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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. PMID:23646116

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



Subcutaneous administration of anticancer agents.  


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



Anticancer agents against malaria: time to revisit?  

PubMed Central

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



Glutamic acid as anticancer agent: An overview  

PubMed Central

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

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



Novel antibodies as anticancer agents  

Microsoft Academic Search

In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's ‘magic bullets’ to a modern age ‘guided missile’. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field

I Zafir-Lavie; Y Michaeli; Y Reiter



Radiation Recall with Anticancer Agents  

PubMed Central

Radiation recall is an acute inflammatory reaction confined to previously irradiated areas that can be triggered when chemotherapy agents are administered after radiotherapy. It remains a poorly understood phenomenon, but increased awareness may aid early diagnosis and appropriate management. A diverse range of drugs used in the treatment of cancer has been associated with radiation recall. As most data come from case reports, it is not possible to determine the true incidence, but to date the antineoplastic drugs for which radiation recall reactions have been most commonly reported include the anthracycline doxorubicin, the taxanes docetaxel and paclitaxel, and the antimetabolites gemcitabine and capecitabine. Radiation recall is drug-specific for any individual patient; it is not possible to predict which patients will react to which drugs, and rechallenge does not uniformly induce a reaction. There are no identifiable characteristics of drugs that cause radiation recall, and thus, it is a possibility that must be kept in mind with use of any drug after radiotherapy, including those from new drug classes. Although it is not yet possible to design treatment regimens to eliminate the risk of radiation recall, it seems likely that risks can be minimized by prolonging the interval between completion of radiotherapy and initiation of chemotherapy. PMID:21045191

Hurtig, Jane



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. PMID:23459471

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



Organoiridium complexes: anticancer agents and catalysts.  


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



Oral anticancer agent medication adherence by outpatients  

PubMed Central

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




Glufosfamide as a new oxazaphosphorine anticancer agent.  


Glufosfamide (?-D-glucose-isophosphoramide mustard, D-19575) belongs to the oxazaphosphorine class. Glufosfamide is a novel glucose conjugate of ifosfamide in which isophosphoramide mustard, the alkylating metabolite of ifosfamide, is glycosidically linked to the ?-D-glucose molecule. Glufosfamide represents an attractive new agent for cancer therapy. Its mode of action on normal and pathological cells is still under experimental and clinical investigations. An assessment of the anticancer potential of glufosfamide is of key importance in therapy. The researchers reviewed the current knowledge available on glufosfamide tested in the preclinical studies/clinical trials, based on a collection of the original papers and conference abstracts published and relevant articles searched in the SCOPUS and MEDLINE database and websites. PMID:21427562

Mazur, Lidia; Opydo-Chanek, Ma?gorzata; Stojak, Marta



Anti-cancer agents counteracting tumor glycolysis  

PubMed Central

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

Granchi, Carlotta



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. PMID:21572642

Chakraborti, Chandra Kanti



Comparative study of microtubule inhibitors--estramustine and natural podophyllotoxin conjugated PAMAM dendrimer on glioma cell proliferation.  


The synthetic estramustine (EM) and natural podophyllotoxin (PODO) anti-mitotic agents that inhibit tubulin polymerization are known anticancer agents. As low bioavailability limits their anticancer properties, we investigated whether conjugation with PAMAM dendrimer (D) could enhance the activity of D-EM and D-PODO by altering their release pattern. Release kinetics indicated synthesized conjugates to be stable against hydrolytic cleavage and showed sustained release characteristics. However, release of D-EM was slow compared to D-PODO conjugate. Antitumor effect of these conjugates on glioma cells revealed (i) increased cell death and cell cycle arrest (ii) decreased migration and (iii) increased tubulin depolymerization as compared to free drug. Importantly, the effects of natural PODO conjugate on glioma cell survival and migration is more pronounced than D-EM. PMID:23954240

Sk, Ugir Hossain; Dixit, Deobrat; Sen, Ellora



Pharmacogenetics and pharmacogenomics of anticancer agents  

Microsoft Academic Search

Abstract Large interindividual variation is observed in both the response and toxicity associated with anticancer therapy. The etiology of this variation is multifactorial, but is due in part to host genetic variations. Pharmacogenetic and pharmacogenomic,studies have,successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. This review provides an overview of the progress made,in the field of

R. Stephanie Huang; Mark J. Ratain



Pyrazoline bearing benzimidazoles: Search for anticancer agent  

Microsoft Academic Search

2-acetyl benzimidazole was allowed to react with substituted aromatic aldehydes to get desired intermediate chalcones (2a–g), the cyclocondensation of these intermediates with hydrazine hydrate and phenyl hydrazine in two separate reactions yielded pyrazoline derivatives (3a–g &4a–g respectively). Among the synthesize compounds, six compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a

Mohammad Shaharyar; M. M. Abdullah; M. A. Bakht; Jaseela Majeed



Microtubule-targeting anticancer agents from marine natural substance.  


Effective novel therapeutics is urgently needed due to increasing incidence of malignant cancer and drug multi-resistance. Natural products and their derivatives have historically been a source of pharmaceutical leads and therapeutic drugs. Microtubule-targeting compounds are among the most promising candidates in the combat against cancer. In particular, marine natural products (MNPs) have demonstrated exceptional potency and potential as anticancer agents. Drug discovery from MNPs provides a new pathway to develop original anticancer agents. In this review, seven classes of typical MNPs with diverse structures are summarized. Bioactive marine compounds isolated from different organisms including invertebrate animals, algae, fungi and bacteria are also discussed. PMID:24533652

Liu, Zhiguo; Xu, Pengfei; Wu, Tao; Zeng, Wenbin



Production of anti-cancer agent using microbial biotransformation.  


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

Roh, Changhyun; Kang, ChanKyu



Chemistry and chemical biology of taxane anticancer agents.  


Taxol (paclitaxel) and Taxotere (docetaxel) are currently considered to be among the most important anticancer drugs in cancer chemotherapy. The anticancer activity of these drugs is ascribed to their unique mechanism of action, i.e., causing mitotic arrest in cancer cells, leading to apoptosis through inhibition of the depolymerization of microtubules. Although both paclitaxel and docetaxel possess potent antitumor activity, treatment with these drugs often results in a number of undesirable side effects, as well as multidrug resistance (MDR). Therefore, it has become essential to develop new anticancer agents with superior pharmacological properties, improved activity against various classes of tumors, and fewer side effects. This paper describes an account of our research on the chemistry of paclitaxel and taxoid anticancer agents at the biomedical interface, including: 1. The structure-activity relationship (SAR) study of taxoids leading to the development of the "second-generation" taxoids, which possess exceptional activity against drug-resistant cancer cells expressing the MDR phenotype. 2. Development of fluorinated taxoids to study the bioactive conformation of paclitaxel and photoaffinity labeling taxoids for mapping of the drug-binding domain on both microtubules and P-glycoprotein. 3. The synthesis of novel macrocyclic taxoids for the investigation into the common pharmacophore for microtubule stabilizing anticancer agents. PMID:11895119

Miller, M L; Ojima, I



Insight into the reactive form of the anticancer agent iproplatin.  


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

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



Pyrazoline bearing benzimidazoles: search for anticancer agent.  


2-acetyl benzimidazole was allowed to react with substituted aromatic aldehydes to get desired intermediate chalcones (2a-g), the cyclocondensation of these intermediates with hydrazine hydrate and phenyl hydrazine in two separate reactions yielded pyrazoline derivatives (3a-g &4a-g respectively). Among the synthesize compounds, six compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the selected compounds, (4f) 2-[5-(3,4-dimethoxyphenyl)-1-phenyl-4,5-dihydro-1H-3-pyrazolyl]-1H-benzimidazole (NSC 748326) was found to be the most active candidate of the series and selected for further evaluation at five dose level screening. PMID:19883957

Shaharyar, Mohammad; Abdullah, M M; Bakht, M A; Majeed, Jaseela



Fucoidan as a marine anticancer agent in preclinical development.  


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. PMID:24477286

Kwak, Jong-Young



Underestimated potential of organometallic rhenium complexes as anticancer agents.  


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

Leonidova, Anna; Gasser, Gilles



RNA molecules as anti-cancer agents  

Microsoft Academic Search

The inhibition of cancer growth and progression is one of the major challenges facing modern medicine. Despite significant progress in the development of therapies against cancer, only in a few cases are these therapies effective. Because cancer is a complex disease, agents that target a single oncogenic pathway have low efficacy, in addition to allowing the emergence of drug resistance.

Inbar Friedrich; Alexei Shir; Shoshana Klein; Alexander Levitzki



Discovery and development of anticancer agents from plants.  


A novel in vitro assay for the discovery of anticancer agents was used to examine aqueous and organic extracts from 1847 plants collected mainly in the U.S. Southwest and West. The assay results were separated into 5 categories: inactive (62%), equally active (36%), equally active and potent (0.5%), solid tumor selective (1.4%), and human selective (0.8%). Extracts from the latter three categories were fractionated using the in vitro assay to biodirect each step. Psorothamnus emoryi extracts were solid tumor selective and yielded two active compounds upon fractionation: dalrubone and 5-methoxydalrubone. Calocedrus decurrens was equally active and potent and yielded deoxypodophyllotoxin as the active compound. Linanthus floribundus was human selective and yielded strophanthidin as the active compound. The potential of this assay to discover novel anticancer agents from the active extracts is discussed. PMID:12416027

Valeriote, Fred; Grieshaber, Charles K; Media, Joseph; Pietraszkewicz, Halina; Hoffmann, Joseph; Pan, Meide; McLaughlin, Steve



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



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. PMID:24183971

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



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


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

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



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. PMID:24205049

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



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



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. PMID:22202049

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



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


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

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



Recent advances in the new generation taxane anticancer agents.  


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

Geney, R; Chen, J; Ojima, I



Chromatin-modifying agents in anti-cancer therapy.  


Epigenetic alterations are involved in every step of carcinogenesis. The development of chromatin-modifying agents (CMAs) has provided the ability to fight cancer by reversing these alterations. Currently, four CMAs have been approved for cancer treatment; two DNA demethylating agents and two deacetylase inhibitors. A number of promising CMAs are undergoing clinical trials in several cancer types. Moreover, already approved CMAs are still under clinical investigation to improve their efficacy and to extend their use to a broader panel of cancers. Combinatorial treatments with CMAs are already considered a promising strategy to improve clinical benefits and to limit side effects. The real mechanisms by which these CMAs allow the improvement and remission of patients are still obscure. A deeper analysis of the molecular features expressed by responding patients should be performed to reveal this information. In this review, we focus on clinical trials with CMAs, discussing the success and the pitfalls of this new class of anti-cancer drugs. PMID:22627380

Seidel, Carole; Florean, Cristina; Schnekenburger, Michael; Dicato, Mario; Diederich, Marc



Monofunctional and Higher-Valent Platinum Anticancer Agents  

PubMed Central

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

Johnstone, Timothy C.; Wilson, Justin J.



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

PubMed Central

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

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



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. PMID:24940431




Selective anti-cancer agents as anti-aging drugs  

PubMed Central

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

Blagosklonny, Mikhail V



Dual extraction of essential oil and podophyllotoxin from Juniperus virginiana  

Microsoft Academic Search

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

Archana J. Gawde; Charles L. Cantrell; Valtcho D. Zheljazkov



2002 Macmillan Magazines Ltd Anticancer agents that target DNA are some of the  

E-print Network

© 2002 Macmillan Magazines Ltd Anticancer agents that target DNA are some of the most effective with high proliferative rates could be treated with alkylating agents,such as the nitrogen mustards displaces a leaving group from the alkylating agent: nu-H + alkyl-Y alkyl-nu + H+ +Y­ . MYELOSUPPRESSION

Gates, Kent. S.


A review of ceramide analogs as potential anticancer agents  

PubMed Central

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

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



Selective cytostatic and cytotoxic anticancer effects of bisfunctional agents: A strategy for the design of DNA binding agents  

Microsoft Academic Search

Various agents have been synthesized and proved useful for the National Cancer Institute’s anticancer testing as potential new drugs, but most agents suffer side effects from their limited selectivity against cancer cells over healthy ones. Therefore, this paper attempts to describe drugs in terms of the level of tumor cell selectivity which they possess to define the features of molecules

Jaros?aw Spycha?a



Metallothionein and anticancer agents: the role of metallothionein in cancer chemotherapy  

Microsoft Academic Search

Summary Metallothioneins (MTs) are intracellular proteins containing the highest amount of thiol groups within the cytoplasm. These thiol groups are able to bind several cytotoxic agents, such as platinum compounds and alkylating agents. Increased levels of MT are one mechanism of resistance to these anticancer drugs, as intracytoplasmic binding of MT prevents the active molecules from reaching their target, the

François Doz; Norbert Roosen; Mark L. Rosenblum



Recent advances in multinuclear complexes as potential anticancer and DNA binding agents.  


In the search for new metal-based anticancer agents as effective candidates for cisplatin, a lot of strategies such as synthesis of cisplatin analogs, trans-platinum compounds and non-platinum metal complexes have been put forward in the last forty years. The concept of multinuclearity for improving the chemotherapeutic activity has been proven in multinuclear platinum complexes such as BBR3464, recently, the effective approach has been successfully transferred to ruthenium complexes. In this review, we highlighted the recent progress in multinuclear platinum complexes and ruthenium complexes as anticancer agents, and their novel DNA binding properties such as phosphate clamps, long range DNA cross links, bisintercalation, interduplex cross links and DNA-protein cross-links were summarized to shed light on the rational design of polynuclear complexes as anticancer agents. PMID:23869783

Wang, Kehua; Gao, Enjun



Nanomicellar carriers for targeted delivery of anticancer agents  

PubMed Central

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

Zhang, Xiaolan; Huang, Yixian; Li, Song



(-)-Arctigenin as a lead compound for anticancer agent.  


(-)-Arctigenin, an important active constituent of the traditional Chinese herb Fructus Arctii, was found to exhibit various bioactivities, so it can be used as a good lead compound for further structure modification in order to find a safer and more potent medicine. (-)-Arctigenin derivatives 1-5 of (-)-arctingen were obtained by modifying with ammonolysis at the lactone ring and sulphonylation at C (6') and C (6?) and O-demethylation at CH3O-C (3'), CH3O-C (3?) and CH3O-C (4?), and their anticancer bioactivities were examined. PMID:23962054

Chen, Gui-Rong; Li, Hong-Fu; Dou, De-Qiang; Xu, Yu-Bin; Jiang, Hong-Shuai; Li, Fu-Rui; Kang, Ting-Guo



Targets of 3-bromopyruvate, a new, energy depleting, anticancer agent.  


3-bromopyruvate (3-BrPA), a pyruvate analog recently proposed as a possible anticancer drug, was investigated in relation to its capacity to inhibit energy production in fractions obtained from normal cells (rat hepatocytes) and in isolated rat thymocytes . Findings were that main targets of the drug were glyceraldehyde 3-phosphate dehydrogenase, and not hexokinase as suggested for hepatoma cells, and succinate -driven ATP synthesis. Consistently with the above findings, in the normal cells studied (thymocytes ) the drug elicited an important fall in ATP levels. The significance of the present findings in concern with a possible therapeutic usefulness of the drug is discussed. PMID:19534685

Dell'Antone, Paolo



Natural products of plant origin as anticancer agents.  


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

Ram, V J; Kumari, S



Hydrogen Peroxide Inducible DNA Cross-Linking Agents: Targeted Anticancer Prodrugs  

PubMed Central

The major concern for anticancer chemotherapeutic agents is the host toxicity. The development of anti-cancer prodrugs targeting the unique biochemical alterations in cancer cells is an attractive approach to achieve therapeutic activity and selectivity. We designed and synthesized a new type of nitrogen mustard prodrug that can be activated by high level of reactive oxygen species (ROS) found in cancer cells to release the active chemotherapy agent. The activation mechanism was determined by NMR analysis. The activity and selectivity of these prodrugs towards ROS was determined by measuring DNA interstrand crosslinks and/or DNA alkylations. These compounds showed 60–90% inhibition toward various cancer cells, while normal lymphocytes were not affected. To the best of our knowledge, this is the first example of H2O2-activated anticancer prodrugs. PMID:22035519

Kuang, Yunyan; Balakrishnan, Kumudha; Gandhi, Varsha; Peng, Xiaohua



Granulocytes as effective anticancer agent in experimental solid tumor models.  


The aim of the study was to elucidate the effects of murine granulocytes on the growth of solid murine tumors when administrated in the vicinity of W256 carcinoma growing in Sprague Dawley rats, and in the vicinity of Ehrlich ascites tumor (EAT) growing in BALBc mice. The administration of granulocytes significantly improved the survival of W256-bearing rats, and increased the tumor regression incidence from 17% up to 75%. Rats with regressing tumors had 2.5 times increased levels of granulocytes in peripheral blood, which were also cytotoxic in vitro for W256 carcinoma cells. However, blood levels of cytokine-induced neutrophil chemoattractant-2, tumor necrosis factor ? and interleukin 6 were similar between rats with regressing tumors and control healthy rats, suggesting that the observed regression of W256 carcinoma was caused by specific anticancer effects of the applied granulocytes. Anticancer effects of granulocytes were also found in BALBc mice bearing solid form of EAT, resulting in a 20% increase of survival in EAT-bearing mice. Therefore, the administration of granulocytes, isolated from healthy animals and applied at the site of solid tumors in rats and in mice, reduced experimental tumor growth, and extended the survival of tumor-bearing animals, while in some rats it even caused a W256 regression. PMID:20122752

Jaganjac, Morana; Poljak-Blazi, Marija; Kirac, Iva; Borovic, Suzana; Joerg Schaur, Rudolf; Zarkovic, Neven



BRCA1 Contributes to Cell Cycle Arrest and Chemoresistance in Response to the Anticancer Agent Irofulven  

Microsoft Academic Search

Tumor suppressor gene BRCA1 is frequently mutated in familial breast and ovarian cancer. BRCA1 plays pivotal roles in main- taining genomic stability by interacting with numerous proteins in cell cycle control and DNA repair. Irofulven (6-hydroxymethyl- acylfulvene, HMAF, MGI 114, NSC 683863) is one of a new class of anticancer agents that are analogs of mushroom- derived illudin toxins. Preclinical

Timothy Wiltshire; Jamie Senft; Yutian Wang; Gregory W. Konat; Sharon L. Wenger; Eddie Reed; Weixin Wang



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



Fluorine in medicinal chemistry: A review of anti-cancer agents  

Microsoft Academic Search

In this review those fluorinated compounds which have found a role as anti-cancer agents are summarized. The emphasis is to highlight the important drugs but also to highlight the latest developments on emerging compounds. This has been done as comprehensively as possible with the objective of informing readers of some of the latest developments in this area.

Chukwuemeka Isanbor; David O’Hagan



Efficient Synthesis of a Novel Resorcyclide as Anticancer Agent Based on Hsp90 Inhibition  

PubMed Central

The highly efficient synthesis of a novel heat shock protein 90 (Hsp90)-based anticancer agent, triazole-cycloproparadicicol (5), is described. The key step involves a fragment coupling using “click chemistry.” The preliminary biological evaluation of triazole-cycloproparadicicol is also reported. PMID:21442009

Lei, Xiaoguang; Danishefsky, Samuel J.



A role for p53 in sensing DNA damage and triggering apoptotic responses to anticancer agents  

Microsoft Academic Search

The p53 tumor suppressor protein plays a major role in cellular responses to anticancer agents that target DNA. DNA damage triggers the accumulation of p53, resulting in the transactivation of genes, which induce cell cycle arrest to allow for repair of the damaged DNA, or signal apoptosis. The exact role that p53 plays in sensing DNA damage and the functional

Geetha Achanta



Inhibition of Nitroso Chemical Carcinogen Activation of Rat Hepatic Guanylate Cyclase by Anticancer Agents  

Microsoft Academic Search

Recent studies have demonstrated that nitroso chemical carcinogens activate guanylate cyclase (EC which catalyzes the production of guanosine 3?,5?-monophosphate. This nucleotide is thought to be involved in normal and abnormal cell growth. We examined the effect of 3 major classes of anticancer chemotherapeutic agents, the antimetabolites (methotrexate and 6-mercaptopurine), antitumor antibiotics (adriamycin and actinomycin D), and alkylating agents (cytoxan,

David L. Vesely; Gerald S. Levey



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

E-print Network

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

Gates, Kent. S.


Tubulin-Interactive Natural Products as Anticancer Agents1  

PubMed Central

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

Kingston, David G. I.



Thioaryl naphthylmethanone oxime ether analogs as novel anticancer agents.  


Employing a rational design of thioaryl naphthylmethanone oxime ether analogs containing functional properties of various anticancer drugs, a series of compounds were identified that displayed potent cytotoxicity toward various cancer cells, out of which 4-(methylthio)phenyl)(naphthalen-1-yl)methanone O-2-(diethylamino)ethyl oxime (MND) exhibited the best safety profile. MND induced apoptosis, inhibited migration and invasion, strongly inhibited cancer stem cell population on a par with salinomycin, and demonstrated orally potent tumor regression in mouse MCF-7 xenografts. Mechanistic studies revealed that MND strongly abrogated EGF-induced proliferation, migration, and tyrosine kinase (TK) signaling in breast cancer cells. However, MND failed to directly inhibit EGFR or other related receptor TKs in a cell-free system. Systematic investigation of a putative target upstream of EGFR revealed that the biological effects of MND could be abrogated by pertussis toxin. Together, MND represents a new nonquinazoline potential drug candidate having promising antiproliferative activity with good safety index. PMID:25198997

Chakravarti, Bandana; Akhtar, Tahseen; Rai, Byanju; Yadav, Manisha; Akhtar Siddiqui, Jawed; Dhar Dwivedi, Shailendra Kumar; Thakur, Ravi; Singh, Anup Kumar; Singh, Abhishek Kumar; Kumar, Harish; Khan, Kainat; Pal, Subhashis; Rath, Srikanta Kumar; Lal, Jawahar; Konwar, Rituraj; Trivedi, Arun Kumar; Datta, Dipak; Mishra, Durga Prasad; Godbole, Madan Madhav; Sanyal, Sabyasachi; Chattopadhyay, Naibedya; Kumar, Atul



Novel shikonin derivatives targeting tubulin as anticancer agents.  


In this study, we report the identification of a new shikonin-phenoxyacetic acid derivative, as an inhibitor of tubulin. A series of compounds were prepared; among them, compound 16 [(R) -1 - (5, 8- dihydroxy-1, 4- dioxo-1, 4- dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2- (4- phenoxyphenyl) acetate] potently inhibited the function of microtubules, inducing cell growth inhibition, apoptosis of cancer cell lines in a concentration and time-dependent manner. Molecular docking involving 16 at the vinblastine binding site of tubulin indicated that a phenoxy moiety interacted with tubulin via hydrogen bonding with asparaginate (Asn) and tyrosine (Tyr). Analysis of microtubules with confocal microscopy demonstrated that 16 altered the microtubule architecture and exhibited a significant reduction in microtubule density. Cell cycle assay further proved that HepG2 cells were blocked in G2/M phase. Our study provides a new, promising compound for the development of tubulin inhibitors by proposing a new target for the anticancer activity of shikonin. PMID:24797889

Guo, Jing; Chen, Xiao-Feng; Liu, Jing; Lin, Hong-Yan; Han, Hong-Wei; Liu, Hong-Chang; Huang, Shou-Cheng; Shahla, Baloch K; Kulek, Andrew; Qi, Jin-Liang; Wang, Xiao-Ming; Ling, Li-Jun; Yang, Yong-Hua



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

SciTech Connect

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

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



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. PMID:22458477

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



Amino acid esters substituted phosphorylated emtricitabine and didanosine derivatives as antiviral and anticancer agents.  


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



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. PMID:25003106

Mantha, Anil K.



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. PMID:21382660

Johnson, Jeremy J.



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


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



[Acquisition of resistance to anticancer agents by overproduction of target enzymes].  


Antimetabolic anticancer agents possess their own target enzymes: that of methotrexate is dihydrofolate reductase; 5-fluorouracil and ZD1604, thymidylate synthase; hydroxyurea, ribonucleotide reductase; 2'-deoxycoformycin, adenosine deaminase; N-(phosphonacetyl)-L-aspartate, aspartate transcarbamylase. Overproduction of each target enzyme has been observed with various animal and human cell lines which acquired resistance to all these agents. These facts suggest that this is a common mechanism for resistance to these agents. Most of these resistant cells showed amplification of the corresponding genes in double minute chromosome or homogeneously stained region of the chromosome. The relation between the degree of resistance and those of enzyme overproduction, the expression and amplification of the gene coding for each enzyme protein in various resistant cell lines are demonstrated and discussed. PMID:9155148

Inaba, M



Association between hTERT rs2736100 polymorphism and sensitivity to anti-cancer agents  

PubMed Central

Background: The rs2736100 single nucleotide polymorphism (SNP) is located in the intron 2 of human telomerase reverse transcriptase (hTERT) gene. Recent genome-wide association studies (GWAS) have consistently supported the strong association between this SNP and risk for multiple cancers. Given the important role of the hTERT gene and this SNP in cancer biology, we hypothesize that rs2736100 may also confer susceptibility to anti-cancer drug sensitivity. In this study we aim to investigate the correlation between the rs2736100 genotype and the responsiveness to anti-cancer agents in the NCI-60 cancer cell panel. Methods and Materials: The hTERT rs2736100 was genotyped in the NCI-60 cancer cell lines. The relative telomere length (RTL) of each cell line was quantified using real-time PCR. The genotype was then correlated with publically available drug sensitivity data of two agents with telomerase-inhibition activity: Geldanamycin (HSP90 inhibitor) and RHPS4/BRACO19 (G-quadruplex stabilizer) as well as additional 110 commonly used agents with established mechanism of action. The association between rs2736100 and mutation status of TP53 gene was also tested. Results: The C allele of the SNP was significantly correlated with increased sensitivity to RHPS4/BRACO19 with an additive effect (r = ?0.35, p = 0.009) but not with Geldanamycin. The same allele was also significantly associated with sensitivity to antimitotic agents compared to other agents (p = 0.003). The highest correlation was observed between the SNP and paclitaxel (r = ?0.36, p = 0.005). The telomere length was neither associated with rs2736100 nor with sensitivity to anti-cancer agents. The C allele of rs2736100 was significantly associated with increased mutation rate in TP53 gene (p = 0.004). Conclusion: Our data suggested that the cancer risk allele of hTERT rs2736100 polymorphism may also affect the cancer cell response to both TERT inhibitor and anti-mitotic agents, which might be attributed to the elevated telomerase-independent activity of hTERT, as well as the increased risk for TP53 gene mutagenesis conferred by the polymorphism. Detailed mechanisms need to be further investigated. PMID:23986774

Kim, Julie; Jones-Hall, Yava L.; Wei, Rongrong; Myers, Jamie; Qi, Yuan; Knipp, Gregory T.; Liu, Wanqing



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


The Anticancer Agent Chaetocin Is a Competitive Substrate and Inhibitor of Thioredoxin Reductase  

PubMed Central

Abstract We recently reported that the antineoplastic thiodioxopiperazine natural product chaetocin potently induces cellular oxidative stress, thus selectively killing cancer cells. In pursuit of underlying molecular mechanisms, we now report that chaetocin is a competitive and selective substrate for the oxidative stress mitigation enzyme thioredoxin reductase-1 (TrxR1) with lower Km than the TrxR1 native substrate thioredoxin (Trx; chaetocin Km?=?4.6?±?0.6??M, Trx Km?=?104.7?±?26??M), thereby attenuating reduction of the critical downstream ROS remediation substrate Trx at achieved intracellular concentrations. Consistent with a role for TrxR1 targeting in the anticancer effects of chaetocin, overexpression of the TrxR1 downstream effector Trx in HeLa cells conferred resistance to chaetocin-induced, but not to doxorubicin-induced, cytotoxicity. As the TrxR/Trx pathway is of central importance in limiting cellular reactive oxygen species (ROS)—and as chaetocin exerts its selective anticancer effects via ROS imposition—the inhibition of TrxR1 by chaetocin has potential to explain its selective anticancer effects. These observations have important implications not just with regard to the mechanism of action and clinical development of chaetocin and related thiodioxopiperazines, but also with regard to the utility of molecular targets within the thioredoxin reductase/thioredoxin pathway in the development of novel candidate antineoplastic agents. Antioxid. Redox Signal. 11, 1097–1106. PMID:18999987

Tibodeau, Jennifer D.; Benson, Linda M.; Isham, Crescent R.; Owen, Whyte G.



Honey as a Potential Natural Anticancer Agent: A Review of Its Mechanisms  

PubMed Central

The main treatment for cancer is by using chemotherapy and radiotherapy which themselves are toxic to other viable cells of the body. Recently, there are many studies focusing on the use of natural products for cancer prevention and treatment. Of these natural products, honey has been extensively researched. The mechanism of the anti-cancer activity of honey as chemopreventive and therapeutic agent has not been completely understood. The possible mechanisms are due to its apoptotic, antiproliferative, antitumor necrosis factor (anti-TNF), antioxidant, anti-inflammatory, estrogenic and immunomodulatory activities. We collate the findings of several studies published in the literature in order to understand the mechanism of its action. PMID:24363771

Ahmed, Sarfraz



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

Microsoft Academic Search

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.

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



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. PMID:22036896

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



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


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



Highly Adaptable Triple-Negative Breast Cancer Cells as a Functional Model for Testing Anticancer Agents  

PubMed Central

A major obstacle in developing effective therapies against solid tumors stems from an inability to adequately model the rare subpopulation of panresistant cancer cells that may often drive the disease. We describe a strategy for optimally modeling highly abnormal and highly adaptable human triple-negative breast cancer cells, and evaluating therapies for their ability to eradicate such cells. To overcome the shortcomings often associated with cell culture models, we incorporated several features in our model including a selection of highly adaptable cancer cells based on their ability to survive a metabolic challenge. We have previously shown that metabolically adaptable cancer cells efficiently metastasize to multiple organs in nude mice. Here we show that the cancer cells modeled in our system feature an embryo-like gene expression and amplification of the fat mass and obesity associated gene FTO. We also provide evidence of upregulation of ZEB1 and downregulation of GRHL2 indicating increased epithelial to mesenchymal transition in metabolically adaptable cancer cells. Our results obtained with a variety of anticancer agents support the validity of the model of realistic panresistance and suggest that it could be used for developing anticancer agents that would overcome panresistance. PMID:25279830

Singh, Balraj; Shamsnia, Anna; Raythatha, Milan R.; Milligan, Ryan D.; Cady, Amanda M.; Madan, Simran; Lucci, Anthony



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


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



DRDE-07 and its analogues as promising cytoprotectants to nitrogen mustard (HN-2)—An alkylating anticancer and chemical warfare agent  

Microsoft Academic Search

Nitrogen mustard (HN-2), also known as mechlorethamine, is an alkylating anticancer agent as well as blister inducing chemical warfare agent. We evaluated the cytoprotective efficacy of amifostine, DRDE-07 and their analogues, and other antidotes of mustard agents against HN-2. Administration of 1 LD50 of HN-2 (20mg\\/kg) percutaneously, decreased WBC count from 24h onwards. Liver glutathione (GSH) level decreased prominently and

Manoj Sharma; R. Vijayaraghavan; Anshoo Gautam



Synthesis of structurally diverse benzosuberene analogues and their biological evaluation as anti-cancer agents.  


Diversely functionalized, fused aryl-alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7]annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds. In order to extend the structure-activity relationship (SAR) knowledge base related to benzosuberene anti-cancer agents, a series of eleven analogues (including KGP18) were prepared in which the methoxylation pattern on the pendant aryl ring as well as functional group incorporation on the fused aryl ring were varied. The synthetic approach to these compounds featured a sequential Wittig olefination, reduction, Eaton's reagent-mediated cyclization strategy to achieve the core benzosuberone intermediate, and represented a higher-yielding synthesis of KGP18 (which we prepared previously through a ring-expansion strategy). Incorporation of a fluorine or chlorine atom at the 1-position of the fused aryl ring or replacement of one of the methoxy groups with hydrogen (on the pendant aryl ring of KGP18) led to benzosuberene analogues that were both strongly inhibitory against tubulin assembly (IC50 approximately 1.0 ?M) and strongly cytotoxic against selected human cancer cell lines (for example, GI50=5.47 nM against NCI-H460 cells with fluoro-benzosuberene analogue 37). A water-soluble phosphate prodrug salt of KGP18 (referred to as KGP265, compound 44) and a water-soluble serinamide salt (compound 48) of KGP156 were also synthesized and evaluated in this study. PMID:24183586

Tanpure, Rajendra P; George, Clinton S; Strecker, Tracy E; Devkota, Laxman; Tidmore, Justin K; Lin, Chen-Ming; Herdman, Christine A; Macdonough, Matthew T; Sriram, Madhavi; Chaplin, David J; Trawick, Mary Lynn; Pinney, Kevin G



Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents  

PubMed Central

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

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



Metronidazole acid acyl sulfonamide: a novel class of anticancer agents and potential EGFR tyrosine kinase inhibitors.  


A series of novel metronidazole derivatives were recently reported as potent anticancer agents targeting EGFR and HER-2 by our group [Qian, Y.; Zhang, H. J.; Zhang, H.; Xu, C.; Zhao, J.; Zhu, H. L. Bioorg. Med. Chem.2010, 18, 4991]. Based on the previous results, we designed and synthesized a new series of metronidazole acid acyl sulfonamide derivatives and a new series of phenylacetyl benzenesulfonamide derivatives and their anticancer activities were evaluated as potential EGFR and HER-2 kinase inhibitors. Among all the compounds, compound 12 displayed the most potent inhibitory activity EGFR and HER-2 (IC(50)=0.39 ?M for EGFR and IC(50)=1.53 ?M for HER-2) and it also showed the most potent growth inhibitory activity against A549 and B16-F10 cancer cell line in vitro, with an IC(50) value of 1.26 ?g/mL for A549 and 0.35 ?g/mL for B16-F10. Docking simulation was further performed to position compound 12 into the EGFR active site to determine the probable binding model. PMID:21920766

Luo, Yin; Li, Yao; Qiu, Ke-Ming; Lu, Xiang; Fu, Jie; Zhu, Hai-Liang



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

PubMed Central

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

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



Development of Taxol and other endophyte produced anti-cancer agents.  


Taxol is a powerful and complex anti-cancer compound that was first isolated from the bark of the Pacific yew Taxus brevifolia. Although it offered huge potential as an anti-cancer agent, it experienced a long development period, attributed to by its low availability from its traditional source. Research into alternate sources and methods of production for Taxol have been crucial in meeting with demand for the drug. Three main avenues of research have resulted. Firstly, chemical syntheses of this complex diterpene consist of multiple steps and are not economically feasible due to their low yield. Developments have therefore concentrated on enhancing production in vivo. Efforts have been made to understand the enzymatic steps involved in the synthesis within the yew and innovations to produce Taxol and Taxol-like substances in high yield from cell cultures of Taxus species. An alternative stream of research focuses on endophytes as the producer of Taxol. Endophytes can be isolated from the yew tree and produce Taxol in culture. Encouraging findings with endophytes resulted in much interest in the prospect of using endophytes as the producer of Taxol and Taxol-like substances. This review also discusses patents and the future prospects of each of the main streams of production. PMID:18289120

Miller, Kristin; Neilan, Brett; Sze, Daniel M Y



Synthesis, molecular modeling, and biological evaluation of cinnamic acid metronidazole ester derivatives as novel anticancer agents.  


