxin 0.5%, approved for patient self-administration, has been used most extensively in the treatment of genital warts. Imiquimod, a novel immune response modifier capable of inducing interferon-? and a variety of cytokines, has been examined as a potential treatment for genital warts. But 0.5% podophyllotoxin and 5%

Jun Yan; Sheng-Li Chen; Hai-Na Wang; Tai-Xiang Wu

2006-01-01

246

Meta-Analysis of 5% Imiquimod and 0.5% Podophyllotoxin in the Treatment of Condylomata Acuminata  

Microsoft Academic Search

Background: Genital warts are a common sexually transmitted disease caused by human papillomaviruses. Podophyllotoxin 0.5%, approved for patient self-administration, has been used most extensively in the treatment of genital warts. Imiquimod, a novel immune response modifier capable of inducing interferon-? and a variety of cytokines, has been examined as a potential treatment for genital warts. But 0.5% podophyllotoxin and 5%

Jun Yan; Sheng-Li Chen; Hai-Na Wang; Tai-Xiang Wu

2006-01-01

247

Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents.  

PubMed

DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a K(i) of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC(50) of 0.42 ?M. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation. PMID:21413798

Charrier, Jean-Damien; Durrant, Steven J; Golec, Julian M C; Kay, David P; Knegtel, Ronald M A; MacCormick, Somhairle; Mortimore, Michael; O'Donnell, Michael E; Pinder, Joanne L; Reaper, Philip M; Rutherford, Alistair P; Wang, Paul S H; Young, Stephen C; Pollard, John R

2011-04-14

248

Enhanced intracellular accumulation of a non-nucleoside anti-cancer agent via increased uptake of its valine ester prodrug through amino acid transporters.  

PubMed

The phenomenon known as multiple-drug resistance, whereby anti-cancer agents are expelled from cancer cells, makes it necessary to develop methods that will reliably increase the accumulation of anti-cancer agents within cancer cells. To accomplish this goal, a new model compound, Val-SN-38, was synthesized by introducing valine to SN-38, an active ingredient of irinotecan. Val-SN-38 improved intracellular accumulation approximately 5-fold in MCF7 cells, compared with SN-38, and rather than changes in membrane permeability, the amino acid transporter ATB(0,+) played a role, whereas the dipeptide transporter PEPT1 did not. Other sodium-dependent amino acid transporters, namely ATA1, ATA2, and ASCT2, were unexpectedly involved in the uptake of Val-SN-38 as well. The efflux of Val-SN-38 by major efflux transporters was variably changed, but not significantly. In summary, the enhanced accumulation of Val-SN-38 in cancer cells was due to augmented uptake via various amino acid transporters. The results of the present study make a compelling argument in favour of a prodrug concept that can improve intracellular accumulation and take advantage of amino acid transporters without significantly inducing multiple-drug resistance. PMID:22233275

Kwak, Eun-Young; Shim, Won-Sik; Chang, Ji-Eun; Chong, Saeho; Kim, Dae-Duk; Chung, Suk-Jae; Shim, Chang-Koo

2012-07-01

249

Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3).  

PubMed

In a continuing effort to develop orally bioavailable small-molecule STAT3 inhibitors as potential therapeutic agents for human cancer, a series of novel diversified analogues based on our identified lead compound HJC0149 (1) (5-chloro-N-(1,1-dioxo-1H-1?(6)-benzo[b]thiophen-6-yl)-2-hydroxybenzamide, Eur. J. Med. Chem. 2013, 62, 498-507) have been rationally designed, synthesized, and pharmacologically evaluated. Molecular docking studies and biological characterization supported our earlier findings that the O-alkylamino-tethered side chain on the hydroxyl group is an effective and essential structural determinant for improving biological activities and druglike properties of these molecules. Compounds with such modifications exhibited potent antiproliferative effects against breast and pancreatic cancer cell lines with IC50 values from low micromolar to nanomolar range. Among them, the newly discovered STAT3 inhibitor 12 (HJC0416) displayed an intriguing anticancer profile both in vitro and in vivo (i.p. & p.o.). More importantly, HJC0416 is an orally bioavailable anticancer agent as a promising candidate for further development. PMID:24904966

Chen, Haijun; Yang, Zhengduo; Ding, Chunyong; Xiong, Ailian; Wild, Christopher; Wang, Lili; Ye, Na; Cai, Guoshuai; Flores, Rudolfo M; Ding, Ye; Shen, Qiang; Zhou, Jia

2014-07-23

250

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

PubMed Central

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.

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

251

Impact of Soil Nutrients and Environmental Factors on Podophyllotoxin Content among 28 Podophyllum Hexandrum Populations of Northwestern Himalayan Region Using Linear and Nonlinear Approaches  

Microsoft Academic Search

Podophyllotoxin is the active ingredient in the rhizome of an endangered Indian medicinal herb, Podophyllum hexandrum. Podophyllotoxin content in the P. hexandrum differs greatly in different natural habitats. The podophyllotoxin content reached more than 6.62% when soil pH value was about 4.82, soil organic carbon (C) was more than 3.23%, and nitrogen (N) content was more than 2.7% of soil

M. Afroz Alam; Pradeep K. Naik

2009-01-01

252

Discovering some novel 7-chloroquinolines carrying a biologically active benzenesulfonamide moiety as a new class of anticancer agents.  

PubMed

Based on the reported anticancer activity of quinolines, a new series of 7-chloroquinoline derivatives bearing the biologically active benzenesulfonamide moiety 2-17 and 19-25 were synthesized starting with 4,7-dichloroquinolne 1. Compound 17 was the most active compound with IC(50) value 64.41, 75.05 and 30.71 µM compared with Doxorubicin as reference drug with IC(50) values 82.53, 88.32 and 73.72 µM on breast cancer cells, skin cancer cells and neuroblastoma, respectively. All the synthesized compounds were evaluated for their in vitro anticancer activity on breast cancer cells, skin cancer cells and neuroblastoma cells. Most of the synthesized compounds showed moderate activity. In order to suggest the mechanism of action for their cytotoxic activity, molecular docking for all synthesized compounds was done on the active site of phosphoinositide kinase (PI3K) and good results were obtained. PMID:23302586

Al-Dosari, Mohammed Salem; Ghorab, Mostafa Mohamed; Al-Said, Mansour Sulaiman; Nissan, Yassin Mohammed

2013-01-01

253

KCN1, a Novel Synthetic Sulfonamide Anticancer Agent: In Vitro and In Vivo Anti-Pancreatic Cancer Activities and Preclinical Pharmacology  

PubMed Central

The purpose of the present study was to determine the in vitro and in vivo anti-cancer activity and pharmacological properties of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1. In the present study, we investigated the in vitro activity of KCN1 on cell proliferation and cell cycle distribution of pancreatic cancer cells, using the MTT and BrdUrd assays, and flow cytometry. The in vivo anti-cancer effects of KCN1 were evaluated in two distinct xenograft models of pancreatic cancer. We also developed an HPLC method for the quantitation of the compound, and examined its stability in mouse plasma, plasma protein binding, and degradation by mouse S9 microsomal enzymes. Furthermore, we examined the pharmacokinetics of KCN1 following intravenous or intraperitoneal injection in mice. Results showed that, in a dose-dependent manner, KCN1 inhibited cell growth and induced cell cycle arrest in human pancreatic cancer cells in vitro, and showed in vivo anticancer efficacy in mice bearing Panc-1 or Mia Paca-2 tumor xenografts. The HPLC method provided linear detection of KCN1 in all of the matrices in the range from 0.1 to 100 µM, and had a lower limit of detection of 0.085 µM in mouse plasma. KCN1 was very stable in mouse plasma, extensively plasma bound, and metabolized by S9 microsomal enzymes. The pharmacokinetic studies indicated that KCN1 could be detected in all of the tissues examined, most for at least 24 h. In conclusion, our preclinical data indicate that KCN1 is a potential therapeutic agent for pancreatic cancer, providing a basis for its future development.

Rayburn, Elizabeth R.; Xu, Hongxia; Zhang, Xiangrong; Zhang, Xu; Nag, Subhasree Ashok; Wu, Xuming; Wang, Ming-Hai; Wang, Hui; Van Meir, Erwin G.; Zhang, Ruiwen

2012-01-01

254

Natural products targeting autophagy via the PI3K/Akt/mTOR pathway as anticancer agents.  

PubMed

The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is a key regulator of authophagy. Natural products show anticancer activity and often induce apoptosis or autophagy. The crosstalk between these two types of cell death makes autophagy an interesting target since drugs targeting this process not only can induce cell death by inducing autophagy but can also sensitize cells to apoptosis. Autophagy is also a protective mechanism associated with increased resistance to chemotherapy. In this review, we discuss natural products known to induce autophagy cell death in cancer cells via the PI3K/Akt/mTOR pathway. PMID:23293890

Sun, Hui; Wang, Zhaoye; Yakisich, Juan Sebastian

2013-09-01

255

Topical treatment of genital warts in men, an open study of podophyllotoxin cream compared with solution  

Microsoft Academic Search

OBJECTIVE--To evaluate the clinical efficacy of a 0.15% and a 0.3% cream formulation of podophyllotoxin in comparison with the 0.5% solution in the treatment of condylomata acuminata and to compare the treatment modalities regarding side effects. DESIGN--The study was designed as an open randomised trial. Ninety male patients with signs of penile HPV infection, with either acuminate or papular lesions,

A Strand; R M Brinkeborn; A Siboulet

1995-01-01

256

The preparation and the recognition property of molecularly imprinted polymer of podophyllotoxin  

Microsoft Academic Search

A selective and affinitive molecularly imprinting polymer (MIP) was prepared to podophyllotoxin (PPT) using a non-covalent imprinting approach. The imprinted conditions including the kind and relative amounts of functional and cross-linking monomers were carefully optimized. The binding characteristics of the imprinted polymer were evaluated in different solvent systems using equilibrium binding experiments. UV spectrum revealed cooperative hydrogen-bonding complex between PPT

Xiufang Zhu; Qiue Cao; Nengbang Hou; Guosong Wang; Zhongtao Ding

2006-01-01

257

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

PubMed Central

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.

2013-01-01

258

Novel anticancer agents for multiple myeloma: a review of the evidence for their therapeutic and economic value.  

PubMed

Recent advances in oncology treatment have improved patient outcomes at the expense of increasing healthcare costs. The indication multiple myeloma is especially characterized by a recent and continuing flood of expensive novel agents. A review encompassing all elements necessary to perform an economic evaluation of novel agents for multiple myeloma was conducted for thalidomide, bortezomib and lenalidomide. Improvements in efficacy have led to a switch from conventional therapy to novel agents as standard therapy. Incremental cost-effectiveness ratios for novel agents alone or in combination with conventional agents were generally regarded to be within acceptable ranges. Conflicting results were reported for the incremental cost-effectiveness of bortezomib versus lenalidomide, as unresolved questions remain regarding their comparative effectiveness. Future economic evaluations will require an assessment of the cost-effectiveness of these agents in terms of sequence within the treatment paradigm and in combination with one another. PMID:22716498

Gaultney, Jennifer G; Redekop, William K; Sonneveld, Pieter; Uyl-de Groot, Carin A

2012-06-01

259

Design, synthesis and pharmacological evaluation of novel substituted quinoline-2-carboxamide derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents.  

PubMed

In continuation of our research for novel human dihydroorotate dehydrogenase (hDHODH) inhibitors, herein we reported design, synthesis and pharmacological evaluation of novel substituted quinoline-2-carboxamide derivatives. Human DHODH enzyme inhibition assay was used to screen the synthesized compounds as hDHODH inhibitors. The synthesized compounds were also evaluated for their antiproliferative effects on the cancer cell lines (HEP-3B and A-375) to establish a proof as anticancer agents. The chemical structures of compounds were confirmed by (1)H, (13)C NMR, IR, MS and elemental analysis. The purity of compounds was also checked by HPLC analysis. Compounds with bulky groups (-OCH3, -OCF3 and -CF3) at C6-position of quinoline ring showed good activity. PMID:24929289

Vyas, Vivek K; Variya, Bhavesh; Ghate, Manjunath D

2014-07-23

260

Design, synthesis and biological evaluation of a novel series of bisintercalating DNA-binding piperazine-linked bisanthrapyrazole compounds as anticancer agents  

PubMed Central

A series of bisintercalating DNA binding bisanthrapyrazole compounds containing piperazine linkers were designed by molecular modeling and docking techniques. Because the anthrapyrazoles are not quinones they are unable to be reductively activated like doxorubicin and other anthracyclines and thus they should not be cardiotoxic. The concentration dependent increase in DNA melting temperature was used to determine the strength of DNA binding and the bisintercalation potential of the compounds. Compounds with more than a three-carbon linker that could span 4 DNA base pairs achieved bisintercalation. All of the bisanthrapyrazoles inhibited human erythroleukemic K562 cell growth in the low to submicromolar concentration range. They also strongly inhibited the decatenation activity of topoisomerase II and the relaxation activity of topoisomerase I. However, as measured by their ability to induce double strand breaks in plasmid DNA, the bisanthrapyrazole compounds did not act as topoisomerase II poisons. In conclusion, a novel group of bisanthrapyrazole compounds were designed, synthesized, and biologically evaluated as potential anticancer agents.

Zhang, Rui; Wu, Xing; Yalowich, Jack C.; Hasinoff, Brian B.

2011-01-01

261

Discovery of (E)-3-((styrylsulfonyl)methyl)pyridine and (E)-2-((styrylsulfonyl)methyl)pyridine derivatives as anticancer agents: synthesis, structure-activity relationships, and biological activities.  

PubMed

ON01910.Na is a highly effective anticancer agent that induces mitotic arrest and apoptosis. Clinical studies with ON01910 in cancer patients have shown efficacy along with an impressive safety profile. While ON01910 is highly active against cancer cells, it has a low oral availability and requires continuous intravenous infusion or multiple gram doses to ensure sufficient drug exposure for biological activity in patients. We have identified two novel series of styrylsulfonyl-methylpyridines. Lead compounds 8, 9a, 18 and 19a are highly potent mitotic inhibitors and selectively cytotoxic to cancer cells. Impressively, these compounds possess excellent pharmaceutical properties and two lead drug candidates 9a and 18 demonstrated antitumor activities in animal models. PMID:24471873

Lu, Tiangong; Goh, Aik Wye; Yu, Mingfeng; Adams, Julian; Lam, Frankie; Teo, Theodosia; Li, Peng; Noll, Ben; Zhong, Longjin; Diab, Sarah; Chahrour, Osama; Hu, Anran; Abbas, Abdullahi Y; Liu, Xiangrui; Huang, Shiliang; Sumby, Christopher J; Milne, Robert; Midgley, Carol; Wang, Shudong

2014-03-27

262

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

DOEpatents

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.

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

2013-04-16

263

Nonsteroidal anti-inflammatory drugs and their analogues as inhibitors of aldo-keto reductase AKR1C3: new lead compounds for the development of anticancer agents.  

PubMed

Nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin, flufenamic acid, and related compounds have been recently identified as potent inhibitors of AKR1C3. We report that some other NSAIDs (diclofenac and naproxen) also inhibit AKR1C3, with the IC(50) values in the low micromolar range. In order to obtain more information about the structure-activity relationship and to identify new leads, a series of compounds designed on the basis of NSAIDs were synthesized and screened on AKR1C3. The most active compounds were 2-[(2,2-diphenylacetyl)amino]benzoic acid 4 (IC(50)=11microM) and 3-phenoxybenzoic acid 10 (IC(50)=0.68microM). These compounds represent promising starting points for the development of new anticancer agents. PMID:16183274

Gobec, Stanislav; Brozic, Petra; Rizner, Tea Lanisnik

2005-12-01

264

Potential therapeutic applications of multifunctional host-defense peptides from frog skin as anti-cancer, anti-viral, immunomodulatory, and anti-diabetic agents.  

PubMed

Frog skin constitutes a rich source of peptides with a wide range of biological properties. These include host-defense peptides with cytotoxic activities against bacteria, fungi, protozoa, viruses, and mammalian cells. Several hundred such peptides from diverse species have been described. Although attention has been focused mainly on antimicrobial activity, the therapeutic potential of frog skin peptides as anti-infective agents remains to be realized and no compound based upon their structures has yet been adopted in clinical practice. Consequently, alternative applications are being explored. Certain naturally occurring frog skin peptides, and analogs with improved therapeutic properties, show selective cytotoxicity against tumor cells and viruses and so have potential for development into anti-cancer and anti-viral agents. Some peptides display complex cytokine-mediated immunomodulatory properties. Effects on the production of both pro-inflammatory and anti-inflammatory cytokines by peritoneal macrophages and peripheral blood mononuclear cells have been observed so that clinical applications as anti-inflammatory, immunosuppressive, and immunostimulatory agents are possible. Several frog skin peptides, first identified on the basis of antimicrobial activity, have been shown to stimulate insulin release both in vitro and in vivo and so show potential as incretin-based therapies for treatment of patients with Type 2 diabetes mellitus. This review assesses the therapeutic possibilities of peptides from frogs belonging to the Ascaphidae, Alytidae, Pipidae, Dicroglossidae, Leptodactylidae, Hylidae, and Ranidae families that complement their potential role as anti-infectives for use against multidrug-resistant microorganisms. PMID:24793775

Conlon, J Michael; Mechkarska, Milena; Lukic, Miodrag L; Flatt, Peter R

2014-07-01

265

Schiff's base derivatives bearing nitroimidazole moiety: new class of antibacterial, anticancer agents and potential EGFR tyrosine kinase inhibitors.  

PubMed

New Schiff's base derivatives 5a-5h have been synthesized by reaction between 1-(4-bromophenyl)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanone 3 and various benzohydrazide 4a-4h in presence of nickel (II) nitrate as a catalyst in ethanol at room temperature in good yield (54-88%). All compounds were tested for antibacterial as well as anticancer and inhibition of EGFR. Of the compounds studied, compounds 5d, 5f and 5g in the case of antiproliferation and inhibition of EGFR as well as compounds 5b, 5c, 5e and 5h in the case of antibacterial activity were found to be most effective compounds in the series. Compound 5f shows effective inhibition (IC50=0.21±0.02 ?M) by binding in to the active pocket of EGFR receptor with minimum binding energy (?Gb=-49.4869 kcal/mol). PMID:24144854

Makawana, Jigar A; Sun, Juan; Zhu, Hai-Liang

2013-12-01

266

Design, synthesis and in vitro cytotoxicity evaluation of 5-(2-carboxyethenyl)isatin derivatives as anticancer agents.  

PubMed

Forty four di- or trisubstituted novel isatin derivatives were designed and synthesized in 5-6 steps in 25-45% overall yields. Their structures were confirmed by (1)H NMR and (13)C NMR as well as LC-MS. The anticancer activity of these new isatin derivatives against three human tumor cell lines, K562, HepG2 and HT-29, were evaluated by MTT assay in vitro. SAR studies suggested that the combination of 1-benzyl and 5-[trans-2-(methoxycarbonyl)ethen-1-yl] substitution greatly enhance their cytotoxic activity, whereas an intact carbonyl functionality on C-3 as present in the parent ring is required to such a potency. This study leads to the identification of two highly active molecules, compounds 2h (IC50=3 nM) and 2k (IC50=6 nM), against human leukemia K562 cells. PMID:24360564

Han, Kailin; Zhou, Yao; Liu, Fengxi; Guo, Qiannan; Wang, Pengfei; Yang, Yao; Song, Binbin; Liu, Wei; Yao, Qingwei; Teng, Yuou; Yu, Peng

2014-01-15

267

Analogue-based design, synthesis and biological evaluation of 3-substituted-(methylenehydrazono)indolin-2-ones as anticancer agents.  

PubMed

The docking studies on CDK2 and GSK-3? inspired us to synthesis a series of indoline-2,3-dione hydrazones 10a-l. Treatment of indoline-2,3-dione derivatives 7a-d with hydrazine gave 3-hydrazonoindolin-2-ones 8a-d which were reacted with the appropriate aldehydes 9a-c to yield 3-substituted-(methylenehydrazono)indolin-2-ones 10a-l. Compounds 10a-l showed a significant anticancer activity against human breast cell line MCF-7. Compounds 10c, f, i exhibited the highest activity almost the same of doxorubicin (IC50 = 6.10 ?M) with IC50 = 7.75, 6.75, 6.25 ?M, respectively. PMID:24686014

Dweedar, Haytham E; Mahrous, Hoda; Ibrahim, Hany S; Abdel-Aziz, Hatem A

2014-05-01

268

Azide derivatized anticancer agents of Vitamin K 3: X-ray structural, DSC, resonance spectral and API studies  

NASA Astrophysics Data System (ADS)

Compound 1 [1-imino (acetyl hydrazino)-Vitamin K 3], displays valence tautomerically related electronic isomers as Form I and Form II. Form I exhibits 2D packing fragment with 1D ribbon chains of N-H⋯O hydrogen bonds and shows EPR silent features. While Form II is EPR active and exhibits biradical nature with double quantum transitions at g = 2.0040. 1H NMR of compound 2, [1-imino (hydrazino carboxylate)-Vitamin K 3] and Form II exhibit ? delocalization via resonance assisted H-bonding [RAHB] effect compared to Form I. Molecular interactions in Form I and II are visualized by DSC. The electronic structures of compounds 1 and 2 have been correlated to their API values by measuring anticancer activities, mitochondrial potentials and DNA shearing patterns. Form II and compound 2 indicate mitochondria mediated apoptosis (˜75% cell death) while Form I causes 35% cell death.

Badave, Kirti; Patil, Yogesh; Gonnade, Rajesh; Srinivas, Darbha; Dasgupta, Rajan; Khan, Ayesha; Rane, Sandhya

2011-12-01

269

Anticancer agents for treatment of tumors in the central nervous system by correspondent substituent substitution and elucidation by pattern recognition methods.  

PubMed

Within the United States, primary brain tumors account for 20 to 25 percent of all pediatric cancers. Chemotherapy utilizing a nitrosourea, notably semustine (MeCCNU) and carmustine (BCNU), has shown significant success in the treatment of tumors found in the central nervous system. In silico optimization of molecular properties by substituent substitution that is followed by pattern recognition analysis is utilized in this study to develop 14 novel anti-cancer drugs for the treatment of malignant cancers of the central nervous system. These 14 agents exhibit molecular properties that are suitable for penetration through the blood-brain barrier (BBB). All 14 agents are nitrosoureas having values of Log P ranging from 2.188 to 2.942, and having a constant total of 5 oxygens and nitrogens with zero violations of the Rule of 5 which indicates favorable bioavailability. Value of Log BB (Log [Cbrain/Cblood]) for these agents does not vary from - 0.441 (BB value of 0.362). The formula weight of the agents is highly correlated to molecular volume (r= 0.9848) and total number of atoms (r= 0.9948), but not correlated to number of rotatable bonds (r= 0.1814). Analysis of similarity (ANOSIM) indicated that all 14 new constructs are similar to the parent compound semustine. The Log P value for all 14 agents predicts favorable attributes for penetrating the BBB. Multiple regression analysis established that number of atoms, number of rotatable bonds, and molecular volume are strong prognosticators for molecular weight of this assemblage of pharmaceuticals. This study attests to the efficacy of in silico optimization of molecular substituents followed by pattern recognition analysis to develop new drug designs based on a successful nitrosourea framework for the treatment of malignant tumors of the brain. PMID:22385186

Bartzatt, Ronald

2012-03-01

270

Synthesis, spectroscopic, and biological studies of novel estolides derived from anticancer active 4- O -podophyllotoxinyl 12-hydroxyl-octadec- Z -9-enoate  

Microsoft Academic Search

Podophyllotoxin is a well-known natural antitumor agent with severe side effects, which led us to synthesize its numerous\\u000a analogs in search of product(s) of improved therapeutic potential. Here, we report an efficient method for the synthesis of\\u000a a series of 4-O-podophyllotoxin estolides with spectral characteristics and their biological studies. The OH of a known molecule, 4-O-podophyllotoxinyl 12-hydroxyl-octadec-Z-9-enoate 2, was coupled

Jamal Mustafa; Shabana I. Khan; Guoyi Ma; Larry A. Walker; Ikhlas A. Khan

2004-01-01

271

Novel biotransformation process of podophyllotoxin to produce podophyllic acid and picropodophyllotoxin by Pseudomonas aeruginosa CCTCC AB93066. Part I: process development.  

PubMed

A novel biotransformation process of podophyllotoxin (1) to produce picropodophyllotoxin (2) and podophyllic acid (3) was developed in this work. Eight bacteria which could modify the structure of podophyllotoxin were screened out from the tested fourteen bacteria. The highest conversion of podophyllotoxin (i.e., 70.2 +/- 8.0%) was obtained when Pseudomonas aeruginosa CCTCC AB93066 was used as biocatalyst, so P. aeruginosa was selected as a typical biocatalyst in the following study. Product (2) and (3) were separated through D312 macroporous resin and sephadex LH-20 gel column chromatograph. On the basis of (1)H NMR, (13)C NMR, ESI-MS and Elemental Analysis, product (2) and (3) were identified as picropodophyllotoxin (2) and podophyllic acid (3), respectively. This suggested the site-specific isomerization and hydrolization of podophyllotoxin occurred during its biotransformation process by P. aeruginosa. For the first time, podophyllotoxin was biotransformed into its hydrolytic derivate (i.e., podophyllic acid). PMID:19115065

Tang, Ya-Jie; Li, Yan; Zhong, Jian-Jiang

2009-08-01

272

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

PubMed Central

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.

Newman, David J.; Cragg, Gordon M.

2014-01-01

273

Discovery and development of anticancer agents from marine sponges: perspectives based on a chemistry-experimental therapeutics collaborative program.  

PubMed

A collaborative program was initiated in 1990 between the natural product chemistry laboratory of Dr. Phillip Crews at the University of California Santa Cruz and the experimental therapeutics laboratory of Dr. Fred Valeriote at the Henry Ford Hospital in Detroit. The program focused on the discovery and development of anticancer drugs from sponge extracts. A novel in vitro disk diffusion, solid tumor selective assay was used to examine 2,036 extracts from 683 individual sponges. The bioassay-directed fractionation discovery component led to the identification of active pure compounds from many of these sponges. In most cases, pure compound was prepared in sufficient quantities to both chemically identify the active compound(s) as well as pursue one or more of the biological development components. The latter included IC50, clonogenic survival-concentration exposure, maximum tolerated dose, pharmacokinetics and therapeutic assessment studies. Solid tumor selective compounds included fascaplysin and 10-bromofascaplysin (Fascaplysinopsis), neoamphimedine, 5-methoxyneoamphimedine and alpkinidine (Xestospongia), makaluvamine C and makaluvamine H (Zyzzya), psymberin (Psammocinia and Ircinia), and ethylplakortide Z and ethyldidehydroplakortide Z (Plakortis). These compounds or analogs thereof continue to have therapeutic potential. PMID:23350352

Valeriote, Frederick A; Tenney, Karen; Media, Joseph; Pietraszkiewicz, Halina; Edelstein, Matthew; Johnson, Tyler A; Amagata, Taro; Crews, Phillip

2012-01-01

274

Benzene-poly-carboxylic acid complex, a novel anti-cancer agent induces apoptosis in human breast cancer cells.  

PubMed

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

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

2014-01-01

275

Structure-Based Design and Synthesis of Potent, Ethylenediamine-Based, Mammalian Farnesyltransferase Inhibitors as Anticancer Agents  

PubMed Central

A potent class of anticancer, human farnesyltransferase (hFTase) inhibitors has been identified by “piggy-backing” on potent, antimalarial inhibitors of Plasmodium falciparum farnesyltransferase (PfFTase). On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating the extensive structure–activity relationship (SAR) study reported herein. Our most potent inhibitor is compound 1f, which exhibited an in vitro hFTase IC50 value of 25 nM and a whole cell H-Ras processing IC50 value of 90 nM. Moreover, it is noteworthy that several of our inhibitors proved highly selective for hFTase (up to 333-fold) over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-I). A crystal structure of inhibitor 1a co-crystallized with farnesyl pyrophosphate (FPP) in the active site of rat FTase illustrates that the para-benzonitrile moiety of 1a is stabilized by a ?–? stacking interaction with the Y361? residue, suggesting a structural explanation for the observed importance of this component of our inhibitors.

Fletcher, Steven; Keaney, Erin Pusateri; Cummings, Christopher G.; Blaskovich, Michelle A.; Hast, Michael A.; Glenn, Matthew P.; Chang, Sung-Youn; Bucher, Cynthia J.; Floyd, Ryan J.; Katt, William P.; Gelb, Michael H.; Van Voorhis, Wesley C.; Beese, Lorena S.; Sebti, Said M.; Hamilton, Andrew D.

2011-01-01

276

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

PubMed Central

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.

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

2014-01-01

277

Atypical fluoroquinolone gold(III) chelates as potential anticancer agents: relevance of DNA and protein interactions for their mechanism of action.  

PubMed

Quinolones are known for their antimicrobial and antitumor activities. Gold(III) compounds constitute an emerging class of biologically active substances, of special interest as potential anticancer agents. In this work three gold(III) complexes of the fluoroquinolones antimicrobial agents norfloxacin (NOR), levofloxacin (LEVO) and sparfloxacin (SPAR) were prepared and characterized with physicochemical and spectroscopic techniques. In these complexes, NOR, LEVO and SPAR act as bidentate neutral ligands bound to gold(III) through the nitrogen atoms of the piperazine ring, which is an unusual mode of coordination for this class of compounds. Two chloride ions occupy the remaining coordination sites. The cytotoxic activity of the fluoroquinolones and their gold(III) complexes was tested against the A20 (murine lymphoma), B16-F10 (murine melanoma) and K562 (human myeloid leukemia) tumor cell lines as well as the L919 (murine lung fibroblasts) and MCR-5 (human lung fibroblasts) normal cells lines. All complexes were more active than their corresponding free ligands. Complex [AuCl(2)(LEVO)]Cl was selected for DNA fragmentation and cell cycle analysis. Spectroscopic titration with calf-thymus DNA (CT DNA) showed that the complexes can bind weakly to CT DNA, probably by an external contact (electrostatic or groove binding). The complexes exhibit good binding propensity to bovine serum albumin (BSA) having relatively high binding constant values. PMID:22835721

Gouvea, Ligiane R; Garcia, Luciene S; Lachter, Daniela R; Nunes, Paula Roberta; de Castro Pereira, Flávia; Silveira-Lacerda, Elisângela P; Louro, Sônia R W; Barbeira, Paulo Jorge S; Teixeira, Letícia R

2012-09-01

278

NK1 receptor antagonists and dexamethasone as anticancer agents in vitro and in a model of brain tumours secondary to breast cancer.  

PubMed

Emend, an NK1 antagonist, and dexamethasone are used to treat complications associated with metastatic brain tumours and their treatment. It has been suggested that these agents exert anticancer effects apart from their current use. The effects of the NK1 antagonists, Emend and N-acetyl-L-tryptophan, and dexamethasone on tumour growth were investigated in vitro and in vivo at clinically relevant doses. For animal experiments, a stereotaxic injection model of Walker 256 rat breast carcinoma cells into the striatum of Wistar rats was used. Emend treatment led to a decrease in tumour cell viability in vitro, although this effect was not replicated by N-acetyl-L-tryptophan. Dexamethasone did not decrease tumour cell viability in vitro but decreased tumour volume in vivo, likely to be through a reduction in tumour oedema, as indicated by the increase in tumour cell density. None of the agents investigated altered tumour cell replication or apoptosis in vivo. Inoculated animals showed increased glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 immunoreactivity indicative of astrocytes and microglia in the peritumoral area, whereas treatment with Emend and dexamethasone reduced the labelling for both glial cells. These results do not support the hypothesis that NK1 antagonists or dexamethasone exert a cytotoxic action on tumour cells, although these conclusions may be specific to this model and cell line. PMID:23407059

Lewis, Kate M; Harford-Wright, Elizabeth; Vink, Robert; Ghabriel, Mounir N

2013-04-01

279

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

PubMed Central

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.

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; Mollmann, Ute

2014-01-01

280

Investigation on pharmacokinetics, tissue distribution and excretion of a novel platinum anticancer agent in rats by Inductively Coupled Plasma Mass Spectrometry (ICP-MS).  

PubMed

Abstract 1.?DN604 is a new platinum agent with encouraging anticancer activity. The present study was to explore the pharmacokinetic profiles, distribution and excretion of platinum in Sprague-Dawley rats after intravenous administration of DN604. A sensitive and selective inductively coupled plasma mass spectrometry (ICP-MS) method was established for determination of platinum in biological specimens. The pharmacokinetic parameters were calculated by a non-compartmental method. 2.?The area under concentration-time curve AUC0-t and AUC0-? for platinum originating from DN604 at 10?mg/kg were 25.15?±?1.29 and 28.72?±?1.04??g/hml, respectively. The mean residence time MRT was 36.59?±?6.65?h. The volume of distribution Vz was 11.42?±?2.49?l/kg and clearance CL was 0.18?±?0.01?l/h/kg. In addition, the elimination half-life T1/2z was 44.83?±?9.75?h. After intravenous administration of DN604, platinum was extensively distributed in most of tested tissues except brain. The majority of platinum excreted via urine, and its accumulative excretion ratio during the period of 120?h was 63.5%?±?7.7% for urine, but only 6.94%?±?0.11% for feces. 3.?The satisfactory half-life, wide distribution and high excretion made this novel platinum agent worthy of further research and development. PMID:24524624

Zhao, Jie; Wen, Yanli; Zhang, Wei; Zhao, Di; Fan, Ali; Zhang, Yongjie; Deng, Shuhua; Wang, Xin; Liu, Qingwang; Lu, Yang; Wang, Zhimei; Gou, Shaohua; Chen, Xijing

2014-08-01

281

Destabilization of the MutS?'s protein-protein interface due to binding to the DNA adduct induced by anticancer agent carboplatin via molecular dynamics simulations.  