A series of novel cinnamic acid metronidazole ester derivatives have been designed and synthesized, and their biological activities were also evaluated as potential EGFR and HER-2 kinase inhibitors. Compound 3h showed the most potent biological activity (IC50=0.62 microM for EGFR and IC50=2.15 microM for HER-2). Docking simulation was performed to position compound 3h into the EGFR active site to determine the probable binding model. Antiproliferative assay results demonstrated that some of these compounds possessed good antiproliferative activity against MCF-7. Compound 3h with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent. PMID:20594859

Qian, Yong; Zhang, Hong-Jia; Zhang, Hao; Xu, Chen; Zhao, Jing; Zhu, Hai-Liang



Synthesis, molecular modeling and biological evaluation of chalcone thiosemicarbazide derivatives as novel anticancer agents.  


A series of novel chalcone thiosemicarbazide derivatives (4a-4x) have been designed, synthesized, structurally determined, and their biological activities were also evaluated as potential EGFR kinase inhibitors. All the synthesized compounds are first reported. Among the compounds, compound 4r showed the most potent biological activity (IC(50) = 0.78 ± 0.05 ?M for HepG2 and IC(50) = 0.35 ?M for EGFR), which is comparable to the positive controls. Docking simulation was also performed to position compound 4r into the EGFR active site to determine the probable binding model. Antiproliferative assay results demonstrated that some of these compounds possessed good antiproliferative activity against HepG2. Compound 4r with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent. PMID:21816517

Zhang, Hong-Jia; Qian, Yong; Zhu, Di-Di; Yang, Xu-Guang; Zhu, Hai-Liang



Diversity-oriented synthesis of ?-aminophosphonates: a new class of potential anticancer agents.  


A small library of structurally diverse ?-aminophosphonates has been synthesized by reacting alkyl/aryl aldehydes, alkyl/aryl amines and alkyl/aryl phosphites in one-pot catalyzed by Amberlite-IR 120 resin (acidic). All the synthesized ?-aminophosphonates were assayed for their in vitro cytotoxic activities against a panel of five human cancer cell lines including A-549, NCI-H23 (Lung), Colo 320DM (Colon), MG-63 (Bone marrow) and Jurkat (Blood T lymphocytes). Compound 4n having (R)-1-phenylethanamine was found to be the most active amongst all the synthesized ?-aminophosphonates against all the five cancer cell lines, most prominent being against Jurkat cell line with an IC50 value of 4 ?M. Surprisingly, compound 4o having (S)-1-phenylethanamine was found to be devoid of any cytotoxicity. Our finding suggests that these chemical entities could further serve as interesting template for the design of potential anticancer agents. PMID:23792352

Bhattacharya, Asish K; Raut, Dnyaneshwar S; Rana, Kalpeshkumar C; Polanki, Innaiah K; Khan, Mohd Sajid; Iram, Sana



Secondary Leukemia Associated with the Anti-Cancer Agent, Etoposide, a Topoisomerase II Inhibitor  

PubMed Central

Etoposide is an anticancer agent, which is successfully and extensively used in treatments for various types of cancers in children and adults. However, due to the increases in survival and overall cure rate of cancer patients, interest has arisen on the potential risk of this agent for therapy-related secondary leukemia. Topoisomerase II inhibitors, including etoposide and teniposide, frequently cause rearrangements involving the mixed lineage leukemia (MLL) gene on chromosome 11q23, which is associated with secondary leukemia. The prognosis is extremely poor for leukemias associated with rearrangements in the MLL gene, including etoposide-related secondary leukemias. It is of great importance to gain precise knowledge of the clinical aspects of these diseases and the mechanism underlying the leukemogenesis induced by this agent to ensure correct assessments of current and future therapy strategies. Here, I will review current knowledge regarding the clinical aspects of etoposide-related secondary leukemia, some probable mechanisms, and strategies for treating etoposide-induced leukemia. PMID:22851953

Ezoe, Sachiko



Patients in phase I trials of anti-cancer agents in Japan: motivation, comprehension and expectations.  

PubMed Central

We attempted to characterize the motivation, comprehension and expectations of patients who had given informed consent to participate in phase I trials of anti-cancer agents at the National Cancer Center of Japan. Thirty-three patients were given a simple multiple-choice questionnaire and asked to return it at a later date. The completed survey was returned by 32 patients. The patients were surveyed before they had received any investigational phase I agents. Nineteen per cent of patients were motivated to participate in the phase I trials by the possibility of therapeutic benefit, 9% because participation seemed a better choice than no treatment and only 6% for altruistic reasons. Most patients comprehended the major features of a phase I trial, namely its investigational nature, the unknown effects of the agent investigated and the unclear benefit to the patients themselves. Fifty-nine per cent of the patients anticipated that they might suffer severe or life-threatening side-effects if they participated in the phase I trial, and 43% were able to indicate accurately the purpose of the phase I trial as a dose determination study. Although only a minority of the patients indicated that their motivation to participate was possible treatment benefit to themselves, when answering questions regarding expectations, more than half indicated that there might be personal benefits of varying degrees by participation. PMID:9218741

Itoh, K.; Sasaki, Y.; Fujii, H.; Ohtsu, T.; Wakita, H.; Igarashi, T.; Abe, K.



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


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

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



Development of lipophilic anticancer agents for the treatment of brain tumors by the esterification of water-soluble chlorambucil  

Microsoft Academic Search

The lipophilic derivatives of the anticancer alkylating agent chlorambucil, chlorambucil-methyl, -isopropyl and -tertiary butyl esters, were synthesized and administered i.v. to anesthetized rats. Plasma and brain concentrations of these agents and of their active metabolites, chlorambucil and phenylacetic mustard, then were determined by high-performance liquid chromatography between 5 and 60 min. Whereas large amounts of chlorambucil-tertiary butyl ester entered and

Shigeru Genka; Joseph Deutsch; Umesha H. Shetty; Paul L. Stahle; Varghese John; Ivan M. Lieberburg; Francis Ali-Osmant; Stanley I. Rapoport; Nigel H. Greig



Assessment of antimicrobial (host defense) peptides as anti-cancer agents.  


Cationic antimicrobial (host defense) peptides (CAPs) are able to kill microorganisms and cancer cells, leading to their consideration as novel candidate therapeutic agents in human medicine. CAPs can physically associate with anionic membrane structures, such as those found on cancer cells, causing pore formation, intracellular disturbances, and leakage of cell contents. In contrast, normal cells are less negatively-charged and are typically not susceptible to CAP-mediated cell death. Because the interaction of CAPs with cells is based on charge properties rather than cell proliferation, both rapidly dividing and quiescent cancer cells, as well as multidrug-resistant cancer cells, are targeted by CAPs, making CAPS potentially valuable as anti-cancer agents. CAPs often exist as families of peptides with slightly different amino acid sequences. In addition, libraries of synthetic peptide variants based on naturally occurring CAP templates can be generated in order to improve upon their action. High-throughput screens are needed to quickly and efficiently assess the suitability of each CAP variant. Here we present the methods for assessing CAP-mediated cytotoxicity against cancer cells (suspension and adherent) and untransformed cells (measured using the tritiated thymidine-release or MTT assay), and for discriminating between cell death caused by necrosis (measured using lactate dehydrogenase- or (51)Cr-release assays), or apoptosis and necrosis (single-stranded DNA content measured by flow cytometry). In addition the clonogenic assay, which assesses the ability of single transformed cells to multiply and produce colonies, is described. PMID:24146403

Douglas, Susan; Hoskin, David W; Hilchie, Ashley L



Design of Enzymatically Cleavable Prodrugs of a Potent Platinum-Containing Anticancer Agent  

PubMed Central

Using a versatile synthetic approach, a new class of potential ester prodrugs of highly potent, but systemically too toxic, platinum–acridine anticancer agents was generated. The new hybrids contain a hydroxyl group, which has been masked with a cleavable lipophilic acyl moiety. Both butanoic (butyric) and bulkier 2-propanepentanoic (valproic) esters were introduced. The goals of this design were to improve the drug-like properties (e.g., logD) and to reduce the systemic toxicity of the pharmacophore. Two distinct pathways by which the target compounds undergo effective ester hydrolysis, the proposed activating step, have been confirmed: platinum-assisted, self-immolative ester cleavage in a low-chloride environment (LC-ESMS, NMR spectroscopy) and enzymatic cleavage by human carboxylesterase-2 (hCES-2) (LC-ESMS). The valproic acid ester derivatives are the first example of a metal-containing agent cleavable by the pro-drug-converting enzyme. They show excellent chemical stability and reduced systemic toxicity. Preliminary results from screening in lung adenocarcinoma cell lines (A549, NCI-H1435) suggest that the mechanism of the valproic esters may involve intracellular deesterification. PMID:25303639

Ding, Song; Pickard, Amanda J.; Kucera, Gregory L.



In Vitro and In Vivo Evaluation of Novel Anticancer Agents in Triple Negative Breast Cancer Models  

PubMed Central

Triple negative breast cancer (TNBC) is subtype of breast disease devoid of the estrogen, progesterone, and Her2/neu receptors which are targets for pharmacological intervention. There is a need for novel anti-breast cancer agents that target TNBC. Therefore, novel isochalcone DJ52 was evaluated using the alamar blue dye exclusion assay, the luciferase colony assay, and xenograft models to determine its efficacy and potency. DJ52 significantly decreased proliferation of cells measured by using the alamar blue dye method and produced IC50 values of DJ52, DJ56, and DJ82 at 10-6M, 10-5M, and 10-5M, respectively. In vivo studies were conducted by injecting MDA-MB-231 cells into SCID mice to determine tumor regression was measured over 20 days. DJ52 at 50mg/kg caused significant decrease in tumor volume (p value <.05) by nearly 50% compared with the control with vehicle alone. These data suggest that DJ52 has merit for further evaluation as a novel anticancer agent. PMID:23395947

Johnson, KiTani Parker; Johnson, Duane E.; Stoute, Diana; Burow, Matthew E.; Rhodes, Lyndsay V.; Gray, Marian; Carriere, Patrick; Tilghman, Syreeta L.; McLachlan, John A.; Ochieng, Josiah



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. PMID:22174561

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



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

PubMed Central

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

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



Design, synthesis and ex vivo evaluation of colon-specific azo based prodrugs of anticancer agents.  


Colon-specific azo based prodrugs of anticancer agents like methotrexate (6), gemcitabine (7) and analogue of oxaliplatin (RTB-4) (8) were synthesized and characterized by modern analytical techniques. The prepared prodrugs were stable in acidic (pH 1.2) and basic (pH 7.4) buffers which showed their stability in upper GIT environment. Further, an assay was performed which demonstrated the presence of azoreductase enzyme in the rat fecal material, rat cecum content and other parts of intestinal content which reduce specifically the azo bond and release the drug. The in vitro cytotoxicity assay was also performed which clearly indicated that these azo based prodrugs are active against human colorectal cancer cell lines (COLO 205, COLO 320 DM and HT-29). The release behavior of prodrugs (10, 11 and 15) was 60-70% after 24h incubation at 37°C. Therefore, the synthesized azo linked prodrugs of methotrexate, gemcitabine and RTB-4 are the potential candidates for colon targeted drug delivery system with minimal undesirable side effects. PMID:23968824

Sharma, Rajiv; Rawal, Ravindra K; Gaba, Tripti; Singla, Nishu; Malhotra, Manav; Matharoo, Sahil; Bhardwaj, T R



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


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



Cytotoxicity of in vitro produced podophyllotoxin from podophyllum hexandrum on human cancer cell line  

Microsoft Academic Search

Podophyllotoxin was produced by cell culture of Podophyllum hexandrum under in vitro culture conditions. A maximum of 4.26?mg\\/L of podophyllotoxin was produced when P. hexandrum was cultivated in 3?L stirred tank bioreactor. The compound extracted from the cell culture was applied to the human breast cancer cell line (MCF-7) and 1?nM podophyllotoxin was able to inhibit the growth of the

Saurabh Chattopadhyay; V. S. Bisaria; A. K. Panda; A. K. Srivastava



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

PubMed Central

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



Next Generation Sequencing in Predicting Gene Function in Podophyllotoxin Biosynthesis*  

PubMed Central

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

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



Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents.  


A series of novel curcumin analogs were synthesized and screened for anti-cancer and anti-angiogenesis activities at Emory University and at the National Cancer Institute (NCI). These compounds are symmetrical alpha,beta-unsaturated and saturated ketones. The majority of the analogs demonstrated a moderate degree of anti-cancer activity. Compounds 10, 11, and 14 exhibited a high degree of cytotoxicity in the NCI in vitro anti-cancer cell line screen. In addition, this screen revealed that these compounds inhibit tumor cell growth with a higher potency than the commonly used chemotherapeutic drug, cisplatin. In independent in vitro screens conducted at Emory, the same compounds plus 4, 5, 8, 9, and 13 exhibited a high degree of cytotoxicity to tumor cells. Analogs that were effective in the anti-cancer screens were also effective in in vitro anti-angiogenesis assays. Compounds 4, 9, 11, and 14 were most effective in the anti-angiogenesis assays run at Emory. In the assays conducted by the NCI, compound 14 was almost as potent as the anti-angiogenic drug TNP-470, which has undergone clinical trials. Based on the favorable in vitro anti-cancer and anti-angiogenesis results with 14, further in vivo tests were conducted. This compound effectively reduced the size of human breast tumors grown in female athymic nude mice and showed little toxicity. This data, coupled with the remarkable in vitro data, suggests that compound 14 may potentially be an effective chemotherapeutic agent. As a follow-up, a 3D quantitative structure relationship based on 14 has been developed. It shows a cross-validated r2(q2) and a predictive r2(p2) = 0.71. COMPARE analysis suggests the compound to be a possible RNA/DNA antimetabolite, but also implies that the compound's cytotoxicity may arise from a presently unknown mechanism. PMID:15210154

Adams, Brian K; Ferstl, Eva M; Davis, Matthew C; Herold, Marike; Kurtkaya, Serdar; Camalier, Richard F; Hollingshead, Melinda G; Kaur, Gurmeet; Sausville, Edward A; Rickles, Frederick R; Snyder, James P; Liotta, Dennis C; Shoji, Mamoru



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

PubMed Central

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

Duenas-Gonzalez, Alfonso; Garcia-Lopez, Patricia; Herrera, Luis Alonso; Medina-Franco, Jose Luis; Gonzalez-Fierro, Aurora; Candelaria, Myrna



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


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



Evaluation of cytotoxic potential of latex of Calotropis procera and Podophyllotoxin in Allum cepa root model  

Microsoft Academic Search

In the present study we have utilized the Allium cepa root tip meristem model to evaluate the cytotoxic and anti-mitotic activities of latex of Calotropis procera (DL) and podophyllotoxin. Standard cyto- toxic drug cyclophosphamide and non-cytotoxic drugs cyproheptadine and aspirin served as controls. Like cyclophosphamide, both DL and podophyllotoxin significantly inhibited the growth of roots and mitotic activity in a



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. PMID:25075217

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



CHIP and gp78-mediated ubiquitination of CYP3A4: Implications for the pharmacology of anticancer agents.  


The autocrine motility factor receptor or glycoprotein-78 (gp78) and C-terminus of Hsp70-interacting protein (CHIP) are E3-ligases required for ubiquitination of cytochrome P450s of the 3A subfamily (CYP3A) in endoplasmic reticulum-associated degradation (ERAD). The CYP isozyme 3A4 (CYP3A4) is responsible for the metabolism of the majority of xenobiotics including anticancer agents. Much variability in clinical response to chemotherapy is observed and it has been suggested that variability in CYP3A4 expression could be a factor. The study reviewed in this journal club comments on the importance of further characterizing gp78 and CHIP as relevant proteins in ERAD of CYP3A4. This study demonstrated how both gp78 and CHIP play direct roles in reducing CYP3A4 protein content as well as CYP3A4 ubiquitination. Interestingly, when gp78 and CHIP were knocked down by siRNAs directed towards each protein, the stabilized CYP3A4 remained functional. This has implications for drug-drug interactions for agents metabolized by CYP3A4, which can influence drug exposure levels. This is relevant because most anticancer agents have very narrow therapeutic windows, thus even slight changes in CYP3A4 levels could alter the exposure of that drug and result in either insufficient efficacy or toxicity. Future studies must explore genetic variability in the ERAD pathway and identify new factors that influence CYP3A ERAD in order to better characterize how CYP3A variability affects anticancer drug pharmacology. PMID:21270532

Peer, Cody J; Sissung, Tristan M; Figg, William D



Evaluation of selected flavonoids as antiangiogenic, anticancer, and radical scavenging agents: an experimental and in silico analysis.  


Developing antiangiogenic agents using natural products has remained a significant hope in the mainstream of anticancer research. In the present investigation series of flavonoids possessing di-, tri-, tetra-, and penta-hydroxy substitutions were evaluated as antiangiogenic agents using in vivo choriallantoic membrane model. The MTT-based cytotoxicity against selected cancer cell lines was carried out to determine the anticancer potential. The kinetics of free radical scavenging activities of these compounds was demonstrated using 2,2-diphenyl-1-picryl hydrazine (DPPH) and superoxide anion radicals (SORs). To understand the possible antiangiogenic mechanism, the selected flavonoids were docked in silico onto the proangiogenic peptides such as vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF-1?), and vascular endothelial growth factor receptor-2 (VEGFR2) from human origin. The results of the study shows that amongst the tested flavonoids, genistein (87.1%), kaempferol, (86.3%), and quercetin (84.7%) were found to be effective inhibitors of angiogenesis in CAM model. The antiangiogenic, cytotoxic, and antioxidant activities are discussed in light of structure-activity relationship using in silico approach and other drug-related properties were also calculated using BioMed CAChe V. 6.1.10. The results of the present study focus the isoflavone genistein, kaempferol, and quercetin as lead molecules for designing novel anti-tumor/antioxidant agents targeting angiogenesis. PMID:21830125

Gacche, Rajesh N; Shegokar, Harshala D; Gond, Dhananjay S; Yang, Zhenzhou; Jadhav, Archana D



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

PubMed Central

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

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



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. PMID:19243174

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



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

PubMed Central

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

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



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


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. PMID:24966524

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



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. PMID:24966524

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



Methylselenocysteine - a Promising Antiangiogenic Agent for Overcoming Drug Delivery Barriers in Solid Malignancies for Therapeutic Synergy with Anticancer Drugs  

PubMed Central

Introduction Despite progress, chemotherapeutic response in solid malignancies has remained limited. While initial results of the use of antiangiogenic agents in combination chemotherapy indicated an enhanced therapeutic response, recent data indicates that the surviving cancer is not only able to surmount therapy, but is actually able to adapt a more aggressive metastatic phenotype. Thus, selecting an antiangiogenic agent that is less likely to lead to tumor resurgence is a key to future therapeutic success of antiangiogenic agents, in a combinatorial setting. Areas covered Against the broad spectrum of currently used antiangiogenic agents in the clinic, the putative benefits of the use of organo selenium (Se) compounds, such as methylselenocysteine (MSC), are discussed in this reiew. Expert opinion MSC, being part of the mammalian physiology, is a well tolerated, versatile and economical antiangiogenic agent. It down regulates multiple key upstream tumor survival markers, and enhances tumor drug delivery, at a given systemic dose of an anticancer agent, while protecting normal tissue from cytotoxic adverse effects. Further clinical trials, especially in poorly differentiated cancers, are warranted. PMID:21473705

Bhattacharya, Arup



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. PMID:24809695

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



Stability studies of anticancer agent bis(4-fluorobenzyl)trisulfide and synthesis of related substances  

Microsoft Academic Search

Bis(4-fluorobenzyl)trisulfide, fluorapacin, has been extensively developed as a promising new anticancer drug candidate. Its degradation products were identified and verified by the newly synthesized compounds bis(4-fluorobenzyl)disulfide (A) and bis(4-fluorobenzyl)tetrasulfide (B) which were resulted from the disproportionation of fluorapacin under forced conditions. A stability-indicating HPLC method was used for the stability evaluation of active pharmaceutical ingredient (API) fluorapacin and finished pharmaceutical

Yimei Bao; Xiaopeng Mo; Xiaoying Xu; Yuyu He; Xiao Xu; Haoyun An



A translational study "case report" on the small molecule "energy blocker" 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside.  


The small alkylating molecule, 3-bromopyruvate (3BP), is a potent and specific anticancer agent. 3BP is different in its action from most currently available chemo-drugs. Thus, 3BP targets cancer cells' energy metabolism, both its high glycolysis ("Warburg Effect") and mitochondrial oxidative phosphorylation. This inhibits/ blocks total energy production leading to a depletion of energy reserves. Moreover, 3BP as an "Energy Blocker", is very rapid in killing such cells. This is in sharp contrast to most commonly used anticancer agents that usually take longer to show a noticeable effect. In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells. Therefore, 3BP can be considered a member, perhaps one of the first, of a new class of anticancer agents. Following 3BP's discovery as a novel anticancer agent in vitro in the Year 2000 (Published in Ko et al. Can Lett 173:83-91, 2001), and also as a highly effective and rapid anticancer agent in vivo shortly thereafter (Ko et al. Biochem Biophys Res Commun 324:269-275, 2004), its efficacy as a potent anticancer agent in humans was demonstrated. Here, based on translational research, we report results of a case study in a young adult cancer patient with fibrolamellar hepatocellular carcinoma. Thus, a bench side discovery in the Department of Biological Chemistry at Johns Hopkins University, School of Medicine was taken effectively to bedside treatment at Johann Wolfgang Goethe University Frankfurt/Main Hospital, Germany. The results obtained hold promise for 3BP as a future cancer therapeutic without apparent cyto-toxicity when formulated properly. PMID:22328020

Ko, Y H; Verhoeven, H A; Lee, M J; Corbin, D J; Vogl, T J; Pedersen, P L



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

SciTech Connect

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

Shashkova, Elena V.; May, Shannon M. [Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902 (United States); Barry, Michael A., E-mail: mab@mayo.ed [Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902 (United States); Department of Immunology, Mayo Clinic, Rochester, MN 55902 (United States); Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902 (United States); Translational Immunovirology Program, Mayo Clinic, Rochester, MN 55902 (United States); Cancer Center, Mayo Clinic, Rochester, MN 55902 (United States)



The synergistic effect and mechanism of doxorubicin-ZnO nanocomplexes as a multimodal agent integrating diverse anticancer therapeutics  

PubMed Central

Background Nanomaterials have emerged as ideal multimodal nanomedicine platforms, each one combining different designs and therapeutic approaches in a single system against cancer. The aim of the current study was to explore the synergistic effect and mechanism of a doxorubicin (Dox)-ZnO nanocomplex as a multimodal drug delivery system, integrating Dox chemotherapy and ZnO-mediated photodynamic therapy, in anticancer therapeutics. Methods Dox was loaded onto ZnO nanomaterials, forming complexes with the transition metal Zn to yield the Dox-ZnO nanocomplexes. After culture with SMMC-7721 hepatocarcinoma cells, the cellular uptake was quantitatively detected by flow cytometry and visualized by fluorescence microscopy. The synergistic effects of the different anticancer therapeutic modalities on the proliferation of SMMC-7721 hepatocarcinoma cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of B-cell lymphoma 2 protein (Bcl-2), Bcl-2 associated X protein (Bax), caspase 9, and caspase 3 were examined by Western blot, to elucidate the possible molecular mechanisms involved. Results Our observations demonstrated that Dox-ZnO nanocomplexes could act as an efficient drug delivery system for importing Dox into SMMC-7721 cells, enhancing its potential chemotherapy efficiency by increasing the intracellular concentration of Dox. With the addition of ultraviolet (UV) illumination, the ZnO nanomaterials showed excellent photodynamic therapeutic properties, attacking the cancer cells further. Thus the caspase-dependent apoptosis was synergistically induced, resulting in distinct improvement in anticancer activity. Conclusion The Dox-ZnO nanocomplex presents a promising multimodal agent for comprehensive cancer treatment. PMID:23674895

Deng, Yuxia; Zhang, Haijun



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

PubMed Central

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 ?M 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 CBP (the cellular paralog of p300), PCAF and GCN5, but not to other acetyltransferases (KAT5, KAT6B and KAT7), histone deacetylases (HDACs) 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, S. Adrian; Planck, Jamie; Geary, Kyla R.; Ma, Haiching; Law, Brian K.; Roush, William R.; Hodder, Peter; Liao, Daiqing



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


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



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


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



Synthesis and characterization of celecoxib derivatives as possible anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV agents.  


A series of novel N-(3-substituted aryl/alkyl-4-oxo-1,3-thiazolidin-2-ylidene)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamides 2a-e were synthesized by the addition of ethyl a-bromoacetate and anhydrous sodium acetate in dry ethanol to N-(substituted aryl/alkylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]benzene sulfonamides 1a-e, which were synthesized by the reaction of alkyl/aryl isothiocyanates with celecoxib. The structures of the isolated products were determined by spectral methods and their anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV NS5B RNA-dependent RNA polymerase (RdRp) activities evaluated. The compounds were also tested for gastric toxicity and selected compound 1a was screened for its anticancer activity against 60 human tumor cell lines. These investigations revealed that compound 1a exhibited anti-inflammatory and analgesic activities and further did not cause tissue damage in liver, kidney, colon and brain compared to untreated controls or celecoxib. Compounds 1c and 1d displayed modest inhibition of HCV NS5B RdRp activity. In conclusion, N-(ethylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (1a) may have the potential to be developed into a therapeutic agent. PMID:23519201

Küçükgüzel, ? Güniz; Co?kun, ?nci; Ayd?n, Sevil; Aktay, Göknur; Gürsoy, ?ule; Çevik, Özge; Özakp?nar, Özlem Bingöl; Özsavc?, Derya; ?ener, Azize; Kaushik-Basu, Neerja; Basu, Amartya; Talele, Tanaji T



Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin  

PubMed Central

The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1) covalently to DNA in a “cleavable complex”. To examine the effects of camptothecin on RNA synthesis genome-wide we used Bru-Seq and show that camptothecin treatment primarily affected transcription elongation. We also observed that camptothecin increased RNA reads past transcription termination sites as well as at enhancer elements. Following removal of camptothecin, transcription spread as a wave from the 5’-end of genes with no recovery of transcription apparent from RNA polymerases stalled in the body of genes. As a result, camptothecin preferentially inhibited the expression of large genes such as proto-oncogenes, and anti-apoptotic genes while smaller ribosomal protein genes, pro-apoptotic genes and p53 target genes showed relative higher expression. Cockayne syndrome group B fibroblasts (CS-B), which are defective in transcription-coupled repair (TCR), showed an RNA synthesis recovery profile similar to normal fibroblasts suggesting that TCR is not involved in the repair of or RNA synthesis recovery from transcription-blocking Top1 lesions. These findings of the effects of camptothecin on transcription have important implications for its anti-cancer activities and may aid in the design of improved combinatorial treatments involving Top1 poisons. PMID:24194914

Veloso, Artur; Biewen, Benjamin; Paulsen, Michelle T.; Berg, Nathan; Carmo de Andrade Lima, Leonardo; Prasad, Jayendra; Bedi, Karan; Magnuson, Brian; Wilson, Thomas E.; Ljungman, Mats



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. PMID:20714427

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



New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer.  


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

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



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

PubMed Central

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

Wei, Linyi



The use of liposomal anticancer agents to determine the roles of drug pharmacodistribution and P-glycoprotein (PGP) blockade in overcoming multidrug resistance (MDR).  


Many attempts to circumvent P-glycoprotein (PGP)-based multidrug resistance (MDR) in cancer chemotherapy have utilized PGP blocking agents (also referred to as MDR modulators), which are co-administered with the anticancer drug. This approach is based on the premise that inhibiting PGP function will result in increased accumulation of many anticancer drugs in the tumor cells and restore full antitumor activity. However, co-administration of MDR modulators with anticancer drugs has often resulted in exacerbated toxicity of the anticancer drugs and limited chemosensitization of MDR tumors. These problems appear to be related to MDR modulator blockade of PGP excretory functions in healthy tissues, such as liver and kidney, which markedly reduces anticancer drug clearance properties. Two consequences of these pharmacokinetic interactions are: 1. Increased toxicity due to modulator-induced changes in biodistribution properties of the anticancer drug. 2. Problems interpreting preclinical and clinical data with respect to: a) Are therapeutic improvements due to altered pharmacokinetics or PGP modulation within the tumor cells? And, b) Does decreasing the anticancer drug dose to that which is equitoxic in the absence of the modulator potentially compromise tumor therapy due to decreased anticancer drug levels in the tumor tissue? Although many of the difficulties associated with co-administration of MDR modulators and anticancer drugs are manifested by toxicity effects, it is ultimately the ability to obtain effective antitumor activity against resistant tumors that will determine the utility of chemosensitization approaches. Liposomes appear to be well suited to solve many of the problems noted above that are associated with conventional anticancer drugs and MDR modulators. In view of these considerations, we have hypothesized that inadequate tumor delivery of anticancer agents and selectivity of PGP modulation are primarily responsible for the attenuated therapy of extravascular MDR solid tumors overexpressing PGP. Liposomal carriers have been utilized to provide tumor selective delivery of anticancer agents as well as to circumvent many toxicities associated with these agents by altering the pharmacodistribution properties of encapsulated drugs (1-4). Given the pharmacokinetic changes induced by the MDR modulators on non-encapsulated doxorubicin (DOX), we proposed that liposomes may limit these effects by virtue of their ability to reduce the exposure of encapsulated DOX to the kidneys and alter clearance of DOX in the liver (5,6). These tissues appear to be key factors involved in modulator-induced DOX pharmacokinetic changes (7). In conjunction with these toxicity buffering effects, the effect of PGP blockade on the cellular uptake of DOX in the tumor may be able to be selectively increased using liposomal carriers. This is based on the ability of small liposomes to passively extravasate in tumors (1,2,8,9) as well as their inability to accumulate in healthy susceptible tissues. By studying the toxicity and efficacy properties of liposome encapsulated DOX in combination with the MDR modulator PSC 833 we have been able to demonstrate that two factors play a major role in determining the effectiveness of chemosensitization approaches to overcome MDR; 1) optimizing selective localization of anticancer drug localization in tumor tissue and 2) effective blockade of PGP in tumor cells under conditions that do not compromise anticancer drug accumulation into the tumor. Failure to achieve both of these conditions simultaneously may be expected to result in substantially reduced therapy of MDR tumors. PMID:10652569

Krishna, R; Mayer, L D



Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents  

Microsoft Academic Search

Metformin, an inexpensive oral agent commonly used to treat type 2 diabetes, has been garnering increasing attention as a\\u000a potential anti-cancer agent. Preclinical, epidemiologic, and clinical evidences suggest that metformin may reduce overall\\u000a cancer risk and mortality, with specific effects in breast cancer. The extensive clinical experience with metformin, coupled\\u000a with its known (and modest) toxicity, has allowed the traditional

Pamela J. Goodwin; Vuk Stambolic; Julie Lemieux; Bingshu E. Chen; Wendy R. Parulekar; Karen A. Gelmon; Dawn L. Hershman; Timothy J. Hobday; Jennifer A. Ligibel; Ingrid A. Mayer; Kathleen I. Pritchard; Timothy J. Whelan; Priya Rastogi; Lois E. Shepherd



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



Membranes affinity of 10-hydroxycamptothecin and SN-38, anticancer agents, 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 this parameter the small unilamellar lipids vesicles i.e. unilamellar liposomes are used as model membranes. The affinities of 10-hydroxycamptothecin and SN-38 to model membranes are determined in this work. Fluorescence spectra of these analogues change in presence of liposomes: the fluorescence intensity increases and besides green band the blue band appears. The spectra of 10-hydroxycamptothecins and SN-38 change over lipids concentration. On the basis of these changes the association constants to membranes are determined.

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



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. PMID:23991094

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.



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


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



RasGRPs are targets of the anti-cancer agent ingenol-3-angelate.  


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. PMID:23991094

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



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

E-print Network

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

Gopal, Sreeja



Explanation of the mechanism of carcinogenesis and syntheses of anticancer agents with high selectivity  

Microsoft Academic Search

In 1979, the mechanism of chemical carcinogenesis, a challenging and difficult scientific problem pending for a number of\\u000a years, was explained by Dai Qianhuan. The mechanism named di-region theory predicted that a carcinogen always metabolizes\\u000a to form a special bi-functional alkylating agent. This agent induces cross-linkages between the complementary base pairs in\\u000a DNA and switches on initial mutageneses in genomes

Qianhuan Dai



The effect of light on gene expression and podophyllotoxin biosynthesis in Linum album cell culture.  


Podophyllotoxin (PTOX) is a naturally occurring phenolic compound isolated as an active anti-tumor agent. The stimulatory influence of light on the formation of phenolic compounds has been reported, but the molecular mechanism underlying the effect of light on the expression of genes involved in phenolic biosynthesis, especially of lignans, is still not fully understood. A series of experiments was carried out using ordinary fluorescent lamps to study the influence of light irradiation on growth and PTOX accumulation in Linum album cell cultures by varying the type of light and periods of exposure. The biosynthesis of PTOX was variably affected according to the quality of light. The enhancing effects of red light on PTOX production was correlated with increased activities of the enzyme phenylalanine ammonia-lyase (PAL), and the expression of some key genes involved in the biosynthesis of this compound, including the PAL gene itself and the cinnamoyl-CoA reductase (CCR) gene. Blue light was found to have similar effects but mainly on the expression level of CCR and pinoresinol lariciresinol reductase (PLR) genes. PMID:22579943

Yousefzadi, Morteza; Sharifi, Mozafar; Behmanesh, Mehrdad; Ghasempour, Alireza; Moyano, Elisabeth; Palazon, Javier



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. PMID:16528970

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



Synthesis of novel 1,2,4-triazoles, triazolothiadiazines and triazolothiadiazoles as potential anticancer agents.  


A series of new N-substituted-3-mercapto-1,2,4-triazoles (3a,b and 7a-d), triazolo[1,3,4]thiadiazines (5a,b) and triazolo[1,3,4]thiadiazoles (4a-d, 6 and 8a-d) have been synthesized starting from isonicotinic acid hydrazide. The structure of the newly synthesized compounds was confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against 6 human cancer cell lines and normal fibroblasts. Seven of the tested compounds (3a,b, 4c, 5a and 8b-d) exhibited significant cytotoxicity against most cell lines. Among these derivatives compound 4c exhibited equivalent cytotoxic effect to the standard CHS 828 against gastric cancer cell line (IC50 = 25 nM). Normal fibroblast cells (WI38) were affected to a much lesser extent (IC50 > 10,000 nM). PMID:25147148

Kamel, Mona M; Megally Abdo, Nadia Y



FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells.  