PubMed

DNA mismatch repair (MMR) proteins maintain genetic integrity in all organisms by recognizing and repairing DNA errors. Such alteration of hereditary information can lead to various diseases, including cancer. Besides their role in DNA repair, MMR proteins detect and initiate cellular responses to certain type of DNA damage. Its response to the damaged DNA has made the human MMR pathway a useful target for anticancer agents such as carboplatin. This study indicates that strong, specific interactions at the interface of MutS? in response to the mismatched DNA recognition are replaced by weak, non-specific interactions in response to the damaged DNA recognition. Data suggest a severe impairment of the dimerization of MutS? in response to the damaged DNA recognition. While the core of MutS? is preserved in response to the damaged DNA recognition, the loss of contact surface and the rearrangement of contacts at the protein interface suggest a different packing in response to the damaged DNA recognition. Coupled in response to the mismatched DNA recognition, interaction energies, hydrogen bonds, salt bridges, and solvent accessible surface areas at the interface of MutS? and within the subunits are uncoupled or asynchronously coupled in response to the damaged DNA recognition. These pieces of evidence suggest that the loss of a synchronous mode of response in the MutS?'s surveillance for DNA errors would possibly be one of the mechanism(s) of signaling the MMR-dependent programed cell death much wanted in anticancer therapies. The analysis was drawn from dynamics simulations. PMID:24061854

Negureanu, Lacramioara; Salsbury, Freddie R

2013-11-01

282

The natural anticancer agent plumbagin induces potent cytotoxicity in MCF-7 human breast cancer cells by inhibiting a PI-5 kinase for ROS generation.  

PubMed

Drug-induced haploinsufficiency (DIH) in yeast has been considered a valuable tool for drug target identification. A plant metabolite, plumbagin, has potent anticancer activity via reactive oxygen species (ROS) generation. However, the detailed molecular targets of plumbagin for ROS generation are not understood. Here, using DIH and heterozygous deletion mutants of the fission yeast Schizosaccharomyces pombe, we identified 1, 4-phopshatidylinositol 5-kinase (PI5K) its3 as a new molecular target of plumbagin for ROS generation. Plumbagin showed potent anti-proliferative activity (GI(50); 10 µM) and induced cell elongation and septum formation in wild-type S. pombe. Furthermore, plumbagin dramatically increased the intracellular ROS level, and pretreatment with the ROS scavenger, N-acetyl cysteine (NAC), protected against growth inhibition by plumbagin, suggesting that ROS play a crucial role in the anti-proliferative activity in S. pombe. Interestingly, significant DIH was observed in an its3-deleted heterozygous mutant, in which ROS generation by plumbagin was higher than that in wild-type cells, implying that its3 contributes to ROS generation by plumbagin in this yeast. In MCF7 human breast cancer cells, plumbagin significantly decreased the level of a human ortholog, 1, 4-phopshatidylinositol 5-kinase (PI5K)-1B, of yeast its3, and knockdown of PI5K-1B using siPI5K-1B increased the ROS level and decreased cell viability. Taken together, these results clearly show that PI5K-1B plays a crucial role in ROS generation as a new molecular target of plumbagin. Moreover, drug target screening using DIH in S. pombe deletion mutants is a valuable tool for identifying molecular targets of anticancer agents. PMID:23028742

Lee, Ju-Hee; Yeon, Ji-Hyun; Kim, Hanna; Roh, Whijae; Chae, Jeiwook; Park, Han-Oh; Kim, Dong-Myung

2012-01-01

283

Oncogenic H-Ras Up-Regulates Expression of ERCC1 to Protect Cells from Platinum-Based Anticancer Agents  

Microsoft Academic Search

Tumors frequently contain mutations in the ras genes, resulting in the constitutive activation of the Ras-activated signaling pathway. The acti- vation of Ras is involved not only in tumor progression but also in the development of resistance of the tumor cells to platinum-based chemo- therapeutic agents. To investigate the potential mechanisms underlying this resistance, we analyzed the effect of activated

Cha-Kyung Youn; Mi-Hwa Kim; Hyun-Ju Cho; Hong-Beum Kim; In-Youb Chang; Myung-Hee Chung; Ho Jin You

2004-01-01

284

An Ideal Selective Anti-Cancer Agent In Vitro: I - Tissue Culture Study of Human Lung Cancer Cells A549  

Microsoft Academic Search

Management of cancer is one of the challenging problems in medical practice as there are no available medical modalities that can se- lectively kill cancer cells without adverse effect on normal living cells or the functions of vital organs. Tissue culture of human lung cancer cells (A549) was used in studying the effect of agent, PM 701, to test its

FATEN A. KHORSHID; SABAH S. MUSHREF; NAGWA T. HEFFNY

2005-01-01

285

Thermal chemistry of podophyllotoxin in ethanol and a comparison of the cytostatic activity of the thermolysis products.  

PubMed

Podophyllotoxin (1) in buffered ethanolic solution is degraded by two pathways. One leads to (a) picropodophyllin (2), which undergoes dehydration to give alpha-apopicropodophyllin (5), which rearranges to give beta-apopicropodophyllin (6), (b) the ethyl ether of picropodophyllotoxin, 8, and (c) the ethyl ether of epipicropodophyllotoxin, 7. The other pathway leads directly to epipodophyllotoxin (10) and the corresponding ethyl ether, 9, and possibly, via a transient 3,4-dehydropodophyllotoxin (5'), to beta-apopicropodophyllin (6). The 1H NMR spectra of these compounds are described, their in vitro cytostatic activity compared, and their syntheses, including that of podophyllotoxin ethyl ether, reported. PMID:3820102

Buchardt, O; Jensen, R B; Hansen, H F; Nielsen, P E; Andersen, D; Chinoin, I

1986-11-01

286

Synthesis and evaluation of the cytotoxicity of a series of 1,3,4-thiadiazole based compounds as anticancer agents.  

PubMed

Objective(s): Nowadays, cancer is an important public health problem in all countries. Limitations of current chemotherapy for neoplastic diseases such as severe adverse reactions and tumor resistance to the chemotherapeutic drugs have been led to a temptation for focusing on the discovery and development of new compounds with potential anticancer activity. Materials and Methods: A new series of 1,3,4-thiadiazole-derived compounds (3a-3l) were synthesized. N-(5-Mercapto-1,3,4-thiadiazol-2-yl)-2-(4-methoxyphenyl) acetamide (2) was prepared through direct amidation of 4-methoxyphenylacetic acid (2) with 5-amino-1,3,4-thiadiazole-2-thiol using EDC (N-Ethyl-N-dimethylaminopropyl carbodiimide) and HOBt (Hydroxybenzotriazole). Then, various derivatives of benzyl chloride containing electron withdrawing and electron donating moieties were reacted with compound 2 to prepare compounds 3a-3l. In vitro cytotoxicity assessment using MTT method was applied and results are presented as IC50. Results: All the synthesized compounds were characterized by (1)H-NMR and IR spectroscopy. Some of the synthesized compounds were also characterized using MS spectroscopy. Related melting points were also recorded. According to the obtained data from MTT assay, all compounds (3a-3l) demonstrated a higher cytotoxic activity against MDA-MB-231 breast cancer cell line in comparison with other cell lines. Conclusion: It is notable that four synthesized compounds 3h (IC50= 11 ± 0.18 µM), 3j (IC50= 10 ± 0.39 µM), 3k (IC50= 11 ± 0.77 µM) and 3l (IC50= 8 ± 0.69 µM) exhibited higher cytotoxic activity against MDA-MB-231 cell line compared to imatinib (IC50= 20 ± 0.69 µM) as the reference drug. PMID:24494064

Aliabadi, Alireza; Eghbalian, Elham; Kiani, Amir

2013-11-01

287

Synthesis and Evaluation of the Cytotoxicity of a Series of 1,3,4-Thiadiazole Based Compounds as Anticancer Agents  

PubMed Central

Objective(s): Nowadays, cancer is an important public health problem in all countries. Limitations of current chemotherapy for neoplastic diseases such as severe adverse reactions and tumor resistance to the chemotherapeutic drugs have been led to a temptation for focusing on the discovery and development of new compounds with potential anticancer activity. Materials and Methods: A new series of 1,3,4-thiadiazole-derived compounds (3a-3l) were synthesized. N-(5-Mercapto-1,3,4-thiadiazol-2-yl)-2-(4-methoxyphenyl) acetamide (2) was prepared through direct amidation of 4-methoxyphenylacetic acid (2) with 5-amino-1,3,4-thiadiazole-2-thiol using EDC (N-Ethyl-N-dimethylaminopropyl carbodiimide) and HOBt (Hydroxybenzotriazole). Then, various derivatives of benzyl chloride containing electron withdrawing and electron donating moieties were reacted with compound 2 to prepare compounds 3a-3l. In vitro cytotoxicity assessment using MTT method was applied and results are presented as IC50. Results: All the synthesized compounds were characterized by 1H-NMR and IR spectroscopy. Some of the synthesized compounds were also characterized using MS spectroscopy. Related melting points were also recorded. According to the obtained data from MTT assay, all compounds (3a-3l) demonstrated a higher cytotoxic activity against MDA-MB-231 breast cancer cell line in comparison with other cell lines. Conclusion: It is notable that four synthesized compounds 3h (IC50= 11 ± 0.18 µM), 3j (IC50= 10 ± 0.39 µM), 3k (IC50= 11 ± 0.77 µM) and 3l (IC50= 8 ± 0.69 µM) exhibited higher cytotoxic activity against MDA-MB-231 cell line compared to imatinib (IC50= 20 ± 0.69 µM) as the reference drug.

Aliabadi, Alireza; Eghbalian, Elham; Kiani, Amir

2013-01-01

288

The antioxidant transcription factor Nrf2 negatively regulates autophagy and growth arrest induced by the anticancer redox agent mitoquinone.  

PubMed

Mitoquinone (MitoQ) is a synthetically modified, redox-active ubiquinone compound that accumulates predominantly in mitochondria. We found that MitoQ is 30-fold more cytotoxic to breast cancer cells than to healthy mammary cells. MitoQ treatment led to irreversible inhibition of clonogenic growth of breast cancer cells through a combination of autophagy and apoptotic cell death mechanisms. Relatively limited cytotoxicity was seen with the parent ubiquinone coenzyme Q(10.) Inhibition of cancer cell growth by MitoQ was associated with G(1)/S cell cycle arrest and phosphorylation of the checkpoint kinases Chk1 and Chk2. The possible role of oxidative stress in MitoQ activity was investigated by measuring the products of hydroethidine oxidation. Increases in ethidium and dihydroethidium levels, markers of one-electron oxidation of hydroethidine, were observed at cytotoxic concentrations of MitoQ. Keap1, an oxidative stress sensor protein that regulates the antioxidant transcription factor Nrf2, underwent oxidation, degradation, and dissociation from Nrf2 in MitoQ-treated cells. Nrf2 protein levels, nuclear localization, and transcriptional activity also increased following MitoQ treatment. Knockdown of Nrf2 caused a 2-fold increase in autophagy and an increase in G(1) cell cycle arrest in response to MitoQ but had no apparent effect on apoptosis. The Nrf2-regulated enzyme NQO1 is partly responsible for controlling the level of autophagy. Keap1 and Nrf2 act as redox sensors for oxidative perturbations that lead to autophagy. MitoQ and similar compounds should be further evaluated for novel anticancer activity. PMID:20805228

Rao, V Ashutosh; Klein, Sarah R; Bonar, Spencer J; Zielonka, Jacek; Mizuno, Naoko; Dickey, Jennifer S; Keller, Paul W; Joseph, Joy; Kalyanaraman, Balaraman; Shacter, Emily

2010-11-01

289

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

PubMed

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

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

2012-11-01

290

Structural characterization of in vitro metabolites of the new anticancer agent EAPB0503 by liquid chromatography-tandem mass spectrometry.  

PubMed

EAPB0503, belonging to the imidazo[1,2-a]quinoxaline series, is an anticancer drug with antitumoral activity against a variety of tumors. Previous studies have shown that this drug undergoes demethylation and oxygenation reactions. In this paper, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) was employed to assess the structures of unknown oxygenated metabolites of EAPB0503. EAPB0503 and its identified demethylated metabolites, EAPB0502 and EAPB0603, were incubated with human, rat, dog and mouse liver microsomes, as well as human, rat and dog hepatocytes. After separation on a C8 analytical column with a gradient elution of acetonitrile-formate buffer, positive ESI-MS/MS experiments were performed. To facilitate metabolite identification, the detailed fragmentation pathways of the parent compounds were first studied using high-resolution MS/MS. Additional hydrogen/deuterium exchange LC-MS/MS experiments were used to support the identification and structural characterization of metabolites. Four hydroxylated metabolites were identified: M'4 and its demethylated derivative M'1 (OH in ortho position on the phenyl substituent in position 1), and M'6 and its demethylated derivative M'3 (OH on the imidazole ring at the C2 position). Three phase II metabolites (Met A, EAPB0602 glucuronide; Met B, M'4 glucuronide; Met C, EAPB0603 glucuronide) were also evidenced. Elucidation of the metabolite structures was performed by comparing the chromatographic behaviors (changes in retention times), by measuring the molecular masses (mass increment), by studying the MS(2) spectral patterns of metabolites with those of parent drugs and for M'1 and M'4 by co-analysis with synthetic standards. The results of the present study provided important structural information relating to the metabolism of EAPB0503. PMID:24176748

Lafaille, Florian; Solassol, Isabelle; Enjalbal, Christine; Bertrand, Benjamin; Doulain, Pierre-Emmanuel; Vappiani, Johanna; Bonnet, Pierre-Antoine; Deleuze-Masquéfa, Carine; Bressolle, Françoise M M

2014-01-01

291

2-[N-Alkyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines as anticancer agents inhibitors of folate enzymes.  

PubMed

Based on our previous results on the ascertained potent growth inhibition effect against a panel of 60 human tumors cell lines at National Cancer Institute of Bethesda (NCI), we have synthesized a novel series of thirty-one 2-[N-methyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines (1-31). The lead compound 1 was previously reported to be endowed with significant inhibition against hDHFR enzyme, with a Ki of 0.2 ?M. Docking studies were performed on compound 1 and here reported to predict its binding conformation to human dihydrofolate reductase (hDHFR). All compounds (1-31) were assayed versus hDHFR and human thymidylate synthase (hTS). From the screening emerged that all compounds inhibited hDHFR with Ki values included between 0.2 and 11 ?M, while only a few (6, 21, 24, 27, 29) showed great activity and selectivity towards hTS. Evaluation of the anticancer activity was performed by NCI, first against the three cell line panel, and only the most active compounds (17, 21, 24, 26, 27) were evaluated on a panel of 60 human tumor cell lines. Compound 21 was the most active against all cell lines with log GI50 equal to -5.49 and log LC50 equal to -4.19 and maintained significant percent of growth inhibition on seven cancer cell lines at the concentration of 1 ?M. Compound 17 was the second most active and moreover showed interesting selectivity against some cell lines (Lung cancer: A549/ATCC, Melanoma: UACC-257, Ovarian Cancer: ovcar-8 and Renal cancer: RXF 393) at all concentration examined (100-0.01 ?M). PMID:24531230

Piras, Sandra; Carta, Antonio; Briguglio, Irene; Corona, Paola; Paglietti, Giuseppe; Luciani, Rosaria; Costi, Maria Paola; Ferrari, Stefania

2014-03-21

292

Differential effects on gastrointestinal and hepatic vagal afferent fibers in the rat by the anti-cancer agent cisplatin  

Microsoft Academic Search

Cisplatin, a cancer chemotherapy agent, like many toxins, produces emesis and nausea. Abdominal vagotomy, or treatment with 5-HT3 receptor antagonists, blocks cisplatin-induced emesis, which suggests that it produces (albeit indirectly) activation of 5-HT3 receptors on vagal afferent fibers. Cisplatin induces a large release of intestinal 5-hydroxytryptamine (5-HT) that enters the hepatic portal vein, which may activate vagal afferent fibers in

Charles C. Horn; Eric J. Richardson; Paul L. R. Andrews; Mark I. Friedman

2004-01-01

293

The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1  

Microsoft Academic Search

Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukaemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from resveratrol by having an additional aromatic hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumours and catalyses aromatic hydroxylation reactions. We report here

G A Potter; L H Patterson; E Wanogho; P J Perry; P C Butler; T Ijaz; K C Ruparelia; J H Lamb; P B Farmer; L A Stanley; M D Burke

2002-01-01

294

Improved clearance of radioiodinated hypericin as a targeted anticancer agent by using a duodenal drainage catheter in rats.  