The inhibition of topoisomerase can suppress the growth of cancer cells and induce apoptosis. The aim of this study was to evaluate the anticancer effects and mechanisms of action of a novel topoisomerase inhibitor, 4-(furan-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-1,10-phenanthroline (FPDHP). FPDHP suppressed the growth of Caki, A549, HT29 and MDA-MB-231 cells, and induced caspase-dependent apoptosis in the Caki cells. In particular, FPDHP also induced caspase-dependent apoptosis and the downregulation of the protein expression levels of cellular FLICE-like inhibitory protein (cFLIP) and the phosphorylation of Akt in Caki cells. Notably, the overexpression of cFLIP, but not that of Akt, in part, blocked the FPDHP-mediated apoptosis in Caki cells. In addition, FPDHP was further shown to induce the caspase-independent detachment of Caki cells from the culture dish; higher populations of apoptotic cells were observed in the detached cells than in the attached cells. To the best of our knoweledge, these results collectively demonstrate for the first time that FPDHP has a killing effect on Caki cells, which is mediated through both caspase-dependent apoptosis and caspase-independent cell detachment. PMID:25092524

Park, Jun Soo; Kim, Wan Tae; Kim, Shin; Kwon, Taeg Kyu; Jang, Byeong-Churl; Lee, Eung-Seok; Park, Jong Wook



Pectenotoxin-2 from Marine Sponges: A Potential Anti-Cancer Agent--A Review  

PubMed Central

Pectenotoxin-2 (PTX-2), which was first identified as a cytotoxic entity in marine sponges, has been reported to display significant cytotoxicity to human cancer cells where it inhibits mitotic separation and cytokinesis through the depolymerization of actin filaments. In the late stage of endoreduplication, the effects of PTX-2 on different cancer cells involves: (i) down-regulation of anti-apoptotic Bcl-2 members and IAP family proteins; (ii) up-regulation of pro-apoptotic Bax protein and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-receptor 1/receptor 2 (DR4/DR5); and (iii) mitochondrial dysfunction. In addition, PTX-2 induces apoptotic effects through suppression of the nuclear factor ?B (NF-?B) signaling pathway in several cancer cells. Analysis of cell cycle regulatory proteins showed that PTX-2 increases phosphorylation of Cdc25c and decreases protein levels of Cdc2 and cyclin B1. Cyclin-dependent kinase (Cdk) inhibitor p21 and Cdk2, which are associated with the induction of endoreduplication, were upregulated. Furthermore, it was found that PTX-2 suppressed telomerase activity through the transcriptional and post-translational suppression of hTERT. The purpose of this review was to provide an update regarding the anti-cancer mechanism of PTX-2, with a special focus on its effects on different cellular signaling cascades. PMID:22163180

Kim, Gi-Young; Kim, Wun-Jae; Choi, Yung Hyun



Imaging of anticancer agent distribution by a slit-scanning Raman microscope  

NASA Astrophysics Data System (ADS)

In recent years, various types of molecular imaging technologies have been developed, but many of them require probes and may have some influence on the distribution of the target molecules. In contrast, Raman microscopic analysis is effective for molecular identification of materials, and molecular imaging methods employing Raman scattering light can be applied to living organisms without use of any exogenous probes. Unfortunately, Raman microscopic imaging is rarely used in the biomedical field due to the weakness of Raman signals. When the conventional Raman microscopes are used, the acquisition of an image of a cell usually takes several hours. Recently, a slit-scanning confocal Raman microscope has been developed. It can acquire images of living cells and tissues with faster scanning speed. In this study, we used the slit-scanning confocal Raman microscope (RAMAN-11) to image the distribution of a drug in living cells. We could acquire images of the distribution of an anticancer reagent in living cells within several minutes. Since the wavelength of Raman scattering light is determined by the frequency of molecular vibration, the in situ mapping of the intracellular drugs without use of a probe is possible, suggesting that laser Raman imaging is a useful method for a variety of pharmacokinetic studies.

Harada, Yoshinori; Ota, Taisuke; Ping, Dai; Yamaoka, Yoshihisa; Hamada, Keisaku; Fujita, Katsumasa; Takamatsu, Tetsuro



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

PubMed Central

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

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



Interpatient pharmacokinetic and pharmacodynamic variability of carrier-mediated anticancer agents.  


Major advances in the field of carrier-mediated agents (CMAs) have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small-molecule counterparts (solubility,duration of exposure, and delivery to the site of action are higher), these agents display substantial variability in systemic clearance (CL) and distribution, tumor delivery, and pharmacologic effects. This review provides an overview of factors that affect the pharmacokinetics (PK) and pharmacodynamics (PD) of CMAs in preclinical models and patients. PMID:22472987

Caron, W P; Song, G; Kumar, P; Rawal, S; Zamboni, W C



Cytotoxic Effects of Topotecan Combined With Various Anticancer Agents in Human Cancer Cell Lines  

Microsoft Academic Search

was calculated. A CI less than 1 indi- cated synergy (i.e., the effect of the combination was greater than that ex- pected from the additive effects of the component agents), a CI equal to 1 in- dicated additivity, and a CI greater than 1 indicated antagonism (the effect of the combination was less than that expected from the additive effects

Scott H. Kaufmann; David Peereboom; Christopher A. Buckwalter; Phyllis A. Svingen; Louise B. Grochow; Ross C. Donehower; Eric K. Rowinsky


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. PMID:22448039

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



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. PMID:23303345

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.



Solvent effect on the photophysical properties of the anticancer agent ellipticine.  


This paper investigates how solution conditions, especially solvent polarity and hydrogen bonding, affect the fluorescence of ellipticine, a natural plant alkaloid with anticancer activity. A total of 16 solvents that cover a wide range of polarities were tested. The ultraviolet (UV) absorption and fluorescence emission of ellipticine were found to be solvent dependent. The absorption and emission maximum shifted to higher wavelengths (red shift) with increased solvent polarity. The difference in absorption and emission maximum (Stokes' shift) was large, approximately 10,000-11,000 cm-1, in polar solvents (with orientation polarizability Deltaf>0.2) but unusually small, approximately 8900 cm-1, in nonpolar solvents (hexane and cyclohexane). Large Stokes' shifts were due to an intramolecular charge transfer (ICT), which was enabled by large solvent polarity and hydrogen bonding of ellipticine with the solvents. Two transitions were found in the Lippert-Mataga plot between (1) nonpolar and semipolar solvents and between (2) semipolar and polar solvents. The first transition reflected the formation of hydrogen bonds between ellipticine and the solvents whereas the second transition indicated that ellipticine underwent an ICT. In addition, the larger extinction coefficients and the longer lifetime of ellipticine obtained in protic solvents were attributed to the formation of stronger hydrogen bonds. The photophysical response of ellipticine to changes in solvent polarity and hydrogen bond formation could be used to infer the location of ellipticine in a heterogeneous medium, namely liposomes in aqueous solution. A relatively large red shift of emission in liposomes indicated that ellipticine may be in a more polar environment with respect to the lipid bilayer, possibly close to the hydrophilic interface. PMID:17020255

Fung, S Y; Duhamel, J; Chen, P



Nanotechnologies to use bisphosphonates as potent anticancer agents: the effects of zoledronic acid encapsulated into liposomes  

Microsoft Academic Search

Zoledronic acid (ZOL) is a potent amino-bisphosphonate used for the treatment of bone metastases with recently reported antitumor activity. However, the short plasma half-life and rapid accumulation in bone limits the use of ZOL as an antitumor agent in extraskeletal tissues. Therefore, we developed stealth liposomes encapsulating ZOL (LipoZOL) to increase extraskeletal drug availability. Compared to free ZOL, LipoZOL induced

Monica Marra; Giuseppina Salzano; Carlo Leonetti; Pierfrancesco Tassone; Marco Scarsella; Silvia Zappavigna; Teresa Calimeri; Renato Franco; Giuseppina Liguori; Giovanni Cigliana; Roberta Ascani; Maria Immacolata La Rotonda; Alberto Abbruzzese; Pierosandro Tagliaferri; Michele Caraglia; Giuseppe De Rosa


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

PubMed Central

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

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



Experimental anticancer therapy with vascular-disruptive peptide and liposome-entrapped chemotherapeutic agent.  


Vasculature is essential for the sustained growth of solid tumors and metastases. Tumor cells surviving vascular-disruptive therapeutic intervention (especially those present at the tumor rim) can contribute to tumor regrowth. The aim was to strengthen, by carrier-mediated delivery of a chemotherapeutic, the curative effects of a bifunctional anti-vascular oligopeptide capable of inducing vascular shutdown and tumor shrinkage. For the in vitro experiments and animal therapy, ACDCRGDCFC-GG-(D)(KLAKLAK)(2) peptide (900 microM in D-PBSA, i.e. Dulbecco's PBS without Ca(2+) and Mg(2+)) and size-calibrated, passively or actively targeted liposomes based on distearoylphosphatidylcholine, cholesterol, and N-carbamoyl-methoxypolyethyleneglycol coupled to distearoylphosphatidylethanolamine (PEG-DSPE) and containing gradient-entrapped doxorubicin were used. The KB (human nasopharyngeal carcinoma) cell line overexpressing folate receptors was used in the fluorescence studies of liposomal uptake. The B16-F10 melanoma cell line was used for confirming, by flow cytometry and confocal microscopy, doxorubicin intracellular transfer as well as to induce experimental tumors in C57BL/6 mice. Animal therapy was achieved with injections of vascular-disrupting peptide, doxorubicin-loaded liposomes, or alternating combined therapy. The results (tumor growth inhibition and survival) were compared using the Mann-Whitney U test and the log-rank test. Necrosis in H&E-stained tumor sections was assessed microscopically by pathologists. Treatment of C57BL/6 mice bearing B16-F10 experimental tumors with a combination of vascular-disruptive peptide and doxorubicin-carrying pegylated liposomes (either passively targeted liposomes (PTL) or folate receptor targeted) gave better therapeutic effects when tumor development was re-challenged with a second cycle of combined therapy. Marked inhibition of tumor growth and a statistically significant extension of the lifespan of the treated mice were observed when the re-challenge involved the use of folate receptor-targeted liposomes (FTL). Anticancer therapy involving vascular-disruptive peptide and doxorubicin delivered via pegylated folate receptor-targeted liposomes is more effective than either monotherapy, especially when tumor growth is re-challenged with the therapeutic combination. PMID:20383751

Sochanik, Aleksander; Mitrus, Iwona; Smolarczyk, Ryszard; Cicho?, Tomasz; Snietura, Miros?aw; Czaja, Maria; Szala, Stanis?aw



Investigation of the interaction of cardiotoxic anticancer agents using the fetal mouse heart organ culture system  

SciTech Connect

The fetal mouse heart organ culture system was utilized in an effort to document and predict the potential cardiotoxic effects of ionizing radiation, Adriamycin (ADR), and Dihydroxyanthraquinone (DHAQ); alone and in combination. These antineoplastic agents have been shown to produce clinical cardiomyopathy which is often dose-limiting. Fetal mouse hearts (gestational day 17) were removed and placed in a culture system of 6-well microtiter plates. A single heart was placed in each well on a piece of aluminium mesh, above the culture medium but bathed by capillary action. The plates were then placed in a 100% oxygen environment and incubated at 37/sup 0/C. Treatments performed on day 1 after culture were Cs-137 irradiation (10, 20, or 40 Gy); ADR (10, 30, or 100 micrograms/ml); DHAQ (5, 20, or 50 micrograms/ml); or various combinations of drugs and radiation. Hearts were checked every day for functional activity as evidenced by continuous heart best. Untreated hearts beat rhythmically for up to 9 days (average = 6.8 days); treated hearts stopped beating between 2 and 7 days after treatment. Using this endpoint of functional retention time (FRT), dose response curves were obtained for all individual agents. Combinations of ADR and DHAQ (at concentrations that resulted in FRTs of 3.5 days) produced no greater effect than either agent alone. However, the combination of radiation (FRT = 5.3 days) with ADR, DHAQ or both drugs was more effective than was drug alone. This system may help to predict the cardiotoxic effects that result from the use of these drugs and radiation.

Kimler, B.F.; Rethorst, R.D.; Cox, G.G.



Targeted Delivery of Anticancer Agents via a Dual Function Nanocarrier with an Interfacial Drug-Interactive Motif.  


We have developed a dual-function drug carrier, polyethylene glycol (PEG)-derivatized farnesylthiosalicylate (FTS). Here we report that incorporation of a drug-interactive motif (Fmoc) into PEG5k-FTS2 led to further improvement in both drug loading capacity and formulation stability. Doxorubicin (DOX) formulated in PEG5k-Fmoc-FTS2 showed sustained release kinetics slower than those of DOX loaded in PEG5k-FTS2. The maximum tolerated dose of DOX- or paclitaxel (PTX)-loaded PEG5k-Fmoc-FTS2 was significantly higher than that of the free drug. Pharmacokinetics and biodistribution studies showed that DOX/PEG5k-Fmoc-FTS2 mixed micelles were able to retain DOX in the bloodstream for a significant amount of time and efficiently deliver the drug to tumor sites. More importantly, drug (DOX or PTX)-loaded PEG5k-Fmoc-FTS2 led to superior antitumor activity over other treatments including drugs formulated in PEG5k-FTS2 in breast cancer and prostate cancer models. Our improved dual function carrier with a built-in drug-interactive motif represents a simple and effective system for targeted delivery of anticancer agents. PMID:25325795

Zhang, Xiaolan; Huang, Yixian; Zhao, Wenchen; Liu, Hao; Marquez, Rebecca; Lu, Jianqin; Zhang, Peng; Zhang, Yifei; Li, Jiang; Gao, Xiang; Venkataramanan, Raman; Xu, Liang; Li, Song



Pharmaceutical development of a parenteral lyophilized formulation of the investigational polymer-conjugated platinum anticancer agent AP 5280.  


AP 5280 is a novel polymer-conjugated platinum anticancer agent showing promising in vitro and in vivo activity against solid tumors. The aim of this study was to develop a parenteral pharmaceutical dosage form for phase I clinical trials. AP 5280 drug substance was characterized by using a wide range of analytical techniques and showed excellent solubility in water. However, as aqueous solutions of AP 5280 proved to be labile upon sterilization by moist heat, it was decided to develop a lyophilized dosage form. Initially, glass vials were used as primary packaging, but this led to a high breakage rate, which could be completely prevented by the use of CZ resin vials. Stability studies to date show that the lyophilized product in glass vials is stable for at least 12 months when stored at 2-8 degrees C in the dark and the lyophilized product in CZ resin vials is stable for at least 6 months under these conditions. Photostability testing revealed photolability of AP 5280 drug substance and lyophilized product in both types of primary container, necessitating storage in the dark. The first clinical experiences indicate that the proposed formulation is fully applicable for use in the clinical setting. PMID:14606662

Bouma, M; Nuijen, B; Harms, R; Rice, J R; Nowotnik, D P; Stewart, D R; Jansen, B A J; van Zutphen, S; Reedijk, J; van Steenbergen, M J; Talsma, H; Bult, A; Beijnen, J H



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

PubMed Central

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

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



Synthesis and biological evaluation of thiazoline derivatives as new antimicrobial and anticancer agents.  


N'-(3,4-Diarylthiazol-2(3H)-ylidene)-2-(arylthio)acetohydrazides were synthesized and evaluated for their antimicrobial activity and cytotoxicity against NIH/3T3 cells. Compound 22 bearing 1-phenyl-1H-tetrazole and p-chlorophenyl moieties was found to be the most promising antibacterial agent against Pseudomonas aeruginosa, whereas compound 23 bearing 1-phenyl-1H-tetrazole and p-bromophenyl moieties was the most promising antifungal agent against Candida albicans. The most effective derivatives were also evaluated for their cytotoxicity against C6 glioma cells. The results indicated that compound 17 bearing 1-phenyl-1H-tetrazole and nonsubstituted phenyl moieties (IC?? = 8.3 ± 2.6 ?g/mL) was more effective than cisplatin (IC?? = 13.7 ± 1.2 ?g/mL) against C6 glioma cells. Compound 17 also exhibited DNA synthesis inhibitory activity on C6 cells. Furthermore, compound 17 showed low toxicity to NIH/3T3 cells (IC?? = 416.7 ± 28.9 ?g/mL). PMID:24480358

Alt?ntop, Mehlika Dilek; Kaplanc?kl?, Zafer As?m; Ciftçi, Gül?en Akal?n; Demirel, Rasime



Evaluation of the bioequivalence of tablets and capsules containing the novel anticancer agent R115777 (Zarnestra) in patients with advanced solid tumors  

Microsoft Academic Search

Summary  R 115777 (Zarnestra) is a novel anticancer agent, currently undergoing phase III clinical testing. An open, cross-over trial\\u000a was performed in 24 patients with solid tumors to compare the bioavailability of a new tablet formulation with the standard\\u000a capsule formulation. Both dosage forms were administered once daily in doses of 300 or 400 mg. Patients received R 115777\\u000a as a

M. Crul; G. J. De Klerk; M. Swart; L. Weiner; P. A. Palmer; C. J. Bol; J. H. Beijnen; J. H. M. Schellens



4-Demethoxy-3*-deamino-3*-aziridinyl-4*-methylsulphonyl-daunorubicin (PNU-159548), a Novel Anticancer Agent Active against Tumor Cell Lines with Different Resistance Mechanisms1  

Microsoft Academic Search

The activity of 4-demethoxy-3*-deamino-3*-aziridinyl-4*-methylsulpho- nyl-daunorubicin (PNU-159548), a new alkycycline with high antitumor activity against a broad range of cancer cells, was evaluated in vitro and in vivo in cells selected for resistance to different anticancer agents. Both in vitro and in vivo, PNU-159548 did retain its activity in cells expressing the multidrug resistance (MDR) phenotype, associated to MDR-1 gene overexpression

Sergio Marchini; Giovanna Damia; Massimo Broggini; Giulia Pennella; Marina Ripamonti; Aurelio Marsiglio; Cristina Geroni


Alleviation of Podophyllotoxin Toxicity Using Coexisting Flavonoids from Dysosma versipellis  

PubMed Central

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

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



Nitric oxide synthases catalyze the activation of redox cycling and bioreductive anticancer agents.  


Nitric oxide synthases (NOSs) play a crucial role in the control of blood flow, memory formation, and the immune response. These proteins can be structurally divided into oxygenase and reductase domains. The reductase domain shares a high degree of sequence homology with P450 reductase, which is thought to be the major enzyme responsible for the one-electron reduction of foreign compounds, including bioreductive antitumor agents currently undergoing clinical trials. In view of the structural similarities between NOS and P450 reductase, we investigated the capacity of NOS to reduce the hypoxic cytotoxin tirapazamine, the antitumor agent doxorubicin, and also the redox cycling compound menadione. All three isoforms exhibited high levels of activity toward these compounds. In the case of doxorubicin and menadione, the activity of NOS II was 5-10-fold higher than the other enzymes, whereas with tirapazamine, the activities were broadly similar. NOS-mediated metabolism of tirapazamine resulted in a large increase in plasmid DNA strand breaks, demonstrating that the reduction was a bioactivation process. In addition, tirapazamine inhibited NOS activity. Because nitric oxide is implicated in maintaining tumor vascular homeostasis, it is conceivable that tirapazamine could potentiate its own toxicity by increasing the degree of hypoxia. This study suggests that the NOSs could play a key role in the therapeutic effects of tirapazamine, particularly because NOS activity is markedly increased in several human tumors. In addition, the presence of NOS in the heart indicates that these enzymes may contribute to the cardiotoxicity of redox cycling drugs, such as doxorubicin. PMID:10213502

Garner, A P; Paine, M J; Rodriguez-Crespo, I; Chinje, E C; Ortiz De Montellano, P; Stratford, I J; Tew, D G; Wolf, C R



Phosphine-gold(I) compounds as anticancer agents: general description and mechanisms of action.  


Gold complexes have been explored as metallodrugs with great potential applications as antitumoral agents. In particular, gold-phosphine derivatives seemed quite promising since the use of the antiarthritic auranofin drug (thiolate-Au-PEt3 complex) presented also biological activity against different cancer cells. So, different auranofin analogues have been explored within this context and for this reason, the main number of phosphine-gold complexes developed with this goal contain thiolate ligands. Other complexes have been also studied such as tetrahedral bis(phosphine)gold(I) and phosphine-gold-halides. Very recently, phosphine-gold-alkynyl complexes have also shown very interesting biological activities although few reports are published related to them. Their mechanism of action seems to be clearly different that the used by platinum drugs (DNA intercalating processes) and recent studies point to be related to the inhibition of Trx reductase. Cellular uptake and biodistribution studies are well reported in the original works but the use of luminescence techniques is relatively less explored. For this, the use of these techniques is also specifically reported in this review. PMID:21864238

Lima, João Carlos; Rodriguez, Laura



Hsp90 inhibitors as anti-cancer agents, from basic discoveries to clinical development.  


Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone which stabilizes various oncogenic kinases, including HER2, EGFR, BCR-ABL, B-Raf and EML4-ALK, which are essential for tumor growth. Several monoclonal antibodies and small molecule kinase inhibitors which target these kinases have been identified as potential new molecular target therapeutics. Previous reports have shown that many oncogenic proteins essential for cancer transformation are chaperoned by the Hsp90 complex, and some of these client proteins have been discovered by using Hsp90 inhibitors, such as geldanamycin (GA) and radicicol (RD).Thus far more than 200 client proteins have been identified. In past derivatives of these natural products have been evaluated in clinical trials, but none of the 1st generation of Hsp90 inhibitors has been approved yet because of their limitations in physico-chemical properties and/or safety profiles. However, recent reports have indicated that more than 10 new agents, 2nd generation of Hsp90 inhibitors with different chemotypes from GA and RD, have entered clinical trials and some of them showed clinical efficacy. In this review article, we describe the discoveries of major Hsp90 client proteins in the cancer field by RD derivatives, the history of KW-2478 discovery and development by Kyowa Hakko Kirin, and gave an update on the current status of new Hsp90 inhibitors in clinical trials. PMID:22920907

Soga, Shiro; Akinaga, Shiro; Shiotsu, Yukimasa



Design, modeling, synthesis and biological activity evaluation of camptothecin-linked platinum anticancer agents.  


The design, modeling, synthesis and biological activity evaluation of two hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex are reported. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and compound 1b, the most active one, was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. Compound 1b exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated via an oxyiminomethyl linker at the 7-position of the camptothecin resulted in a new class of effective antitumor compounds. PMID:23517728

Cincinelli, Raffaella; Musso, Loana; Dallavalle, Sabrina; Artali, Roberto; Tinelli, Stella; Colangelo, Donato; Zunino, Franco; De Cesare, Michelandrea; Beretta, Giovanni Luca; Zaffaroni, Nadia



Characterization of short-lived electrophilic metabolites of the anticancer agent laromustine (VNP40101M).  


Laromustine (VNP40101M; 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino) carbonylhydrazine) is a novel sulfonylhydrazine alkylating agent. Phase 1 metabolism of laromustine was reported recently and showed that laromustine undergoes rearrangement, dehalogenation, and hydrolysis at physiological pH to form active moieties. (1) A mechanism for the rearrangement was proposed on the basis of fragmentation ions. (1) (,) (2) In this article, we report the phase II conjugates of VNP40101M and VNP4090CE which were formed after incubation of VNP40101M or VNP4090CE with pooled human liver microsomes (HLM) and cofactors nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), N-acetylecysteine (NAC), and cysteine (CYS). Eight novel phase II conjugates (M-1 to M-8) were identified and characterized by hydrogen-deuterium exchange (H-D), stable isotope ((13)C-labeled VNP40101M), and MS(n) experiments. M-4 and M-5 were further confirmed by nuclear magnetic resonance spectroscopy (NMR). The short-lived CH(3)SO(2)CH(2)CH(2)-, methylformamide and CH(3)SO(2)NHN?CHCH(2)- moieties were generated from VNP40101M. The reactive intermediates CH(3)SO(2)CH(2)CH(2)- and methylformamide formed conjugates with GSH, CYS, and NAC. The CH(3)SO(2)NHN?CHCH(2)- moiety formed conjugates with GSH and NAC. M-2, M-4, and M-6 were only detected from the incubation of VNP40101M because VNP4090CE does not contain a methylformamide group. All other conjugates were formed by both VNP40101M and VNP4090CE. The in vitro studies found that VNP40101M and VNP4090CE undergo activation in human liver microsomes. The results from this study showed that laromustine produces several reactive intermediates that may play a role in the toxicities seen in the clinical trials. PMID:21361357

Nassar, A-E F; King, I; Du, J



HER2-specific affibody-conjugated thermosensitive liposomes (Affisomes) for improved delivery of anticancer agents.  


Thermosensitive liposomes are attractive vehicles for the delivery and release of drugs to tumors. To improvethe targeting efficacy for breast cancer treatment, an 8.3-kDa HER2-specific Affibody molecule (Z(HER2:342)-Cys) was conjugated to the surface of liposomes. The effects of this modification on physical characteristics and stability of the resulting nanoparticles denoted as "Affisomes" were investigated. Thermosensitive small unilamellar vesicle (SUV) liposomes of (80-100 nm) a diameter consisting of dipalmitoyl phosphatidylcholine (DPPC, Tm 41 degrees C) as the matrix lipid and a maleimide-conjugated pegylated phospholipid (DSPE-MaL-PEG2000) were prepared by probe sonication. Fluorescent probes were incorporated into liposomes for biophysical and/or biochemical analysis and/or triggered-release assays. Affibody was conjugated to these liposomes via its C-terminal cysteine by incubation in the presence of a reducing agent (e.g., tributylphosphine) for 16-20 hours under an argon atmosphere. Lipid-conjugated affibody molecule was visible as an 11.3-kDa band on a 4-12% Bis/Tris gel under reducing conditions. Affibody conjugation yields were approximately 70% at a protein-lipid ratio of 20 microg/mg, with an average number of 200 affibody molecules per Affisome. Affibody conjugation to thermosensitive liposomes did not have any significant effect on the hydrodynamic size distribution of the liposomes. Thermosensitivity of Affisomes was determined by monitoring the release of entrapped calcein (a water-soluble fluorescent probe, lambdaex/em 490/515 nm) as a function of temperature. Calcein was released from Affisomes (thermosensitive liposomes with affibody-Targeted SUV) as well as nontargeted SUV (thermosensitive liposomes without affibody) in a temperature-dependent manner, with optimal leakage (90-100%) at 41 degrees C. In contrast, liposomes prepared from Egg phosphatidyl choline (Egg PC, Tm approximately 0 degrees C) under similar conditions released only 5-10% calcein at 41 degrees C. Affisomes, when stored at room temperature, retained > 90% entrapped calcein up to 7 days. Moreover, incubation of liposomes in phosphate-buffered saline, supplemented with 10% heat-inactivated serum (fetal bovine serum) did not result in a destabilization of liposomes. Therefore, Affisomes present promising, novel drug-delivery candidates for breast cancer targeting. PMID:18937120

Puri, Anu; Kramer-Marek, Gabriela; Campbell-Massa, Ryan; Yavlovich, Amichai; Tele, Shrikant C; Lee, Sang-Bong; Clogston, Jeffrey D; Patri, Anil K; Blumenthal, Robert; Capala, Jacek



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

PubMed Central

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




Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents  

Microsoft Academic Search

A series of novel curcumin analogs were synthesized and screened for anti-cancer and anti-angiogenesis activities at Emory University and at the National Cancer Institute (NCI). These compounds are symmetrical ?,?-unsaturated and saturated ketones. The majority of the analogs demonstrated a moderate degree of anti-cancer activity. Compounds 10, 11, and 14 exhibited a high degree of cytotoxicity in the NCI in

Brian K. Adams; Eva M. Ferstl; Matthew C. Davis; Marike Herold; Serdar Kurtkaya; Richard F. Camalier; Melinda G. Hollingshead; Gurmeet Kaur; Edward A. Sausville; Frederick R. Rickles; James P. Snyder; Dennis C. Liotta; Mamoru Shoji



Suppression of autophagy by FIP200 deletion impairs DNA damage repair and increases cell death upon treatments with anti-cancer agents  

PubMed Central

Autophagy is a lysosomal bulk degradation process for intracellular protein and organelles. FIP200 (200 kDa FAK-family interacting protein) is an essential component of mammalian autophagy that is implicated in breast cancer in recent studies. Here we show that inactivation of FIP200 resulted in deficient repair of DNA damage induced by ionizing radiation and anticancer agents in mouse embryonic fibroblasts (MEFs). The persistent DNA damage correlated to increased apoptosis and reduced survival of FIP200 knockout (KO) MEFs after treatments with camptothecin (CPT), a topoisomerase I inhibitor and chemotherapeutic agent. Re-expression of FIP200 in FIP200 KO MEFs restored both efficient DNA damage repair and cell survival. Furthermore, knock-down of the increased p62 expression in FIP200 KO MEFs rescued the impaired DNA damage repair and CPT-induced cell death. In contrast, treatment of cells with N-acetyl-cysteine did not affect these defects in FIP200 KO MEFs. Lastly, FIP200 KO MEFs also showed deficient DNA damage repair and increased cell death compared to control MEFs, when treated with etoposide, a topoisomerase II inhibitor and another anticancer agent. Together, these results identify a new function for FIP200 in the regulation of DNA damage response and cell survival through its activity in autophagy, and suggest the possibility of FIP200 or other autophagy proteins as a potential target for treatment to enhance the efficiency of cancer therapy using DNA damage-inducing agents. PMID:21807966

Bae, Heekyong; Guan, Jun-Lin



Apoptins: selective anticancer agents.  


Therapies that selectively target cancer cells for death have been the center of intense research recently. One potential therapy may involve apoptin proteins, which are able to induce apoptosis in cancer cells leaving normal cells unharmed. Apoptin was originally discovered in the Chicken anemia virus (CAV); however, human gyroviruses (HGyV) have recently been found that also harbor apoptin-like proteins. Although the cancer cell specific activity of these apoptins appears to be well conserved, the precise functions and mechanisms of action are yet to be fully elucidated. Strategies for both delivering apoptin to treat tumors and disseminating the protein inside the tumor body are now being developed, and have shown promise in preclinical animal studies. PMID:25164066

Rollano Peñaloza, Oscar M; Lewandowska, Magdalena; Stetefeld, Joerg; Ossysek, Karolina; Madej, Mariusz; Bereta, Joanna; Sobczak, Mateusz; Shojaei, Shahla; Ghavami, Saeid; ?os, Marek J



Design and synthesis of novel 1,2,3-triazole-pyrimidine hybrids as potential anticancer agents.  


A series of novel 1,2,3-triazole-pyrimidine hybrids were designed, synthesized and evaluated for their anticancer activity against four selected cancer cell lines (MGC-803, EC-109, MCF-7 and B16-F10). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Compound 17 showed the most excellent anticancer activity with single-digit micromolar IC50 values ranging from 1.42 to 6.52 ?M. Further mechanism studies revealed that compound 17 could obviously inhibit the proliferation of EC-109 cancer cells by inducing apoptosis and arresting the cell cycle at G2/M phase. PMID:25180925

Ma, Li-Ying; Pang, Lu-Ping; Wang, Bo; Zhang, Miao; Hu, Biao; Xue, Deng-Qi; Shao, Kun-Peng; Zhang, Bao-Le; Liu, Ying; Zhang, En; Liu, Hong-Min



A novel anti-cancer agent, acetyltanshinone IIA, inhibits oestrogen receptor positive breast cancer cell growth by down-regulating the oestrogen receptor.  


In this paper we show that acetyltanshinone IIA (ATA), a novel anti-cancer agent, preferentially inhibits cell growth of oestrogen receptor positive (ER+) breast cancer cells and that it is more potent than the commonly used anti-breast cancer agent, tamoxifen. The metabolic product of ATA, hydroquinone tanshinone IIA (HTA) binds to the ER? and causes its degradation mainly in the nucleus via an ubiquitin-mediated proteasome-dependent pathway. In addition, ATA also reduced the mRNA levels of the ER? encoding gene, ESR1, distinguishing ATA from another anti-breast cancer drug, fulvestrant. Finally, ATA reduced the transcription of an ER-responsive gene, GREB1. PMID:24374015

Yu, Ting; Zhou, Zhicai; Mu, Yuguang; de Lima Lopes, Gilberto; Luo, Kathy Qian



Synthetic strategies for the design of platinum anticancer drug candidates  

E-print Network

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

Wilson, Justin Jeff



Design, Synthesis, and Biological Evaluation of Shikonin and Alkannin Derivatives as Potential Anticancer Agents via a Prodrug Approach.  


To minimize the cytotoxicity of shikonin and alkannin that arises through the generation of reactive oxygen species (ROS) and alkylation of the naphthazarin ring, two series of novel core-scaffold-modified shikonin and alkannin derivatives were designed. These derivatives, which differ in their configurational and positional isomerism (R-, S-, and 2- and 6-isomers) were synthesized in high enantiomeric excess (>99?%?ee). The selectivity of the dimethylated derivatives was significantly higher than the parent shikonin in vitro, but some side effects were still observed in vivo. Surprisingly, the dimethylated diacetyl derivatives with poor anticancer activity in vitro showed tumor-inhibiting effects similar to paclitaxel without any toxicity in vivo. The anticancer activity of these derivatives is in agreement with their low ROS generation and alkylating capacity, emphasizing their potential as prodrugs. This strategy provides means to address the nonspecific cytotoxicity of naphthazarin analogues toward normal cells. PMID:25234005

Wang, Ru-Bing; Zhou, Wen; Meng, Qing-Qing; Zhang, Xu; Ding, Jing; Xu, Yan; Song, Hua-Long; Yang, Kai; Cui, Jia-Hua; Li, Shao-Shun



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

PubMed Central

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

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



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. PMID:23028659

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



X-ray crystal structure of tetrachloro(trans-d,l-1,2-diaminocyclohexane) platinum(IV) complex: a potential anticancer agent.  


Tetrachloro(trans-d,l-1,2-diaminocyclohexane)platinum(IV) complex (tetraplatin or ormaplatin) has been recognized as a potential anticancer agent. We have determined the crystal structure of this compound by x-ray single crystal diffraction. It has a unique space group and rare molecular packing. Parameters are as follows: space group R3c (rhombohedral), a = 26.425(4) A, alpha = 54.50(1) degrees; V = 11375A3, Z = 36. The coordination about Pt atoms is a slightly distorted octahedron owing to the presence of the geometrically strained five-membered ring (avg. N-Pt-N angle = 82.9 degrees). An intricate network of intermolecular hydrogen bonds holds the crystal lattice together. Three independent ormaplatin molecules surround each water molecule, forming the three shortest A...B contacts and thus the three strongest hydrogen bonds. PMID:8228978

Khokhar, A R; Xu, Q; al-Baker, S



Thieno[3,2-c]pyran-4-one based novel small molecules: their synthesis, crystal structure analysis and in vitro evaluation as potential anticancer agents.  