PubMed

We sought to reduce the radioactive intestinal waste after intravenous injection of necrosis avid iodine-131-labeled hypericin in dual-targeting anticancer radiotherapy and to study its pharmacokinetics in rats using a newly designed catheter. Iodine-123-labeled hypericin was prepared with iodogen as oxidant and characterized by high-performance liquid chromatography and mass spectrometry. After iodine-123-labeled hypericin administration, duodenal juice was collected via a catheter from groups of rats (n?=?5) at intervals of 0-4, 4-8 or 20-24?h. The content was assessed by gamma-counting. The biodistribution and pharmacokinetics of iodine-123-labeled hypericin were investigated in rats without (n?=?5) and with continuous catheterization (n?=?5) for 9?h. After labeling, a high radiochemical yield was obtained with iodine-123-labeled hypericin (>95%), as confirmed by high-performance liquid chromatography and mass spectrometry. In the duodenal aspirate from animals with intermittent catheterization during 24?h, radioactivity accounted for 46% of the total with two peaks at 3?h and 8?h, suggesting enterohepatic circulation. Rats with 9?h of catheterization exhibited one peak representing 20% of the radioactivity. Major metabolites appeared to be conjugated iodine-123-labeled hypericin forms. In rats without and with catheter, iodine-123-labeled hypericin showed exponential elimination from plasma with no significant dehalogenation. Delayed iodine-123-labeled hypericin excretion, a higher maximum concentration (Cmax), larger area under concentration-time curve [AUC(0-?)] and a longer mean residence time were observed in non-catheterized animals (P?

Cona, Marlein Miranda; Feng, Yuanbo; Verbruggen, Alfons; Oyen, Raymond; Ni, Yicheng

2013-12-01

295

CoMFA and CoMSIA studies of 1,2-dihydropyridine derivatives as anticancer agents.  

PubMed

Taking advantage of our in-house experimental data on 3-cyano-2-imino-1, 2-dihydropyridine and 3-cyano-2- oxo-1,2-dihydropyridine derivatives as inhibitors of the growth of the human HT-29 colon adenocarcinoma tumor cell line, we have established a highly significant CoMFA and CoMSIA models (q2cv=0.70/0.639). The models were investigated to assure their stability and predictivity (r2pred=0.65/0.61) and successfully applied to design two new potential cell growth inhibitory agents with IC50s in the submicromolar range. PMID:22530888

Salama, Ismail; Abdel-Fattah, Mohamed A O; Hany, Marwa S; El-Sharif, Shaimaa A; El-Naggar, Mahmoud A M; Rashied, Rasha M H; Piazza, Gary A; Abadi, Ashraf H

2012-05-01

296

Two Case Reports of Resensitization to Previous Chemotherapy with the Novel Hypoxia-Activated Hypomethylating Anticancer Agent RRx-001 in Metastatic Colorectal Cancer Patients.  

PubMed

The development of chemoresistance is a persistent problem during the treatment of cancer. Although reversion or modification of acquired chemoresistance has been previously observed, no systematic exploration has been undertaken. Here, we report a case study of 2 male patients, 62 and 66 years old, both with histologically proven, radiologically progressing, extensively pretreated, metastatic and refractory (?2 conventional regimens and drug therapy) colorectal adenocarcinoma that was previously treated with FOLFIRI. The patients were resensitized to FOLFIRI after exposure to RRx-001 in the context of a phase-1 study. RRx-001 is a novel, hypomethylating and free-radical-inducing anticancer agent that activates nitrite reduction to NO under hypoxia and has an impact on epigenetic pathways. The repression of DNA methyltransferase 1 by RRx-001 may lead to demethylation and reexpression of silenced tumor suppressor genes, leading to resensitization. These examples provide insight into a nascent strategy to improve the prognosis in heavily pretreated cancer patients and suggest routes for further exploration. PMID:24575021

Reid, T; Dad, S; Korn, R; Oronsky, B; Knox, S; Scicinski, J

2014-01-01

297

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

PubMed

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

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

2010-04-01

298

EpoK, a cytochrome P450 involved in biosynthesis of the anticancer agents epothilones A and B. Substrate-mediated rescue of a P450 enzyme.  

PubMed

The epothilones are a new class of highly promising anticancer agents with a mode of action akin to that of paclitaxel but with distinct advantages over that drug. The principal natural compounds are epothilones A and B, which have an epoxide in the macrocyclic lactone ring, and C and D, which have a double bond instead of the epoxide group. The epoxidation of epothilones C and D to A and B, respectively, is mediated by EpoK, a cytochrome P450 enzyme encoded in the epothilone gene cluster. Here we report high-yield expression of EpoK, characterization of the protein, demonstration that the natural substrate can prevent-and even reverse-denaturation of the protein, identification of ligands and surrogate substrates, development of a high-throughput fluorescence activity assay based on the H(2)O(2)-dependent oxidation of 7-ethoxy-4-trifluoromethylcoumarin, and identification of effective inhibitors of the enzyme. These results will facilitate improvements in the yields of epothilones C and D and the engineering of EpoK to prepare novel epothilone analogues. Furthermore, the finding that the denatured enzyme is rescued by the substrate offers a potential paradigm for control of the P450 catalytic function. PMID:15544342

Ogura, Hiroshi; Nishida, Clinton R; Hoch, Ute R; Perera, Roshan; Dawson, John H; Ortiz de Montellano, Paul R

2004-11-23

299

ICAM-3 endows anticancer drug resistance against microtubule-damaging agents via activation of the ICAM-3-AKT/ERK-CREB-2 pathway and blockage of apoptosis.  

PubMed

In a previous study, we showed that induction of ICAM-3 endows radioresistance in cervical cancer [1]. To ascertain whether ICAM-3 also promotes anticancer drug resistance, mock control (H1299/pcDNA3) or ICAM-3-expressing stable transfectants (H1299/ICAM-3) of the non-small cell lung cancer (NSCLC) cell line, NCI-H1299, were generated and treated with the microtubule-damaging agents, paclitaxel (TXL) and vincristine (VCS). TXL-/VCS-treated H1299/ICAM-3 cells showed significantly lower levels of apoptosis, activation of caspases-3, 8 or 9, and decrease in anti-apoptotic protein levels, compared to H1299/pcDNA3 cells. Our data clearly indicate that ICAM-3 promotes drug resistance via inhibition of apoptosis. We additionally showed that Akt, ERK, and CREB-2 are located downstream of ICAM-3, and activation of the ICAM-3-Akt/ERK-CREB-2 pathway induces resistance against TXL and VCS. ICAM-3-expressing stable NCI-H460/ICAM-3 transfectant cells and radioresistant SiHa cells endogenously overexpressing ICAM-3 additionally showed drug resistance against TXL and VCS via activation of the ICAM-3-Akt/ERK-CREB-2 pathway. The finding that ICAM-3 endows drug resistance as well as radioresistance supports its potential utility as a major therapeutic target against cancer. PMID:24177012

Ahn, Kwang-Chul; Choi, Jae Yeon; Kim, Jae-Sung; Hwang, Sang-Gu; Kim, Wun-Jae; Park, Jong Kuk; Um, Hong-Duck

2013-11-15

300

Comparative chemogenomics to examine the mechanism of action of dna-targeted platinum-acridine anticancer agents.  

PubMed

Platinum-based drugs have been used to successfully treat diverse cancers for several decades. Cisplatin, the original compound of this class, cross-links DNA, resulting in cell cycle arrest and cell death via apoptosis. Cisplatin is effective against several tumor types, yet it exhibits toxic side effects and tumors often develop resistance. To mitigate these liabilities while maintaining potency, we generated a library of non-classical platinum-acridine hybrid agents and assessed their mechanisms of action using a validated genome-wide screening approach in Saccharomyces cerevisiae and in the distantly related yeast Schizosaccharomyces pombe. Chemogenomic profiles from both S. cerevisiae and S. pombe demonstrate that several of the platinum-acridines damage DNA differently than cisplatin based on their requirement for distinct modules of DNA repair. PMID:22928710

Cheung-Ong, Kahlin; Song, Kyung Tae; Ma, Zhidong; Shabtai, Daniel; Lee, Anna Y; Gallo, David; Heisler, Lawrence E; Brown, Grant W; Bierbach, Ulrich; Giaever, Guri; Nislow, Corey

2012-11-16

301

Comparative chemogenomics to examine the mechanism of action of DNA-targeted platinum-acridine anticancer agents  

PubMed Central

Platinum-based drugs have been used to successfully treat diverse cancers for several decades. Cisplatin, the original compound of this class, cross-links DNA, resulting in cell cycle arrest and cell death via apoptosis. Cisplatin is effective against several tumor types, yet it exhibits toxic side effects and tumors often develop resistance. To mitigate these liabilities while maintaining potency, we generated a library of non-classical platinum-acridine hybrid agents and assessed their mechanisms of action using a validated genome-wide screening approach in Saccharomyces cerevisiae and in the distantly related yeast Schizosaccharomyces pombe. Chemogenomic profiles from both S. cerevisiae and S. pombe demonstrate that several of the platinum-acridines damage DNA differently than cisplatin based on their requirement for distinct modules of DNA repair.

Cheung-Ong, Kahlin; Song, Kyung Tae; Ma, Zhidong; Shabtai, Daniel; Lee, Anna Y.; Gallo, David; Heisler, Lawrence E.; Brown, Grant W.; Bierbach, Ulrich; Giaever, Guri; Nislow, Corey

2012-01-01

302

Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies.  

PubMed

In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials. PMID:20449627

Soto, Elena; Keizer, Ron J; Trocóniz, Iñaki F; Huitema, Alwin D R; Beijnen, Jos H; Schellens, Jan H M; Wanders, Jantien; Cendrós, Josep María; Obach, Rosendo; Peraire, Concepción; Friberg, Lena E; Karlsson, Mats O

2011-10-01

303

Anti-cancer effects of novel flavonoid vicenin-2 as a single agent and in synergistic combination with docetaxel in prostate cancer.  

PubMed

The present study was conducted to determine the efficacy of novel flavonoid vicenin-2 (VCN-2), an active constituent of the medicinal herb Ocimum Sanctum Linn or Tulsi, as a single agent and in combination with docetaxel (DTL) in carcinoma of prostate (CaP). VCN-2 effectively induced anti-proliferative, anti-angiogenic and pro-apoptotic effect in CaP cells (PC-3, DU-145 and LNCaP) irrespective of their androgen responsiveness or p53 status. VCN-2 inhibited EGFR/Akt/mTOR/p70S6K pathway along with decreasing c-Myc, cyclin D1, cyclin B1, CDK4, PCNA and hTERT in vitro. VCN-2 reached a level of 2.6±0.3?mol/l in serum after oral administration in mice which reflected that VCN-2 is orally absorbed. The i.v. administration of docetaxel (DTL), current drug of choice in androgen-independent CaP, is associated with dose-limiting toxicities like febrile neutropenia which has lead to characterization of alternate routes of administration and potential combinatorial regimens. In this regard, VCN-2 in combination with DTL synergistically inhibited the growth of prostate tumors in vivo with a greater decrease in the levels of AR, pIGF1R, pAkt, PCNA, cyclin D1, Ki67, CD31, and increase in E-cadherin. VCN-2 has been investigated for radioprotection and anti-inflammatory properties. This is the first study on the anti-cancer effects of VCN-2. In conclusion, our investigations collectively provide strong evidence that VCN-2 is effective against CaP progression along with indicating that VCN-2 and DTL co-administration is more effective than either of the single agents in androgen-independent prostate cancer. PMID:21803027

Nagaprashantha, Lokesh Dalasanur; Vatsyayan, Rit; Singhal, Jyotsana; Fast, Spence; Roby, Rhonda; Awasthi, Sanjay; Singhal, Sharad S

2011-11-01

304

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

PubMed

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

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

2013-01-01

305

Synthesis and biological evaluation of 2-substituted-4-(3?,4?,5?-trimethoxyphenyl)-5-aryl thiazoles as anticancer agents  

PubMed Central

Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH3> Me ? N(CH3)2. The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1–2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC50 values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.

Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Camacho, M. Encarnacion; Preti, Delia; Tabrizi, Mojgan Aghazadeh; Bassetto, Marcella; Brancale, Andrea; Hamel, Ernest; Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro

2012-01-01

306

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

PubMed Central

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 ?M. The anti-proliferation activity of all compounds was more pronounced than that of standard reference drug 5-flourouracil (IC50 =19.2 ?M). 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 ?M. Based on the results it can be concluded that, the bis-benzimidazolium salts could probably be the potential source of chemotherapeutic drugs.

2012-01-01

307

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

NASA Astrophysics Data System (ADS)

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.

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

2013-02-01

308

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

PubMed

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

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

2014-04-01

309

Synthesis, aqueous reactivity, and biological evaluation of carboxylic acid ester-functionalized platinum-acridine hybrid anticancer agents.  

PubMed

The synthesis of platinum-acridine hybrid agents containing carboxylic acid ester groups is described. The most active derivatives and the unmodified parent compounds showed up to 6-fold higher activity in ovarian cancer (OVCAR-3) and breast cancer (MCF-7, MDA-MB-231) cell lines than cisplatin. Inhibition of cell proliferation at nanomolar concentrations was observed in pancreatic (PANC-1) and nonsmall cell lung cancer cells (NSCLC, NCI-H460) of 80- and 150-fold, respectively. Introduction of the ester groups did not affect the cytotoxic properties of the hybrids, which form the same monofunctional-intercalative DNA adducts as the parent compounds, as demonstrated in a plasmid unwinding assay. In-line high-performance liquid chromatography and electrospray mass spectrometry (LC-ESMS) shows that the ester moieties undergo platinum-mediated hydrolysis in a chloride concentration-dependent manner to form carboxylate chelates. Potential applications of the chloride-sensitive ester hydrolysis as a self-immolative release mechanism for tumor-selective delivery of platinum-acridines are discussed. PMID:22871158

Graham, Leigh A; Suryadi, Jimmy; West, Tiffany K; Kucera, Gregory L; Bierbach, Ulrich

2012-09-13

310

Synthesis, Aqueous Reactivity, and Biological Evaluation of Carboxylic Acid Ester-Functionalized Platinum-Acridine Hybrid Anticancer Agents  

PubMed Central

The synthesis of platinum–acridine hybrid agents containing carboxylic acid ester groups is described. The most active derivatives and the unmodified parent compounds showed up to 6-fold higher activity in ovarian cancer (OVCAR-3) and breast cancer (MCF-7, MDA-MB-23) cell lines than cisplatin. Inhibition of cell proliferation at nanomolar concentrations was observed in pancreatic (PANC-1) and non-small cell lung cancer cells (NSCLC, NCI-H460) of 80- and 150-fold, respectively. Introduction of the ester groups did not affect the cytotoxic properties of the hybrids, which form the same monofunctional–intercalative DNA adducts as the parent compounds, as demonstrated in a plasmid unwinding assay. In-line high-performance liquid chromatography and electrospray mass spectrometry (LC-ESMS) shows that the ester moieties undergo platinum-mediated hydrolysis in a chloride concentration-dependent manner to form carboxylate chelates. Potential applications of the chloride-sensitive ester hydrolysis as a self-immolative release mechanism for tumor-selective delivery of platinum–acridines are discussed.

Graham, Leigh A.; Suryadi, Jimmy; West, Tiffany K.; Kucera, Gregory L.; Bierbach, Ulrich

2012-01-01

311

Biological evaluation of morin and its new oxovanadium(IV) complex as antioxidant and specific anti-cancer agents.  