Novel thieno[3,2-c]pyran-4-one based small molecules were designed as potential anticancer agents. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of few steps such as Gewald reaction, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of thiophene ring followed by the fused pyranone moiety and then functionalization at C-7 position of the resultant thieno[3,2-c]pyran-4-one framework. Some of the compounds synthesized showed selective growth inhibition of cancer cells in vitro among which two compounds for example, 5d and 6c showed IC(50) values in the range of 2.0-2.5 ?M. The crystal structure analysis of an active compound along with hydrogen bonding patterns and molecular arrangement present within the molecule is described. PMID:22632935

Nakhi, Ali; Adepu, Raju; Rambabu, D; Kishore, Ravada; Vanaja, G R; Kalle, Arunasree M; Pal, Manojit



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


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

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



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



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


New Schiff's base derivatives 5a-j have been synthesized by reaction between 2-phenoxyquinoline-3-carbaldehydes 3a-j and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide 4 in presence of nickel(II) nitrate as a catalyst in ethanol under reflux in good yield (78-92%). All compounds were tested for anticancer and inhibition of EGFR. Of the compounds studied, majority of the compounds showed effective antiproliferation and inhibition of EGFR and HER-2 activities. Compound 5h showed most effective inhibition (IC50=0.12±0.05 ?M) by binding in to the active pocket of EGFR receptor with minimum binding energy (?Gb=-58.3691 kcal/mol). The binding was stabilized by two hydrogen bonds, two ?-cation and one ?-sigma interactions. Compound 5d showed most effective inhibition (IC50=0.37±0.04 ?M). PMID:24630412

Makawana, Jigar A; Sangani, Chetan B; Lin, Lin; Zhu, Hai-Liang



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


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



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

SciTech Connect

Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 {mu}M) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca{sup 2+} efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP{sup +} transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds. - Graphical abstract: Guttiferone-A permeabilizes mitochondrial membrane and induces cancer cell death Display Omitted Highlights: > We addressed the involvement of mitochondria in guttiferone (GA) toxicity toward cancer cells. > GA promoted membrane permeabilization, membrane potential dissipation, NAD(P)H depletion, ROS accumulation and ATP depletion. > These actions could be implicated in the well-documented anti-cancer property of GA/structure related compounds.

Pardo-Andreu, Gilberto L., E-mail: [Centro de Estudio para las Investigaciones y Evaluaciones Biologicas, Instituto de Farmacia y Alimentos, Universidad de La Habana, ave. 23 21425 e/214 and 222, La Coronela, La Lisa, CP 13600, Ciudad Habana (Cuba); Departamento de Fisica e Quimica, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Av. Cafe s/n, 14040-903 Ribeirao Preto, SP (Brazil); Nunez-Figueredo, Yanier [Centro para las Investigaciones y Desarrollo de Medicamentos, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600, Ciudad Habana (Cuba); Tudella, Valeria G. [Departamento de Fisica e Quimica, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Av. Cafe s/n, 14040-903 Ribeirao Preto, SP (Brazil); Cuesta-Rubio, Osmany [Departamento de Quimica, Instituto de Farmacia y Alimentos, Universidad de La Habana, ave. 23 21425 e/214 and 222, La Coronela, La Lisa, CP 13600, Ciudad Habana (Cuba); Rodrigues, Fernando P.; Pestana, Cezar R. [Departamento de Fisica e Quimica, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Av. Cafe s/n, 14040-903 Ribeirao Preto, SP (Brazil); Uyemura, Sergio A.; Leopoldino, Andreia M. [Departamento de Analises Clinicas, Toxicologicas e Bromatologicas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Av. Cafe s/n, 14040-903 Ribeirao Preto, SP (Brazil); Alberici, Luciane C.; Curti, Carlos [Departamento de Fisica e Quimica, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Av. Cafe s/n, 14040-903 Ribeirao Preto, SP (Brazil)



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

E-print Network

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 ...

Fedeles, Bogdan I.


Temperature-triggered tumor-specific delivery of anticancer agents by cRGD-conjugated thermosensitive liposomes.  


One of the most effective methods to treat cancer is the specific delivery of anticancer drugs to the target site. To achieve this goal, we designed an anticancer drug with mild hyperthermia-mediated triggering and tumor-specific delivery. To enhance the thermosensitive drug release, we incorporated elastin-like polypeptide (ELP), which is known to be a thermally responsive phase transition peptide into the dipalmitoylphosphatidylcholine (DPPC)-based liposome surface. Additionally, cyclic arginine-glycine-aspartic acid (cRGD) binds to ?v?3 integrin, which is overexpressed in angiogenic vasculature and tumor cells, was introduced on the liposome. ELP-modified liposomes with the cRGD targeting moiety were prepared using a lipid film hydration method, and doxorubicin (DOX) was loaded into the liposome by the ammonium sulfate-gradient method. The cRGD-targeted and ELP-modified DOX-encapsulated liposomes (RELs) formed spherical vesicles with a mean diameter of 181 nm. The RELs showed 75% and 83% DOX release at 42°C and 45°C, respectively. The stability of RELs was maintained up to 12h without the loss of their thermosensitive function for drug release. Flow cytometry results showed that the cellular uptake of DOX in RELs into ?v?3 integrin-overexpressing U87MG and HUVEC cells was 8-fold and 10-fold higher, respectively, than that of non-targeting liposomes. Confocal microscopy revealed that REL released DOX only under the mild hyperthermia condition at 42°C by showing the localization of DOX in nuclei and the liposomes in the cytosol. The cell cytotoxicity results demonstrated that REL can efficiently kill U87MG cells through cRGD targeting and thermal triggering. The in vivo tumoral accumulation measurement showed that the tumor-targeting effect of RELs was 5-fold higher than that of non-targeting liposomes. This stable, target-specific, and thermosensitive liposome shows promise to enhance therapeutic efficacy if it is applied along with a relevant external heat-generating medical system. PMID:24441178

Kim, Min Sang; Lee, Don-Wook; Park, Kitae; Park, Sang-Jun; Choi, Eun-Jung; Park, Eun Sung; Kim, Hyun Ryoung



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. PMID:19130268

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



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


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

Miller, Marvin J; 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; Kurt Dolence, E; Dong, Li; Franzblau, Scott; Malouin, Francois; Möllmann, Ute



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


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



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 Central

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 possible 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



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

PubMed Central

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

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



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. PMID:24424355

Newman, David J.; Cragg, Gordon M.



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. PMID:20822181

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.



Synthesis and in vitro evaluation of new nitro-substituted thiazolyl hydrazone derivatives as anticandidal and anticancer agents.  


Fourteen new thiazolyl hydrazone derivatives were synthesized and evaluated for their anticandidal activity using a broth microdilution assay. Among the synthesized compounds, 2-[2-((5-(4-chloro-2-nitrophenyl)furan-2-yl)methylene)hydrazinyl]-4-(4-fluorophenyl)thiazole and 2-[2-((5-(4-chloro-2-nitrophenyl)furan-2-yl)methylene) hydrazinyl]-4-(4-methoxyphenyl)thiazole were found to be the most effective antifungal compounds against Candida utilis, with a MIC value of 250 µg/mL, when compared with fluconazole (MIC=2 µg/mL). Additionally, the synthesized compounds were evaluated for their in vitro cytotoxic effects on the MCF-7 and NIH/3T3 cell lines. As a result, 2-[2-((5-(4-chloro-2-nitrophenyl)furan-2-yl)methylene)hydrazinyl]-4-(4-chlorophenyl)thiazole was identified as the most promising anticancer compound against MCF-7 cancer cells due to its inhibitory effects (IC50=125 µg/mL) and relatively low toxicity towards the NIH/3T3 cell line (IC50>500 µg/mL). PMID:25232704

Alt?ntop, Mehlika Dilek; Özdemir, Ahmet; Turan-Zitouni, Gülhan; Ilg?n, Sinem; Atl?, Özlem; Demirci, Fatih; Kaplanc?kl?, Zafer As?m



In vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents  

Microsoft Academic Search

Purpose  Artemisinins are now established drugs for treatment of malaria. These agents have been shown to possess impressive anti-cancer\\u000a properties. We have investigated the role of artemisone (ATM), a novel derivative of artemisinin (ART) in a cancer setting\\u000a both alone and in combination with established chemotherapeutic agents.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  The anti-proliferative effects of ART and ATM were tested on a panel of human

Andrew M. GravettWai; Wai M. Liu; Sanjeev Krishna; Wing-Chi Chan; Richard K. Haynes; Natalie L. Wilson; Angus G. Dalgleish



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


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



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. PMID:24494064

Aliabadi, Alireza; Eghbalian, Elham; Kiani, Amir



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


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



The Antioxidant Transcription Factor Nrf2 Negatively Regulates Autophagy and Growth Arrest Induced by the Anticancer Redox Agent Mitoquinone*  

PubMed Central

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 Q10. Inhibition of cancer cell growth by MitoQ was associated with G1/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 G1 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



An ion-current-based, comprehensive and reproducible proteomic strategy for comparative characterization of the cellular responses to novel anti-cancer agents in a prostate cell model  

PubMed Central

Proteome-level investigation of the molecular targets in anticancer action of promising pharmaceutical candidates is highly desirable but remains challenging due to the insufficient proteome coverage, limited capacity for biological replicates, and largely unregulated false positive biomarker discovery of current methods. This study described a practical platform strategy to address these challenges, using comparison of drug response proteomic signatures by two promising anti-cancer agents (KX01/KX02) as the model system for method development/optimization. Drug-treated samples were efficiently extracted followed by precipitation/on-pellet-digestion procedure that provides high, reproducible peptide recovery. High-resolution separations were performed on a 75-cm-long, heated nano-LC column with a 7-hr gradient, with a highly reproducible nano-LC/nanospray configuration. An LTQ Orbitrap hybrid mass spectrometer with a charge overfilling approach to enhance sensitivity was used for detection. Analytical procedures were optimized and well-controlled to achieve high run-to-run reproducibility that permits numerous replicates in one set, and an ion-current-based approach was utilized for quantification. The false positives of biomarker discovery arising from technical variability was controlled based on FBDR measurement by comparing biomarker numbers in each drug-treated group vs. “sham samples”, which were analyzed in an order randomly interleaved with the analysis drug-treated samples. More than 1500 unique protein groups were quantified under stringent criteria, and of which about 30% displayed differential expression with FBDR of 0.3-2.1% across groups. Comparison of drug-response proteomic signatures and the subsequent immunoassay revealed that the action mechanisms of KX01/KX02 are similar but significantly different from vinblastine, which correlates well with clinical and pre-clinical observations. Furthermore, the results strongly supported the hypothesis that KX01/KX02 are dual-action agents (through inhibition of tubulin and Src). Moreover, informative insights into the drug-actions on cell cycle, growth/proliferation, and apoptosis were obtained. This platform technology provides extensive evaluation of drug candidates and facilitates in-depth mechanism studies. PMID:22982362

Hangauer, David; Qu, Jun



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


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

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



Heritable and cancer risks of exposures to anticancer drugs: inter-species comparisons of covalent deoxyribonucleic acid-binding agents  

Microsoft Academic Search

In the past years, several methodologies were developed for potency ranking of genotoxic carcinogens and germ cell mutagens. In this paper, we analyzed six sub-classes of covalent deoxyribonucleic acid (DNA) binding antineoplastic drugs comprising a total of 37 chemicals and, in addition, four alkyl-epoxides, using four approaches for the ranking of genotoxic agents on a potency scale: the EPA\\/IARC genetic

Ekkehart W. Vogel; Alain Barbin; Madeleine J. M. Nivard; H. Frank Stack; Michael D. Waters; Paul H. M. Lohman



Synthesis and biological evaluation of podophyllotoxin congeners as tubulin polymerization inhibitors.  


A series of new podophyllotoxin derivatives containing structural modifications at C-7, C-8, and C-9 were synthesized and evaluated for their cytotoxic activity against three human cancer cell lines. All the synthesized compounds showed significant growth inhibition with GI50 values in micromolar levels while some of the compounds were several times more potent against MCF-7 and HeLa cell lines than MIAPACA cell line. Three compounds (12a, 12d and 12e) emerged as potent compounds with broad spectrum of cytotoxic activity against all the tested cell lines with GI50 values in the range of 0.01-2.1?M. These compounds induce microtubule depolymerization and arrests cells at the G2/M phase of the cell cycle. Moreover, compounds 12d and 12e disrupted microtubule network and accumulated tubulin in the soluble fraction in a similar manner to their parent podophyllotoxin scaffold. In addition, structure activity relationship studies within the series were also discussed. Molecular docking studies of these compounds into the colchicine-binding site of tubulin, revealed possible mode of inhibition by these compounds. PMID:25131956

Kamal, Ahmed; Srinivasa Reddy, T; Polepalli, Sowjanya; Shalini, Nekkanti; Reddy, V Ganga; Subba Rao, A V; Jain, Nishant; Shankaraiah, Nagula



3-Bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective "small molecule" anti-cancer agent taken from labside to bedside: introduction to a special issue.  


Although the "Warburg effect", i.e., elevated glucose metabolism to lactic acid (glycolysis) even in the presence of oxygen, has been recognized as the most common biochemical phenotype of cancer for over 80 years, its biochemical and genetic basis remained unknown for over 50 years. Work focused on elucidating the underlying mechanism(s) of the "Warburg effect" commenced in the author's laboratory in 1969. By 1985 among the novel findings made two related most directly to the basis of the "Warburg effect", the first that the mitochondrial content of tumors exhibiting this phenotype is markedly decreased relative to the tissue of origin, and the second that such mitochondria have markedly elevated amounts of the enzyme hexokinase-2 (HK2) bound to their outer membrane. HK2 is the first of a number of enzymes in cancer cells involved in metabolizing the sugar glucose to lactic acid. At its mitochondrial location HK2 binds at/near the protein VDAC (voltage dependent anion channel), escapes inhibition by its product glucose-6-phosphate, and gains access to mitochondrial produced ATP. As shown by others, it also helps immortalize cancer cells, i.e., prevents cell death. Based on these studies, the author's laboratory commenced experiments to elucidate the gene basis for the overexpression of HK2 in cancer. These studies led to both the discovery of a unique HK2 promoter region markedly activated by both hypoxic conditions and moderately activated by several metabolites (e.g., glucose), Also discovered was the promoter's regulation by epigenetic events (i.e., methylation, demethylation). Finally, the author's laboratory turned to the most important objective. Could they selectively and completely destroy cancerous tumors in animals? This led to the discovery in an experiment conceived, designed, and conducted by Young Ko that the small molecule 3-bromopyruvate (3BP), the subject of this mini-review series, is an incredibly powerful and swift acting anticancer agent. Significantly, in subsequent experiments with rodents (19 animals with advanced cancer) Ko led a project in which 3BP was shown in a short treatment period to eradicate all (100%). Ko's and co-author's findings once published attracted global attention leading world-wide to many other studies and publications related to 3BP and its potent anti-cancer effect. This Issue of the Journal of Bioenergetics and Biomembranes (JOBB 44-1) captures only a sampling of research conducted to date on 3BP as an anticancer agent, and includes also a Case Report on the first human patient known to the author to be treated with specially formulated 3BP. Suffice it to say in this bottom line, "3BP, a small molecule, results in a remarkable therapeutic effect when it comes to treating cancers exhibiting a "Warburg effect". This includes most cancer types. PMID:22382780

Pedersen, Peter L



Development and Validation of a HPLC Method for Quantitation of BA-TPQ, a Novel Iminoquinone Anticancer Agent, and an Initial Pharmacokinetic Study in Mice  

PubMed Central

We herein describe the development and validation of a high performance liquid chromatography (HPLC) method for the quantitation of 7-(benzylamino)-1, 3, 4, 8-tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one (BA-TPQ), a newly synthesized iminoquinone anticancer agent. BA-TPQ was extracted from plasma and tissue samples by first precipitating proteins with acetonitrile followed by a liquid-liquid extraction with ethyl acetate. Chromatographic separation was carried out using a gradient flow rate on a Zorbax SB C-18 column, and the effluent was monitored by UV detection at 346 nm. The method was found to be precise, accurate, and specific, with a linear range from 3.91 to 1955.0 ng/mL in plasma, 19.55 to 1955.0 ng/mL in spleen, brain, and liver homogenates, and 19.55 to 3910.0 ng/mL in heart, lung and kidney homogenates. The method was stable under all relevant conditions. Using this method, we also carried out an initial study determining plasma pharmacokinetics and tissue distribution of BA-TPQ in mice following intravenous administration. In summary, this simple and sensitive HPLC method can be used in future preclinical and clinical studies of BA-TPQ. PMID:20845374

Wang, Wei; Xu, Hongxia; Rayburn, Elizabeth R.; Zhang, Xu; Gurpinar, Evrim; Yang, Xinyi; Sommers, Charnell I.; Velu, Sadanandan E.; Zhang, Ruiwen



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


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

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



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



Development and validation of a liquid chromatography-ultraviolet absorbance detection assay using derivatisation for the novel marine anticancer agent ES285·HCl [(2 S,3 R)-2-amino-3-octadecanol hydrochloride] and its pharmaceutical dosage form  

Microsoft Academic Search

ES-285·HCl [(2S,3R)-2-amino-3-octadecanol hydrochloride] is a novel investigational anticancer agent, which has shown in vitro and in vivo cytotoxic activity against various tumor cell lines with selectivity for certain solid tumors. The pharmaceutical development of ES-285·HCl warranted the availability of an assay for the quantification and purity determination of ES-285·HCl active pharmaceutical ingredient (API) and its pharmaceutical dosage form. A liquid

Monique W. J den Brok; Bastiaan Nuijen; Elena Miranda; Pablo Floriano; Simon Munt; Ignacio Manzanares; Jos H Beijnen



Cycloisomerization of 1,6-enynes in organoaqueous medium: an efficient and eco-friendly access to furan derivatives. Synthesis of a key intermediate of podophyllotoxin  

Microsoft Academic Search

The first cycloisomerization of enynes catalyzed by Pd(TPPTS)3 catalyst in aqueous medium to give functionalized furans is described. This new reaction has been applied to the synthesis of podophyllotoxin analog.

Jean-Christophe Galland; Sonia Dias; Monique Savignac; Jean-Pierre Genêt



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

SciTech Connect

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

Almassian, B.



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


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



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


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

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



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

PubMed Central

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

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



A Combined DNA-Affinic Molecule and N-Mustard Alkylating Agent Has an Anti-Cancer Effect and Induces Autophagy in Oral Cancer Cells  

PubMed Central

Although surgery or the combination of chemotherapy and radiation are reported to improve the quality of life and reduce symptoms in patients with oral cancer, the prognosis of oral cancer remains generally poor. DNA alkylating agents, such as N-mustard, play an important role in cancer drug development. BO-1051 is a new 9-anilinoacridine N-mustard-derivative anti-cancer drug that can effectively target a variety of cancer cell lines and inhibit tumorigenesis in vivo. However, the underlying mechanism of BO-1051-mediated tumor suppression remains undetermined. In the present study, BO-1051 suppressed cell viability with a low IC50 in oral cancer cells, but not in normal gingival fibroblasts. Cell cycle analysis revealed that the tumor suppression by BO-1051 was accompanied by cell cycle arrest and downregulation of stemness genes. The enhanced conversion of LC3-I to LC3-II and the formation of acidic vesicular organelles indicated that BO-1501 induced autophagy. The expression of checkpoint kinases was upregulated as demonstrated with Western blot analysis, showing that BO-1051 could induce DNA damage and participate in DNA repair mechanisms. Furthermore, BO-1051 treatment alone exhibited a moderate tumor suppressive effect against xenograft tumor growth in immunocompromised mice. Importantly, the combination of BO-1051 and radiation led to a potent inhibition on xenograft tumorigenesis. Collectively, our findings demonstrated that BO-1051 exhibited a cytotoxic effect via cell cycle arrest and the induction of autophagy. Thus, the combination of BO-1051 and radiotherapy may be a feasible therapeutic strategy against oral cancer in the future. PMID:22489152

Lo, Wen-Liang; Chu, Pen-Yuan; Lee, Tsung-Heng; Su, Tsann-Long; Chien, Yueh; Chen, Yi-Wei; Huang, Pin-I; Tseng, Ling-Ming; Tu, Pang-Hsien; Kao, Shou-Yen; Lo, Jeng-Fan



Identification and Characterization of Distinct Apoptotic Pathways in Cancer Cells Activated in Response to Treatment with Different Anti-Cancer Agents.  

National Technical Information Service (NTIS)

Apoptosis is a programmed form of cell death that plays an important role in malignancy by shifting the balance from tumor proliferation to its regression. Anticancer drugs act by activating apoptosis in tumor cells. Mutations in apoptotic pathways can le...

J. Polyakov



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

PubMed Central

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

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



Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 9. Novel heterobimetallic macrocycles and related hydrosoluble hexacations as potentially active photo/chemotherapeutic anticancer agents.  


New homo- and heterobimetallic porphyrazine complexes of general formula [(M'Cl(2))LM] (L = tetrakis-2,3-[5,6-di-(2-pyridyl)pyrazino]porphyrazinato dianion), with M = Zn(II), Mg(II)(H(2)O), or Pd(II) in the central cavity and one M'Cl(2) unit (M' = Pd(II), Pt(II)) peripherally coordinated at the pyridine N atoms of one of the dipyridinopyrazine fragments, were prepared and characterized by elemental analyses and IR/UV-visible spectroscopy. Related water-soluble salt-like species, carrying the hexacations [(PtCl(2))(CH(3))(6)LM](6+) (neutralized by I(-) ions), were also prepared and similarly characterized. Retention of clathrated water molecules is a common feature of all the compounds. A detailed (1)H and (13)C NMR investigation in dimethylformamide (DMF-d(7)) and dimethyl sulfoxide (DMSO-d(6)) provided useful information on the type of arrangement in the neutral and hexacationic species of the metalated dipyridinopyrazine fragments, in which the metal centers (Pd(II)/Pt(II)) are bound to the pyridine N atoms ("py-py" coordination) with formation of N(2(pyr))PdCl(2) or N(2(pyr))PtCl(2) coordination sites, the latter one featuring a cis-platin-like functionality. Data obtained in DMF solution of the quantum yield (?(?)) for the generation of singlet oxygen, (1)O(2), the cytotoxic agent in photodynamic therapy (PDT), indicate that all the neutral and charged complexes, among them particularly those carrying centrally Zn(II) or Pd(II), exhibit excellent photosensitizing properties, this qualifying the externally platinated complexes as potential bimodal PDT/chemotherapeutic anticancer agents. Fluorescence data (?(F)) provided additional information on the photoactivity of all the species studied. The following companion paper describes the observed interaction of the Zn(II) hexacation [(PtCl(2))(CH(3))(6)LZn](6+) with a G-quadruplex (G4) structure of the telomeric DNA sequence 5'-d[AGGG(TTAGGG)(3)]-3' in water. PMID:21770399

Donzello, Maria Pia; Vittori, Daniela; Viola, Elisa; Manet, Ilse; Mannina, Luisa; Cellai, Luciano; Monti, Sandra; Ercolani, Claudio



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. PMID:21394282

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



Strychnopentamine, a potential anticancer agent.  


We analysed the effects of strychnopentamine, an alkaloid isolated from Strychnos usambarensis, on an Ehrlich ascites tumor growing in the mouse after inoculation. Four subcutaneous injections of 1.5 mg strychnopentamine (1 per day) induce a significant decrease of the number of tumor cells and a significant increase of the survival of the treated mice. Observed side effects are partial haemolysis and some liver damage. PMID:8441783

Quetin-Leclercq, J; Bouzahzah, B; Pons, A; Greimers, R; Angenot, L; Bassleer, R; Barbason, H



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.



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

PubMed Central

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

Pawlowska, Monika; Augustin, Ewa; Mazerska, Zofia



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

PubMed Central

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

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



Synthesis of (1,4)-naphthoquinono-[3,2-c]-1H-pyrazoles and their (1,4)-naphthohydroquinone derivatives as antifungal, antibacterial, and anticancer agents.  


A series of (1,4)-naphthoquinono [3,2-c]-1H-pyrazoles and their (1,4)-naphthohydroquinone derivatives 2-7 were synthesized and evaluated for antifungal, antibacterial, and anticancer activities. The structure-activity relationship of these compounds was studied and the results show that the compound 2b exhibited in vitro antifungal activity against Candida albicans and Cryptococcus neoformans, and also possessed antibacterial profile against Klebsiella pneumoniae and Escherichia coli whereas 1c showed anticancer activity against Walker 256 Carcinosarcoma in rats. PMID:15913995

Tandon, Vishnu K; Yadav, Dharmendra B; Chaturvedi, Ashok K; Shukla, Praveen K



Therapeutic Drug Monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometry.  


The treatment of some cancer patients has shifted from traditional, non-specific cytotoxic chemotherapy to chronic treatment with molecular targeted therapies. Imatinib mesylate, a selective inhibitor of tyrosine kinases (TKIs) is the most prominent example of this new era and has opened the way to the development of several additional TKIs, including sunitinib, nilotinib, dasatinib, sorafenib and lapatinib, in the treatment of various hematological malignancies and solid tumors. All these agents are characterized by an important inter-individual pharmacokinetic variability, are at risk for drug interactions, and are not devoid of toxicity. Additionally, they are administered for prolonged periods, anticipating the careful monitoring of their plasma exposure via Therapeutic Drug Monitoring (TDM) to be an important component of patients' follow-up. We have developed a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) requiring 100 microL of plasma for the simultaneous determination of the six major TKIs currently in use. Plasma is purified by protein precipitation and the supernatant is diluted in ammonium formate 20 mM (pH 4.0) 1:2. Reverse-phase chromatographic separation of TKIs is obtained using a gradient elution of 20 mM ammonium formate pH 2.2 and acetonitrile containing 1% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 20 min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization-triple quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effects variability (<9.6%), overall process efficiency (87.1-104.2%), as well as TKIs short- and long-term stability in plasma. The method is precise (inter-day CV%: 1.3-9.4%), accurate (-9.2 to +9.9%) and sensitive (lower limits of quantification comprised between 1 and 10 ng/mL). This is the first broad-range LC-MS/MS assay covering the major currently in-use TKIs. It is an improvement over previous methods in terms of convenience (a single extraction procedure for six major TKIs, reducing significantly the analytical time), sensitivity, selectivity and throughput. It may contribute to filling the current knowledge gaps in the pharmacokinetics/pharmacodynamics relationships of the latest TKIs developed after imatinib and better define their therapeutic ranges in different patient populations in order to evaluate whether a systematic TDM-guided dose adjustment of these anticancer drugs could contribute to minimize the risk of major adverse reactions and to increase the probability of efficient, long lasting, therapeutic response. PMID:19505856

Haouala, A; Zanolari, B; Rochat, B; Montemurro, M; Zaman, K; Duchosal, M A; Ris, H B; Leyvraz, S; Widmer, N; Decosterd, L A



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


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



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

PubMed Central

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

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



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.  


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



Utility of L-norephedrine in the semisynthesis of novel thiourea and thiazolidine derivatives as a new class of anticancer agents.  


The natural alkaloid 1-norephedrine 1 was utlized in the synthesis of some novel thiourea derivatives 2, 5 and thiazolidinones 4a,b and 6, 7. Structures of the synthesized compounds were confirmed by analytical and spectral data. The synthesized compounds were evaluated in vitro for anticancer activity against the human breast (MCF-7), human liver (HEPG2) and human colon (HCT116) cancer cell lines. Thiazolidinone derivative 7 was the most active against all the cell lines with values IC50 = 2.60, 2.80 and 2.60 microg/mL compared with doxorubicin (IC50 = 5.40, 2.97 and 5.26 microg/mL). Thiazolidinone derivative 6 exhibited higher activity with IC50 value (3.20 microg/mL) against HCT116 when compared with doxorubicin with IC50 value (5.26 microg/mL) as positive control. PMID:25272887

Ghorab, Mostafa M; Alqasoumi, Saleh I; Abdel-Kader, Maged S; Alsaid, Mansour S



Synthesis of triplex-forming oligonucleotide conjugates of the anticancer drug temodal.  

E-print Network

??Covalent attachment of the anticancer drugs temozolomide (Temodal) and mitozolomide to triplex-forming oligonucleotides (TFOs) is a potential way of targeting these alkylating agents to specific… (more)

Walsh, Andrew J.



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


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



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

PubMed Central

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

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



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


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

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



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


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

Tang, Wen-Jian; Yang, Yong-An; Xu, He; Shi, Jing-Bo; Liu, Xin-Hua



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.



Anticancer activity of bisphosphonic acids in methylnitrosourea-induced mammary carcinoma of the rat — benefit of combining bisphosphonates with cytostatic agents  

Microsoft Academic Search

This study primarily describes the cytostatic activity of a bisphosphonate and of an alkylating agent linked bisphosphonate toward mammary carcinomas in vivo. Bisphosphonates had been shown to be therapeutically active in bone metastases. There is no animal tumor model available in which both primary mammary carcinomas and bone metastases can be studied simultaneously. Therefore, the Walker carcinosarcoma model, which was

F. Wingen; B. L. Pool; P. Klein; T. Klenner; D. Schmähl



Curr. Med. Chem. -Anti-Cancer Agents, 2005, 5, 327-338 327 1568-0118/05 $50.00+.00 2005 Bentham Science Publishers Ltd.  

E-print Network

significant effects in stabilizing DNA, RNA, and hybrid triple helices. When compared with minor groove binders or intercalators, neomycin excels at triple helical stabilization in most cases. Molecular with intercalators such as BQQ (a potent triple helix intercalating agent designed by Hélène), we have progressed

Stuart, Steven J.


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.  


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



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. PMID:23102993

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



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

Microsoft Academic Search

Glutathione transferase (GST) displaying enhanced activity with the cytostatic drug 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) and structurally related alkylating agents was obtained by molecular evolution. Mutant libraries created by recursive recombination of cDNA coding for human and rodent Theta-class GSTs were heterologously expressed in Escherichia coli and screened with the surrogate substrate 4-nitrophenethyl bromide (NPB) for enhanced alkyltransferase activity. A mutant with a

Anna-Karin Larsson; Abeer Shokeer; Bengt Mannervik



Synthesis and evaluation of a new generation of orally efficacious benzimidazole-based poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors as anticancer agents.  


Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic amine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC(50) and cellular EC(50) values were as low as 1 nM or below. Compounds 24 (EC(50) = 3.7 nM) and 44 (EC(50) = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model. PMID:19888760

Tong, Yunsong; Bouska, Jennifer J; Ellis, Paul A; Johnson, Eric F; Leverson, Joel; Liu, Xuesong; Marcotte, Patrick A; Olson, Amanda M; Osterling, Donald J; Przytulinska, Magdalena; Rodriguez, Luis E; Shi, Yan; Soni, Nirupama; Stavropoulos, Jason; Thomas, Sheela; Donawho, Cherrie K; Frost, David J; Luo, Yan; Giranda, Vincent L; Penning, Thomas D



Hyperthermia-triggered intracellular delivery of anticancer agent to HER2+ cells by HER2-specific Affibody (ZHER2-GS-Cys)-Conjugated Thermosensitive Liposomes (HER2+ Affisomes)  

PubMed Central

We previously reported the formulation and physical properties of HER2 (Human Epidermal Growth Factor Receptor 2)-specific Affibody (ZHER2:342-Cys) conjugated thermosensitive liposomes (HER2+ Affisomes). Here we examined localized delivery potential of these Affisomes by monitoring cellular interactions, intracellular uptake, and hyperthermia-induced effects on drug delivery. We modified ZHER2:342-Cys by introducing a glycine-serine spacer before the C-terminus cysteine (called ZHER2-GS-Cys) to achieve accessibility to cell-surface expressed HER2. This modification did not affect HER2-specific binding and ZHER2-GS-Cys retained its ability to conjugate to the liposomes containing dipalmitoyl phosphatidyl choline: DSPE-PEG2000-Malemide, 96:04 mole ratios (HER2+ Affisomes). HER2+ Affisomes were either (i) fluorescently labeled with rhodamine-PE and calcein or (ii) loaded with an anticancer drug Doxorubicin (DOX). Fluorescently labeled HER2+ Affisomes showed at least 10 fold increase in binding to HER2+ cells (SK-BR-3) when compared to HER2? cells (MDA-MB-468) at 37°C. A competition experiment using free ZHER2-GS-Cys blocked HER2+ Affisomes-SK-BR-3 cell associations. Imaging with confocal microscopy showed that HER2+ Affisomes accumulated in the cytosol of SK-BR-3 cells at 37°C. Hyperthermia-induced intracellular release experiments showed that the treatment of HER2+ Affisome/SK-BR-3 cell complexes with a 45°C (±1°C) pre-equilibrated buffer resulted in cytosolic delivery of calcein. Substantial calcein release was observed within 20 minutes at 45°C, with no effect on cell viability under these conditions. Similarly, DOX-loaded HER2+ Affisomes showed at least 2–3 fold higher accumulation of DOX in SK-BR-3 cells as compared to control liposomes. DOX-mediated cytotoxicity was more pronounced in SK-BR-3 cells especially at lower doses of HER2+ Affisomes. Brief exposure of liposome-cell complexes at 45°C prior to the onset of incubations for cell killing assays resulted in enhanced cytotoxicity for Affisomes and control liposomes. However, Doxil (a commercially available liposome formulation) showed significantly lower toxicity under identical conditions. Therefore, our data demonstrate that HER2+ Affisomes encompass both targeting and triggering potential and hence may prove to be viable nano drug delivery carriers for breast cancer treatment. PMID:21501640

Smith, Brandon; Lyakhov, Ilya; Loomis, Kristin; Needle, Danielle; Baxa, Ulrich; Yavlovich, Amichai; Capala, Jacek; Blumenthal, Robert; Puri, Anu



Ocular toxicity of systemic anticancer chemotherapy  

PubMed Central

The increased use of chemotherapeutic agents has resulted in longer cancer patient survival. Consequently the ophthalmologist is seeing more patients with adverse ocular side effects secondary to these antineoplastic agents. Ocular toxicity induced by cancer chemotherapy includes a broad spectrum of disorders, reflecting the unique anatomical, physiological and biochemical features of the eye. Understanding the ocular side effects will assist the ophthalmologist and oncologist to recognize them early and intervene before blindness occurs. Anticipation of various treatment-related toxicities may also provide the opportunity for pharmacists to develop intervention strategies that could minimize or eliminate an expected side effect. The ophthalmologist should examine patients on anticancer therapy at baseline and three monthly thereafter. The various ocular side effects of anticancer chemotherapeutic agents, tamoxifen, and interferon on the adnexia, anterior segment, posterior segment and neuro-ophthalmic structures were reviewed.

Omoti, Afekhide Ernest; Omoti, Caroline Edijana


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. PMID:23437140

Liu, Kai; Guo, Tai L.; Hait, Nitai C.; Allegood, Jeremy; Parikh, Hardik I.; Xu, Wenfang; Kellogg, Glen E.; Grant, Steven; Spiegel, Sarah; Zhang, Shijun



[An in vitro sensitivity assay of anti-cancer agents by measuring the inhibition rate of DNA synthesis (3H-thymidine uptake) of cancer cells--clinical study].  