PubMed

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

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

312

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

PubMed

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

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

2011-09-30

313

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

PubMed Central

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

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

2011-01-01

314

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

PubMed

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

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

2012-03-15

315

Self-treatment using 0.25%-0.50% podophyllotoxin-ethanol solutions against penile condylomata acuminata: a placebo-controlled comparative study  

Microsoft Academic Search

OBJECTIVE--To compare the efficacy of 0.50% and 0.25% podophyllotoxin preparations against previously untreated penile warts. DESIGN--The study was performed as a double-blind, placebo-controlled investigation on 57 males randomly allocated to one of three groups of 19 males in each, receiving either the placebo solution (70% ethanolic vehicle) or one of the two podophyllotoxin preparations for 1-2 self-treatment courses b.i.d. for

G von Krogh; E Szpak; M Andersson; I Bergelin

1994-01-01

316

In vitro pharmacokinetic study of the novel anticancer agent E7070: red blood cell and plasma protein binding in human blood.  

PubMed

E7070 is a novel sulfonamide anticancer agent that arrests the G(1)/S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics (PK) of the drug. A population PK analysis revealed that the human plasma concentration-time data were best described by a three-compartment model with non-linear distribution. We have studied the in vitro interaction of 14C-radiolabeled E7070 with red blood cells (RBC) and its binding to plasma proteins in the concentration range where non-linearity in disposition was observed in humans to get more insight into the behavior of the drug. After the addition of E7070 to whole blood at 37 degrees C, the drug is taken up or binds to RBC in a concentration-dependent manner. The addition of sodium azide, however, did not result in a decrease of drug uptake by RBC, indicating passive diffusion processes. A non-linear increase in drug uptake was observed at incubation concentrations above 4 microg/ml E7070 in whole blood. This non-linearity was confirmed by lower partition coefficients between RBC and plasma at higher incubation concentrations (from 2.37 at 4 microg/ml to 0.31 at 200 microg/ml). The plasma protein binding of E7070 was high (98-99%) and linear in the concentration range studied (20-200 microg/ml). In conclusion, E7070 in whole blood is preferentially bound to RBC and exhibits high plasma protein binding. The non-linear distribution of E7070 in humans can be caused, in part at least, by saturable binding of E7070 to RBC. PMID:12853880

Bongard, H J G D van den; Pluim, D; Waardenburg, R C A M van; Ravic, M; Beijnen, J H; Schellens, J H M

2003-07-01

317

Enantioselective formal synthesis of (-)-podophyllotoxin from (2S,3R)-3-arylaziridine-2-carboxylate.  

PubMed

Meyers' 4-aryl-1-tetralone-lactone and ent-Zhang's 2-diarylmethyl-4-oxobutanoate were synthesized in the formal synthesis of (-)-podophyllotoxin from (2S,3R)-3-arylaziridine-2-carboxylate, via 3,3-diarylpropanoate as a common intermediate, in an overall 42% yield through 10 steps and 31% yield through 6 steps, respectively. The key steps in the synthesis were regio- and diastereoselective ring opening with an aromatic nucleophile, samarium iodide promoted reductive C-N bond cleavage, and Stille coupling for introducing the vinyl functionality. The starting aziridine was enantioselectively prepared from 3,4,5-trimethoxybenzaldehyde by guanidinium ylide mediated asymmetric aziridination. All nitrogen components used in the reaction sequence are reusable as the starting guanidinium source. PMID:23496308

Takahashi, Masato; Suzuki, Noriyuki; Ishikawa, Tsutomu

2013-04-01

318

Crude drugs as anticancer agents  

PubMed Central

Although tremendous progress has been made in basic cancer biology and in the development of novel cancer treatments, cancer remains a leading cause of death in the world. The etiopathogenesis of cancer is complex. Besides genetic predisposition, known environmental factors associated with cancer are: diet, lifestyle, and environmental toxins. Toxicity of drugs and eventual relapse of cancers contribute to high cancer death rates. Current therapeutic interventions for cancer- surgery, chemotherapy, radiotherapy, thermotherapy, etc. are far from being curative for many forms of cancer. Chemotherapy, in particular, though the most commonly used cancer treatment, is usually associated with side effects with varying degrees of severity. The purpose of this brief review is to assemble current literature on some crude drugs and to focus on their beneficial roles and drug targets in cancer therapy and chemo-prevention. Although their pharmacological mechanisms and biochemical roles in cancer biology and tumor chemo-prevention are not fully understood, crude drugs are believed to have nutriceutical effects upon cancer patients.

Mou, Xiaoyang; Kesari, Santosh; Wen, Patrick Y; Huang, Xudong

2011-01-01

319

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

PubMed

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, (1)H, (13)C NMR, and elemental analysis data. The substances were screened for antibacterial and antifungal activities (100 ?g) 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 ?M) 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

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

2013-03-01

320

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

PubMed Central

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 ?g) 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 ?M) 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.

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

2013-01-01

321

Synthesis of 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one analogs and their biological evaluation as anticancer agents: mTOR inhibitors.  

PubMed

A microwave assisted strategy for synthesis of series of 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones has been developed and their biological evaluation as anticancer agents is described. The synthetic protocol involves simple procedure by oxidative coupling of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide with different aldehydes in presence of K2S2O8 offering 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds in excellent yields. The in vitro anticancer activity screening against human cancer cell lines HeLa, CAKI-I, PC-3, MiaPaca-2, A549 gave good results. The in detailed mechanistic correlation studies of compound 3m revealed that the compound shows anticancer activity through apoptosis mechanism and also inhibits mTOR with nonomolar potency. The design was based on docking with mTOR protein. The concentration dependent cell cycle analysis, western blotting experiment and nuclear cell morphology studies have been described. PMID:24780597

Reddy, G Lakshma; Guru, Santosh Kumar; Srinivas, M; Pathania, Anup Singh; Mahajan, Priya; Nargotra, Amit; Bhushan, Shashi; Vishwakarma, Ram A; Sawant, Sanghapal D

2014-06-10

322

Apoptosis induced by anticancer drugs  

Microsoft Academic Search

Most of the cytotoxic anticancer drugs in current use have been shown to induce apoptosis in susceptible cells. The fact that disparate agents, which interact with different targets, induce cell death with some common features (endonucleolytic cleavage of DNA, changes in chromatin condensation) suggests that cytotoxicity is determined by the ability of the cell to engage this so-called ‘programmed’ cell

John A. Hickman

1992-01-01

323

Anticancer chemotherapy  

SciTech Connect

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)

Weller, R.E.

1991-10-01

324

Comparison of the Cytotoxic Effects of the High and Low-Molecular-Weight Anticancer Agents on Multidrug-resistant Chinese Hamster Ovary Cells in Vitro1  

Microsoft Academic Search

Neocarzinostatin (NCS), styrene-maleic acid copolymer-conjugated neocarzinostatin (SMANCS), and ricin exhibited cytotoxicity against two different types of Chinese hamster ovary cells, parental AUXB1 cells and the multidrug-resistant (MI )K) subline CHRC5cells at the nanomolar range. These doses were much lower than those of the other anticancer drugs tested (micromolar range), even after a short incubation. MDK CHRC5cells were 20 to 900

Yoichi Miyamoto; Tatsuya Od; Hiroshi Maeda

325

Synthesis and evaluation of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)nicotinamides as potential anticancer agents that inhibit tubulin polymerization.  

PubMed

A series of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)nicotinamides (4) was synthesized and tested for their anticancer activity against a panel of 60 human cancer cell lines. Some of the representative compounds such as 4a, 4b, 4f, 4g, 4i and 4t were selected for the five dose study and amongst them 4g and 4i displayed significant anticancer activity with GI50 values ranging from 0.25 to 8.34 and 1.42 to 5.86?M, respectively. Cell cycle analysis revealed that these compounds induced cell cycle arrest at G2/M phase in MCF-7 cells. The most active compound in this series 4g also inhibited tubulin polymerization with IC50 value 1.93?M superior to that of E7010. Moreover, assay to investigate the effect on caspase-9, Hoechst staining and DNA fragmentation analysis suggested that these compounds induced cell death by apoptosis. Docking experiments showed that they interact and bind efficiently with tubulin protein. Overall, the results demonstrate that N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)nicotinamide scaffold possess anticancer property by inhibiting the tubulin polymerization. PMID:24835786

Kamal, Ahmed; Reddy, N V Subba; Nayak, V Lakshma; Bolla, Narasimha Rao; Subba Rao, A V; Prasad, B

2014-07-01

326

HPLC-DAD and HPLC-ESI-MS separation, determination and identification of the spin-labeled diastereoisomers of podophyllotoxin.  

PubMed

Spin-labeled nitroxide derivatives of podophyllotoxin had better antitumor activity and less toxicity than that of the parent compounds. However, the 2-H configurations of these spin-labeled derivatives cannot be determined by nuclear magnetic resonance (NMR) methods. In the present paper, a high-performance liquid chromatography-diode array detection (HPLC-DAD) and a high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI/MS/MS) method were developed and validated for the separation, identification of four pairs of diastereoisomers of spin-labeled derivatives of podophyllotoxin at C-2 position. In the HPLC-ESI/MS spectra, each pair of diastereoisomers of the spin-labeled derivatives in the mixture was directly confirmed and identified by [M+H](+) ions and ion ratios of relative abundance of [M-ROH+H](+) (ion 397) to [M+H](+). When the [M-ROH+H](+) ions (at m/z 397) were selected as the precursor ions to perform the MS/MS product ion scan. The product ions at m/z 313, 282, and 229 were the common diagnostic ions. The ion ratios of relative abundance of the [M-ROH+H](+) (ion 397) to [M+H](+), [A+H](+) (ion 313) to [M-ROH+H](+), [A+H-OCH(3)](+) (ion 282) to [M-ROH+H](+) and [M-ROH-ArH+H](+) (ion 229) to [M-ROH+H](+) of each pair of diastereoisomers of the derivatives specifically exhibited a stereochemical effect. Thus, by using identical chromatographic conditions, the combination of DAD and MS/MS data permitted the separation and identification of the four pairs of diastereoisomers of spin-labeled derivatives of podophyllotoxin at C-2 in the mixture. PMID:19350581

Zhao, Lei; Liu, Zhen-Ling; Fan, Peng-Cheng; Zhang, Zhi-Wei; Liu, Xiong; Zhan, Yun-Jing; Tian, Xuan

2009-05-01

327

Simultaneous determination of the novel thiosemicarbazone anti-cancer agent, Bp4eT, and its main phase I metabolites in plasma: application to a pilot pharmacokinetic study in rats.  

PubMed

Novel thiosemicarbazone metal chelators are extensively studied anti-cancer agents with marked and selective activity against a wide variety of cancer cells, as well as human tumor xenografts in mice. This study describes the first validated LC-MS/MS method for the simultaneous quantification of 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT) and its main metabolites (E/Z isomers of the semicarbazone structure, M1-E and M1-Z, and the amidrazone metabolite, M2) in plasma. Separation was achieved using a C18 column with ammonium formate/acetonitrile mixture as the mobile phase. Plasma samples were treated using solid-phase extraction on 96-well plates. This method was validated over the concentration range of 0.18-2.80 ?M for Bp4eT, 0.02-0.37 ?M for both M1-E and M1-Z, and 0.10-1.60 ?M for M2. This methodology was applied to the analysis of samples from in vivo experiments, allowing for the concentration-time profile to be simultaneously assessed for the parent drug and its metabolites. The current study addresses the lack of knowledge regarding the quantitative analysis of thiosemicarbazone anti-cancer drugs and their metabolites in plasma and provides the first pharmacokinetic data on a lead compound of this class. PMID:24254882

Stariat, Ján; Suprunová, Vlasta; Roh, Jaroslav; Šesták, Vít; Eisner, Tomáš; Filipský, Tomáš; Mlad?nka, P?emysl; Nobilis, Milan; Šim?nek, Tomáš; Klimeš, Ji?í; Kalinowski, Danuta S; Richardson, Des R; Kova?íková, Petra

2014-05-01

328

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

PubMed Central

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

2012-01-01

329

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)

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.

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

2008-04-01

330

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

PubMed

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

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

2013-02-01

331

Potential anticancer properties of bisphosphonates.  

PubMed

Bisphosphonates inhibit osteoclast-mediated bone resorption, which is increased when cancer cells invade bone, and are used in the treatment of metastatic bone disease to reduce the risk of skeletal-related events. In addition, preclinical studies have shown that bisphosphonates, especially potent nitrogen-containing bisphosphonates, have direct anticancer actions. Anticancer activity includes induction of apoptosis, and inhibition of invasion, in addition to synergistic activity with chemotherapy agents, antiangiogenic properties, and modulating effects on the immune system. In terms of potential clinical anticancer activity, early data suggest that zoledronic acid may have a role to play in preventing metastatic disease. The definitive answer is not known as yet; however, with more than 20,000 patients with breast, prostate, or lung cancer currently participating in adjuvant bisphosphonate randomized trials, results should be available in the next few years. This will establish whether bisphosphonates given early in the course of cancer will be able to prevent formation of metastases, in or out of the bone environment. This review will focus on emerging evidence of the anticancer activities of bisphosphonates and possible underlying mechanisms of action. PMID:20682373

Neville-Webbe, Helen L; Gnant, Michael; Coleman, Robert E

2010-06-01

332

A quantitative chemical proteomics approach to profile the specific cellular targets of andrographolide, a promising anticancer agent that suppresses tumor metastasis.  

PubMed

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

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

2014-03-01

333

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)

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

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

334

New anticancer agents: in vitro and in vivo evaluation of the antitumor and antimetastatic actions of various compounds isolated from medicinal plants.  

PubMed

In this review, in the search for the development of new anticancer drugs, the effects of compounds isolated from various medicinal plants on tumor growth and metastasis, using mice bearing a highly metastatic drug-resistant mouse tumor, were studied. The antitumor and antimetastatic actions of stilbene derivatives isolated from Polygonum and Cassia species were examined. Among the stilbene derivatives, resveratrol and cassiagrol A (stilbene dimer) displayed antitumor and antimetastatic actions through the inhibition of tumor-induced neovascularization in in vitro and in vivo models. It was found that two chalcone derivatives from Angelica keiskei roots also inhibited tumor growth and metastasis in tumor-bearing mice through the inhibition of tumor-induced neovascularization and/or the inhibition of immune suppression caused by tumors. Recently, basidiomycete fungi have been used for the treatment of cancer. Then, the low molecular weight substances were isolated from Agaricus blazei and Ganoderma lucidum as antitumor and antimetastatic substances. It is suggested that these substances of basidiomycete also inhibited tumor growth and metastasis to the lung through the inhibition of tumor-induced neovascularization and/or the inhibition of immune suppression caused by tumors. PMID:15796155

Kimura, Yoshiyuki

2005-01-01

335

Synthesis, quantitative structure-activity relationship and biological evaluation of 1,3,4-oxadiazole derivatives possessing diphenylamine moiety as potential anticancer agents.  

PubMed

Synthesis of 2,5-disubstituted-1,3,4-oxadiazole (2a-c), 3-substituted aminomethyl-5-substituted-1,3,4-oxadiazole-2(3H)-thione (4a-m) and 2-substituted thio-5-substituted-1,3,4-oxadiazole (5a, b) had been described. All the synthesized derivatives were screened for anticancer activity against HT29 and MCF7 cancer cell lines using Sulfo-Rodamine B (SRB) standard method. Most of the tested compounds exploited potent antiproliferative activity against HT29 cancer cell line rather than MCF7 cancer cell line. Compounds 2a-c, 4f and 5a exhibited potent cytotoxicity (IC(50) 1.3-2.0 µM) and selectivity against HT29 cancer cell line. Quantitative structure-activity relationship (QSAR) study was applied to find a correlation between the experimental antiproliferative activities of the newly synthesized oxadiazole derivatives with their physicochemical parameter and topological index. PMID:23370194

Abdel Rahman, Doaa Ezzat

2013-01-01

336

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

PubMed

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

Tomitsuka, Eriko; Kita, Kiyoshi; Esumi, Hiroyasu

2012-08-01

337

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

PubMed Central

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.

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

2014-01-01

338

Potential new inorganic antitumour agents from combining the anticancer traditional Chinese medicine (TCM) liriodenine with metal ions, and DNA binding studies.  

PubMed

Liriodenine (), an active component of the anticancer traditional Chinese medicine (TCM), was isolated from Zanthoxylum nitidum. Its reactions with Pt(II) and Ru(II) afforded three metal complexes: cis-[PtCl2(L)] (), cis-[PtCl2(L)(DMSO)] (), and cis-[RuCl2(L)(DMSO)2].1.5H2O (), the crystal structures of , and were determined by single-crystal X-ray diffraction methods. These complexes were fully characterized by elemental analysis, IR spectrophotometry, 1H and 13C NMR spectroscopies, and ES mass spectrometry. The in vitro cytotoxicity of and complexes against 11 human tumour cell lines was assayed. The metal-based compounds exhibit enhanced cytotoxicity vs. free , suggesting that these compounds display synergy in the combination of metal ions and liriodenine. The binding properties of and its complexes to ct-DNA were investigated through UV-vis, fluorescence, CD spectra, viscosity and agarose gels electrophoretic measurements. PMID:19089006

Chen, Zhen-Feng; Liu, Yan-Cheng; Liu, Li-Min; Wang, Heng-Shan; Qin, San-Hai; Wang, Bo-Long; Bian, He-Dong; Yang, Bin; Fun, Hoong-Kun; Liu, Hua-Gang; Liang, Hong; Orvig, Chris

2009-01-14

339

Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX.  