In this paper, we demonstrated a selection system of anti-cancer agents (ACA) using discontinuous Ficoll density gradient method (DFDGM) for purification of tumor cells and 3H-Thymidine for evaluation of DNA synthesis of tumor cells. The tumor cells, purified to more than 80% by DFDGM, were contacted with ACAs for 3 days from the culture initiation and tumor suppression rate (TSR) by ACAs were calculated by following formula; TSR = ACA(-)cpm-ACA(+)cpm-background cpm divided by ACA(-)cpm-background cpm X 100% 7 ACAs; Mitomycin C (MMC), Adriamycin (ADM), 5-Fluorouracil (5-FU), Cytosine Arabinoside (Ara-C), Carbazilquinone (CQ), ACNU and Cis-platinum (CDDP) were examined in 106 cancers; 60 breast cancers, 18 gastric cancers, 23 colorectal cancers and 5 others. ADM and CQ showed high TSR against breast cancers, CQ against gastric cancers, and 5-FU and CQ against colorectal cancers, respectively. The reliability of this ACA selection system should be evaluated by future clinical studies, however, we stress that ACA should be selected by not only the effect on tumor cells but also the effect on immunity of the host, in future. PMID:3974569

Nio, Y; Inamoto, T; Ohgaki, K; Kan, N; Hori, T; Nakayama, N; Yamasaki, N; Hikasa, Y



Biochemical and Proteomic Analysis of a Potential Anticancer Agent: Palladium(II) Saccharinate Complex of Terpyridine Acting through Double Strand Break Formation.  


Metal based chemotherapeutic drugs are widely used as an effective method to defeat various cancers. In this study, the mechanism of action of a novel therapeutic agent, [Pd(sac)(terpy)](sac)·4H2O (sac = saccharinate, and terpy = 2,2':6',2?-terpyridine) was studied. To better understand the proteomic changes in response to this agent, we performed nano LC-MS/MS analyses in human breast cancer cells (MDA-MB-231). Thirty proteins were identified to be differentially expressed more than 40% after drug treatment. Many cellular pathways were affected, including proteins involved in DNA repair, apoptosis, energy metabolism, protein folding, cytoskeleton, pre-mRNA maturation, or protein translation. The changes in protein expression were further verified for XRCC5, which plays a role in double strand break (DSB) repair, and ubiquitin, which is involved in protein degradation and apoptosis. The elevated XRCC5 levels were suggestive of increased DSBs. The presence of DSBs was confirmed by smearing of plasmid DNA in vitro and induction of ?H2AX foci in vivo. There was also increased intracellular reactive oxygen species (ROS) formation, as detected by 2',7'-dichlorofluorescein diacetate (DCFDA) staining. Scavenging ROS by N-acetylcysteine rescued cell death in response to Pd(II) treatment, potentially explaining how the Pd(II) complex damaged the DNA. The details of this analysis and the significance will be discussed during the scope of this work. PMID:25210790

Adiguzel, Zelal; Baykal, Ahmet Tarik; Kacar, Omer; Yilmaz, Veysel T; Ulukaya, Engin; Acilan, Ceyda



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

PubMed Central

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

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



Advanced native kidney renal cell carcinoma in renal transplant recipients: role of sirolimus as dual anti-cancer and anti-rejection agent.  


The incidence of native kidney renal cell carcinoma (RCC) in renal transplant recipients is 15 times higher than the general population. These tumors are often found incidentally when imaging is performed for another indication. At that stage tumors are usually small and asymptomatic but it is possible that they may escape detection until a more advanced stage. Early stage RCC can be treated with radical nephrectomy but the treatment of advanced RCC may be more complicated and is associated with a poorer prognosis. RCC in context of renal transplant presents a special therapeutic challenge; balancing treatment of a potentially lethal malignancy in a redundant organ whilst maintaining good allograft function.We describe 2 cases of advanced renal cell carcinoma of native kidneys in renal transplant recipients and present our experience with sirolimus as a dual immunosuppressive and anti-tumor agent. PMID:23364206

Javaid, Muhammad M; Chowdhury, Simon; Henderson, Alastair; Olsburgh, Jonathon



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


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

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



Behavioural and hypothalamic molecular effects of the anti-cancer agent cisplatin in the rat: A model of chemotherapy-related malaise?  


Many cancer patients receiving chemotherapy experience fatigue, disturbed circadian rhythms, anorexia and a variety of dyspeptic symptoms including nausea. There is no animal model for this 'chemotherapy-related malaise' so we investigated the behavioural and molecular effects of a potent chemotherapeutic agent, cisplatin (CP, 6 mg/kg, i.p.) in rats. Dark-phase horizontal locomotor activity declined post-CP reaching a nadir on day 3 (P < 0.001), before recovering after 7 days. CP's effect was most marked in the late part (05.00-07.00) of the dark-phase. Food intake reached a nadir (P > 0.001) at 2 days, coincident with an increase in gastric contents (cisplatin 9.04+/-0.8 vs. saline 2.32+/-0.3 g; P < 0.001). No changes occurred in hypothalamic mRNA expression for AGRP, NPY, HCRT, CRH, IL-1, IL-6, TNFalpha, ABCG1, SLC6A4, PPIA and HPRT mRNA but tryptophan hydroxylase (TPH) mRNA was decreased (47%, P < 0.05) at day 21 post-CP. This shows that despite marked behavioural effects of cisplatin, only a discrete change (TPH) was found in hypothalamic mRNA expression and that occurred when the animals' behaviour had recovered. Findings are discussed in relation to the neuropharmacology of chemotherapy-induced malaise. PMID:16443263

Malik, N M; Moore, G B T; Smith, G; Liu, Y-L; Sanger, G J; Andrews, P L R



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. PMID:23878592

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



Anthracyclines as effective anticancer drugs.  


Anthracyclines have received significant attention due to their effectiveness and extensive use as anticancer agents. At present, the clinical use of these drugs is offset by drug resistance in tumours and cardiotoxicity. Therefore, a relentless search for the 'better anthracycline' has been ongoing since the inception of these drugs > 30 years ago. This review focuses on the most recent pharmacology and medicinal chemistry developments on the design and use of anthracyclines. Based on their crystal structures as well as molecular modelling, a more detailed mechanism of topoisomerase poisoning by these new anthracyclines has emerged. Chemical modifications of anthracyclines have been found to possibly change the target selectivity among various topoisomerases and, thus, vary their anticancer activity. Additionally, recent sugar modifications of anthracyclines have also been found to overcome P-glycoprotein-mediated drug resistance in cancer therapy. The continued improvement of anthracycline clinical applications so far and the clinical trials of the 'third generation' of anthracyclines (such as sabarubicin) are also discussed. To finally find the 'better' anthracycline, further areas of research still need to be explored such as: the elucidation of the topoisomerase and P-glycoprotein crystal structures, molecular modelling based on crystal structure in order to design the next generation of better anthracycline drugs, the continued modifications of the anthracycline sugar moieties, and the further improvement of anthracycline drug delivery methods. PMID:23506066

Nadas, Janos; Sun, Duxin



Identification of novel inhibitors of human Chk1 using pharmacophore-based virtual screening and their evaluation as potential anti-cancer agents.  


Kinases are one of the major players in cancer development and progression. Serine threonine kinases such as human checkpoint kinase-1 (Chk1), Mek1 and cyclin-dependent kinases have been identified as promising targets for cancer treatment. Chk1 is an important kinase with vital role in cell cycle arrest and many potent inhibitors targeted to Chk1 have been reported and few are currently in clinical trials. Considering the emerging importance of Chk1 inhibitors in cancer treatment there is a need to widen the chemical space of Chk1 inhibitors. In this study, we are reporting an integrated in silico approach to identify novel competitive Chk1 inhibitors. A 4-features pharmacophore model was derived from a co-crystallized structure of known potent Chk1 inhibitor and subjected to screen Maybridge compound library. Hits obtained from the screening were docked into the Chk1 active site and filtered on the basis of docking score and the number of pharmacophoric features showing conserved interaction within the active site of Chk1. Further, five compounds from the top ranking hits were subjected to in vitro evaluation as Chk1 inhibitor. After the kinase assay, four compounds were found to be active against human Chk1 (IC50 range from 4.2 to 12.5 µM). Subsequent study using the cdc25-22 mutant yeast cells revealed that one of compound (SPB07479; IC50 = 4.24 µM) promoted the formation of multinucleated cells, therefore overriding the cell cycle checkpoint. Validation studies using normal and human cancer cell lines, indicated that SPB07479 significantly inhibited proliferation of cervical cancer cells as a single agent and chemosensitized glioma and pancreatic cancer cell lines to standard chemotherapy while sparing normal cells. Additionally SPB07479 did not show significant cytotoxicity in normal cells. In conclusion we report that SPB07479 appear promising for further development of Chk1 inhibitors. This study also highlights the role of conserved water molecules in the active site of Chk1 for the successful identification of novel inhibitors. PMID:25312395

Kumar, Vikash; Khan, Saman; Gupta, Priyanka; Rastogi, Namrata; Mishra, Durga Prasad; Ahmed, Shakil; Siddiqi, Mohammad Imran



5H-Dibenzo[c,h]1,6-naphthyridin-6-ones: novel topoisomerase I-targeting anticancer agents with potent cytotoxic activity.  


5H-Dibenzo[c,h]1,6-naphthyridine-6-ones can exhibit potent antitumor activity. The effect of varied substituents at the 5-position of 5H-8,9-dimethoxy-2,3-methylenedioxydibenzo[c,h]1,6-naphthyridine on relative cytotoxicity and topoisomerase I-targeting activity was evaluated. Potent TOP-1-targeting activity is observed when the 5-position is substituted with either a 2-(N,N-dimethylamino)ethyl group, as in 3a, or a 2-(pyrrolidin-1-yl)ethyl substituent, 3c. In contrast, the addition of a beta-methyl group or a beta-hydroxymethyl group to compound 3a, as in 3b and 3j, results in a loss of significant TOP1-targeting activity. While the presence of a 3-(N,N-dimethylamino)propyl substituent at the 5-position or a methyl(2-tetrahydrofuranyl) group allows for retention of TOP1-targeting activity, the 2-(4-methyl-1-piperazinyl)ethyl analogue, 3d, did not exhibit significant activity. Replacement of the N,N-dimethylamino group of 3a with either C(2)H(5) or OH, as in 3f and 3h, respectively, also had a negative impact on both cytotoxicity and TOP1-targeting activity. Treatment of 3a with LAH gave the 5,6-dihydrodibenzo[c,h]naphthyridine, 4a. This dihydro derivative has approximately 2/3 the potency of 3a as a TOP1-targeting agent. Compounds 3a, 3b, 3h, 3i, and 4a were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line, MDA-MB-435, was used in these assays. Compound 3a proved to be effective in regressing tumor growth in vivo when administered either by ip injection or orally 3x week at a dose of 2.0mg/kg. Compound 4a when administered orally 5x weekly at a dose of 40 mg/kg also suppressed tumor growth. PMID:12670657

Ruchelman, Alexander L; Singh, Sudhir K; Ray, Abhijit; Wu, Xiao Hua; Yang, Jin-Ming; Li, Tsai-Kun; Liu, Angela; Liu, Leroy F; LaVoie, Edmond J



Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 12. New heteropentanuclear complexes carrying four exocyclic cis-platin-like functionalities as potential bimodal (PDT/cis-platin) anticancer agents.  


Heteropentanuclear porphyrazines having the formula [(PtCl2)4LM] where L = tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato dianion and M = Zn(II), Mg(II)(H2O), Pd(II), Cu(II) or Co(II) were characterized by elemental analyses, IR-UV-visible spectroscopy and electrochemistry and the data compared to new and previously published results for the corresponding homopentanuclear compound [(PtCl2)4LPt]. This latter species has four external N2(py)PtCl2 coordination sites which closely resemble cis-platin, (NH3)2PtCl2, the potent chemotherapeutic anticancer drug, and is able to act as a photosensitizer for the generation of (1)O2, the cytotoxic agent in photodynamic therapy (PDT). UV-visible spectra and half wave potentials for reduction of [(PtCl2)4LM], [(PtCl2)4LPt], the parallel series of mononuclear [LM] compounds and the pentanuclear [(PdCl2)4LM] compounds were examined in the nonaqueous solvents dimethyl sulfoxide, pyridine, and dimethylformamide. The complete set of available data indicate that external coordination of the PtCl2 and PdCl2 units significantly increases the level of the electron-deficiency of the entire molecular framework despite the fact that these groups are far away from the central porphyrazine ?-ring system and have coordination sites nearly orthogonal to the plane of the macrocycle. The pentanuclear species [(M'Cl2)4LM] (M' = Pt(II), Pd(II)) undergo multiple one-electron transfers and exhibit an easier reducibility as compared to related electrode reactions of the parent compounds [LM] having the same central metal. Aggregation phenomena and reducibility of the porphyrazines to their monoanionic form (prevalently in DMF) are observed for some of the examined compounds and were analyzed and accurately taken into account. Quantum yields of (1)O2 (??), of interest in PDT, were measured for [(PtCl2)4LM] with M = Zn(II), Mg(II)(H2O), or Pd(II) and the related macrocycles [(PdCl2)4LM] and [LM] in dimethylformamide (DMF) and/or DMF preacidified with HCl (DMF/HCl, [HCl]: 1-2 × 10(-4) M). Excellent ?? values (0.5-0.6) which qualify the compounds as potent photosensitizers in PDT were obtained for the pentanuclear species having Zn(II) or Pd(II) as central metal ions. The [(PtCl2)4LZn] and [(PtCl2)4LPd] complexes are of special interest as potential bimodal anticancer agents because of the incorporated four cis-platin-like functionalities. PMID:23121685

Donzello, Maria Pia; Viola, Elisa; Ercolani, Claudio; Fu, Zhen; Futur, David; Kadish, Karl M



Are isothiocyanates potential anti-cancer drugs?  

PubMed Central

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

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



PARP inhibitors for anticancer therapy.  


PARP-1 [poly(ADP-ribose) polymerase-1], which plays a key role in DNA repair, was discovered 50 years ago. PARPi (PARP inhibitors), originally made to probe the function of the enzyme, inhibit DNA repair and increase the potency of anticancer cytotoxic agents. PARPi of increasing potency were developed as chemo- and radio-sensitizers and first entered clinical trial in cancer patients in 2003. However, it was the revelation in 2005 that they were synthetically lethal in cells with DNA repair defects, found almost exclusively in some tumours, that led to a major interest in this class of drug. Several PARPi have entered clinical trials and show promising activity in breast, ovarian and other cancers associated with BRCA (breast cancer early-onset) mutations or other defects in homologous recombination DNA repair. It is likely that at least one of these will be licensed soon. The present review describes key events from the discovery to clinical application of PARPi. PMID:24450632

Curtin, Nicola



Anticancer agents: Unleash the forces within  

NASA Astrophysics Data System (ADS)

Liposomes are a leading drug-delivery platform in cancer chemotherapy. Now they can be used to destroy cancer cells through a method that converts chemical energy to mechanical force. These localized disruptions can cause cell death while minimizing the collateral damage to neighbouring cells.

Gao, Weiwei; Zhang, Liangfang



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



Experimental Evaluation of Potential Anticancer Agents  

Microsoft Academic Search

SUMMARY In quantitative therapeutic studies 1,3-bis(2-chloroethyl)-1-nitrosourea (NSC 409962) and 1-(2.-chloroethyl)-1-nitrosourea (NSC-47547) have been shown to have marked activity against intraperitoneal (I.P.) L1210 leukemia when administered by the I.P., subcutaneous, or oral route. This class of compounds is the first to be ob served to possess an encouraging degree of activity against intracerebrally inoculated L1210 leukemia. Ofthe“active” derivatives of1-methyl-1-nitrosourea studied to



Anticancer properties of Monascus metabolites.  


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



Oncolytic Viruses as Anticancer Vaccines  

PubMed Central

Oncolytic virotherapy has shown impressive results in preclinical studies and first promising therapeutic outcomes in clinical trials as well. Since viruses are known for a long time as excellent vaccination agents, oncolytic viruses are now designed as novel anticancer agents combining the aspect of lysis-dependent cytoreductive activity with concomitant induction of antitumoral immune responses. Antitumoral immune activation by oncolytic virus infection of tumor tissue comprises both, immediate effects of innate immunity and also adaptive responses for long lasting antitumoral activity, which is regarded as the most prominent challenge in clinical oncology. To date, the complex effects of a viral tumor infection on the tumor microenvironment and the consequences for the tumor-infiltrating immune cell compartment are poorly understood. However, there is more and more evidence that a tumor infection by an oncolytic virus opens up a number of options for further immunomodulating interventions such as systemic chemotherapy, generic immunostimulating strategies, dendritic cell-based vaccines, and antigenic libraries to further support clinical efficacy of oncolytic virotherapy. PMID:25101244

Woller, Norman; Gurlevik, Engin; Ureche, Cristina-Ileana; Schumacher, Anja; Kuhnel, Florian



Isocorydine derivatives and their anticancer activities.  


In order to improve the anticancer activity of isocorydine (ICD), ten isocorydine derivatives were prepared through chemical structure modifications, and their in vitro and in vivo activities were experimentally investigated. 8-Amino-isocorydine (8) and 6a,7-dihydrogen-isocorydione (10) could inhibit the growth of human lung (A549), gastric (SGC7901) and liver (HepG2) cancer cell lines in vitro. Isocorydione (2) could inhibit the tumor growth of murine sarcoma S180-bearing mice, and 8-acetamino-isocorydine (11), a pro-drug of 8-amino-isocorydine (8), which is instable in water solution at room temperature, had a good inhibitory effect on murine hepatoma H22-induced tumors. The results suggested that the isocorydine structural modifications at C-8 could significantly improve the biological activity of this alkaloid, indicating its suitability as a lead compound in the development of an effective anticancer agent. PMID:25120059

Zhong, Mei; Liu, Yanjuan; Liu, Junxi; Di, Duolong; Xu, Mengrou; Yang, Yaya; Li, Wenguang; Chen, Yali; Liu, Jinxia



Alkylating Agents  

Microsoft Academic Search

\\u000a Alkylating agents were the first anticancer molecules developed and are still used today. The family contains 6 major classes:\\u000a nitrogen mustards, aziridines, alkyl sulfonates, epoxides, nitrosoureas and triazene compounds. Due to their chemical properties,\\u000a these drugs can, either directly or after biological activation react and form covalent bonds with macromolecules such as\\u000a DNA, RNA and proteins. Their cytotoxic properties are

Laurent Gate; Kenneth D. Tew


Liposomal anticancer therapy: pharmacokinetic and clinical aspects.  


Liposomes, which are vesicles composed of a phospholipid bilayer surrounding an aqueous milieu, represent a new strategy for anticancer drug delivery. Extravasation and accumulation of liposomal drugs within neoplastic tissues are possible because of the leaky vasculature and scarce lymphatic vessels of tumours (the enhanced permeability and retention effect). Furthermore, liposomal chemotherapeutic agents display distinctive pharmacokinetic characteristics, because they possess longer elimination half-lives, reduced clearance and smaller volume of distribution with respect to corresponding free drugs. Taken together, these features lead to highest levels of cytotoxic agents in tumours, as demonstrated in preclinical models and clinical trials, whereas healthy tissues are spared from toxicity. In fact, liposomal drugs (i.e., doxorubicin), alone or in combination with other cytotoxic agents, lead to improved clinical effectiveness and ameliorated toxicity profile with respect to corresponding free drugs when they are used for the treatment of metastatic breast and ovarian cancers, and Kaposi's sarcoma. PMID:15688620

Di Paolo, A



Anticancer effects of fucoidan.  


Recently, there has been an increased interest in the pharmacologically active natural compounds isolated and used for remedies of various kinds of diseases, including cancer. The great deal of interest has been developed to isolate bioactive compounds from marine resources because of their numerous health beneficial effects. Among marine resources, marine algae are valuable sources of structurally diverse bioactive compounds. Fucoidan is a sulfated polysaccharide derived from brown seaweeds and has been used as an ingredient in some dietary supplement products. Fucoidan has various biological activities including antibacterial, antioxidant, anti-inflammatory, anticoagulant, and antitumor activities. So this chapter deals with anticancer effects of fucoidan. PMID:25081084

Senthilkumar, Kalimuthu; Kim, Se-Kwon



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



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. PMID:18078805

Hoskin, David W.; Ramamoorthy, Ayyalusamy



Anticancer substances of mushroom origin.  


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



Fenbendazole as a Potential Anticancer Drug  

PubMed Central

Background/Aims To evaluate the anticancer activity of fenbendazole, a widely used antihelminth with mechanisms of action that overlap with those of the hypoxia-selective nitroheterocyclic cytotoxins/radiosensitizers and the taxanes. Materials and Methods We used EMT6 mouse mammary tumor cells in cell culture and as solid tumors in mice to examine the cytotoxic and antitumor effects of fenbendazole as a single agent and in combination regimens. Results Intensive treatments with fenbendazole were toxic to EMT6 cells in vitro; toxicity increased with incubation time and under conditions of severe hypoxia. Fenbendazole did not alter the dose-response curves for radiation or docetaxel; instead, the agents produced additive cytotoxicities. Febendazole in maximally-intensive regimens did not alter the growth of EMT6 tumors, or increase the antineoplastic effects of radiation. Conclusion These studies provided no evidence that fenbendazole would have value in cancer therapy, but suggested that this general class of compounds merits further investigation. PMID:23393324




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

PubMed Central

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

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



Recent development of anticancer therapeutics targeting Akt.  


The serine/threonine kinase Akt has proven to be a significant signaling target, involved in various biological functions. Because of its cardinal role in numerous cellular responses, Akt has been implicated in many human diseases, particularly cancer. It has been established that Akt is a viable and feasible target for anticancer therapeutics. Analysis of all Akt kinases reveals conserved homology for an N-terminal regulatory domain, which contains a pleckstrin-homology (PH) domain for cellular translocation, a kinase domain with serine/threonine specificity, and a C-terminal extension domain. These well defined regions have been targeted, and various approaches, including in silico methods, have been implemented to develop Akt inhibitors. In spite of unique techniques and a prolific body of knowledge surrounding Akt, no targeted Akt therapeutics have reached the market yet. Here we will highlight successes and challenges to date on the development of anticancer agents modulating the Akt pathway in recent patents as well as discuss the methods employed for this task. Special attention will be given to patents with focus on those discoveries using computer-aided drug design approaches. PMID:21110830

Morrow, John K; Du-Cuny, Lei; Chen, Lu; Meuillet, Emmanuelle J; Mash, Eugene A; Powis, Garth; Zhang, Shuxing



The synthesis, structural study and anticancer activity evaluation of emodin derivatives containing conjugative groups.  


Eight new emodin derivatives that contain large conjugative system have been synthesized and their anticancer activities also have been evaluated. The result shows that large conjugative system can not enhance the anticancer activities of emodin derivatives, but the introduction of an alkylating center can make emodin derivative effective against cancer cell lines. Compound 12 has the highest alkylating ability, but its anticancer activity is not remarkable, which indicates that there is not a direct correlation between the chemical reactivity of the alkylating agent and the toxic effects. PMID:22920154

Wen-Feng, Wang; Feng-Sen, Zhang; Wen-Na, Zhao; Ze-Dong, Bai; Hui-Jun, Yang; Jing-Wei, Shao; Yao-Feng, Yuan



Protein in blood exerts natural anti-cancer protection

Researchers from Thomas Jefferson University’s Kimmel Cancer Center have discovered that decorin, a naturally occurring protein that circulates in the blood, acts as a potent inhibitor of tumor growth modulating the tumor microenvironment. The study, published June 24 online in the Proceedings of the National Academy of Sciences, suggests it may be possible to harness the power of this naturally occurring anticancer agent as a way to treat cancer, including metastases.


Immediate effects of anticancer drugs on mitochondrial oxygen consumption  

Microsoft Academic Search

The evolving role of mitochondria as a target for many anticancer drugs (e.g. platinum-based compounds, alkylating agents and anthracyclines) prompted us to investigate their immediate effects on the mitochondrial respiratory chain. For this purpose, we used a phosphorescence analyzer that measures [O2] in solution. The [O2] of solutions containing an appropriate substrate and various cell lines, tumors from patients or

Abdul-Kader Souid; Kirk A. Tacka; Karen A. Galvan; Harvey S. Penefsky



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


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

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



Addition of amino acid moieties to lapatinib increases the anti-cancer effect via amino acid transporters.  


Anti-cancer agents delivered to cancer cells often show multi-drug resistance (MDR) due to expulsion of the agents. One way to address this problem is to increase the accumulation of anti-cancer agents in cells via amino acid transporters. Thus, val-lapatinib and tyr-lapatinib were newly synthesized by adding valine and tyrosine moieties, respectively, to the parent anti-cancer agent lapatinib without stability issues in rat plasma. Val-lapatinib and tyr-lapatinib showed enhanced anti-cancer effects versus the parent lapatinib in various cancer cell lines, including human breast cancer cells (MDA-MB-231, MCF7) and lung cancer cells (A549), but not in non-cancerous MDCK-II cells. A glutamine uptake study revealed that both val-lapatinib and tyr-lapatinib, but not the parent lapatinib, inhibited glutamine transport in MDA-MB-231 and MCF7 cells, suggesting the involvement of amino acid transporters. In conclusion, val-lapatinib and tyr-lapatinib have enhanced anti-cancer effects, likely due to an increased uptake of the agents into cancer cells via amino acid transporters. The present data suggest that amino acid transporters may be an effective drug delivery target to increase the uptake of anti-cancer agents, leading to one method of overcoming MDR in cancer cells. PMID:24151179

Maeng, Han-Joo; Kim, Eun-Seo; Chough, Chieyeon; Joung, Misuk; Lim, Jee Woong; Shim, Chang-Koo; Shim, Won-Sik



Synergistic anti-cancer effect of phenformin and oxamate.  


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

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



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

PubMed Central

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

Lee, Gyeong Jin; Kang, Joo-Hee



Anticancer Activity of Amauroderma rude  

PubMed Central

More and more medicinal mushrooms have been widely used as a miraculous herb for health promotion, especially by cancer patients. Here we report screening thirteen mushrooms for anti-cancer cell activities in eleven different cell lines. Of the herbal products tested, we found that the extract of Amauroderma rude exerted the highest activity in killing most of these cancer cell lines. Amauroderma rude is a fungus belonging to the Ganodermataceae family. The Amauroderma genus contains approximately 30 species widespread throughout the tropical areas. Since the biological function of Amauroderma rude is unknown, we examined its anti-cancer effect on breast carcinoma cell lines. We compared the anti-cancer activity of Amauroderma rude and Ganoderma lucidum, the most well-known medicinal mushrooms with anti-cancer activity and found that Amauroderma rude had significantly higher activity in killing cancer cells than Ganoderma lucidum. We then examined the effect of Amauroderma rude on breast cancer cells and found that at low concentrations, Amauroderma rude could inhibit cancer cell survival and induce apoptosis. Treated cancer cells also formed fewer and smaller colonies than the untreated cells. When nude mice bearing tumors were injected with Amauroderma rude extract, the tumors grew at a slower rate than the control. Examination of these tumors revealed extensive cell death, decreased proliferation rate as stained by Ki67, and increased apoptosis as stained by TUNEL. Suppression of c-myc expression appeared to be associated with these effects. Taken together, Amauroderma rude represented a powerful medicinal mushroom with anti-cancer activities. PMID:23840494

Yang, Xiangling; Li, Haoran; Li, Xiang-Min; Pan, Hong-Hui; Cai, Mian-Hua; Zhong, Hua-Mei; Yang, Burton B.



Recent Trends in Targeted Anticancer Prodrug and Conjugate Design  

PubMed Central

Anticancer drugs are often nonselective antiproliferative agents (cytotoxins) that preferentially kill dividing cells by attacking their DNA at some level. The lack of selectivity results in significant toxicity to noncancerous proliferating cells. These toxicities along with drug resistance exhibited by the solid tumors are major therapy limiting factors that results into poor prognosis for patients. Prodrug and conjugate design involves the synthesis of inactive drug derivatives that are converted to an active form inside the body and preferably at the site of action. Classical prodrug and conjugate design has focused on the development of prodrugs that can overcome physicochemical (e.g., solubility, chemical instability) or biopharmaceutical problems (e.g., bioavailability, toxicity) associated with common anticancer drugs. The recent targeted prodrug and conjugate design, on the other hand, hinges on the selective delivery of anticancer agents to tumor tissues thereby avoiding their cytotoxic effects on noncancerous cells. Targeting strategies have attempted to take advantage of low extracellular pH, elevated enzymes in tumor tissues, the hypoxic environment inside the tumor core, and tumor-specific antigens expressed on tumor cell surfaces. The present review highlights recent trends in prodrug and conjugate rationale and design for cancer treatment. The various approaches that are currently being explored are critically analyzed and a comparative account of the advantages and disadvantages associated with each approach is presented. PMID:18691040

Singh, Yashveer; Palombo, Matthew; Sinko, Patrick J.



[Matrikines: a new anticancer therapeutic strategy].  


Tumor microenvironment is a complex system composed of a largely altered extracellular matrix (ECM) with different cell types that determine the angiogenic response. Upon the influence of hypoxia, tumor cells secrete cytokines that activate stromal cells to produce proteases and angiogenic factors. The proteases degrade the stromal ECM and participate in the release of various ECM fragments, named matrikines or matricryptins, capable to control tumor invasion and metastasis dissemination. We will focus on the matrikines derived from the NC1 domains of the different constitutive chains of basement membrane-associated collagens and mainly collagen IV. The putative targets of the matrikine action are the proliferation and invasive properties of tumor or inflammatory cells, and the angiogenic and lymphangiogenic responses. For example, canstatin, tumstatin and tetrastatin, respectively derived from the NC1 domains of ?2, ?3 and ?4 chains of collagen IV, inhibit in vivo tumor growth in various experimental cancer models. Their anti-cancer activity comprises an anti-proliferative effect on tumor cells and on endothelial cells by induction of cell apoptosis or cell cycle blockade and the induction of a loss of their migratory phenotype. Matrikines constitute a new family of potent anticancer agents that could be used under various therapeutic strategies: i) induction of their overexpression by cancer cells or by the host cells, ii) use of recombinant proteins or synthetic peptides or structural analogues designed from the structure of the active sequences. These matrikines could be used in combination with conventional chemotherapy or radiotherapy to limit tumor progression. PMID:22748049

Monboisse, Jean Claude; Sénéchal, Karine; Thevenard, Jessica; Ramont, Laurent; Brassart-Pasco, Sylvie; Maquart, François-Xavier



Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs  

PubMed Central

Histone deacetylase (HDAC) inhibitors are a relatively new class of anti-cancer agents that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis, and cell cycle arrest in cancer cells. Recently, their use has been clinically validated in cancer patients resulting in the approval of two HDAC inhibitors, vorinostat and depsipetide, by the FDA. Also, clinical trials of several HDAC inhibitors for use as anti-cancer drugs (alone or in combination with other anti-cancer therapeutics) are ongoing. However, the molecular mechanisms underlying the response to HDAC inhibitors in cancer patients are not fully understood. In this review, we summarize our understanding of the molecular and biological events that underpin the anticancer effects of HDAC inhibitors and the outcomes of recent clinical trials involving these drugs. PMID:21416059

Kim, Hyun-Jung; Bae, Suk-Chul



Antifolate inhibitors of thymidylate synthase as anticancer drugs.  


Inhibitors of thymidylate synthase (TS) play an essential role in the pharmacological management of several tumors. Two antifolates, Raltitrexed and Pemetrexed, are licensed anticancer drugs, with Pemetrexed, unlike Raltitrexed, undergoing further intense clinical development. Other antifolate TS inhibitors, recently/currently tested in clinical studies, that show encouraging anticancer activities are Plevitrexed, GW7904L and Nolatrexed. A new prospect among antifolates, demonstrating a very desirable pattern of pharmacological properties, is BGC 945 that showed promising antitumor activities and has been nominated for clinical development. In this paper, apart from reviewing their biochemical and pharmacological properties, up-to-date characteristics of clinical development of all the mentioned agents are presented. In addition, trends and perspectives for developing improved antifolate inhibitors of TS and future drugs are discussed. Drug resistance is the main barrier to more effective treatment of cancers with antifolates; therefore, mechanisms of antifolate resistance and currently applied approaches to overcome it are also pointed out in the review. PMID:20854257

Jarmu?a, A



Anticancer Principles from Medicinal Piper (?? H? Ji?o) Plants  

PubMed Central

The ethnomedical uses of Piper (?? Hú Ji?o) plants as anticancer agents, in vitro cytotoxic activity of both extracts and compounds from Piper plants, and in vivo antitumor activity and mechanism of action of selected compounds are reviewed in the present paper. The genus Piper (Piperaceae) contains approximately 2000 species, of which 10 species have been used in traditional medicines to treat cancer or cancer-like symptoms. Studies have shown that 35 extracts from 24 Piper species and 32 compounds from Piper plants possess cytotoxic activity. Amide alkaloids account for 53% of the major active principles. Among them, piplartine (piperlongumine) shows the most promise, being toxic to dozens of cancer cell lines and having excellent in vivo activity. It is worthwhile to conduct further anticancer studies both in vitro and in vivo on Piper plants and their active principles. PMID:24872928

Wang, Yue-Hu; Morris-Natschke, Susan L.; Yang, Jun; Niu, Hong-Mei; Long, Chun-Lin; Lee, Kuo-Hsiung



Dose standardisation of anticancer drugs  

Microsoft Academic Search

Objective of the study Body size based dosing is often used for prescribing anticancer drugs. However the scientific and the clinical rationales\\u000a of this historical method have recently been criticized. As a result, alternative dosing strategies have been suggested, as\\u000a flat-fixed dosing regimens, but not implemented in routine practice. Dose standardisation is a first step in order to rationalise\\u000a chemotherapy

Anne-Lise Pouliquen; Laurence Escalup; Nathalie Jourdan; Paul Cottu; Pierre Faure; Isabelle Madelaine-Chambrin



Topoisomerase I-related Parameters and Camptothecin Activity in the Colon Carcinoma Cell Lines from the National Cancer Institute Anticancer Screen1  

Microsoft Academic Search

Camptothecin (CPT) derivatives are a new family of anticancer agents which are selective inhibitors of DNA topoisomerase I (topi) and have entered clinical trials with promising results. The cellular determinants for CPT activity were studied in the seven cell lines of the National Cancer Institute anticancer screen. These cell lines exhibit natural differences in sensitivity to CPT and can be

Francois Goldwasser; Insoo Bae; Monica Valenti; Keila Torres; Yves Pommier


Pharmacokinetic Scaling of Anticancer Drugs in Dogs.  