PubMed

E7070 [N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide] is an anticancer drug candidate under clinical development for the treatment of several types of cancers. We prove here that this compound also acts as a potent carbonic anhydrase (CA) inhibitor. Similarly to the clinically used drugs acetazolamide, methazolamide and topiramate, E7070 showed inhibition constants in the range of 15-31nM against isozymes I, II and IX, being slightly less effective as a CA IV inhibitor (K(i) of 65nM). The X-ray crystal structure of the adduct of hCA II with E7070 revealed unprecedented interactions between the inhibitor and the active site, with three different conformations of the chloroindole fragment of the inhibitor interacting with different amino acid residues/water molecules of the enzyme. A superimposition of these conformations with those of other sulfonamide/sulfamate CA inhibitors indicated that similar regions of the hCA II active site could be involved in the interaction with inhibitors. PMID:14684331

Abbate, Francesco; Casini, Angela; Owa, Takashi; Scozzafava, Andrea; Supuran, Claudiu T

2004-01-01

340

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

PubMed Central

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.

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

2012-01-01

341

Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing.  

PubMed

Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC(50) of 0.04 ?M). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2? (FRS2?). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design. PMID:23409720

Ho, H K; Németh, G; Ng, Y R; Pang, E; Szántai-Kis, C; Zsákai, L; Breza, N; Greff, Z; Horváth, Z; Pató, J; Szabadkai, I; Szokol, B; Baska, F; ?rfî, L; Ullrich, A; Kéri, G; Chua, B T

2013-01-01

342

Pharmacokinetics and absorption of the anticancer agents dasatinib and GDC-0941 under various gastric conditions in dogs--reversing the effect of elevated gastric pH with betaine HCl.  

PubMed

Changes in gastric pH can impact the dissolution and absorption of compounds presenting pH-dependent solubility. We assessed, in dogs, the effects of gastric pH-modifying agents on the oral absorption of two weakly basic anticancer drugs, dasatinib and GDC-0941. We also tested whether drug-induced hypochlorhydria could be temporarily mitigated using betaine HCl. Pretreatments with pentagastrin, famotidine, betaine HCl, or combinations of famotidine and betaine HCl were administered orally to dogs prior to drug dosing. The gastric pH was measured under each condition for up to 7 h, and the exposure of the compounds tested was calculated. The average gastric pH in fasted dogs ranged from 1.45 to 3.03. Pentagastrin or betaine HCl treatments lowered the pH and reduced its variability between dogs compared to control animals. In contrast, famotidine treatment maintained gastric pH at values close to 7 for up to 5 h, while betaine HCl transiently reduced the pH to approximately 2 in the famotidine-treated dogs. Famotidine pretreatment lowered GDC-0941 exposure by 5-fold, and decreased dasatinib measurable concentrations 30-fold, compared to the pentagastrin-treated dogs. Betaine HCl restored GDC-0941 AUC in famotidine-treated dogs to levels achieved in control animals, and increased dasatinib AUC to 1.5-fold that measured in control dogs. The results confirmed the negative impact of acid-reducing agents on the absorption of weakly basic drugs. They also suggested that betaine HCl coadministration may be a viable strategy in humans treated with acid-reducing agents in order to temporarily reduce gastric pH and restore drug exposure. PMID:23980865

Pang, Jodie; Dalziel, Gena; Dean, Brian; Ware, Joseph A; Salphati, Laurent

2013-11-01

343

S9, a Novel Anticancer Agent, Exerts Its Anti-Proliferative Activity by Interfering with Both PI3K-Akt-mTOR Signaling and Microtubule Cytoskeleton  

PubMed Central

Background Deregulation of the phosphatidylinositol 3-kinases (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway plays a central role in tumor formation and progression, providing validated targets for cancer therapy. S9, a hybrid of ?-methylene-?-lactone and 2-phenyl indole compound, possessed potent activity against this pathway. Methodology/Principal Findings Effects of S9 on PI3K-Akt-mTOR pathway were determined by Western blot, immunofluorescence staining and in vitro kinas assay. The interactions between tubulin and S9 were investigated by polymerization assay, CD, and SPR assay. The potential binding modes between S9 and PI3K, mTOR or tubulin were analyzed by molecular modeling. Anti-tumor activity of S9 was evaluated in tumor cells and in nude mice bearing human cancer xenografts. S9 abrogated EGF-activated PI3K-Akt-mTOR signaling cascade and Akt translocation to cellular membrane in human tumor cells. S9 possessed inhibitory activity against both PI3K and mTOR with little effect on other tested 30 kinases. S9 also completely impeded hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin. S9 unexpectedly arrested cells in M phase other than G1 phase, which was distinct from compounds targeting PI3K-Akt-mTOR pathway. Further study revealed that S9 inhibited tubulin polymerization via binding to colchicine-binding site of tubulin and resulted in microtubule disturbance. Molecular modeling indicated that S9 could potentially bind to the kinase domains of PI3K p110? subunit and mTOR, and shared similar hydrophobic interactions with colchicines in the complex with tubulin. Moreover, S9 induced rapid apoptosis in tumor cell, which might reflect a synergistic cooperation between blockade of both PI3-Akt-mTOR signaling and tubulin cytoskeleton. Finally, S9 displayed potent antiproliferative activity in a panel of tumor cells originated from different tissue types including drug-resistant cells and in nude mice bearing human tumor xenografts. Conclusions/Significance Taken together, S9 targets both PI3K-Akt-mTOR signaling and microtubule cytoskeleton, which combinatorially contributes its antitumor activity and provides new clues for anticancer drug design and development.

Yang, Chun-hao; Ding, Hua-sheng; Luo, Cheng; Zhang, Yu; Wu, Mao-jiang; Zhang, Xiong-wen; Shen, Xu; Jiang, Hua-liang; Meng, Ling-hua; Ding, Jian

2009-01-01

344

1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine: An anticancer agent targeting hypoxic cells  

PubMed Central

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 ?M 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.

Seow, Helen A.; Penketh, Philip G.; Shyam, Krishnamurthy; Rockwell, Sara; Sartorelli, Alan C.

2005-01-01

345

Intravenous-to-oral switch in anticancer chemotherapy : focus on taxanes and gemcitabine  

Microsoft Academic Search

Most anticancer chemotherapeutic drugs are given intravenously. However, there is a growing interest in developing anticancer drugs for oral application. Different classes of anticancer drugs are already orally available and widely applied such as the tyrosine kinase inhibitors (imatinib, erlotinib, gefitinib, sorafenib and sunitinib), alkylating agents (temozolamide and cyclophosphamide) and the 5FU prodrug, capecitabine, a drug for which the intravenous-to-oral

S. L. W. Koolen

2011-01-01

346

Hyponatremia related to medical anticancer treatment  

Microsoft Academic Search

Hyponatremia is a common potential complication in cancer patients. It can be related to anticancer medical therapy. Vincristine, vinblastine, cisplatin and cyclophosphamide are the chemotherapeutic agents most frequently associated with hyponatremia. More recently, analogs such as carboplatin and ifosfamide have also been. incriminated. Hyponatremia is also associated with new immunomodulators (interferon, interleukin-2 and levamisole) and monoclonal antibodies. The mechanism by

T. Berghmans

1996-01-01

347

Dual role of immunomodulation by anticancer chemotherapy  

PubMed Central

The anticancer efficacy of conventional chemotherapies seems to be due, in part, to augmentation of the host immune reactivity. However, a new study reveals that two common chemotherapeutic agents, gemcitabine and 5-fluorouracil, can also activate immune regulatory cells, which stimulates the emergence of protumorigenic cytokines via inflammasome pathways, limiting the antitumor efficacy of the drugs (pages 57–64).

Shurin, Michael R

2014-01-01

348

[An in vitro sensitivity assay for anti-cancer agents by measuring the inhibition rate of DNA synthesis (3H-thymidine uptake of cancer cells). II. Clinical study of 110 cases of breast cancer].  

PubMed

The sensitivity of cancer cells to anti-cancer agents (ACA) was assessed in 110 cases of breast cancer (87 primary cases and 23 recurrent cases). The cancer cells were cultured with ACAs: Mitomycin C (MMC), Adriamycin (ADR), 5-Fluorouracil (5-FU), Cytosine Arabinoside (Ara-C), Carboquone (CQ), Nimustine Hydrochloride (ACNU), Cis-platinum Diammine Dichloride (CPDD) or Vincristine (VCR) for 3 days and their sensitivity was estimated by the inhibition rate (I.R.) of DNA synthesis (3H-thymidine uptake) of cancer cells. The DNA synthesis was higher in recurrent cases than in primary cases. The primary cases showed high sensitivity to ADR or CQ, and the recurrent cases showed high sensitivity to ADR. Histologically, papillotubular or medullary tubular carcinoma showed high sensitivity to CQ, and scirrhous carcinoma showed high sensitivity to ADR, CQ or 5-FU. The sensitivities of medullary tubular or scirrhous carcinoma to ADR, 5-FU and CQ in patients with stage III and IV were lower than those in patients with stages I and II. No difference of ACA sensitivity was observed between estrogen receptor (+) and (-) cases. All recurrent cases were treated with 5-FU or its derivatives. The 50% survival period in the 5-FU high sensitivity (I.R. greater than 80%) group was 7.0 months and that of the low sensitivity (I.R. less than 80%) group 3.0 months, respectively. PMID:3016495

Nio, Y; Ohgaki, K; Inamoto, T; Kan, N; Kodama, H; Tobe, T

1986-06-01

349

Biological Characterization of 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145) as a Selective Sphingosine Kinase-2 Inhibitor and Anticancer Agent  

PubMed Central

In our effort to develop selective sphingosine kinase-2 (SphK2) inhibitors as pharmacological tools, a thiazolidine-2,4-dione analogue, 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145), was synthesized and biologically characterized. Biochemical assay results indicate that K145 is a selective SphK2 inhibitor. Molecular modeling studies also support this notion. In vitro studies using human leukemia U937 cells demonstrated that K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways. K145 also significantly inhibited the growth of U937 tumors in nude mice by both intraperitoneal and oral administration, thus demonstrating its in vivo efficacy as a potential lead anticancer agent. The antitumor activity of K145 was also confirmed in a syngeneic mouse model by implanting murine breast cancer JC cells in BALB/c mice. Collectively, these results strongly encourage further optimization of K145 as a novel lead compound for development of more potent and selective SphK2 inhibitors.

Liu, Kai; Guo, Tai L.; Hait, Nitai C.; Allegood, Jeremy; Parikh, Hardik I.; Xu, Wenfang; Kellogg, Glen E.; Grant, Steven; Spiegel, Sarah; Zhang, Shijun

2013-01-01

350

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

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.

2014-01-01

351

Topical Treatment of Penile Condylomata acuminata with Podophyllotoxin 0.3% Solution, 0.3% Cream and 0.15% Cream  

Microsoft Academic Search

The purpose of this comparative open study was to determine the clinical efficacy of 0.3% podophyllotoxin both in 70% ethanolic solution and cream preparations on genital warts. Three parallel trial preparations, 0.3% solution, 0.3% and 0.15% cream, were randomly allocated to 60 circumcised Asian males (mean age 19.5 years), with the diagnosis of genital condyloma. Patients applied the trial preparation

T. A. Syed; S. Lundin

1993-01-01

352

Management of genital warts in women with human leukocyte interferon-? vs. podophyllotoxin in cream: a placebo-controlled, double-blind, comparative study  

Microsoft Academic Search

The purpose of this double-blind, placebo-controlled, comparative study was to evaluate the specific clinical efficacy and tolerance of human leukocyte interferon-a (2×l06 IU\\/g) and podophyllotoxin 0.5% incorporated in a hydrophilic cream to cure genital warts. Preselected Asian women (n=60) aged 18–40 years (mean 22.9), with a clinical and biopsy-confirmed diagnosis of genital warts, harboring 322 lesions (mean 5.36) were randomly

T. A. Syed; M. Khayyami; D. Kriz; K. Svanberg; R. C. Kahlon; S. A. Ahmad

1995-01-01

353

Topical Treatment of Penile Condylomata acuminata with Podophyllotoxin 0.3% Solution, 0.3% Cream and 0.15% Cream  

Microsoft Academic Search

The purpose of this comparative open study was to determine the clinical efficacy of 0.3% podophyllotoxin both in 70% ethanolic solution and cream preparations on genital warts. Three parallel trial preparations, 0.3% solution, 0.3% and 0.15% cream, were randomly allocated to 60 circumcised Asian males (mean age 19.5 years), with the diagnosis of genital condyloma. Patients applied the trial preparation

T. A. Syed; S. Lundin

1993-01-01

354

Evaluation of a novel bis-naphthalimide anticancer agent, DMP 840, against human xenografts derived from adult, juvenile, and pediatric cancers.  

PubMed

The new bis-naphthalimide antitumor agent (R,R)2,2'-[1,2-ethanediylbis[imino(1-methyl-2.1-ethanediyl)]-bis(5 -nitro 1H-benz[de]-isoquinoline-1,3-2H) dione] dimethanesulfonate (DMP 840) was evaluated against parental and multidrug-resistant human KB cell lines in vitro and against these lines growing as xenografts in immune-deprived mice. In vitro, KB8-5 cells were 50-fold resistant to vincristine but only 16-fold resistant to DMP 840 as measured by clonogenic survival. For in vivo evaluation, DMP 840 was given by i.v. injection daily for 9 days or for 5 days/week for 2 consecutive weeks [(dx5)2]. In contrast to the cross-resistance of KB cell lines in vitro, both KB3-1 and KB8-5 tumors were highly and equally sensitive to DMP 840; only KB3-1 xenografts demonstrated sensitivity to vincristine, which was consistent with the in vitro results. DMP 840 was also evaluated against a panel of human tumors comprising colon adenocarcinoma and rhabdomyosarcoma xenografts. Against eight lines of colon adenocarcinoma, DMP 840 caused a high frequency of partial and complete regressions in two lines and significant inhibition of growth in two lines. DMP 840 caused complete regressions in five of six lines of advanced rhabdomyosarcomas, demonstrating a broad range of effective dose levels. The pattern of activity against this tumor panel was similar but not identical to that of two inhibitors of topoisomerase I. There was no cross-resistance to DMP 840 in xenografts selected for resistance to vincristine or in a rhabdomyosarcoma selected for resistance to the topoisomerase I inhibitor topotecan. In contrast, a colon tumor selected for topotecan resistance was completely resistant to DMP 840. Slight cross-resistance to DMP 840 was demonstrated in a rhabdomyosarcoma xenograft that was selected for primary resistance to melphalan and was cross-resistant to topoisomerase I inhibitors. The pattern of activity and cross-resistance in these tumors was compared with that shown by two agents that inhibit topoisomerase I: topotecan and CPT-11. PMID:8281618

Houghton, P J; Cheshire, P J; Hallman, J C; Gross, J L; McRipley, R J; Sun, J H; Behrens, C H; Dexter, D L; Houghton, J A

1994-01-01

355

Dihydrofolate reductase and cell growth activity inhibition by the beta-carboline-benzoquinolizidine plant alkaloid deoxytubulosine from Alangium lamarckii: its potential as an antimicrobial and anticancer agent.  

PubMed

Beta-carboline-benzoquinolizidine plant alkaloid deoxytubulosine (DTB) was evaluated and assessed for the first time for its biochemical and biological activity employing the biomarker dihydrofolate reductase (DHFR) (5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 1.5.1.3) as the probe enzyme, a key target in cancer chemotherapy. DHFR, employed in the present investigations was purified from Lactobacillus leichmannii. DTB, isolated from the Indian medicinal plant Alangium lamarckii was demonstrated to exhibit potent cytotoxicity. The alkaloid potently inhibited the cell growth of L. leichmannii and the cellular enzyme activity of DHFR (IC50=40 and 30 microM for the cell growth and enzyme inhibitions, respectively). DTB concentrations >75 microM resulted in a total loss of the DHFR activity, thus suggesting that the beta-carboline-benzoquinolizidine plant alkaloid is a promising potential antitumor agent. Our results are also suggestive of its potential antimicrobial activity. DTB binding to DHFR appears to be slow and reversible. Inhibition kinetics revealed that DHFR has a Ki value of 5x10(-6) M for DTB and that the enzyme inhibition is a simple linear 'non-competitive' type. PMID:10428380

Rao, K N; Venkatachalam, S R

1999-06-01

356

Mechanisms of action of the novel sulfonamide anticancer agent E7070 on cell cycle progression in human non-small cell lung cancer cells.  