E-print Network

??Anticancer drugs are characterized by a narrow therapeutic index and wide inter-individual variability in therapeutic outcome, disposition, and toxicity. The accurate calculation and administration of… (more)

Achanta, Satyanarayana



Detection of Alkylating Agents using Electrical and Mechanical Means  

Microsoft Academic Search

Alkylating agents are reactive molecules having at least one polar bond between a carbon atom and a good leaving group. These often simple molecules are frequently used in organic synthesis, as sterilizing agents in agriculture and even as anticancer agents in medicine. Unfortunately, for over a century, some of the highly reactive alkylating agents are also being used as blister

Yulia Gerchikov; Elena Borzin; Yair Gannot; Ariel Shemesh; Shai Meltzman; Carmit Hertzog-Ronen; Shay Tal; Sara Stolyarova; Yael Nemirovsky; Nir Tessler; Yoav Eichen



Genetic Interactions of STAT3 and Anticancer Drug Development  

PubMed Central

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

Fang, Bingliang



Newly Engineered Magnetic Erythrocytes for Sustained and Targeted Delivery of Anti-Cancer Therapeutic Compounds  

Microsoft Academic Search

Cytotoxic chemotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can they be selectively improved? Alternative pharmaceutical formulations of anti-cancer agents have been investigated in order to improve conventional chemotherapy treatment. These formulations are associated with problems like severe

Caterina Cinti; Monia Taranta; Ilaria Naldi; Settimio Grimaldi; Steven Ellis



Identification of potential anticancer compounds from Oplopanax horridus  

PubMed Central

Oplopanax horridus is a plant native to North America. Previous reports have demonstrated that this herb has antiproliferative effects on cancer cells but study mostly focused on its extract or fractions. Because there has been limited phytochemical study on this herb, its bioactive compounds are largely unknown. We recently isolated and identified 13 compounds, including six polyynes, three sesquiterpenes, two triterpenoids, and two phenolic acids, of which five are novel compounds. In this study, we systemically evaluated the anticancer effects of compounds isolated from O. horridus. Their antiproliferative effects on a panel of human colorectal and breast cancer cells were determined using the MTS assay. Cell cycle distribution and apoptotic effects were analyzed by flow cytometry. The in vivo antitumor effect was examined using a xenograft tumor model. Among the 13 compounds, strong antiproliferative effects were observed from falcarindiol and a novel compound oplopantriol A. Falcarindiol showed the most potent antiproliferative effects, significantly inducing pro-apoptosis and cell cycle arrest in the S and G2/M phases. The anticancer potential of falcarindiol was further verified in vivo, significantly inhibiting HCT-116 tumor growth in an athymic nude mouse model at 15 mg/kg. We also analyzed the relationship between polyyne structures and their pharmacological activities. We observed that both the terminal hydroxyl group and double bond obviously affected their anticancer potential. Results from this study supplied valuable information for future semi-synthesis of polyyne derivatives to develop novel cancer chemopreventive agents. PMID:23746754

Wang, Chong-Zhi; Zhang, Zhiyu; Huang, Wei-Hua; Du, Guang-Jian; Wen, Xiao-Dong; Calway, Tyler; Yu, Chunhao; Nass, Rachael; Zhao, Jing; Du, Wei; Li, Shao-Ping; Yuan, Chun-Su



Mesenchymal stem cells for anti-cancer drug delivery.  


Self renewal, extensive proliferation and multilineage differentiation ability in vitro and in vivo make mesenchymal stem cells (MSCs) powerful tools for tissue engineering. Beyond their potential uses in regenerative medicine, an emerging field of research aims to utilize MSCs for anti-cancer treatment. These strategies are based on the remarkable ability of MSCs to localize and integrate into tumor stroma and deliver anti-cancer agents (US20100055167, US20120207725, US20120010499). Genetically engineered MSCs can specifically target different tumor types and locally secrete therapeutic proteins such as interferons ? and ?, interleukins 2 and 12 or chemokine CX3CL1 (US20110027239, US20120087901, WO2012071527). In addition, MSCs have also been engineered to deliver oncolytic viruses, for targeted chemotherapy using enzyme prodrug conversion or for inducing tumor cell apoptosis by delivering tumor necrosis factor-related apoptosis inducing ligand (TRAIL) (WO2012106281). The patent databases FPO and Delphion were used to locate patents that were published between 2005 and 2013. Here, we present the current progress and the most recent patents on MSC anti-cancer drug delivery systems and discuss future directions in the field. PMID:23688246

Gjorgieva, Darinka; Zaidman, Nathan; Bosnakovski, Darko



Nanocarriers for anticancer drugs--new trends in nanomedicine.  


This review provides a brief overview of the variety of carriers employed for targeted drug delivery used in cancer therapy and summarizes advantages and disadvantages of each approach. Particularly, the attention was paid to polymeric nanocarriers, liposomes, micelles, polyethylene glycol, poly(lactic-co-glycolic acid), dendrimers, gold and magnetic nanoparticles, quantum dots, silica nanoparticles, and carbon nanotubes. Further, this paper briefly focuses on several anticancer agents (paclitaxel, docetaxel, camptothecin, doxorubicin, daunorubicin, cisplatin, curcumin, and geldanamycin) and on the influence of their combination with nanoparticulate transporters to their properties such as cytotoxicity, short life time and/or solubility. PMID:23687925

Drbohlavova, Jana; Chomoucka, Jana; Adam, Vojtech; Ryvolova, Marketa; Eckschlager, Tomas; Hubalek, Jaromir; Kizek, Rene



PP2A-Mediated Anticancer Therapy  

PubMed Central

PP2A is a family of mammalian serine/threonine phosphatases that is involved in the control of many cellular functions including protein synthesis, cellular signaling, cell cycle determination, apoptosis, metabolism, and stress responses through the negative regulation of signaling pathways initiated by protein kinases. Rapid progress is being made in the understanding of PP2A complex and its functions. Emerging studies have correlated changes in PP2A with human diseases, especially cancer. PP2A is comprised of 3 subunits: a catalytic subunit, a scaffolding subunit, and a regulatory subunit. The alternations of the subunits have been shown to be in association with many human malignancies. Therapeutic agents targeting PP2A inhibitors or activating PP2A directly have shed light on the therapy of cancers. This review focuses on PP2A structure, cancer-associated mutations, and the targeting of PP2A-related molecules to restore or reactivate PP2A in anticancer therapy, especially in digestive system cancer therapy. PMID:24307892

Jiang, Chunping



Potent anticancer activity of cystine-based dipeptides and their interaction with serum albumins  

PubMed Central

Background Cancer is a severe threat to the human society. In the scientific community worldwide cancer remains a big challenge as there are no remedies as of now. Cancer is quite complicated as it involves multiple signalling pathways and it may be caused by genetic disorders. Various natural products and synthetic molecules have been designed to prevent cell proliferation. Peptide-based anticancer drugs, however, are not explored properly. Though peptides have their inherent proteolytic instability, they could act as anticancer agents. Results In this present communication a suitably protected cystine based dipeptide and its deprotected form have been synthesized. Potent anticancer activities were confirmed by MTT assay (a laboratory test and a standard colorimetric assay, which measures changes in colour, for measuring cellular proliferation and phase contrast images. The IC50 value, a measure of the effectiveness of a compound in inhibiting biological or biochemical function, of these compounds ranges in the sub-micromolar level. The binding interactions with serum albumins (HSA and BSA) were performed with all these molecules and all of them show very strong binding at sub-micromolar concentration. Conclusions This study suggested that the cystine-based dipeptides were potential anticancer agents. These peptides also showed very good binding with major carrier proteins of blood, the serum albumins. We are currently working on determining the detailed mechanism of anticancer activity of these molecules. PMID:23705891



Next-generation metal anticancer complexes: multitargeting via redox modulation.  


Platinum complexes are widely used anticancer drugs. New generations of metal chemotherapeutics offer the prospect of combating platinum resistance and expanding the range of treatable cancers. Such new complexes might be effective if they form distinctly different lesions on DNA. In this Forum Article, we discuss the possibility that targeting the redox balance in cancer cells may also be a highly effective strategy, especially because it is a multiple-site approach and offers selectivity over normal cells. Metal complexes can interfere in cellular redox chemistry in several ways: directly through metal or ligand redox centers or indirectly by binding to biomolecules involved in cellular redox pathways. We illustrate that a surprisingly large number of active metal anticancer agents have a potential redox arm to their mechanism of action. For such complexes, the possibility arises of using combination therapy together with redox modulators to increase the anticancer potency: attractive for lowering the doses of metal complexes that need to be administered. We illustrate that organometallic ruthenium(II) and osmium(II) arene complexes and iridium(III) cyclopentadienyl complexes of the type [(arene/Cp(xPh))M(N,N)Cl/I](n+) can achieve nanomolar potency toward cancer cells in combination with the redox modulator l-buthionine sulfoximine. Our discussion highlights the importance of determining not only the distribution of metal anticancer complexes in cells but also their speciation, the chemical form of the metal complex, including the oxidation state of the metal, the fate of the ligands, and dynamic processes such as efflux. This will be aided in the future by proteomic and genomic analyses but needs to be supplemented by new analytical methods that have the sensitivity and spatial and temporal resolution to reveal such information. To achieve this, major new funding programs are needed that support global research on the design of novel metal-based drugs with new mechanisms of action, tailored to patient needs. PMID:23879584

Romero-Canelón, Isolda; Sadler, Peter J



[Anticancer drugs and ABC transporters].  


Anticancer drugs interact directly with their molecular targets in cancer cells for effective cancer chemotherapy. The direct interaction between drug and cancer cell depends on the pharmacokinetics, which consists of absorption, distribution, metabolism, and excretion phases. In the excretion phase, ATP-binding cassette (ABC) transporters are the most important proteins in cell membranes. The ABC transporters export drugs out of cells by ATP-dependent energy, leading to drug resistance with reduced concentrations of intracellular drugs. In addition, the transporters sequestrate intracellular drugs into membrane vesicles in cytoplasm, also resulting in drug resistance. On the other hand, they are also involved in drug absorption. To date, 48 ABC genes have been isolated and classified into the seven groups of ABCA to ABCG. Among them, P-glycoprotein/ABCB 1, MRP 1/ ABCC 1, MRP 2/ABCC 2, MRP 3/ABCC 3, and BCRP/ABCG 2 strongly confer anticancer drug resistance, and they have different substrate drugs. Interestingly, recent molecular-targeted drugs, such as imatinib and gefitinib, were very recently found to be substrates for P-glycoprotein and/or BCRP. Additionally, polymorphism of ABC genes affects pharmacokinetics, drug effectiveness, and adverse events. Thus, ABC transporters are clinically important molecules, and much information is needed in the clinic. PMID:15918555

Oka, Mikio; Fukuda, Minoru; Soda, Hiroshi



Terrestrial Plant-Derived Anticancer Agents and Plant Species Used in Anticancer Research  

Microsoft Academic Search

Cancer is a major cause of death and the number of new cases, as well as the number of individuals living with cancer, is expanding continuously. Due to the enormous propensity of plants that synthesize mixtures of structurally diverse bioactive compounds, the plant kingdom is potentially a very diverse source of chemical constituents with tumor cytotoxic activity. Despite the successful

Spiridon E. Kintzios



Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug.  


The Warburg effect refers to the phenomenon whereby cancer cells avidly take up glucose and produce lactic acid under aerobic conditions. Although the molecular mechanisms underlying tumor reliance on glycolysis remains not completely clear, its inhibition opens feasible therapeutic windows for cancer treatment. Indeed, several small molecules have emerged by combinatorial studies exhibiting promising anticancer activity both in vitro and in vivo, as a single agent or in combination with other therapeutic modalities. Therefore, besides reviewing the alterations of glycolysis that occur with malignant transformation, this manuscript aims at recapitulating the most effective pharmacological therapeutics of its targeting. In particular, we describe the principal mechanisms of action and the main targets of 3-bromopyruvate, an alkylating agent with impressive antitumor effects in several models of animal tumors. Moreover, we discuss the chemo-potentiating strategies that would make unparalleled the putative therapeutic efficacy of its use in clinical settings. PMID:22328057

Cardaci, Simone; Desideri, Enrico; Ciriolo, Maria Rosa



Bisphosphonamidate Clodronate Prodrug Exhibits Potent Anticancer Activity in Non-Small Cell Lung Cancer cells  

PubMed Central

Bisphoshonates are used clinically to treat disorders of calcium metabolism, hypercalcemia and osteoporosis, and malignant bone disease. Although these agents are commonly used in cancer patients and have potential direct anticancer effects, their use for the treatment of extraskeletal disease is limited as a result of poor cellular uptake. We have designed and synthesized bisphosphonamidate prodrugs that undergo intracellular activation to release the corresponding bisphosphonate and require only two enzymatic activation events to unmask multiple negative charges. We demonstrate efficient bisphosphonamidate activation and significant enhancement in anticancer activity of two bisphosphonamidate prodrugs in vitro compared to the parent bisphosphonate. These data suggest a novel approach to optimizing the anticancer activities of commonly used bisphosphonates. PMID:21863853

Webster, Marie R.; Zhao, Ming; Rudek, Michelle A.; Hann, Christine L.; Freel Meyers, Caren L.



Molecular Mechanisms of Cannabinoids as Anti-cancer Agents  

E-print Network

Cancer is a growing health concern world-wide and is the second most common cause of death after heart diseases. Current treatment strategies such as surgery, chemotherapy and radiation provide some relief to cancer patients but the toxic side...

Sreevalsan, Sandeep



Plant anticancer agents. XXX: Cucurbitacins from Ipomopsis aggregata (Polemoniaceae).  


Isocucurbitacin B (I), 3-epi-isocucurbitacin B (II), and cucurbitacin B (III) were identified as the principal cytotoxic constituents of Ipomopsis aggregata (Pursh) V. Grant (Polemoniaceae). The structure of the new compound, II, was determined through analysis of its spectrometric characteristics. PMID:6546946

Arisawa, M; Pezzuto, J M; Kinghorn, A D; Cordell, G A; Farnsworth, N R



Iminosugar-ferrocene conjugates as potential anticancer agents.  


We prepared a series of new iminosugar-ferrocene hybrids displaying potent inhibition of fucosidase (bovine kidney) and inactivation of MDA-MB-231 breast cancer cells proliferation at low micromolar concentrations. The synthetic route brought to light an unprecedented isomerisation of a 2-ethanalylpyrrolidine. PMID:22717621

Hottin, Audrey; Dubar, Faustine; Steenackers, Agata; Delannoy, Philippe; Biot, Christophe; Behr, Jean-Bernard



7-Azaindenoisoquinolines as Topoisomerase I Inhibitors and Potential Anticancer Agents  

PubMed Central

A series of 7-azaindenoisoquinoline topoisomerase I (Top1) inhibitors have been prepared to investigate the effect of increased electron affinity of the aromatic system on the ability to stabilize the Top1-DNA cleavage complex. Ab initio calculations suggest that introduction of nitrogen into the aromatic system of the indenoisoquinolines would facilitate charge transfer complex formation with DNA, thus improving the ?-? stacking interactions. The present study shows that 7-azaindenoisoquinolines demonstrate improved water solubility without any decrease in Top1 inhibitory activity or cytotoxicity. Analysis of the biological results reveals that smaller lactam ring substituents enable intercalation into both free DNA and Top1-DNA cleavage complex, whereas larger substituents only allow binding to the cleavage complex, but not free DNA. Free DNA binding suppresses Top1-catalyzed DNA cleavage at high drug concentrations, whereas DNA-cleavage and inhibition of re-ligation occurs at low drug concentration. PMID:21823606

Kiselev, Evgeny; DeGuire, Sean; Morrell, Andrew; Agama, Keli; Dexheimer, Thomas S.; Pommier, Yves; Cushman, Mark



Reprogramming Urokinase into an Antibody-Recruiting Anticancer Agent  

PubMed Central

Synthetic compounds for controlling or creating human immunity have the potential to revolutionize disease treatment. Motivated by challenges in this arena, we report herein a strategy to target metastatic cancer cells for immune-mediated destruction by targeting the urokinase-type plasminogen activator receptor (uPAR). Urokinase-type plasminogen activator (uPA) and uPAR are overexpressed on the surfaces of a wide range of invasive cancer cells and are believed to contribute substantially to the migratory propensities of these cells. The key component of our approach is an antibody-recruiting molecule that targets the urokinase receptor (ARM-U). This bifunctional construct is formed by selectively, covalently attaching an antibody-binding small molecule to the active site of the urokinase enzyme. We demonstrate that ARM-U is capable of directing antibodies to the surfaces of target cancer cells and mediating both antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) against multiple human cancer cell lines. We believe that the reported strategy has the potential to inform novel treatment options for a variety of deadly, invasive cancers. PMID:22098560

Jakobsche, Charles E.; McEnaney, Patrick J.; Zhang, Andrew X.



Developments in the chemistry and nanodelivery of platinum anticancer agents  

E-print Network

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

Johnstone, Timothy Charles



Pharmacokinetic profiles of anticancer herbal medicines in humans and the clinical implications.  


A number of herbal medicines are increasingly used by cancer patients worldwide, despite the fact that the clinical evidence that supports their use to fight cancer is weak or lacking. Pharmacokinetic studies have been integrated into modern drug development, but they are generally not needed for herbal remedies. To update our knowledge in this field, this paper highlights the pharmacokinetic properties of anticancer herbal medicines and the clinical relevance. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase ((all from inception to May 2011). An extensive literature search indicatesthat there are limited data on the pharmacokinetic properties of anticancer herbal medicines in humans. There are increasing pharmacokinetic studies of anticancer herbal remedies, but these studies are mainly focused on a small number of herbal medicines including curcumin, ginseng, ginkgo, ginger and milk thistle. For an anticancer herbal medicine, the pharmacological activity is gained when the active agents or the active metabolites reach and sustain proper levels at their sites of action. Both the dose levels and pharmacokinetic processes of active herbal components in the body determine their target-site concentrations and thus the anticancer effect. In this regard, a safe and optimal use of anticancer herbal medicines requires a full understanding of their pharmacokinetic profiles. To optimize the use of anticancer herbal remedies, further studies to explore their pharmacokinetic properties and the relevance to pharmacodynamics and toxicity in humans are certainly warranted. PMID:21671861

Chen, X-W; Sneed, K B; Zhou, S-F



Interrelation of antioxidant, anticancer and antilieshmania effects of some selected Egyptian plants and their phenolic constituents.  


Medicinal plants are the most potential resource of new therapeutic agents. They are diverse, largely productive, biologically active and chemically unique; among their constituents "polyphenol compounds group" one of the main determinant factors in evaluating the pharmacological potentials i.e. polyphenols display an array of pharmacological properties such as antioxidant, immunostimulant, antitumor and antiparasitic effects. Cancer is a dreadful human disease, increasing with changing life style, nutrition and global warming while current available anticancer drugs cause serious side effects in most instances. Several reports suggested the relationship between antioxidant, anticancer and antiparasitic effects; they suggested that they act indirectly through promoting host resistance, restabilizing body equilibrim and conditioning body tissues in addition to their direct effect on certain parasites involved in cancer etiology. This work was conducted for estimation of total phenolic, flavonoids, phenylethanoid glycoside and iridoid content of twenty-three selected Egyptian plants as well as screening of their anticancer, antioxidant and antileishmanial effects, the overall gained results for suggest that the most suitable medicinal plant used as anticancer and antioxidant is Petrea volubilis L. which contain adequate mixture of total phenolic compounds 88.7 mg% and flavonoids 50.80 mg% and also suggest that flavonoid compounds are the category of phenolic compounds possess significant antioxidant and anticancer effects while the antilieshamnia screening revealed that Thymus decussatus Benth. extract exhibited the highest effect due to the presence of flavonoids and iridoids in adequate combination where iridoid compounds 201 mg% and flavonoid content was 128 mg%. PMID:22435170

Abdel-Hady, Nevein M; Dawoud, Gouda T M; El-Hela, Atef A; Morsy, Tosson A



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

NASA Astrophysics Data System (ADS)

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

Adeniyi, Adebayo A.; Ajibade, Peter A.



Nanoscale coordination polymers for anticancer drug delivery  

NASA Astrophysics Data System (ADS)

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

Phillips, Rachel Huxford


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

PubMed Central

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

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



Anti-Cancer Effects of Xanthones from Pericarps of Mangosteen  

PubMed Central

Mangosteen, Garcinia mangostana Linn, is a tree found in South East Asia, and its pericarps have been used as traditional medicine. Phytochemical studies have shown that they contain a variety of secondary metabolites, such as oxygenated and prenylated xanthones. Recent studies revealed that these xanthones exhibited a variety of biological activities containing anti-inflammatory, anti-bacterial, and anti-cancer effects. We previously investigated the anti-proliferative effects of four prenylated xanthones from the pericarps; ?-mangostin, ?-mangostin, ?-mangostin, and methoxy-?-mangostin in various human cancer cells. These xanthones are different in the number of hydroxyl and methoxy groups. Except for methoxy-?-mangostin, the other three xanthones strongly inhibited cell growth at low concentrations from 5 to 20 ?M in human colon cancer DLD-1 cells. Our recent study focused on the mechanism of ?-mangostin-induced growth inhibition in DLD-1 cells. It was shown that the anti-proliferative effects of the xanthones were associated with cell-cycle arrest by affecting the expression of cyclins, cdc2, and p27; G1 arrest by ?-mangostin and ?-Mangostin, and S arrest by ?-mangostin. ?-Mangostin found to induce apoptosis through the activation of intrinsic pathway following the down-regulation of signaling cascades involving MAP kinases and the serine/threonine kinase Akt. Synergistic effects by the combined treatment of ?-mangostin and anti-cancer drug 5-FU was to be noted. ?-Mangostin was found to have a cancer preventive effect in rat carcinogenesis bioassay and the extract from pericarps, which contains mainly ?-mangostin and ?-mangostin, exhibited an enhancement of NK cell activity in a mouse model. These findings could provide a relevant basis for the development of xanthones as an agent for cancer prevention and the combination therapy with anti-cancer drugs. PMID:19325754

Akao, Yukihiro; Nakagawa, Yoshihito; Iinuma, Munekazu; Nozawa, Yoshinori



FK506 binding proteins as targets in anticancer therapy.  


FK506 binding proteins (FKBPs) are the intracellular ligands of FK506 and rapamycin, two natural compounds with powerful and clinically efficient immunosuppressive activity. In recent decades, a relevant role for immunosuppressants as anticancer agents has emerged. Especially, rapamycin and its derivatives are used, with successful results, across a variety of tumors. Of note, rapamycin and FK506 bind to FKBP12, and the resulting complexes interfere with distinct intracellular signaling pathways driven, respectively, by the mammalian target of rapamycin and calcineurin phosphatase. These pathways are related to T-cell activation and growth. Hyperactivation of the mammalian target of rapamycin (mTOR), particularly in cancers that have lost the tumor suppressor gene PTEN, plays an important pathogenetic role in tumor transformation and growth. The signaling pathway involving calcineurin and nuclear factors of activated T-lymphocytes is also involved in the pathogenesis of different cancer types and in tumor metastasis, providing a rationale for use of FK506 in anticancer therapy. Recent studies have focused on FKBPs in apoptosis regulation: Targeting of FKBP12 promotes apoptosis in chronic lymphocytic leukemia, FKBP38 knockdown sensitizes hepatoma cells to apoptosis, and FKBP51 silencing overcomes resistance to apoptosis in acute lymphoblastic leukemia, prostate cancer, melanoma, and glioma. Interestingly, derivatives of FK506 that have the same FKBP12-binding properties as FK506 but lack functional immunosuppressant activity, exert the same apoptotic effect as FK506 in chronic lymphocytic leukemia.These findings suggest that a direct FKBP inhibition represents a further mechanism of immunosuppressants.' anticancer activity. In this review, we focus on the role of FKBP members in apoptosis control and summarize the data on the antitumor effect of selective targeting of FKBP. PMID:21182472

Romano, Simona; Di Pace, Annalaura; Sorrentino, Antonio; Bisogni, Rita; Sivero, Luigi; Romano, Maria Fiammetta



Systemic anticancer therapy in gynecological cancer patients with renal dysfunction.  


Chronic kidney disease is a common occurrence in patients with gynecological cancer. Systemic anticancer treatment in such patients is a challenge for clinicians because of altered drug pharmacokinetics. For those drugs that are excreted mainly by the kidneys, decreased renal function may lead to increased systemic exposure and increased toxicity. Dose adjustment based on pharmacokinetic changes is required in this situation to avoid life-threatening toxicity. In this review, we summarize the nephrotoxicity and pharmacokinetic data of agents commonly used in systemic anticancer treatment of gynecological cancers and dose adjustment guidelines in the presence of impaired renal function. We review 17 medications that need dose adjustment (cisplatin, carboplatin, doxorubicin, epirubicin, cyclophosphamide, ifosfamide, topotecan, irinotecan, etoposide, capecitabine, bleomycin, methotrexate, actinomycin D, granulocyte-macrophage colony-stimulating factor, metoclopramide, cimetidine, and diphenhydramine) as well as 27 drugs that do not (paclitaxel, docetaxel, pegylated liposomal doxorubicin, gemcitabine, oxaliplatin, fluorouracil, vincristine, letrozole, anastrozole, tamoxifen, leuprorelin, megestrol, gefitinib, erlotinib, trastuzumab, leucovorin, granulocyte colony-stimulating factor, erythropoietin, ondansetron, granisetron, palonosetron, tropisetron, dolasetron, aprepitant, dexamethasone, lorazepam, and diazepam). We also review the formulae commonly used to estimate creatinine clearance, including Cockcroft-Gault, Chatelut, Jelliffe, Wright, and the Modification of Diet in Renal Disease study formulae. PMID:17309673

Li, Y F; Fu, S; Hu, W; Liu, J H; Finkel, K W; Gershenson, D M; Kavanagh, J J



Involvement of P-glycoprotein and CYP 3A4 in the enhancement of etoposide bioavailability by a piperine analogue  

Microsoft Academic Search

Etoposide, a semi-synthetic derivative of podophyllotoxin, is widely used anticancer agent. Etoposide presents low bioavailability with wide inter-, and intra-patient variability after oral dosing. In an earlier study a piperine analogue, namely, 4-ethyl 5-(3, 4-methylenedioxyphenyl)-2E,4E-pentadienoic acid piperidide (PA-1), was shown to cause 2.32-fold enhancement of the absolute bioavailability of co-dosed etoposide in mice. In the present investigation a mechanistic evaluation

I. A. Najar; S. C. Sharma; G. D. Singh; S. Koul; P. N. Gupta; S. Javed; R. K. Johri



Unfolded protein response to autophagy as a promising druggable target for anticancer therapy  

PubMed Central

The endoplasmic reticulum (ER) is responsible for protein processing. In rapidly proliferating tumor cells, the ER tends to be overloaded with unfolded and misfolded proteins due to high metabolic demand. With the limited protein-folding capacity of the ER, tumor cells often suffer from more ER stress than do normal cells. Thus, cellular stress responses to cope with ER stress, such as the unfolded protein response (UPR) and autophagy, might be more activated in cancer cells than in normal cells. The complex signaling pathways from the UPR to autophagy provide promising druggable targets; a number of UPR/autophagy-targeted anticancer agents are currently in development in preclinical and clinical studies. In this short review we will discuss the potential anticancer efficacy of modulators of cellular stress responses, especially UPR and autophagy, on the basis of their signaling pathways. In addition, the current developmental status of the UPR/autophagy-targeted agents will be discussed. PMID:23050960

Suh, Dong Hoon; Kim, Mi-Kyung; Kim, Hee Seung; Chung, Hyun Hoon; Song, Yong Sang



Identification of non-cross-resistant platinum compounds with novel cytotoxicity profiles using the NCI anticancer drug screen and clustered image map visualizations  

Microsoft Academic Search

The widespread clinical use of platinum compounds in cancer chemotherapy has prompted a search for new platinum agents. To search for platinum agents with novel profiles of activity, we used clustered image maps, the COMPARE algorithm, and other numerical methods to analyze platinum compounds submitted to the National Cancer Institute's anticancer drug screen and tested against the screen's 60 diverse

Tito Fojo; Nick Farrell; Waldo Ortuzar; Hideyuki Tanimura; John Weinstein; Timothy G. Myers



Cerebral air embolism after intrathoracic anti-cancer drug administration.  


We report a case of cerebral arterial air embolism that was followed by a brain computed tomographic scan and magnetic resonance imaging during the first week after onset. A 73-year-old man was admitted for treatment of pleural dissemination that was a recurrence after right lower bilectomy for advanced lung cancer. Thirty minutes after an anti-drug administration through the chest drainage tube, he lost consciousness shortly after coughing. A bubble in the inferior sagittal sinus was observed on the day of the stroke, which then disappeared within 24 hours. It seems that the anti-cancer agent evoked inflammation at the visceral pleura and the subject inhaled massive air flow into the systemic circulation. PMID:16928561

Yamashita, Yoshinori; Mukaida, Hidenori; Hirabayashi, Naoki; Takiyama, Wataru



Safe and targeted anticancer therapy for ovarian cancer using a novel class of curcumin analogs.  


A diagnosis of advanced ovarian cancer is the beginning of a long and arduous journey for a patient. Worldwide, approximately half of the individuals undergoing therapy for advanced cancer will succumb to the disease, or consequences of treatment. Well-known and widely-used chemotherapeutic agents such as cisplatin, paclitaxel, 5-fluorouracil, and doxorubicin are toxic to both cancer and non-cancerous cells, and have debilitating side effects Therefore, development of new targeted anticancer therapies that can selectively kill cancer cells while sparing the surrounding healthy tissues is essential to develop more effective therapies. We have developed a new class of synthetic curcumin analogs, diarylidenyl-piperidones (DAPs), which have higher anticancer activity and enhanced bio-absorption than curcumin. The DAP backbone structure exhibits cytotoxic (anticancer) activity, whereas the N-hydroxypyrroline (-NOH) moiety found on some variants functions as a cellular- or tissue-specific modulator (antioxidant) of cytotoxicity. The anticancer activity of the DAPs has been evaluated using a number of ovarian cancer cell lines, and the safety has been evaluated in a number of non-cancerous cell lines. Both variations of the DAP compounds showed similar levels of cell death in ovarian cancer cells, however the compounds with the -NOH modification were less toxic to non-cancerous cells. The selective cytotoxicity of the DAP-NOH compounds suggests that they will be useful as safe and effective anticancer agents. This article reviews some of the key findings of our work with the DAP compounds, and compares this to some of the targeted therapies currently used in ovarian cancer therapy. PMID:23663277

Rath, Kellie S; McCann, Georgia A; Cohn, David E; Rivera, Brian K; Kuppusamy, Periannan; Selvendiran, Karuppaiyah



Safe and targeted anticancer therapy for ovarian cancer using a novel class of curcumin analogs  

PubMed Central

A diagnosis of advanced ovarian cancer is the beginning of a long and arduous journey for a patient. Worldwide, approximately half of the individuals undergoing therapy for advanced cancer will succumb to the disease, or consequences of treatment. Well-known and widely-used chemotherapeutic agents such as cisplatin, paclitaxel, 5-fluorouracil, and doxorubicin are toxic to both cancer and non-cancerous cells, and have debilitating side effects Therefore, development of new targeted anticancer therapies that can selectively kill cancer cells while sparing the surrounding healthy tissues is essential to develop more effective therapies. We have developed a new class of synthetic curcumin analogs, diarylidenyl-piperidones (DAPs), which have higher anticancer activity and enhanced bio-absorption than curcumin. The DAP backbone structure exhibits cytotoxic (anticancer) activity, whereas the N-hydroxypyrroline (-NOH) moiety found on some variants functions as a cellular- or tissue-specific modulator (antioxidant) of cytotoxicity. The anticancer activity of the DAPs has been evaluated using a number of ovarian cancer cell lines, and the safety has been evaluated in a number of non-cancerous cell lines. Both variations of the DAP compounds showed similar levels of cell death in ovarian cancer cells, however the compounds with the -NOH modification were less toxic to non-cancerous cells. The selective cytotoxicity of the DAP–NOH compounds suggests that they will be useful as safe and effective anticancer agents. This article reviews some of the key findings of our work with the DAP compounds, and compares this to some of the targeted therapies currently used in ovarian cancer therapy. PMID:23663277



Antioxidant, antimicrobial and anticancer activity of the lichens Cladonia furcata, Lecanora atra and Lecanora muralis  

PubMed Central

Background The aim of this study is to investigate in vitro antioxidant, antimicrobial and anticancer activity of the acetone extracts of the lichens Cladonia furcata, Lecanora atra and Lecanora muralis. Methods Antioxidant activity was evaluated by five separate methods: free radical scavenging, superoxide anion radical scavenging, reducing power, determination of total phenolic compounds and determination of total flavonoid content. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration by the broth microdilution method against six species of bacteria and ten species of fungi. Anticancer activity was tested against FemX (human melanoma) and LS174 (human colon carcinoma) cell lines using MTT method. Results Of the lichens tested, Lecanora atra had largest free radical scavenging activity (94.7% inhibition), which was greater than the standard antioxidants. Moreover, the tested extracts had effective reducing power and superoxide anion radical scavenging. The strong relationships between total phenolic and flavonoid contents and the antioxidant effect of tested extracts were observed. Extract of Cladonia furcata was the most active antimicrobial agent with minimum inhibitory concentration values ranging from 0.78 to 25 mg/mL. All extracts were found to be strong anticancer activity toward both cell lines with IC50 values ranging from 8.51 to 40.22 ?g/mL. Conclusions The present study shows that tested lichen extracts demonstrated a strong antioxidant, antimicrobial and anticancer effects. That suggest that lichens may be used as as possible natural antioxidant, antimicrobial and anticancer agents to control various human, animal and plant diseases. PMID:22013953



AlgiMatrix(TM) Based 3D Cell Culture System as an In-Vitro Tumor Model for Anticancer Studies  

PubMed Central

Background Three-dimensional (3D) in-vitro cultures are recognized for recapitulating the physiological microenvironment and exhibiting high concordance with in-vivo conditions. Taking the advantages of 3D culture, we have developed the in-vitro tumor model for anticancer drug screening. Methods Cancer cells grown in 6 and 96 well AlgiMatrix™ scaffolds resulted in the formation of multicellular spheroids in the size range of 100–300 µm. Spheroids were grown in two weeks in cultures without compromising the growth characteristics. Different marketed anticancer drugs were screened by incubating them for 24 h at 7, 9 and 11 days in 3D cultures and cytotoxicity was measured by AlamarBlue® assay. Effectiveness of anticancer drug treatments were measured based on spheroid number and size distribution. Evaluation of apoptotic and anti-apoptotic markers was done by immunohistochemistry and RT-PCR. The 3D results were compared with the conventional 2D monolayer cultures. Cellular uptake studies for drug (Doxorubicin) and nanoparticle (NLC) were done using spheroids. Results IC50 values for anticancer drugs were significantly higher in AlgiMatrix™ systems compared to 2D culture models. The cleaved caspase-3 expression was significantly decreased (2.09 and 2.47 folds respectively for 5-Fluorouracil and Camptothecin) in H460 spheroid cultures compared to 2D culture system. The cytotoxicity, spheroid size distribution, immunohistochemistry, RT-PCR and nanoparticle penetration data suggested that in vitro tumor models show higher resistance to anticancer drugs and supporting the fact that 3D culture is a better model for the cytotoxic evaluation of anticancer drugs in vitro. Conclusion The results from our studies are useful to develop a high throughput in vitro tumor model to study the effect of various anticancer agents and various molecular pathways affected by the anticancer drugs and formulations. PMID:23349734

Godugu, Chandraiah; Patel, Apurva R.; Desai, Utkarsh; Andey, Terrick; Sams, Alexandria; Singh, Mandip



Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications  

PubMed Central

Abstract Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2?). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2? inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 00, 000–000. PMID:22900902



Anticancer activity of Ficus religiosa engineered copper oxide nanoparticles.  