PubMed

E7070 is a novel sulfonamide antitumor agent that exhibits potent antitumor activity in vitro and in vivo. This compound affects cell cycle progression in human tumor cells. To elucidate the mechanisms by which E7070 inhibits tumor cell growth, we established and characterized an E7070-resistant subline, A549/ER, from a human non-small cell lung cancer cell line A549. Flow cytometric analyses demonstrated an increase in G0/G1 and a decrease in S phase populations in cells treated with E7070 at 20 or 100 microg/ml for 24 h. Longer exposure to E7070, i.e. 48 and 72 h, increased the G2/M phase fraction in A549 cells. These inhibitory actions of E7070 on cell cycle progression were not observed in A549/ER cells. E7070 inhibited the phosphorylation of pRb, decreased expressions of cyclin A, B1, CDK2, and CDC2 proteins, and suppressed CDK2 catalytic activity with the induction of p53 and p21 proteins in A549 cells but not in A549/ER cells. Taken together, these results suggest that E7070 exerts its antitumor effects by disturbing the cell cycle at multiple points, including both the G1/S and the G2/M transition, in human lung cancer cells. PMID:11561678

Fukuoka, K; Usuda, J; Iwamoto, Y; Fukumoto, H; Nakamura, T; Yoneda, T; Narita, N; Saijo, N; Nishio, K

2001-01-01

357

BlueBerry Isolate, Pterostilbene, Functions as a Potential Anticancer Stem Cell Agent in Suppressing Irradiation-Mediated Enrichment of Hepatoma Stem Cells  

PubMed Central

For many malignancies, radiation therapy remains the second option only to surgery in terms of its curative potential. However, radiation-induced tumor cell death is limited by a number of factors, including the adverse response of the tumor microenvironment to the treatment and either intrinsic or acquired mechanisms of evasive resistance, and the existence of cancer stem cells (CSCs). In this study, we demonstrated that using different doses of irradiation led to the enrichment of CD133+ Mahlavu cells using flow cytometric method. Subsequently, CD133+ Mahlavu cells enriched by irradiation were characterized for their stemness gene expression, self-renewal, migration/invasion abilities, and radiation resistance. Having established irradiation-enriched CD133+ Mahlavu cells with CSC properties, we evaluated a phytochemical, pterostilbene (PT), found abundantly in blueberries, against irradiation-enriched CSCs. It was shown that PT treatment dose-dependently reduced the enrichment of CD133+ Mahlavu cells upon irradiation; PT treatment also prevented tumor sphere formation, reduced stemness gene expression, and suppressed invasion and migration abilities as well as increasing apoptosis of CD133+ Mahlavu CSCs. Based on our experimental data, pterostilbene could be used to prevent the enrichment of CD133+ hepatoma CSCs and should be considered for future clinical testing as a combined agent for HCC patients.

Lee, Chi-Ming; Su, Yen-Hao; Huynh, Thanh-Tuan; Lee, Wei-Hwa; Chiou, Jeng-Fong; Lin, Yen-Kuang; Hsiao, Michael; Wu, Chih-Hsiung; Lin, Yuh-Feng; Wu, Alexander T. H.; Yeh, Chi-Tai

2013-01-01

358

Discovery and Optimization of a Series of 2-Aryl-4-Amino-5-(3?,4?,5?-trimethoxybenzoyl)Thiazoles as Novel Anticancer Agents  

PubMed Central

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.

Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Preti, Delia; Tabrizi, Mojgan Aghazadeh; Brancale, Andrea; Fu, Xian-Hua; Li, Jun; Zhang, Su-Zhan; Hamel, Ernest; Bortolozzi, Roberta; Porcu, Elena; Basso, Giuseppe; Viola, Giampietro

2012-01-01

359

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751  

PubMed Central

Objective ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751. Methods UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes. Results UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (> 2) was associated with an average 34% increase in ABT-751 clearance (P= 0.044), an 18% reduction in ABT-751 AUC (P = 0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P =0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 Ctrough (P = 0.009). Conclusion These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.

Innocenti, Federico; Ramirez, Jacqueline; Obel, Jennifer; Xiong, Julia; Mirkov, Snezana; Chiu, Yi-Lin; Katz, David A.; Carr, Robert A.; Zhang, Wei; Das, Soma; Adjei, Araba; Moyer, Ann M.; Chen, Pei Xian; Krivoshik, Andrew; Medina, Diane; Gordon, Gary B.; Ratain, Mark J.; Sahelijo, Leonardo; Weinshilboum, Richard M.; Fleming, Gini F.; Bhathena, Anahita

2013-01-01

360

Thiosemicarbazone Cu(II) and Zn(II) complexes as potential anticancer agents: Syntheses, crystal structure, DNA cleavage, cytotoxicity and apoptosis induction activity.  

PubMed

Four novel thiosemicarbazone metal complexes, [Cu(Am4M)(OAc)]·H2O (1), [Zn(HAm4M)Cl2] (2), [Zn2(Am4M)2Br2] (3) and [Zn2(Am4M)2(OAc)2]·2MeOH (4) [HAm4M=(Z)-2-(amino(pyridin-2-yl)methylene)-N-methylhydrazinecarbothioamide], have been synthesized and characterized by X-ray crystallography, elemental analysis, ESI-MS and IR. X-ray analysis revealed that complexes 1 and 2 are mononuclear, which possess residual coordination sites for Cu(II) ion in 1 and good leaving groups (Cl(-)) for Zn(II) ion in 2. Both 3 and 4 displayed dinuclear units, in which the metal atoms are doubly bridged by S atoms of two Am4M(-) ligands in 3 and by two acetate ions in bi- and mono-dentate forms, respectively, in 4. Their antiproliferative activities on human epithelial cervical cancer cell line (HeLa), human liver hepatocellular carcinoma cell line (HepG-2) and human gastric cancer cell line (SGC-7901) were screened. Inspiringly, IC50 value (11.2±0.9?M) of complex 1 against HepG-2 cells was nearly 0.5 fold of that against human hepatic cell lines LO2, showing a lower toxicity to human liver cells. Additionally, it displayed a stronger inhibition on the viability of HepG-2 cells than cisplatin (IC50=25±3.1?M), suggesting complex 1 might be a potential high efficient antitumor agent. Furthermore, fluorescence microscopic observation and flow cytometric analysis revealed that complex 1 could significantly suppress HepG-2 cell viability and induce apoptosis. Several indexes, such as DNA cleavage, reactive oxygen species (ROS) generation, comet assay and cell cycle analysis indicated that the antitumor mechanism of complex 1 on HepG-2 cells might be via ROS-triggered apoptosis pathway. PMID:24690556

Shao, Jia; Ma, Zhong-Ying; Li, Ang; Liu, Ya-Hong; Xie, Cheng-Zhi; Qiang, Zhao-Yan; Xu, Jing-Yuan

2014-07-01

361

Docetaxel nanotechnology in anticancer therapy.  

PubMed

Taxanes have been recognized as a family of very efficient anticancer drugs, but the formulation in use for the two main taxanes-Taxol for paclitaxel and Taxotere for docetaxel-have shown dramatic side effects. Whereas several new formulations for paclitaxel have recently appeared, such as Abraxane and others currently in various phases of clinical trials, there is no new formulation in clinical trials for the other main taxane, docetaxel, except BIND-014, a polymeric nanoparticle, which recently entered phase I clinical testing. Therefore, we review herein the state of the art and recent abundance in published results of academic approaches toward nanotechnology-based drug-delivery systems containing nanocarriers and targeting agents for docetaxel formulations. These efforts will certainly enrich the spectrum of docetaxel treatments in the near future. Taxotere's systemic toxicity, low water solubility, and other side effects are significant problems that must be overcome. To avoid the limitations of docetaxel in clinical use, researchers have developed efficient drug-delivery assemblies that consist of a nanocarrier, a targeting agent, and the drug. A wide variety of such engineered nanosystems have been shown to transport and eventually vectorize docetaxel more efficiently than Taxotere in vitro, in vivo, and in pre-clinical administration. Recent progress in drug vectorization has involved a combined therapy and diagnostic ("theranostic") approach in a single drug-delivery vector and could significantly improve the efficiency of such an anticancer drug as well as other drug types. PMID:22517723

Zhao, Pengxiang; Astruc, Didier

2012-06-01

362

Development and validation of limited sampling strategies for prediction of the systemic exposure to the novel anticancer agent E7070 (N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide)  

PubMed Central

Aims E7070 is a novel, sulphonamide anticancer agent currently under clinical development for the treatment of solid tumours. The aim of this study was to develop and validate limited sampling strategies for the prediction of E7070 exposure in two different treatment schedules for phase II studies using the Bayesian estimation approach. Methods Data from two phase I dose finding studies were used in which E7070 was administered either as a single 1 h infusion or as a daily 1 h infusion for 5 days. Plasma concentration-time data from 75 patients were randomly divided into an index data set, used for the development of the strategies, and a validation data set. Population pharmacokinetic parameters were derived on the basis of the index data set. The D-optimality algorithm was used for the selection of optimal time points for both treatment schedules. The developed strategies were compared by assessment of their predictive performance of exposure, expressed as AUC (area under the plasma concentration vs time curve), in the validation data set. Results The developed population pharmacokinetic model comprised three compartments, with saturable distribution to one peripheral compartment and both linear and saturable elimination from the central compartment. For the 1 h infusion, a four sample strategy was selected which resulted in unbiased and accurate predictions of AUC (bias 0.74%, precision 13%). A five sample strategy was generated for the daily times five schedule yielding unbiased (bias 3.2%) and precise (12% precision) predictions of AUC. Conclusions Optimal sampling strategies were developed and validated for estimation of E7070 exposure in two different treatment schedules. Both schedules enabled accurate and unbiased predictions of AUC.

van Kesteren, Charlotte; Mathot, R A A; Raymond, E; Armand, J P; Fumoleau, P; Punt, C; Ravic, M; Wanders, J; Beijnen, J H; Schellens, J H M

2002-01-01

363

Selective anticancer agents suppress aging in Drosophila  

PubMed Central

Mutations of the PI3K, TOR, iNOS, and NF-?B 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-?B (pyrrolidin dithiocarbamate and QNZ), and the combined effects of inhibitors: PI3K (wortmannin) and TOR (rapamycin), NF-?B (pyrrolidin dithiocarbamates) and PI3K (wortmannin), NF-?B (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-?B, and iNOS increases lifespan of Drosophila without decreasing quality of life. The greatest lifespan expanding effect was achieved by a combination of rapamycin (5 ?M) and wortmannin (5 ?M) (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.

Danilov, Anton; Shaposhnikov, Mikhail; Plyusnina, Ekaterina; Kogan, Valeria; Fedichev, Peter; Moskalev, Alexey

2013-01-01

364

Aurora-kinase inhibitors as anticancer agents  

Microsoft Academic Search

Errors in mitosis can provide a source of the genomic instability that is typically associated with tumorigenesis. Many mitotic regulators are aberrantly expressed in tumour cells. These proteins could therefore make useful therapeutic targets. The kinases Aurora-A, -B and -C represent a family of such targets and several small-molecule inhibitors have been shown to block their function. Not only have

Stephen Taylor; Nicholas Keen

2004-01-01

365

Selective anticancer agents suppress aging in Drosophila.  

PubMed

Mutations of the PI3K, TOR, iNOS, and NF-?B 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-?B (pyrrolidin dithiocarbamate and QNZ), and the combined effects of inhibitors: PI3K (wortmannin) and TOR (rapamycin), NF-?B (pyrrolidin dithiocarbamates) and PI3K (wortmannin), NF-?B (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-?B, and iNOS increases lifespan of Drosophila without decreasing quality of life. The greatest lifespan expanding effect was achieved by a combination of rapamycin (5 ?M) and wortmannin (5 ?M) (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

Danilov, Anton; Shaposhnikov, Mikhail; Plyusnina, Ekaterina; Kogan, Valeria; Fedichev, Peter; Moskalev, Alexey

2013-09-01

366

Anti-Cancer Potential of a Novel SERM Ormeloxifene  

PubMed Central

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.

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

2014-01-01

367

Anti-cancer potential of a novel SERM ormeloxifene.  

PubMed

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

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

2013-01-01

368

Effects of Microtubule-Depolymerizing Agents on the Transfection of Cultured Vascular Smooth Muscle Cells: Enhanced Expression with Free Drug and Especially with Drug–Gene Lipoplexes  

Microsoft Academic Search

The microtubule-depolymerizing agents colchicine, vinblastine (VB), vincristine, nocodazole, and podophyllotoxin were found to increase dramatically the transfection of cationic phospholipid–DNA (CMV–?-gal) complexes on cultured vascular smooth muscle cells (VSMCs). Pretreatment of cells with free colchicine before addition of lipoplexes increased transgene expression both in the presence and in the absence of serum. Free vinblastine had similar effects; however, vinblastine was

Li Wang; Robert C. MacDonald

2004-01-01

369

Fungal metabolites: structural diversity as incentive for anticancer drug development  

Microsoft Academic Search

Natural products play an important role in the development of anticancer drugs. To date, predominantly metabolites from plants\\u000a and bacteria served as lead structures for anticancer agents. Fungal metabolites and derivatives thereof are much less investigated\\u000a for their potential in cancer therapy. There are, however, some promising candidates derived from fungi in clinical phases\\u000a I and II studies. This review

Hendrik Greve; Ietidal E. Mohamed; Alexander Pontius; Stefan Kehraus; Harald Gross; Gabriele M. König

2010-01-01

370

Anti-cancer action of retinoids.  

PubMed Central

The anti-cancer action of retinyl acetate (Vitamin-A acetate, VAA), chosen as a representative retinoid substance, is attributed to its power to exercise immunopotentiation, though other possibilities are considered. The reasons for forming this opinion were: (1) chronic administration of VAA brought about enlargement of the thymus and peripheral lymph nodes; (2) the administration of VAA curtailed the life of skin allografts though (3) its action could be reversed by the concomitant administration of immunosuppressive agents.

Medawar, P B; Hunt, R

1981-01-01

371

Anticancer activity of ferrocenylthiosemicarbazones.  

PubMed

Aliphatic and aromatic ferrocenylthiosemicarbazones were synthesized. The characterization of the new ferrocenylthiosemicarbazones was done by IR, (1)H-NMR and (13)C-NMR spectroscopy, elemental analysis and X-ray diffraction studies. The biological activity of the obtained compounds was assessed in terms of anticancer activity. Their activity against U251 (human glyoblastoma), PC-3 (human prostatic adenocarcinoma), K562 (human chronic myelogenous leukemia), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma) and SKLU-1 (human lung adenocarcinoma) cell lines was studied and compared with cisplatin. All tested compounds showed good activity and the aryl-chloro substituted ferrocenylthiosemicarbazones showed the best anticancer activity. PMID:24144199

Sandra, Cortez-Maya; Elena, Klimova; Marcos, Flores-Alamo; Elena, Martínez-Klimova; Arturo, Ramírez-Ramírez; Teresa, Ramírez Apan; Marcos, Martínez-García

2014-03-01

372

X-ray structure, solution properties, and biological activity profile of vanadocene(IV) acetylacetonate complex, [VCp 2(acac)](CF 3SO 3): a dual-function anti-cancer agent with anti-angiogenic and anti-mitotic properties  

Microsoft Academic Search

The structure of [V(?5-C5H5)2(CH3C(O)CHC(O)CH3)](O3SCF3) (1) (=[VCp2(acac)](O3SCF3)), a dual-function anti-cancer agent with anti-angiogenic and anti-mitotic properties, was determined by single-crystal X-ray diffraction. The geometry is well described as a pseudo-tetrahedral like structure with the centroids of the cyclopentadienyl rings and the two oxygen atoms of the acetylacetonate ring in the ancillary positions of the central vanadium (IV) atom. The bisector of

Phalguni Ghosh; Sutapa Ghosh; Christopher Navara; Rama Krishna Narla; Alexey Benyumov; Fatih M Uckun

2001-01-01

373

Cell Death Signaling and Anticancer Therapy  

PubMed Central

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.