The design, synthesis, characterization and application of biologically synthesized nanomaterials have become a vital branch of nanotechnology. There is a budding need to develop a method for environmentally benign metal nanoparticle synthesis, that do not use toxic chemicals in the synthesis protocols to avoid adverse effects in medical applications. Here, it is a report on an eco-friendly process for rapid synthesis of copper oxide nanoparticles using Ficus religiosa leaf extract as reducing and protecting agent. The synthesized copper oxide nanoparticles were confirmed by UV-vis spectrophotometer, absorbance peaks at 285nm. The copper oxide nanoparticles were analyzed with field emission-scanning electron microscope (FE-SEM), Fourier transform infrared (FT-IR) spectroscopy, dynamic light scattering (DLS) and X-ray diffraction (XRD) spectrum. The FE-SEM and DLS analyses exposed that copper oxide nanoparticles are spherical in shape with an average particle size of 577nm. FT-IR spectral analysis elucidates the occurrence of biomolecules required for the reduction of copper oxide ions. Zeta potential studies showed that the surface charge of the formed nanoparticles was highly negative. The XRD pattern revealed that synthesized nanoparticles are crystalline in nature. Further, biological activities of the synthesized nanoparticles were confirmed based on its stable anti-cancer effects. The apoptotic effect of copper oxide nanoparticles is mediated by the generation of reactive oxygen species (ROS) involving the disruption of mitochondrial membrane potential (??m) in A549 cells. The observed characteristics and results obtained in our in vitro assays suggest that the copper nanoparticles might be a potential anticancer agent. PMID:25280701

Sankar, Renu; Maheswari, Ramasamy; Karthik, Selvaraju; Shivashangari, Kanchi Subramanian; Ravikumar, Vilwanathan



Inhibition of Both Thioredoxin Reductase and Glutathione Reductase may Contribute to the Anticancer Mechanism of TH-302  

Microsoft Academic Search

Selenium-containing thioredoxin reductase (TrxR) is an important target of cancer therapy. Many useful anticancer agents including\\u000a bis-alkylating agents, cisplatin, and arsenic trioxide are known to interact with the selenocysteine dipeptide in the carboxy\\u000a terminal region of thioredoxin reductase and inactivate its ability to reduce thioredoxin. Some investigators have postulated\\u000a that the inactivation of TrxR may add to the cytotoxic potential

Shengrong Li; Jinsong Zhang; Jun Li; Dongming Chen; Mark Matteucci; John Curd; Jian-Xin Duan



Magnetic polymer nanospheres for anticancer drug targeting  

NASA Astrophysics Data System (ADS)

Poly(D,L-lactide-co-glycolide) polymer (PLGA) nanospheres loaded with biocom-patible magnetic fluid as a magnetic carrier and anticancer drug Taxol were prepared by the modified nanoprecipitation method with size of 200-250 nm in diameter. The PLGA polymer was utilized as a capsulation material due to its biodegradability and biocompatibility. Taxol as an important anticancer drug was chosen for its significant role against a wide range of tumours. Thermal properties of the drug-polymer system were characterized using thermal analysis methods. It was determined the solubility of Taxol in PLGA nanospheres. Magnetic properties investigated using SQUID magnetometry showed superparamagnetism of the prepared magnetic polymer nanospheres.

Juríková, A.; Csach, K.; Koneracká, M.; Závišová, V.; Mú?ková, M.; Tomašovi?ová, N.; Lancz, G.; Kop?anský, P.; Timko, M.; Miškuf, J.



Anticancer Evaluation of Adiantum venustum Don  

PubMed Central

Cancer is a malignant disease that is characterized by rapid and uncontrolled formation of abnormal cells which may mass together to form a growth or tumor, or proliferate throughout the body. Next to heart disease, cancer is a major killer of mankind. This study aims at a preliminary phytochemical screening and anticancer evaluation of Adiantum venustum Don against Ehrlich Ascites Carcinoma in animal model. The findings indicate that ethanolic extract of A. venustum Don possesses significant anticancer activity and also reduces elevated level of lipid peroxidation due to the presence of terpenoids and flavonoids. Thus, ethanolic extract of A. venustum Don could have vast therapeutic application against cancer. PMID:21607054

Viral, D; Shivanand, P; Jivani, NP



Telomerase inhibitory effects of medicinal mushrooms and lichens, and their anticancer activity.  


Telomerase has been widely accepted as a cancer marker and a promising therapeutic target for novel anticancer drugs. The aim of this study was to investigate the in vitro telomerase inhibitory effects of mushrooms and their anticancer properties. The inhibitory effects of mushrooms and lichens against telomerase activity of HL-60 cells were systematically assessed using polymerase chain reaction based on assay of telomeric repeat amplification protocol. Telomerase inhibitory samples were further tested for antiproliferation effects against the gastric cell line SNU-1 using the MTT method. Ethyl acetate extract of Pleurotus ostreatus, ethyl acetate and water extracts of Lasiosphaera fenzlii, hexane extract of Strobilomyces floccopus, water extract of Sarcodon aspratus, and hexane, ethyl acetate, and water extracts from Umbilicaria esculenta showed strong positive telomerase inhibitory activity. Hexane extract of S. floccopus and water extracts from the edible lichen U. esculenta exhibited strong anticancer effects against SNU-1 cells through antiproliferation assay. The water extract of U. esculenta has a great potential to be developed into an anticancer agent that targets telomerase. PMID:24940901

Xu, Baojun; Li, Chantian; Sung, Changkeun



Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targeting.  


Effective cancer therapy remains one of the most challenging tasks to the scientific community, with little advancement on overall cancer survival landscape during the last two decades. A major limitation inherent to most conventional anticancer chemotherapeutic agents is their lack of tumor selectivity. One way to achieve selective drug targeting to solid tumors is to exploit abnormalities of tumor vasculature, namely hypervascularization, aberrant vascular architecture, extensive production of vascular permeability factors stimulating extravasation within tumor tissues, and lack of lymphatic drainage. Due to their large size, nano-sized macromolecular anticancer drugs administered intravenously (i.v.) escape renal clearance. Being unable to penetrate through tight endothelial junctions of normal blood vessels, their concentration builds up in the plasma rendering them long plasma half-life. More importantly, they can selectively extravasate in tumor tissues due to its abnormal vascular nature. Overtime the tumor concentration will build up reaching several folds higher than that of the plasma due to lack of efficient lymphatic drainage in solid tumor, an ideal application for EPR-based selective anticancer nanotherapy. Indeed, this selective high local concentration of nano-sized anticancer drugs in tumor tissues has proven superior in therapeutic effect with minimal side effects in both preclinical and clinical settings. PMID:20217587

Greish, Khaled



A gold(I) phosphine complex selectively induces apoptosis in breast cancer cells: Implications for anticancer therapeutics targeted to mitochondria  

Microsoft Academic Search

Bis-chelated gold(I) phosphine complexes have shown great potential as anticancer agents, however, their efficacy has been limited by their high toxicity and lack of selectivity for cancer cells. Here, we have investigated the anticancer activity of a new bis-chelated Au(I) bidentate phosphine complex of the novel water soluble ligand 1,3-bis(di-2-pyridylphosphino)propane (d2pypp). We show that this gold complex [Au(d2pypp)2]Cl, at submicromolar

Oliver Rackham; Scott J. Nichols; Peter J. Leedman; Susan J. Berners-Price; Aleksandra Filipovska



Recent Development in Carbohydrate Based Anticancer Vaccines  

Microsoft Academic Search

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

Zhaojun Yin; Xuefei Huang



Novel Agents on the Horizon for Cancer Therapy  

Microsoft Academic Search

Although cancer remains a devastating diagnosis, several decades of preclinical progress in cancer biology and biotechnology have recently led to successful development of several biological agents that substantially improve survival and quality of life for some patients. There is now a rich pipeline of novel anticancer agents in early phase clinical trials. The specific tumor and stromal aberrancies targeted can

Wen W. Ma; Alex A. Adjei


Mechanisms of resistance to alkylating agents  

Microsoft Academic Search

Alkylating agents are the most widely used anticancer drugs whose main target is the DNA, although how exactly the DNA lesions\\u000a cause cell death is still not clear. The emergence of resistance to this class of drugs as well as to other antitumor agents\\u000a is one of the major causes of failure of cancer treatment. This paper reviews some of

G. Damia; M. D‘Incalci



Anticancer effects of different seaweeds on human colon and breast cancers.  


Seafoods and seaweeds represent some of the most important reservoirs of new therapeutic compounds for humans. Seaweed has been shown to have several biological activities, including anticancer activity. This review focuses on colorectal and breast cancers, which are major causes of cancer-related mortality in men and women. It also describes various compounds extracted from a range of seaweeds that have been shown to eradicate or slow the progression of cancer. Fucoidan extracted from the brown algae Fucus spp. has shown activity against both colorectal and breast cancers. Furthermore, we review the mechanisms through which these compounds can induce apoptosis in vitro and in vivo. By considering the ability of compounds present in seaweeds to act against colorectal and breast cancers, this review highlights the potential use of seaweeds as anticancer agents. PMID:25255129

Moussavou, Ghislain; Kwak, Dong Hoon; Obiang-Obonou, Brice Wilfried; Maranguy, Cyr Abel Ogandaga; Dinzouna-Boutamba, Sylvatrie-Danne; Lee, Dae Hoon; Pissibanganga, Ordelia Gwenaelle Manvoudou; Ko, Kisung; Seo, Jae In; Choo, Young Kug



Synthesis and anti-cancer activity evaluation of new dimethoxylated chalcone and flavanone analogs.  


A novel series of chalcones and flavanones discriminated by the presence of a 3,4-dimethoxyphenyl moiety in their structures were synthesized as anti-cancer agents. The cytotoxicity evaluation of the analogs against the MCF-7, MDA-MB-231 (human breast cancer), and SK-N-MC (human neuroblastoma) cell lines demonstrated that the introduction of a halogen on the 3,4-dimethoxyphenyl part of both series and the attachment of a pyrrolidinylethoxy group on the C-7 position of the flavanone derivatives increased their activity. Indeed, 3-halogenated chalcones (1c and 1d) were more potent than the standard drug etoposide against all tested cell lines. Fluorescence microscopy and flow cytometry analyses confirmed that the anti-cancer effect of the most potent compounds 1c and 1d occurs via apoptosis induction. PMID:25201534

Ketabforoosh, Shima H M E; Kheirollahi, Asma; Safavi, Maliheh; Esmati, Nasim; Ardestani, Sussan K; Emami, Saeed; Firoozpour, Loghman; Shafiee, Abbas; Foroumadi, Alireza



Anticancer Effects of Different Seaweeds on Human Colon and Breast Cancers  

PubMed Central

Seafoods and seaweeds represent some of the most important reservoirs of new therapeutic compounds for humans. Seaweed has been shown to have several biological activities, including anticancer activity. This review focuses on colorectal and breast cancers, which are major causes of cancer-related mortality in men and women. It also describes various compounds extracted from a range of seaweeds that have been shown to eradicate or slow the progression of cancer. Fucoidan extracted from the brown algae Fucus spp. has shown activity against both colorectal and breast cancers. Furthermore, we review the mechanisms through which these compounds can induce apoptosis in vitro and in vivo. By considering the ability of compounds present in seaweeds to act against colorectal and breast cancers, this review highlights the potential use of seaweeds as anticancer agents. PMID:25255129

Moussavou, Ghislain; Kwak, Dong Hoon; Obiang-Obonou, Brice Wilfried; Ogandaga Maranguy, Cyr Abel; Dinzouna-Boutamba, Sylvatrie-Danne; Lee, Dae Hoon; Manvoudou Pissibanganga, Ordelia Gwenaelle; Ko, Kisung; Seo, Jae In; Choo, Young Kug



In vitro anticancer potential of tree extracts from the Walloon Region forest.  


Forty-eight extracts from 16 common Belgian trees from the Walloon Region forest were evaluated for in vitro growth inhibitory activity against the human LoVo colon cancer, PC3 prostate cancer, and U373 glioblastoma cell lines. Our study was performed with the aim of selecting plant candidates in order to later isolate new anticancer compounds from an easily affordable tree material. Extracts from Alnus glutinosa (stem bark), Carpinus betulus (leaves and stem bark), Castanea sativa (stem bark), Fagus sylvatica (leaves), Ilex aquifolium (leaves), Larix decidua (leaves), Quercus petraea (stem bark), and Quercus robur (leaves) showed for the first time potent in vitro growth inhibitory activity and could become easily affordable sources of potential new anticancer agents. Root extracts from Robinia pseudoacacia, already known for containing cytotoxic lectins, also showed interesting activity. PMID:19579185

Frédérich, Michel; Marcowycz, Aline; Cieckiewicz, Ewa; Mégalizzi, Véronique; Angenot, Luc; Kiss, Robert



A review of the anticancer and immunomodulatory effects of Lycium barbarum fruit.  


The anticancer effects of traditional Chinese medicine (TCM) have attracted the attention of the public vis-à-vis existing cancer therapies with various side effects. Lycium barbarum fruit, commonly known as Gou Qi Zi in China, is a potential anticancer agent/adjuvant. Its major active ingredients, L. barbarum polysaccharides (LBP), scopoletin and 2-O-?-D-glucopyranosyl-L-ascorbic acid (AA-2?G), are found to have apoptotic and antiproliferative effects on cancer cell lines. Moreover, LBP also contributes to body's immunomodulatory effects and enhances effects of other cancer therapies. It is not known whether there are any undesirable effects. Further studies on its pharmacological mechanisms and toxicology could facilitate a safe usage of this TCM herb. PMID:22189914

Tang, Wai-Man; Chan, Enoch; Kwok, Ching-Yee; Lee, Yee-Ki; Wu, Jian-Hong; Wan, Chun-Wai; Chan, Robbie Yat-Kan; Yu, Peter Hoi-Fu; Chan, Shun-Wan



FDG-PET imaging for the evaluation of antiglioma agents in a rat model  

Microsoft Academic Search

The increasing development of novel anticancer agents demands parallel advances in the methods used to rap- idly assess their therapeutic efficacy (TE) in the preclini - cal phase. We evaluated the ability of small-animal PET, using the 18F-fluoro-deoxy-D-glucose (FDG) radiotracer, to predict the TE of a number of anticancer agents in the rat C6 glioma model following 3 days of

Sarah Assadian; Antonio Aliaga; Rolando F. Del Maestro; Alan C. Evans; Barry J. Bedell


Flavonoids: A versatile source of anticancer drugs  

PubMed Central

An exponential increase in the number of studies investigating how different components of the diet interact at the molecular and cellular level to determine the fate of a cell has been witnessed. In search for anticancer drugs compelling data from laboratories, epidemiologic investigations, and human clinical trials showed that flavonoids have important effects on cancer chemoprevention and chemotherapy. In many molecular mechanisms of action for prevention against cancer, flavonoids play a major role by interacting between different types of genes and enzymes. Many mechanisms of action have been identified, including carcinogen inactivation, antiproliferation, cell cycle arrest, induction of apoptosis, inhibition of angiogenesis, antioxidation, and reversal of multidrug resistance or a combination of these mechanisms. This review focuses on the anticancer activity of flavonoids as well as their molecular mechanisms, including the treatment of mammary and prostate cancer. This review also highlights some advanced derivatives of flavonoids, which play an important role against cancer. PMID:22096313

Chahar, Maheep K.; Sharma, Neelu; Dobhal, Mahabeer P.; Joshi, Yogesh C.



[Introduction of a new anticancer drug, novantrone].  


Novantrone (mitoxantrone) is a novel anticancer drug, having an anthraquinone structure. This compound was selected from many candidate compounds for purpose to find out a drug having lesser cardiac toxicity than doxorubicin and excellent antitumor activities. In the Japanese clinical trials, Novantrone was proved to be active against breast cancer, malignant lymphoma and acute leukemia. Major side effects observed in the clinical trials were: GI-tract toxicities, and mild alopecia, mild disturbance in the circulatory organs, fever and dermatological toxicities. PMID:3314715

Tsukagoshi, S



Anticancer Drugs from Marine Flora: An Overview  

PubMed Central

Marine floras, such as bacteria, actinobacteria, cyanobacteria, fungi, microalgae, seaweeds, mangroves, and other halophytes are extremely important oceanic resources, constituting over 90% of the oceanic biomass. They are taxonomically diverse, largely productive, biologically active, and chemically unique offering a great scope for discovery of new anticancer drugs. The marine floras are rich in medicinally potent chemicals predominantly belonging to polyphenols and sulphated polysaccharides. The chemicals have displayed an array of pharmacological properties especially antioxidant, immunostimulatory, and antitumour activities. The phytochemicals possibly activate macrophages, induce apoptosis, and prevent oxidative damage of DNA, thereby controlling carcinogenesis. In spite of vast resources enriched with chemicals, the marine floras are largely unexplored for anticancer lead compounds. Hence, this paper reviews the works so far conducted on this aspect with a view to provide a baseline information for promoting the marine flora-based anticancer research in the present context of increasing cancer incidence, deprived of the cheaper, safer, and potent medicines to challenge the dreadful human disease. PMID:21461373

Sithranga Boopathy, N.; Kathiresan, K.



Anticancer and immunostimulatory compounds from Andrographis paniculata.  


Andrographis paniculata extract is traditionally used as a medicine to treat different diseases in India, China and Southeast Asia. In the present study, we evaluated the anticancer and immunomodulatory activity of the methanolic extract of Andrographis paniculata in human cancer and immune cells. The methanolic extract of Andrographis paniculata was fractionated into dichloromethane, petroleum ether and aqueous extracts and screened for bioactivity. Our results indicate that the dichloromethane fraction of the methanolic extract retains the active compounds contributing for both the anticancer and immunostimulatory activity. Dichloromethane fraction significantly inhibits the proliferation of HT-29 (colon cancer) cells and augments the proliferation human peripheral blood lymphocytes (HPBLs) at low concentrations. On further fractionation of the dichloromethane extract we could isolate three diterpene compounds, i.e. [1] andrographolide, [2] 14-deoxyandrographolide and [3] 14-deoxy-11,12-didehydroandrographolide. Andrographolide showed anticancer activity on diverse cancer cells representing different types of human cancers. Whereas all the three molecules showed enhanced proliferation and interleukin-2 (IL-2) induction in HPBLs. PMID:15138014

Kumar, R Ajaya; Sridevi, K; Kumar, N Vijaya; Nanduri, S; Rajagopal, S



A new concentrated perfluorochemical emulsion and carbogen breathing as an adjuvant to treatment with antitumor alkylating agents  

Microsoft Academic Search

Summary Many anticancer drugs require oxygen to be cytotoxic or are selectively cytotoxic toward cells under oxygenated conditions. The effects of the dilute perfluorochemical emuolsion Fluosol with a wide variety of chemotherapeutic agents have been explored; however, it has not been possbile to determine the optimal level of circulating perfluorochemical emulsion with anticancer drugs because the volume of Fluosol that

Beverly A. Teicher; Sylvia A. Holden; Gulshan Ara; Chul Soo Ha; Terence S. Herman; David Northey



A Novel Anticancer Agent, 8-Methoxypyrimido[4?,5?:4,5]thieno(2,3-b) Quinoline-4(3H)-One Induces Neuro 2a Neuroblastoma Cell Death through p53-Dependent, Caspase-Dependent and -Independent Apoptotic Pathways  

PubMed Central

Neuroblastoma is the most common cancer in infants and fourth most common cancer in children. Despite recent advances in cancer treatments, the prognosis of stage-IV neuroblastoma patients continues to be dismal which warrant new pharmacotherapy. A novel tetracyclic condensed quinoline compound, 8-methoxypyrimido [4?,5?:4,5]thieno(2,3-b) quinoline-4(3H)-one (MPTQ) is a structural analogue of an anticancer drug ellipticine and has been reported to posses anticancer property. Study on MPTQ on neuroblastoma cells is very limited and mechanisms related to its cytotoxicity on neuroblastoma cells are completely unknown. Here, we evaluated the anticancer property of MPTQ on mouse neuro 2a and human SH-SY5Y neuroblastoma cells and investigated the mechanisms underlying MPTQ-mediated neuro 2a cell death. MPTQ-mediated neuro 2a and SH-SY5Y cell deaths were found to be dose and time dependent. Moreover, MPTQ induced cell death reached approximately 99.8% and 90% in neuro 2a and SH-SY5Y cells respectively. Nuclear oligonucleosomal DNA fragmentation and Terminal dUTP Nick End Labelling assays indicated MPTQ-mediated neuro 2a cell death involved apoptosis. MPTQ-mediated apoptosis is associated with increased phosphorylation of p53 at Ser15 and Ser20 which correlates with the hyperphosphorylation of Ataxia-Telangiectasia mutated protein (ATM). Immunocytochemical analysis demonstrated the increased level of Bax protein in MPTQ treated neuro 2a cells. MPTQ-mediated apoptosis is also associated with increased activation of caspase-9, -3 and -7 but not caspase-2 and -8. Furthermore, increased level of caspase-3 and cleaved Poly (ADP Ribose) polymerase were observed in the nucleus of MPTQ treated neuro 2a cells, suggesting the involvement of caspase-dependent intrinsic but not extrinsic apoptotic pathway. Increased nuclear translocation of apoptosis inducing factor suggests additional involvement of caspase-independent apoptosis pathway in MPTQ treated neuro 2a cells. Collectively, MPTQ-induced neuro 2a cell death is mediated by ATM and p53 activation, and Bax-mediated activation of caspase-dependent and caspase-independent mitochondrial apoptosis pathways. PMID:23824039

Sahu, Upasana; Sidhar, Himakshi; Ghate, Pankaj S.; Advirao, Gopal M.; Raghavan, Sathees C.; Giri, Ranjit K.



Design, synthesis and evaluation of novel 2-thiophen-5-yl-3H-quinazolin-4-one analogues as inhibitors of transcription factors NF-kappaB and AP-1 mediated transcriptional activation: Their possible utilization as anti-inflammatory and anti-cancer agents.  


In an attempt to discover novel inhibitors of NF-kappaB and AP-1 mediated transcriptional activation utilizing the concept of chemical lead based medicinal chemistry and bioisosterism a series of 2-(2,3-disubstituted-thiophen-5-yl)-3H-quinazolin-4-one analogs was designed. A facile and simple route for the synthesis of the designed molecules was developed. Synthesized molecules were evaluated for their activity as inhibitors towards NF-kappaB and AP-1 mediated transcriptional activation in a cell line report-based assay. This series provides us with a substantial number of compounds inhibiting the activity of NF-kappaB and/or AP-1 mediated transcriptional activation. These compounds also exhibit anti-inflammatory and anti-cancer activity in in vivo models of inflammation and cancer. The 4-pyridyl group is found to be the most important pharmacophore on the third position of thiophene ring for inhibiting NF-kappaB and AP-1 mediated transcriptional activation. The relationships between the activities shown by these compounds in the in vivo and in vitro models have been established by using FVB transgenic mice model. These results suggest the suitability of the designed molecular framework as a potential scaffold for the design of molecules with inhibitory activity towards NF-kappaB and AP-1 mediated transcriptional activation, which may also exhibit anti-inflammatory and anti-cancer activity. This series of molecules warrants further study to explore their potential as therapies for use in chronic inflammatory conditions and cancer. Development of the synthetic protocol for the synthesis of this series of molecules, biological activities and a structure-activity relationship (SAR) have been discussed herein. PMID:20335039

Giri, Rajan S; Thaker, Hardik M; Giordano, Tony; Williams, Jill; Rogers, Donna; Vasu, Kamala K; Sudarsanam, Vasudevan



Oral anticancer drugs: how limited dosing options and dose reductions may affect outcomes in comparative trials and efficacy in patients.  


Historically, cancer medicine has avoided the problem of unequal dosing by comparing maximum-tolerated doses of intravenous regimens with proportionate dose reductions for toxicity. However, in recent years, with the development of numerous oral anticancer agents, dosing options are arbitrarily and increasingly limited by the size of pills. We contend that an underappreciated consequence of pill size is unequal dosing in comparative clinical trials and that this can have an impact on outcomes. We discuss how comparative effectiveness trials can be unbalanced and how the use of doses that are not sustainable might affect outcomes, especially marginal ones. We further argue that because of their poor tolerability and their limited dosing options, which often result in large dose adjustments in response to toxicity, the real-world clinical effectiveness of oral anticancer agents may be diminished and may not emulate results achieved in registration trials. PMID:24711558

Prasad, Vinay; Massey, Paul R; Fojo, Tito



New microtubular agents in pediatric oncology.  


The taxanes are a new group of anticancer agents with a novel mechanism of action. They promote microtubule assembly and stabilize the microtubules. Paclitaxel (Taxol), the first agent in this group in clinical trials was isolated from the Pacific yew, Taxus brevifolia in 1971. Both in preclinical and clinical studies, paclitaxel and its semisynthetic analog docetaxel exhibit significant antitumor activity. This review will provide an overview of the clinical experience with the group of anti-microtubular agents, the taxanes in pediatric oncology. PMID:8880393

Seibel, N L; Reaman, G H



Thioredoxin reductase is inhibited by the carbamoylating activity of the anticancer sulfonylhydrazine drug Laromustine  

PubMed Central

The thioredoxin system facilitates proliferative processes in cells and is upregulated in many cancers. The activities of both thioredoxin (Trx) and its reductase (TrxR) are mediated by oxidation/reduction reactions among cysteine residues. A common target in preclinical anticancer research, TrxR is reported here to be significantly inhibited by the anticancer agent Laromustine. This agent, which has been in clinical trials for acute myelogenous leukemia and glioblastoma multiforme, is understood to be cytotoxic principally via interstrand DNA crosslinking that originates from a 2-chloroethylating species generated upon activation in situ. The spontaneous decomposition of Laromustine also yields methyl isocyanate, which readily carbamoylates thiols and primary amines. Purified rat liver TrxR was inhibited by Laromustine with a clinically relevant IC50value of 4.65 µM. A derivative of Laromustine that lacks carbamoylating activity did not appreciably inhibit TrxR while another derivative, lacking only the 2-chloroethylating activity, retained its inhibitory potency. Furthermore, in assays measuring TrxR activity in murine cell lysates, a similar pattern of inhibition among these compounds was observed. These data contrast with previous studies demonstrating that glutathione reductase, another enzyme that relies on cysteine-mediated redox chemistry, was not inhibited by methylcarbamoylating agents when measured in cell lysates. Mass spectrometry of Laromustine-treated enzyme revealed significant carbamoylation of TrxR, albeit not on known catalytically active residues. However, there was no evidence of 2-chloroethylation anywhere on the protein. The inhibition of TrxR is likely to contribute to the cytotoxic, anticancer mechanism of action for Laromustine. PMID:22864532

Rice, Kevin P.; Klinkerch, Edmund J.; Gerber, Scott A.; Schleicher, Tyler R.; Kraus, Tara J.; Buros, Christopher M.



Development of new estradiol-cationic lipid hybrids: Ten-carbon twin chain cationic lipid is a more suitable partner for estradiol to elicit better anticancer activity.  


The present study illustrates the synthesis and anticancer evaluation of six, ten, twelve and fourteen carbon chain containing cationic lipidated-estradiol hybrids. Previously, we have established the lipidation strategy to introduce anticancer activities in various pharmacophores including estradiol (ES). In this structure activity study the length of the carbon chain is narrowed down between C6-C14 to screen out the most potent anticancer molecule among the class. Among the newly developed ES-cationic lipid conjugates, ten-carbon chain containing derivative, ES-C10 (5c) exhibited 4-12 folds better anticancer activity than the previously established derivative, ES-C8 (5b) in various cancer cells of different origin. Moreover cytotoxicity of this molecule was not observed in non-cancer cells. Notably, in spite of bearing estrogenic moiety, ES-C10 exhibited anticancer activity irrespective of estrogen receptor (ER) expression status. ES-C10 exhibited prominent sub-G0 arrest of cancer cells with concomitant induction of apoptosis and demonstrated significant inhibition of tumor growth in mouse melanoma model. Collectively, ES-C10 exemplifies the development of an anticancer agent with broader activity against cancer cells of different origins. PMID:25222876

Sudhakar, Godeshala; Bathula, Surendar Reddy; Banerjee, Rajkumar



[Oral toxicity of targeted anticancer therapies].  


While toxicity of targeted anticancer therapies on the oral mucosa seems relatively frequent in clinical practice, it has not been properly characterized to date, apart from aphthous-like lesions due to mTOR inhibitors. Herein, we report the main oral lesions associated with these new therapies, with a description of the most frequent but also the most characteristic clinical manifestations of these drugs, such as anti-EGFR-induced mucositis, BRAF-inhibitor-associated hyperkeratosis, benign migratory glossitis and osteonecrosis of the jaw observed with angiogenesis inhibitors, as well as lesions more specifically linked with imatinib. PMID:24835648

Sibaud, V; Boralevi, F; Vigarios, E; Fricain, J-C



Progress on understanding the anticancer mechanisms of medicinal mushroom: inonotus obliquus.  


Cancer is a leading cause of death worldwide. Recently, the demand for more effective and safer therapeutic agents for the chemoprevention of human cancer has increased. As a white rot fungus, Inonotus obliquus is valued as an edible and medicinal resource. Chemical investigations have shown that I. obliquus produces a diverse range of secondary metabolites, including phenolic compounds, melanins, and lanostane-type triterpenoids. Among these are active components for antioxidant, antitumoral, and antiviral activities and for improving human immunity against infection of pathogenic microbes. Importantly, their anticancer activities have become a hot recently, but with relatively little knowledge of their modes of action. Some compounds extracted from I. obliquus arrest cancer cells in the G0/G1 phase and then induce cell apoptosis or differentiation, whereas some examples directly participate in the cell apoptosis pathway. In other cases, polysaccharides from I. obliquus can indirectly be involved in anticancer processes mainly via stimulating the immune system. Furthermore, the antioxidative ability of I. obliquus extracts can prevent generation of cancer cells. In this review, we highlight recent findings regarding mechanisms underlying the anticancer influence of I. obliquus, to provide a comprehensive landscape view of the actions of this mushroom in preventing cancer. PMID:23679238

Song, Fu-Qiang; Liu, Ying; Kong, Xiang-Shi; Chang, Wei; Song, Ge



Glioblastoma-specific anticancer activity of pheophorbide a from the edible red seaweed Grateloupia elliptica.  


The chlorophyll-related compound pheophorbide a (Pa) was successively purified from an edible red seaweed, Grateloupia elliptica, using silica, octadecyl silica column chromatography and reversed phase-high-performance liquid chromatography, as well as the cell cycle inhibitory and apoptotic effects of Pa being investigated in U87MG glioblastoma cells. The Pa exhibited strong anticancer effects in the absence of direct photo-irradiation against various cancer cell lines, including U87MG, SK-OV-3, and HeLa cells. Among the cancer cells, the strongest anticancer activity of Pa exhibited on U87MG cells with IC50 values of 2.8 ?g/ml. In addition, Pa specifically had cytostatic activity on glioblastoma cells rather than human umbilical vein endothelial cells. Analysis of the cell cycle distribution showed that Pa induced G0/G1 arrest of U87 MG cells. In addition, arrested cells induced late apoptosis and DNA degradation under dark condition. These results suggest that Pa isolated from G. elliptica is a potential glioblastoma-specific anticancer agent without side effects on normal cells. PMID:24296458

Cho, Myounglae; Park, Gab-Man; Kim, Su-Nam; Amna, Touseef; Lee, Seokjoon; Shin, Woon-Seob



Identification of mitochondria-targeting anticancer compounds by an in vitro strategy.  


Mitochondria play a pivotal role in determining the point-of-no-return of the apoptotic process. Therefore, anticancer drugs that directly target mitochondria hold great potential to evade resistance mechanisms that have developed toward conventional chemotherapeutics. In this study, we report the development of an in vitro strategy to quickly identify the therapeutic agents that induce apoptosis via directly affecting mitochondria. This result is achieved by treating isolated mitochondria with potential anticancer compounds, followed by simultaneously measuring the side scatter and mitochondrial membrane potential (??(m)) fluorescence of individual mitochondria using a laboratory-built high-sensitivity flow cytometer. The feasibility of this method was tested with eight widely used anticarcinogens. Dose-dependent ??(m) losses were observed for paclitaxel, antimycin A, betulinic acid, curcumin, ABT-737, and triptolide, but not for cisplatin or actinomycin D, which agrees well with their mechanisms of apoptosis induction reported in the literature. The as-developed method offers an effective approach to identify mitochondria-targeting anticancer compounds. PMID:24823627

Zhang, Xiang; Zhang, Shuyue; Zhu, Shaobin; Chen, Sha; Han, Jinyan; Gao, Kaimin; Zeng, Jin-zhang; Yan, Xiaomei



Bis-demethoxy curcumin analog nanoparticles: synthesis, characterization, and anticancer activity in vitro.  


We have optimized a protocol for the preparation of bisdemethoxy curcumin analog nanoparticles (BDMCA-NP) by the solvent assisted process. The structural similarities between bulk and nano BDMCA were determined by Co-TLC, NMR and F-TIR. This shows that our synthesis protocol enhanced the dispersibility and reduce the size of BDMCA without altering the integrity of functional moieties and structure, which is crucial for anticancer and antioxidant activities. The morphology and size of BDMCA-NP as determined by SEM, HRTEM and DLS was found to be around 80 nm. BDMCA-NP treated breast cancer cell lines (MCF 7) showed cell death as characterized by MTT assay. Flow cytometric analysis of BDMCA-NP treated MCF 7 cell lines showed an increase of cell count in G2/M phase indicates the cell cycle arrest. Western blot analysis revealed the presence of caspase 3, caspase 9, cleaved fragments of PARP and Bax proteins in the BDMCA-NP treated MCF 7 cell lines, but not in untreated cell lines. To recap, we have prepared BDMCA-NP by solvent assisted process, which exerted anticancer activity against breast cancer cells, which may be due to (i) enhanced dispersibility and surface: volume ratio, (ii) apoptosis (iii) mitochondrial pathway induced cell death, (iv) G2/M phase cell cycle arrest and (v) disassembly of mitotic spindle of the cancer cells. Thus, nano BDMCA can be used as a potent anticancer agent. PMID:24757955

Francis, Arul Prakash; Murthy, Prakhya Balakishna; Devas, Thiyagarajan



Applications of fluorescence spectroscopy and dynamic light scattering in biotechnology of camptothecins: promising anticancer drugs  

NASA Astrophysics Data System (ADS)

Methods of optical measurements are widely used in biomedical research. Applications of these methods in determining of properties of camptothecins -- S-phase anticancer agents are described in this paper. Under physiological conditions CPT hydrolyses, and converts into inactive carboxylate form. Decrease of active form of CPT occurs especially fast in plasma of human blood. One of camptothecin analogues -- DB-67, exhibits, in contrary to CPT, relatively high stability in human blood. Fluorescence spectroscopy methods were used to determine physical and to predict biological properties of camptothecins, including DB-67. The dynamic light scattering (DLS) methods were applied to control the sizes of liposomes used as DB-67 delivery system.

Kruszewski, Stefan; Burke, Thomas G.



Impedimetric detection of in situ interaction between anti-cancer drug bleomycin and DNA.  