Galluzzi, Lorenzo; Vitale, Ilio; Vacchelli, Erika; Kroemer, Guido

2011-01-01

374

Anticancer drug pharmacodynamics  

Microsoft Academic Search

Summary A considerable amount of information is available on the pharmacokinetics of anticancer drugs, but much less is known of their pharmacodynamics, that is of the relationship between therapeutic or toxic response and drug concentration. Drug dosage regimens which are to achieve defined therapeutic objectives can only be designed when both the pharmacokinetic and the pharmacodynamic characteristics of a drug

Garth Powis

1985-01-01

375

"Nutritional and chemopreventive anti-cancer agents up-regulate expression of p27Kip1, a cyclin-dependent kinase inhibitor, in mouse JB6 epidermal and human MCF7, MDA-MB-321 and AU565 breast cancer cells"  

PubMed Central

Background p27(Kip1) is a cyclin-dependent kinase inhibitor. When up-regulated, p27 inhibits G1-to-S phase transition of the cell cycle. This report addresses the question of whether various nutritional and chemopreventive anti-cancer agents up-regulate the expression of p27 in preneoplastic and neoplastic cells. Results Experimental evidence presented in the first half of this report shows that these agents fairly faithfully up-regulate expression of p27 in mouse epidermal (JB6) and human breast cancer (MCF7, MDA-MB-321, and AU565) cells. Up-regulation appears to be specific to p27 because expression of cyclin D1, E, and A, and p21Cip1/Waf1 was not modulated by these agents. Up-regulation of the expression of p27 is likely due to the activation of translation rather than transcription of p27 because (a) up-regulation is mediated by the 5'-untranslated region (-575) of the p27 gene and (b) the antibiotic actinomycin D, an inhibitor of transcription, did not attenuate the up-regulation of p27. This latter finding is likely to preclude the existence of cryptic transcription factor binding site(s) in the 5'-untranslated region of p27 gene. The experimental evidence, presented in the second half of this report, was obtained using the 5'-untranslated region (-575) of p27 gene. The evidence suggests that cancer preventive agents up-regulate expression of p27 by at least four different molecular signaling pathways: (a) Caloric restriction is likely to up-regulate p27 expression via 5'-AMP-activated protein kinase (AMPK; a metabolic energy sensor or cellular fuel gauge), tuberous sclerosis complex (TSC), and mammalian target of rapamycin (mTOR). Amino acid deficiencies also up-regulate the expression of p27 using some components of this pathway. (b) 4-Hydroxytamoxifen (but not tamoxifen), genistein (but not genistin), daidzein, and probably other nutritional and chemopreventive anti-cancer agents could up-regulate expression of p27 via receptor protein tyrosine kinases (RPTKs), phosphoinositide 3-kinase (PI3K), phosphoinosite-dependent kinase (PDK), Akt/PKB and mTOR. (c) Expression of p27 could also be up-regulated via RPTKs followed by MAPKs – MEK, ERK and p38MAPK – and probably MNK. Finally, (d) global hypomethylation of 5'-m7G cap of mRNAs could also up-regulate expression of p27. Conclusion Based on these findings, we conclude that various nutritional and chemopreventive anti-cancer agents up-regulate expression of p27 in (pre)neoplastic cells.

Eto, Isao

2006-01-01

376

Anticancer properties of Monascus metabolites.  

PubMed

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

Yang, Tao; Liu, Junwen; Luo, Feijun; Lin, Qinlu; Rosol, Thomas J; Deng, Xiyun

2014-08-01

377

Anticancer attributes of desert plants: a review.  

PubMed

The ever-increasing emergence of the resistance of mammalian tumor cells to chemotherapy and its severe side effects reduces the clinical efficacy of a large variety of anticancer agents that are currently in use. Thus, despite the significant progress in cancer therapeutics in the last decades, the need to discover and to develop new, alternative, or synergistic anticancer agents remains. Cancer prevention or chemotherapy based on bioactive fractions or pure components derived from desert plants with known cancer-inhibiting properties suggests promising alternatives to current cancer therapy. Plants growing on low nutrient soils and/or under harsh climatic conditions, such as extreme temperatures, intense solar radiation, and water scarcity, are particularly susceptible to attack from reactive oxygen species and have evolved efficient antioxidation defense systems. The many examples of desert plants displaying anticancer effects as presented here indicates that the same defensive secondary metabolites protecting them against the harsh environment may also play a protective or a curative role against cancer, as they also do against diabetes, neurodegenerative, and other acute and chronic diseases. The present review highlights a plethora of studies focused on the antineoplastic properties of desert plants and their prinicipal phytochemicals, such as saponins, flavonoids, tannins, and terpenes. Although many desert plants have been investigated for their antitumor properties, there are many that still remain to be explored - a challenge for the prospective cancer therapy of the future. PMID:22217921

Harlev, Eli; Nevo, Eviatar; Lansky, Ephraim P; Lansky, Shifra; Bishayee, Anupam

2012-03-01

378

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

PubMed

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

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

2013-03-15

379

RIBONUKLEÁZY \\/RNÁZY\\/ V PROTINÁDOROVÉ TERAPII RIBONUCLEASES \\/RNASES\\/ IN ANTI-CANCER TREATMENT  

Microsoft Academic Search

One of perspective trends in the systemic anti-cancer treatment is the use of enzymes splitting ribo- nucleic acid - ribonucleases \\/RNases\\/. A number of both natural and genetically modified RNases are currently being subjected to different stages of studies and some of them are promising as efficient anticancer agents. RNase from frog eggs and embryos - onconase (ranpirnase) - is

T. ECKSCHLAGER; P. POUâKOVÁ; J. MATOU

2005-01-01

380

Total Synthesis of Bryostatin 16 using a Pd-Catalyzed Diyne-Coupling as Macrocyclization Method and Synthesis of C20-epi-Bryostatin 7 as a Potent Anticancer Agent  

PubMed Central

Asymmetric total synthesis of bryostatin 16 was achieved in 26 steps in the longest linear sequence/39 total steps from aldehyde 10. A Pd-catalyzed alkyne-alkyne coupling was employed for the first-time as a macrocyclization method in a natural product synthesis. A route to convert bryostatin 16 to a new family of bryostatin analogues was developed. Toward the end, 20-epi-bryostatin 7, was synthesized from a bryostatin 16-like intermediate; and the key step involves a Re-catalyzed epoxidation/ring-opening reaction. Preliminary biological studies indicated that this new analogue exhibits nanomolar anti-cancer activity against several cancer cell lines.

Trost, Barry M.; Dong, Guangbin

2010-01-01

381

Poly( l-glutamic acid)–anticancer drug conjugates  

Microsoft Academic Search

Chemotherapy has had limited success in the treatment of cancer over the years, due, in part, to the untoward toxicity of the therapeutic agent to normal cells. The design of tailor-made polymer conjugates provides a synthetic approach that can overcome some of the problems. Several synthetic polymer-based anticancer drug conjugates have entered clinical studies. This report reviews the chemistry, physicochemical

Chun Li

2002-01-01

382

Studies on Anticancer Activities of Antimicrobial Peptides  

PubMed Central

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.

Hoskin, David W.; Ramamoorthy, Ayyalusamy

2008-01-01

383

Indisulam: an anticancer sulfonamide in clinical development.  

PubMed

Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, E7070) is a novel sulfonamide anticancer agent in clinical development for the treatment of solid tumours. Its mechanism of action is multifactorial, as indisulam arrests cell cycle in the G1 phase, strongly inhibits carbonic anhydrase, a critical enzyme involved in many physiological processes and whose association with cancer became obvious in the last period, and markedly alters gene expression levels of at least 60 transcripts. Four Phase I clinical trials gave promising results, showing the compound to possess nonlinear pharmacokinetics. Presently this compound is in Phase II trials in Europe and USA for the treatment of solid tumours. PMID:12556221

Supuran, Claudiu T

2003-02-01

384

Use of plasma cytotoxic activity to model cytotoxic pharmacodynamics of anticancer drugs  

Microsoft Academic Search

We have developed a pharmacokinetic\\/pharmacodynamic approach that integrates the disposition, cytotoxic activity and interaction of anticancer drugs. Fundamental to this approach is the measurement of the cytotoxicity, against a “target” cell line, of patient plasma collected at different times after administration of the anticancer agent(s). To illustrate this approach, we have studied the plasma cytotoxic activity (PCA), against HL-60 cells,

Dominique L. de Valeriola; Douglas D. Ross; Alan Forrestl; Dennis P. Cuddyl; Merrill J. Egorinl

1991-01-01

385

Novel anticancer therapeutics targeting telomerase.  

PubMed

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

Ruden, Maria; Puri, Neelu

2013-08-01

386

Synthesis, molecular modeling and biological evaluation of N-benzylidene-2-((5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)thio)acetohydrazide derivatives as potential anticancer agents.  

PubMed

A series of new 1,3,4-oxadiazole derivatives (6a-6x) containing pyridine and acylhydrazone moieties were synthesized and developed as potential telomerase inhibitors. The bioassay tests demonstrated that compounds 6n, 6o, 6q, 6s and 6t exhibited significant broad-spectrum anticancer activity with IC?? range from 0.76 to 9.59 ?M against the four cancer cell lines (HEPG2, MCF7, SW1116 and BGC823). Moreover, all the title compounds were assayed for telomerase inhibition using the TRAP-PCR-ELISA assay. Compound 6s showed the highest anticancer activity with IC?? of 0.76-1.54 ?M against the tested cancer cell lines and exhibited the most potent telomerase inhibitory activity with IC?? of 1.18 ± 0.14 ?M. The docking simulation was carried out to investigate a possible binding mode of compound 6s into the active site of telomerase (pdb. 3DU6) while the QSAR model was built to check the previous work as well as to introduce new directions. PMID:24286761

Zhang, Fei; Wang, Xiao-Liang; Shi, Jing; Wang, She-Feng; Yin, Yong; Yang, Yu-Shun; Zhang, Wei-Ming; Zhu, Hai-Liang

2014-01-01

387

Melatonin anticancer effects: review.  

PubMed

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

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

2013-01-01

388

Anticancer Effects of Glutamate Antagonists  

Microsoft Academic Search

The discovery of anticancer activity of glutamate antagonists provides new challenges for cancer biologists and the pharmaceutical industry. One crucial issue to resolve is determining whether glutamate antagonists exert similar anticancer activityin vivo. It will be important to decipher the molecular pathways that glutamate antagonists utilize to limit tumor growth, invasiveness, and migration. The electrophysiological and binding properties of glutamate

Wojciech Rzeski; Lechoslaw Turski; Chrysanthy Ikonomidou

389

Anticancer substances of mushroom origin.  

PubMed

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

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

2014-06-01

390

Synthesis and biological evaluation of some novel 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazin-3(2H)-ones as anti-cancer, antimicrobial, and anti-inflammatory agents.  

PubMed

A series of 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazin-3(2H)-ones (2a-j) were synthesized by condensation of the appropriate beta-aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol and tested for anti-cancer, anti-inflammatory, and antimicrobial actions. According to the protocol of the National Cancer Institute (NCI) in vitro disease-oriented human cells screening panel assay, compound 2g showed high activity against HL-60 (TB) (leukemia), SR (leukemia), NCI-H522 (non-small-cell lung cancer), and BT-549 (breast cancer) with a GI(50) value of less than 2 microM. Two compounds (2c and 2f) were found to have promising anti-inflammatory activity, while a fair number of compounds showed good antifungal activity. PMID:20038271

Ahmad, Shamim; Rathish, I G; Bano, Sameena; Alam, M S; Javed, Kalim

2010-04-01

391

Ribonucleases as potential modalities in anticancer therapy  

PubMed Central

Antitumor ribonucleases are small (10–28 kDa) basic proteins. They were found among members of both, ribonuclease A and T1 superfamilies. Their cytotoxic properties are conferred by enzymatic activity, i.e., the ability to catalyze cleavages of phosphodiester bonds in RNA. They bind to negatively charged cell membrane, enter cells by endocytosis and translocate to cytosol where they evade mammalian protein ribonuclease inhibitor and degrade RNA. Here, we discuss structures, functions and mechanisms of antitumor activity of several cytotoxic ribonucleases with particular emphasis to the amphibian Onconase, the only enzyme of this class that reached clinical trials. Onconase is the smallest, very stable, less catalytically efficient and more cytotoxic than most RNase A homologues. Its cytostatic, cytotoxic and anticancer effects were extensively studied. It targets tRNA, rRNA, mRNA as well as the non-coding RNA (microRNAs). Numerous cancer lines are sensitive to Onconase; their treatment with 10 – 100 nM enzyme leads to suppression of cell cycle progression, predominantly through G1, followed by apoptosis or cell senescence. Onconase also has anticancer properties in animal models. Many effects of this enzyme are consistent with the microRNAs, one of its critical targets. Onconase sensitizes cells to a variety of anticancer modalities and this property is of particular interest, suggesting its application as an adjunct to chemotherapy or radiotherapy in treatment of different tumors. Cytotoxic RNases as exemplified by Onconase represent a new class of antitumor agents, with an entirely different mechanism of action than the drugs currently used in the clinic. Further studies on animal models including human tumors grafted on severe combined immunodefficient (SCID) mice and clinical trials are needed to explore clinical potential of cytotoxic RNases.

Ardelt, Wojciech; Ardelt, Barbara; Darzynkiewicz, Zbigniew

2009-01-01

392

Ribonucleases as potential modalities in anticancer therapy.  

PubMed

Antitumor ribonucleases are small (10-28 kDa) basic proteins. They were found among members of both, ribonuclease A and T1 superfamilies. Their cytotoxic properties are conferred by enzymatic activity, i.e., the ability to catalyze cleavages of phosphodiester bonds in RNA. They bind to negatively charged cell membrane, enter cells by endocytosis and translocate to cytosol where they evade mammalian protein ribonuclease inhibitor and degrade RNA. Here, we discuss structures, functions and mechanisms of antitumor activity of several cytotoxic ribonucleases with particular emphasis to the amphibian Onconase, the only enzyme of this class that reached clinical trials. Onconase is the smallest, very stable, less catalytically efficient and more cytotoxic than most RNase A homologues. Its cytostatic, cytotoxic and anticancer effects were extensively studied. It targets tRNA, rRNA, mRNA as well as the non-coding RNA (microRNAs). Numerous cancer lines are sensitive to Onconase; their treatment with 10-100 nM enzyme leads to suppression of cell cycle progression, predominantly through G(1), followed by apoptosis or cell senescence. Onconase also has anticancer properties in animal models. Many effects of this enzyme are consistent with the microRNAs, one of its critical targets. Onconase sensitizes cells to a variety of anticancer modalities and this property is of particular interest, suggesting its application as an adjunct to chemotherapy or radiotherapy in treatment of different tumors. Cytotoxic RNases as exemplified by Onconase represent a new class of antitumor agents, with an entirely different mechanism of action than the drugs currently used in the clinic. Further studies on animal models including human tumors grafted on severe combined immunodefficient (SCID) mice and clinical trials are needed to explore clinical potential of cytotoxic RNases. PMID:19825371

Ardelt, Wojciech; Ardelt, Barbara; Darzynkiewicz, Zbigniew

2009-12-25

393

The immunomodulatory and anticancer properties of propolis.  

PubMed

Propolis, a waxy substance produced by the honeybee, has been adopted as a form of folk medicine since ancient times. It has a wide spectrum of alleged applications including potential anti-infection and anticancer effects. Many of the therapeutic effects can be attributed to its immunomodulatory functions. The composition of propolis can vary according to the geographic locations from where the bees obtained the ingredients. Two main immunopotent chemicals have been identified as caffeic acid phenethyl ester (CAPE) and artepillin C. Propolis, CAPE, and artepillin C have been shown to exert summative immunosuppressive function on T lymphocyte subsets but paradoxically activate macrophage function. On the other hand, they also have potential antitumor properties by different postulated mechanisms such as suppressing cancer cells proliferation via its anti-inflammatory effects; decreasing the cancer stem cell populations; blocking specific oncogene signaling pathways; exerting antiangiogenic effects; and modulating the tumor microenvironment. The good bioavailability by the oral route and good historical safety profile makes propolis an ideal adjuvant agent for future immunomodulatory or anticancer regimens. However, standardized quality controls and good design clinical trials are essential before either propolis or its active ingredients can be adopted routinely in our future therapeutic armamentarium. PMID:22707327

Chan, Godfrey Chi-Fung; Cheung, Ka-Wai; Sze, Daniel Man-Yuen

2013-06-01

394

Combination therapy: opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines.  

PubMed

The discovery of new molecular targets and the subsequent development of novel anticancer agents are opening new possibilities for drug combination therapy as anticancer treatment. Polymer-drug conjugates are well established for the delivery of a single therapeutic agent, but only in very recent years their use has been extended to the delivery of multi-agent therapy. These early studies revealed the therapeutic potential of this application but raised new challenges (namely, drug loading and drugs ratio, characterisation, and development of suitable carriers) that need to be addressed for a successful optimisation of the system towards clinical applications. PMID:19699247