Surface confined interaction of anti-cancer drug bleomycin (BLM) with nucleic acids: single stranded and double stranded DNA was investigated herein by using electrochemical impedance spectroscopy (EIS) technique in combination with a graphite sensor technology. The experimental conditions were optimized: such as, dsDNA concentration, BLM concentration and interaction time. The main features of impedimetric DNA biosensor, such as its detection limit and the repeatability, were also discussed. The in situ interaction of BLM with dsDNA was also tested impedimetrically in the absence or presence of other chemotherapeutic agents, such as mitomycin C (MC) and cis-platin (cis-DDP) for testing the selectivity. PMID:23892034

Erdem, Arzum; Congur, Gulsah



Study on slow release anti-cancer drugs prepared by radiation induced polymerization  

NASA Astrophysics Data System (ADS)

This paper reports the research results which the anticancer drugs Ara-C with controlled slow release were made by radiation induced polymerization of monomers such as methacrylates at room temperature. Our studies showed that not only hydrophilic synthetic polymers but also hydrophobic polymers such as hydrophobic methacrylates (including MMA, EMA, and BMA) could be used to the immobilization. In vitro the rate of drugs release was controlled by the many factors such as the content of drugs, the monomer material, the crosslinking agent, the irradiation dose and the water content, etc.

Huaijiang, Xie; Juzhong, Song; Tao, Peng



Synthesis and anticancer activity of 2-benzylidene indanones through inhibiting tubulin polymerization.  


In an attempt to discover a potent and selective anticancer agent, gallic acid has been modified to benzylidene indanones as tubulin polymerization inhibitors. These compounds were evaluated against several human cancer cell lines and also evaluated for inhibition of tubulin polymerase in in vitro assays. Three of the analogues exhibited strong cytotoxicity against human cancer cell lines IC(50)=10-880 nM and also showed tubulin polymerization inhibition (IC(50)=0.62-2.04 ?M). Compound 9j, the best candidate of the series was found to be non-toxic in acute oral toxicity in Swiss-albino mice up to 1000 mg/kg dose. PMID:22472045

Prakasham, A P; Saxena, A K; Luqman, Suaib; Chanda, Debabrata; Kaur, Tandeep; Gupta, Atul; Yadav, D K; Chanotiya, C S; Shanker, Karuna; Khan, F; Negi, Arvind S



Pharmacokinetics of peptide mediated delivery of anticancer drug ellipticine.  


The amino acid pairing peptide EAK16-II (EAK) has shown the ability to stabilize the hydrophobic anticancer agent ellipticine (EPT) in aqueous solution. In this study, we investigate pharmacokinetics of the formulation of EAK-EPT complexes in vivo. The developed formulation can achieve a sufficiently high drug concentration required in vivo animal models. The nanostructure and surface properties of EAK-EPT complexes or nanoparticle were characterized by transmission electron microscopy (TEM) and zeta potential measurements, respectively. 12 healthy male SD rats were divided into EPT group and EAK-EPT group randomly. Rats in EPT group were tail intravenously injected with the EPT (20 mg/kg); rats in EAK-EPT group were injected with EAK-EPT complexes (EPT's concentration is 20 mg/kg). EPT was extracted from rat plasma with dexamethasone sodium phosphate as internal standards (IS). The pharmacokinetic parameters were obtained using high pressure liquid chromatography (HPLC). Significant differences in main pharmacokinetic parameters between EPT and EAK-EPT complexes were observed, demonstrating that the complexation with EAK prolongs the residence time of the drug and enlarges the area under the concentration-time curve (AUC). This means that EAK can serve as a suitable carrier to increase the bioavailability of EPT. PMID:22952737

Ma, Weina; Lu, Sheng; Pan, Pei; Sadatmousavi, Parisa; Yuan, Yongfang; Chen, P



Synthesis and Anticancer Properties of Water-Soluble Zinc Ionophores  

PubMed Central

Several water-solubilized versions of the zinc ionophore 1-hydroxypyridine-2-thione (ZnHPT), synthesized as part of the present study, have been found both to increase the intracellular concentrations of free zinc and to produce an antiproliferative activity in exponential phase A549 human lung cancer cultures. Gene expression profiles of A549 cultures treated with one of these water-soluble zinc ionophores, PCI-5002, reveal the activation of stress response pathways under the control of metal-responsive transcription factor 1 (MTF-1), hypoxia-inducible transcription factor 1 (HIF-1), and heat shock transcription factors. Additional oxidative stress response and apoptotic pathways were activated in cultures grown in zinc-supplemented media. We also show that these water-soluble zinc ionophores can be given to mice at 100 ?mol/kg (300 ?mol/m2) with no observable toxicity and inhibit the growth of A549 lung and PC3 prostate cancer cells grown in xenograft models. Gene expression profiles of tumor specimens harvested from mice 4 h after treatment confirmed the in vivo activation of MTF-1–responsive genes. Overall, we propose that water-solubilized zinc ionophores represent a potential new class of anticancer agents. PMID:18593933

Magda, Darren; Lecane, Philip; Wang, Zhong; Hu, Weilin; Thiemann, Patricia; Ma, Xuan; Dranchak, Patricia K.; Wang, Xiaoming; Lynch, Vincent; Wei, Wenhao; Csokai, Viktor; Hacia, Joseph G.; Sessler, Jonathan L.



Biogenic gold nano-triangles: Cargos for anticancer drug delivery.  


We present synthesis of biogenic gold nano triangles (GNTs) using Azadirachta indica leaf extract at inherent pH (5.89) and its application in efficient drug delivery of doxorubicin (DOX) (anticancer drug). The main idea was to take advantage of large surface area of GNTs which has 3 dimensions and use the plant peptides coated on these triangles as natural linkers for the attachment of DOX. Sucrose density gradient centrifugation (SDGC) and dialysis methods were used for separation of the GNT from mixture of GNPs. Flocculation parameter (FP) was used to check stability of GNT which was found to be exceptionally high (0-0.75) due to the biological capping agents. DOX attachment to GNT was verified using Fourier transformed infra-red (FTIR) spectroscopy. The complex thus formed was found to be less toxic to normal cells (MDCK cells) and significantly toxic for the cancerous cells (HeLa cells). Drug loading efficiency was found to be 99.81% and DOX release followed first order release kinetics. Percentage drug release was found to be more than 4.5% in both acidic (5.8) as well as physiological pH (7.2) which is suitable for tumor targeting. PMID:25280684

Dharmatti, Roopa; Phadke, Chinmay; Mewada, Ashmi; Thakur, Mukeshchand; Pandey, Sunil; Sharon, Madhuri



Optical Interferometric Response of Living Tissue to Cytoskeletal Anticancer Drugs  

NASA Astrophysics Data System (ADS)

Living tissue illuminated by short-coherence light can be optically sectioned in three dimensions using coherent detection such as interferometry. We have developed full-field coherence-gated imaging of tissue using digital holography. Two-dimensional image sections from a fixed depth are recorded as interference fringes with a CCD camera located at the optical Fourier plane. Fast Fourier transform of the digital hologram yields the depth-selected image. When the tissue is living, highly dynamic speckle is observed as fluctuating pixel intensities. The temporal autocorrelation functions are directly related to the degree of motility at depth. We have applied the cytoskeletal drugs nocodazole and colchicine to osteogenic sarcoma multicellular spheroids and observed the response holographically. Colchicine is an anticancer drug that inhibits microtubule polymerization and hence prevents spindle formation during mitosis. Nocodazole, on the other hand, depolymerizes microtubules. Both drugs preferentially inhibit rapidly-dividing cancer cells. We observe dose-response using motility as an effective contrast agent. This work opens the possibility for studies of three-dimensional motility as a multiplexed assay for drug discovery.

Nolte, David; Jeong, Kwan; Turek, John



Combinatorial Effects of Thymoquinone on the Anticancer Activity and Hepatotoxicity of the Prodrug CB 1954  

PubMed Central

Background: One of the major causes of clinical trial termination is the liver toxicity induced by chemotherapeutic agents. Treatment with anticancer drugs like CB 1954 (5-(Aziridin-1-yl)-2,4-dinitrobenzamide) is associated with significant hepatotoxicity. Thymoquinone (TQ), extracted from Nigella sativa, is reported to possess anticancer and hepatoprotective effects. The aims of the present study were to use TQ to reduce hepatotoxicity associated with CB 1954 and to augment its anticancer activity against the resistant mouse mammary gland cell line (66 cl-4-GFP). Method: Balb/C mice were transplanted with the 66cl-4-GFP cell line and in vivo antitumor activity was assessed for CB 1954 (141 mg/kg), TQ (10 mg/kg), and a combination of CB 1954 and TQ. Changes in tumor size and body weight were measured for each treatment. Histological examination of tumors and liver tissue samples was performed using the standard hematoxylin/eosin staining protocol, and serum levels of the liver enzymes AST and ALT were used as biomarkers of hepatotoxicity. Results: Severe liver damage and elevated plasma levels of AST and ALT were observed in the group treated with CB 1954. Treatment of tumor-bearing mice with a combination of CB 1954 and TQ caused a significant regression in tumor size and induced extensive necrosis in these tumors. The combination also protected the liver from drug-induced damage and reduced the plasma levels of AST and ALT to their normal ranges. Conclusion: These results suggest that the use of TQ with CB 1954 can reduce CB 1954-induced hepatotoxicity and enhance its anticancer activity, indicating the potential use of this combination in clinical studies. PMID:23833717

Talib, Wamidh H.; AbuKhader, Majed M.



Potential anticancer activity of carvone in N2a neuroblastoma cell line.  


Carvone (CVN) is a monocyclic monoterpene found in the essential oils of Mentha spicata var. crispa (Lamiaceae) and Carum carvi L. (Apiaceae) plants and has been reported to have antioxidant, antimicrobial, anticonvulsant, and antitumor activities. The beneficial health properties of CVN have encouraged us to look into its anticancer activity. To the best of our knowledge, reports are not available on the anticancer activity of CVN in cultured primary rat neuron and N2a neuroblastoma (NB) cells. Therefore, the present study is an attempt toward exploring the potential anticancer activity of CVN, if any, in cultured primary rat neuron and N2a NB cells. Our results indicated that CVN (only at 25 mg/L) treatment led to an increase in the total antioxidant capacity levels in cultured primary rat neuron cells compared with control cells. Also, CVN (at concentrations higher than 100 mg/L) treatment led to an increase in the total oxidative stress levels in both cell types. The mean values of the total scores of cells showing DNA damage (for comet assay) were not found to be significantly different from the control values in both cells (p > 0.05). On the other hand, after 24 h treatment with CVN, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay showed that CVN application significantly reduced the cell viability rates in both cell types at concentrations higher than 100 mg/L. Summarizing, our data suggest that CVN represents little potential for promising anticancer agent to improve brain tumors therapy. PMID:23552268

Aydin, Elanur; Türkez, Hasan; Keles, Mevlüt Sait



Molecular dynamics simulation studies for DNA sequence recognition by reactive metabolites of anticancer compounds.  


The discovery of novel anticancer molecules 5F-203 (NSC703786) and 5-aminoflavone (5-AMF, NSC686288) has addressed the issues of toxicity and reduced efficacy by targeting over expressed Cytochrome P450 1A1 (CYP1A1) in cancer cells. CYP1A1 metabolizes these compounds into their reactive metabolites, which are proven to mediate their anticancer effect through DNA adduct formation. However, the drug metabolite-DNA binding has not been explored so far. Hence, understanding the binding characteristics and molecular recognition for drug metabolites with DNA is of practical and fundamental interest. The present study is aimed to model binding preference shown by reactive metabolites of 5F-203 and 5-AMF with DNA in forming DNA adducts. To perform this, three different DNA crystal structures covering sequence diversity were selected, and 12 DNA-reactive metabolite complexes were generated. Molecular dynamics simulations for all complexes were performed using AMBER 11 software after development of protocol for DNA-reactive metabolite system. Furthermore, the MM-PBSA/GBSA energy calculation, per-nucleotide energy decomposition, and Molecular Electrostatic Surface Potential analysis were performed. The results obtained from present study clearly indicate that minor groove in DNA is preferable for binding of reactive metabolites of anticancer compounds. The binding preferences shown by reactive metabolites were also governed by specific nucleotide sequence and distribution of electrostatic charges in major and minor groove of DNA structure. Overall, our study provides useful insights into the initial step of mechanism of reactive metabolite binding to the DNA and the guidelines for designing of sequence specific DNA interacting anticancer agents. PMID:24446378

Tumbi, Khaled M; Nandekar, Prajwal P; Shaikh, Naeem; Kesharwani, Siddharth S; Sangamwar, Abhay T



[Serotonin and anticancer drug-induced emesis].  


Cytotoxic drug-induced nausea and vomiting are the side effects most feared by cancer patients. Emesis is an instinctive defense reaction caused by the somato-autonomic nerve reflex, which is integrated in the medulla oblongata. Emesis caused by anticancer drugs is associated with an increase in the concentration of serotonin (5-HT) (5-HT) in the intestinal mucosa and brainstem. 5-HT released from the enterochromaffin (EC) cells, which synthesize and secrete 5-HT, stimulates the 5-HT receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex. 5-HT released from EC cells appears to mediate the cisplatin-induced emesis sensitive to 5-HT(3) receptor antagonists. The precise role of 5-HT in the occurrence of vomiting has not been fully elucidated. The present review describes the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release and afferent vagal nerve activity. Various models and methods for predicting emesis are also evaluated. PMID:15297719

Minami, Masaru; Endo, Toru; Hamaue, Naoya; Hirafuji, Masahiko



Investigating the optimal size of anticancer nanomedicine.  


Nanomedicines (NMs) offer new solutions for cancer diagnosis and therapy. However, extension of progression-free interval and overall survival time achieved by Food and Drug Administration-approved NMs remain modest. To develop next generation NMs to achieve superior anticancer activities, it is crucial to investigate and understand the correlation between the physicochemical properties of NMs (particle size in particular) and their interactions with biological systems to establish criteria for NM optimization. Here, we systematically evaluated the size-dependent biological profiles of three monodisperse drug-silica nanoconjugates (NCs; 20, 50, and 200 nm) through both experiments and mathematical modeling and aimed to identify the optimal size for the most effective anticancer drug delivery. Among the three NCs investigated, the 50-nm NC shows the highest tumor tissue retention integrated over time, which is the collective outcome of deep tumor tissue penetration and efficient cancer cell internalization as well as slow tumor clearance, and thus, the highest efficacy against both primary and metastatic tumors in vivo. PMID:25316794

Tang, Li; Yang, Xujuan; Yin, Qian; Cai, Kaimin; Wang, Hua; Chaudhury, Isthier; Yao, Catherine; Zhou, Qin; Kwon, Mincheol; Hartman, James A; Dobrucki, Iwona T; Dobrucki, Lawrence W; Borst, Luke B; Lezmi, Stéphane; Helferich, William G; Ferguson, Andrew L; Fan, Timothy M; Cheng, Jianjun



Synthesis of (-)-arctigenin derivatives and their anticancer activity.  


The natural dibenzylbutyrolactone type lignanolide (-)-arctigenin, which was prepared from fructus arctii, showed obvious anticancer activity. The synthesis of four new (-)-arctigenin derivatives and their anticancer bioactivities were examined. The structures of the four new synthetic derivatives were elucidated. PMID:21867457

Gui-Rong, Chen; Li-Ping, Cai; De-Qiang, Dou; Ting-Guo, Kang; Hong-Fu, Li; Fu-Rui, Li; Ning, Jiang



Sensitive Agent: Sensitive Agent  

E-print Network

social interaction must be simulated. Conventional agents already have rich communication skills including nonverbal communication; however, lack the sensitivity that is necessary for social interaction-78. [13] MIT, Affective Computing, [14] Helmut Prendinger

Nakanishi, Hideyuki


Inhibition of the tumour necrosis factor-alpha autocrine loop enhances the sensitivity of multiple myeloma cells to anticancer drugs.  


Several autocrine soluble factors, including macrophage inflammatory protein-1? and tumour necrosis factor-alpha (TNF-?), promote the survival and growth of multiple myeloma (MM) cells. We hypothesised that inhibition of the TNF-? autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines. In the present study, a TNF-?-neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of anticancer drugs on MM cells. In addition, combination treatment with the TNF-?-neutralizing antibody and the chemotherapy agent melphalan inhibited nuclear factor ?B (NF-?B) p65 nuclear translocation and mammalian target of rapamycin (mTOR) activation and upregulated the expression of Bax and Bim. Treatment of ARH-77 cells with the NF-?B inhibitor dimethyl fumarate or the mTOR inhibitor rapamycin suppressed NF-?B p65 nuclear translocation and enhanced the cytotoxic effect of melphalan. Furthermore, infliximab, a monoclonal antibody against TNF-?, also enhanced the cytotoxic effect of anticancer drugs in ARH-77 cells. These results indicated that TNF-?-neutralizing antibodies or infliximab enhanced the cytotoxic effect of anticancer drugs by suppressing the TNF receptor/mTOR/NF-?B pathways. The inhibition of TNF-? may thus provide a new therapeutic approach to control tumour progression and bone destruction in MM patients. PMID:23932230

Tsubaki, Masanobu; Komai, Makiko; Itoh, Tatsuki; Imano, Motohiro; Sakamoto, Kotaro; Shimaoka, Hirotaka; Ogawa, Naoki; Mashimo, Kenji; Fujiwara, Daichiro; Takeda, Tomoya; Mukai, Junji; Sakaguchi, Katsuhiko; Satou, Takao; Nishida, Shozo



Synthesis, anticancer activity and structure-activity relationship of some anticancer agents based on cyclopenta (b) thiophene scaffold.  


Methods for the synthesis of new heterocyclic systems of thieno (3,2-d)- (1,2,3)-triazine derivatives and N-(3-cyano-5,6-dihydro-4H-cyclopenta (b) thiophene derivatives have been developed. The newly synthesized compounds were tested in vitro against human breast carcinoma cell line (MCF-7). Compounds 7 and 9 have shown the highest activity among the two synthesized series. The results of this study have led to the identification of two lead compounds with good inhibitory activities that can confirm the design of the next generation inhibitors of tyrosine kinase with fewer side effects such as hepatotoxicity and resistance. PMID:25015456

Said, Mohamed; Elshihawy, Hosam



Anticancer activity of Pupalia lappacea on chronic myeloid leukemia K562 cells  

PubMed Central

Background Cancer is one of the most prominent human diseases which has enthused scientific and commercial interest in the discovery of newer anticancer agents from natural sources. Here we demonstrated the anticancer activity of ethanolic extract of aerial parts of Pupalia lappacea (L) Juss (Amaranthaceae) (EAPL) on Chronic Myeloid Leukemia K562 cells. Methods Antiproliferative activity of EAPL was determined by MTT assay using carvacrol as a positive control. Induction of apoptosis was studied by annexin V, mitochondrial membrane potential, caspase activation and cell cycle analysis using flow cytometer and modulation in protein levels of p53, PCNA, Bax and Bcl2 ratio, cytochrome c and cleavage of PARP were studied by Western blot analysis. The standardization of the extract was performed through reverse phase-HPLC using Rutin as biomarker. Results The results showed dose dependent decrease in growth of K562 cells with an IC50 of 40?±?0.01??g/ml by EAPL. Induction of apoptosis by EAPL was dose dependent with the activation of p53, inhibition of PCNA, decrease in Bcl2/Bax ratio, decrease in the mitochondrial membrane potential resulting in release of cytochrome c, activation of multicaspase and cleavage of PARP. Further HPLC standardization of EAPL showed presence 0.024% of Rutin. Conclusion Present study significantly demonstrates anticancer activity of EAPL on Chronic Myeloid Leukemia (K562) cells which can lead to potential therapeutic agent in treating cancer. Rutin, a known anti cancer compound is being reported and quantified for the first time from EAPL. PMID:23351440



Double-edged effects of arsenic compounds: anticancer and carcinogenic effects.  


Although arsenic is known to cause cancers of lung, skin and kidney, arsenic trioxide (As2O3) has been recently recognized as one of the most effective novel anticancer agent for the treatment of acute promyelocytic leukemia (APL). These paradoxical effects of arsenic may be dose-dependent, associated with its distinctive metabolism, or correlated with its direct or indirect effects on different cellular pathways which may result in altered cellular functions. The basic mechanism through which As2O3 induces molecular remission in APL patients include direct targeting of PML and retinoic acid receptor alpha fusion protein (PML-RAR?) by arsenic resulting in oncoprotein degradation leading to partial differentiation. Many in vitro studies have also indicated that the anticancer properties of As2O3 against non-APL blood cancers predominantly occur through induction of apoptotic pathway. Especially, release of cytochrome c or activation of the caspase cascades and apoptosis-related proteins by arsenic is thought to occur by directly targeting mitochondria. The mechanisms and the selective target sites that have been usually associated with the cytotoxic effects of arsenicals are discussed here with reference to their contribution towards the anticancer properties of arsenic. In this review we have particularly explained the in vivo or in vitro arsenic toxicity based on arsenic metabolic pathway and its different metabolites. These multiple effects and different selective target sites for arsenic and its metabolites emphasize the need for better understanding of paradoxical effects of arsenic which may provide the appropriate use of this agent in the treatment of various malignancies. PMID:24164099

Rehman, Kanwal; Naranmandura, Hua



Nanocarriers for delivery of platinum anticancer drugs?  

PubMed Central

Platinum based anticancer drugs have revolutionized cancer chemotherapy, and continue to be in widespread clinical use especially for management of tumors of the ovary, testes, and the head and neck. However, several dose limiting toxicities associated with platinum drug use, partial anti-tumor response in most patients, development of drug resistance, tumor relapse, and many other challenges have severely limited the patient quality of life. These limitations have motivated an extensive research effort towards development of new strategies for improving platinum therapy. Nanocarrier-based delivery of platinum compounds is one such area of intense research effort beginning to provide encouraging preclinical and clinical results and may allow the development of the next generation of platinum chemotherapy. This review highlights current understanding on the pharmacology and limitations of platinum compounds in clinical use, and provides a comprehensive analysis of various platinum–polymer complexes, micelles, dendrimers, liposomes and other nanoparticles currently under investigation for delivery of platinum drugs. PMID:24113520

Oberoi, Hardeep S.; Nukolova, Natalia V.; Kabanov, Alexander V.; Bronich, Tatiana K.



Radiobiological features of the anti-cancer strategies involving synchrotron X-rays.  


Synchrotrons are opening new paths in innovative anti-cancer radiotherapy strategies. Indeed, the fluence of X-rays induced by synchrotrons is so high (10(6) times higher than standard medical irradiators) that it enables the production of X-ray beams tunable in energy (monochromatic beams) and in size (micrometric beams). Monochromatic synchrotron X-ray beams theoretically permit photoactivate high-Z elements to be introduced in or close to tumours in order to increase the yield of damage by enhanced energy photoabsorption. This is notably the case of attempts with iodinated contrast agents used in tumour imaging (the computed tomography therapy approach) and with platinated agents used in chemotherapy (the PAT-Plat approach). Micrometric synchrotron X-ray beams theoretically permit very high radiation doses to accumulate in tumours by using arrays of parallel microplanar beams that spare the surrounding tissues (the microbeam radiation therapy approach). These anti-cancer applications of synchrotron radiation have been developed at the European Synchrotron Radiation Facility to be applied to glioma, one of the tumour tissues most refractory to standard treatments. In the present paper the molecular and cellular mechanisms involved in these three approaches are reviewed, in the context of recent advances in radiobiology. Furthermore, by considering the unavoidable biases, an attempt to propose a comparison of the different results obtained in preclinical trials dealing with rats bearing tumours is given. PMID:18097081

Bencokova, Zuzana; Balosso, Jacques; Foray, Nicolas



Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics.  


Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1 = Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community. PMID:24889915

Paci, Angelo; Veal, Gareth; Bardin, Christophe; Levêque, Dominique; Widmer, Nicolas; Beijnen, Jos; Astier, Alain; Chatelut, Etienne



Systemic anticancer neural stem cells in combination with a cardiac glycoside for glioblastoma therapy.  


The tumor-tropic properties of neural stem cells (NSCs) have been shown to serve as a novel strategy to deliver therapeutic genes to tumors. Recently, we have reported that the cardiac glycoside lanatoside C (Lan C) sensitizes glioma cells to the anticancer agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we engineered an FDA-approved human NSC line to synthesize and secrete TRAIL and the Gaussia luciferase (Gluc) blood reporter. We showed that upon systemic injection, these cells selectively migrate toward tumors in the mice brain across the blood-brain barrier, target invasive glioma stem-like cells, and induce tumor regression when combined with Lan C. Gluc blood assay revealed that 30% of NSCs survived 1 day postsystemic injection and around 0.5% of these cells remained viable after 5 weeks in glioma-bearing mice. This study demonstrates the potential of systemic injection of NSCs to deliver anticancer agents, such as TRAIL, which yields glioma regression when combined with Lan C. PMID:24801379

Teng, Jian; Hejazi, Seyedali; Badr, Christian E; Tannous, Bakhos A



Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis.  


Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial. PMID:19738048

Drygin, Denis; Siddiqui-Jain, Adam; O'Brien, Sean; Schwaebe, Michael; Lin, Amy; Bliesath, Josh; Ho, Caroline B; Proffitt, Chris; Trent, Katy; Whitten, Jeffrey P; Lim, John K C; Von Hoff, Daniel; Anderes, Kenna; Rice, William G



Anti-cancer IAP Inhibition Increases Bone Metastasis via Unexpected Osteoclast Activation  

PubMed Central

IAP (inhibitor of apoptosis) proteins play a central role in many types of cancer, and IAP antagonists are in development as anti-cancer agents. IAP antagonists cause apoptosis in many cells, but they also activate alternative NF-?B signaling through NIK, which regulates osteoclasts. In bone metastasis, a positive feedback loop between tumors and osteoclasts promotes tumor growth and osteolysis. We therefore tested the effect of IAP antagonists on the bone microenvironment for metastasis. In both drug-sensitive and drug-resistant tumors, growth in bone was favored compared to other sites during IAP antagonist treatment. These drugs also caused osteoporosis and increased osteoclastogenesis, mediated by NIK, and enhanced tumor-associated osteolysis. Co-treatment with zoledronic acid, a potent osteoclast inhibitor, reduced IAP antagonist-enhanced tumor growth in bone and osteolysis. Thus, IAP-based cancer treatment may be compromised by osteoporosis and enhanced skeletal metastasis which may be prevented by anti-resorptive agents. PMID:23269702

Yang, Chang; Davis, Jennifer L.; Zeng, Rong; Vora, Paras; Su, Xinming; Collins, Lynne I.; Vangveravong, Suwanna; Mach, Robert H.; Piwnica-Worms, David; Weilbaecher, Katherine N.; Faccio, Roberta; Novack, Deborah Veis



Chemical and preclinical studies on Hedyotis diffusa with anticancer potential.  


This paper presents the chemical and preclinical anticancer research on Hedyotis diffusa Willd. in detail, one of the most renowned herbs often prescribed in the polyherbal formulas for cancer treatment in traditional Chinese medicine. Anthraquinones, flavonoids, and terpenoids constitute the majority of the 69 compounds that have been isolated and identified from H. diffusa. The anticancer effects of the methanolic, ethanolic, and aqueous extracts in various preclinical cancer models have been described. This review also summarized the anticancer activity of constituents of the herb and the mechanisms of action. All the studies suggest that H. diffusa has enormous potential in the therapy of cancer and warrants further chemical and pharmacological investigation. PMID:23600735

Niu, Yu; Meng, Qiu-Xia



Anticancer drugs discovery and development from marine organism.  


The chemical and biological diversity of the different marine evolutionary group is endless and therefore, this is an amazing resource for the discovery of new anticancer drugs. Comprising 34 of the 36 Phyla of life, marine ecosystems are indeed our last genetic diversity and biotechnological boundary; terrestrial systems possess only 17 Phyla. Sponges, coelenterates and microorganisms are the foremost resources of therapeutic compounds. Algae, echinoderms, tunicates, mollusks, bryozoans are also the sources of anticancer drugs from marine resources. We highlight the past and current status of marine anticancer pharmacology using different marine groups. PMID:19903164

Chakraborty, Chiranjib; Hsu, Chi-Hsin; Wen, Zhi-Hong; Lin, Chan-Shing



Potent Anticancer Effects of Bioactive Mushroom Extracts (Phellinus linteus) on a Variety of Human Cancer Cells  

PubMed Central

Background Although several therapeutic options are currently available for patients with various cancers, the outcomes are often disappointing and a more effective modality needs to be promptly established. We have been exploring an alternative approach using natural agents and two bioactive mushroom extracts isolated from Phellinus linteus (PL), namely PL-ES and PL-I-ES, were of our interest. As anticancer effects of similar extracts have been reported in several cancers, we investigated whether PL-ES and PL-I-ES might have such anticancer activities on a variety of human cancer cells in vitro. Methods Ten different types of human cancer cell lines, including three metastatic prostate, bladder, kidney, lung, breast, stomach, liver, and brain cancer cells, were employed and tested with PL-ES or PL-I-ES. Cell growth/viability, exertion of oxidative stress, and induction of apoptosis were assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay, lipid peroxidation (LPO) assay, and specific enzymatic assay, respectively. Results PL-ES (100 µg/mL) exhibited potent anticancer activity, resulting in a significant (40-80%) growth reduction in all 10 cancer cells at 72 hours. PL-I-ES (100 µg/mL) was effective on only four cancer cells but its higher concentration at 250 µg/mL led to a significant (25-90%) growth reduction in seven cancer cells. LPO assays indicated that such a significant growth reduction by PL-ES (100 µg/mL) or PL-I-ES (100 or 250 µg/mL) could result from cell death due to a cytotoxic effect of oxidative stress (through free radicals). Moreover, enzymatic assays for caspase-3 (Csp-3) and caspase-9 (Csp-9), the pro-apoptotic regulators, showed that both enzymes were significantly activated by PL-ES or PL-I-ES, indicating that cell death due to oxidative stress was more likely associated with apoptosis. Conclusions The present study shows that both PL-ES and PL-I-ES indeed have anticancer effects on a variety of cancer cells, although PL-ES appears to be more potent than PL-I-ES. Such an anticancer effect is presumably attributed to oxidative stress, which will ultimately lead to apoptosis. Therefore, these two bioactive mushroom extracts may have clinical implications in a more effective therapeutic option for a variety of human malignancies.

Konno, Sensuke; Chu, Kevin; Feuer, Nicholas; Phillips, John; Choudhury, Muhammad



Evaluation of Anticancer, Antioxidant, and Possible Anti-inflammatory Properties of Selected Medicinal Plants Used in Indian Traditional Medication  

PubMed Central

The present study was carried out to evaluate the anticancer, antioxidant, and possible anti-inflammatory properties of diverse medicinal plants frequently used in Indian traditional medication. The selected botanicals such as Soymida fembrifuga (Roxb.) A. Juss. (Miliaceae), Tinospora cordifolia (Willd.) Miers. (Menispermaceae), Lavandula bipinnata (L.) O. Ktze. (Lamiaceae), and Helicteres isora L. (Sterculiaceae) extracted in different solvents were evaluated for their in vitro anticancer and antioxidant activities. The results obtained indicate that H. isora has potent cytotoxic activity toward the selected cancer cells such as HeLa-B75 (34.21 ± 0.24%), HL-60 (30.25 ± 1.36%), HEP-3B (25.36 ± 1.78%), and PN-15 (29.21 ± 0.52%). Interestingly, the selected botanicals selectively inhibited cyclooxygenase-2 (COX-2) more than (COX-1), which are the key enzymes implicated in inflammation. COX-2 inhibition was observed to be in the range of 19.66-49.52% as compared to COX-1 inhibition (3.93-19.61%). The results of the antioxidant study revealed that the selected plants were found to be effective 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl (OH), and superoxide radical (SOR) scavenging agents. High-performance thin layer chromatography (HPTLC) fingerprint of flavonoids was used as a measure of quality control of the selected plant samples. The results of the present findings strengthen the potential of the selected plants as a resource for the discovery of novel anticancer, anti-inflammatory, and antioxidant agents. PMID:25379467

Shaikh, Rafik; Pund, Mahesh; Dawane, Ashwini; Iliyas, Sayyed



The Conyza triloba extracts with high chlorophyll content and free radical scavenging activity had anticancer activity in cell lines.  


The discovery of anticancer agents paradigm has been shifted to natural resources to overcome the toxicity of many synthetic agents at early clinical stages. In the present study, the antimutagenic, anticancer, phytochemistry, and free radical scavenging activities of five extracts of Conyza triloba were investigated. Extracts II (water : methanol), III (methylene chloride), and IV (methylene chloride : methanol) had the highest chlorophyll content and the highest superoxide scavenging, and metal chelating activities comparable to that of trolox. They also showed DPPH(•) scavenging activities better than that of ? -tocopherol. Virtually all extracts exerted a strong (>40% reduction) antimutagenic activity against sodium azide and benzopyrene. Extracts II, III, and IV showed a remarkable growth inhibition profile with GI50 of 0.07-0.87 ?g for Hepa1c1c7 and H4IIE1, A549, HT29, and PC3 cell lines and totally abated the growth of all cell lines, except for the breast cells, at 0.3-7.0 ?g. The present study found a strong correlation between the chlorophyll content of Conyza extracts and their DDPH scavenging, metal chelating, and in vitro cytotoxic and cytostatic activities most probably through triggering apoptosis. This study could offer a platform for future studies and help selecting the vital features that identify the extract with potential anticancer activities. PMID:23781512

El-Sayed, Wael M; Hussin, Warda A; Mahmoud, Ahmed A; AlFredan, Mohamed A



Mitochondrial permeability transition as target of anticancer drugs.  


Mitochondria are the cell powerhouses but also contain the mechanisms leading to cell death. Many signals converge on mitochondria to cause the permeabilization of mitochondrial membranes by the mitochondrial permeability transition (MPT) induction and the opening of transition pores (PTPs). These events cause loss of ionic homeostasis, matrix swelling, outer membrane rupture leading to pro-apoptotic factors release, and impairment of bioenergetics functions. The molecular mechanism underlying MPT induction is not completely elucidated however, a growing body of evidence supports the concept that pharmacological induction of PTPs in mitochondria of neoplastic cells is an effective and promising strategy for therapeutic approaches against cancer. The first part of this article presented as a review also evidences the main constituents of PTP and several compounds targeting them for inducing the phenomenon. The second part of the article regards the recent experimental development in the field, in particular, the effects of peniocerol (PEN), a sterol isolated from the root of Myrtillocactus geometrizans, at cellular and mitochondrial level. PEN exhibits a cytotoxic activity on some human tumor cell lines, whose mechanism is attributable to the oxidation of critical thiols located on adenine nucleotide translocase, the protein mainly involved in PTP. This event in the presence of Ca(2+) induces the MPT with the release of the pro-apoptotic factors cytochrome c and apoptosis inducing factor. These observations evidence that PEN may trigger both the caspase-dependent and caspaseindependent apoptotic pathways. This characteristic renders PEN a very interesting compound that could be developed to obtain more effective antiproliferative agents targeting mitochondria for anticancer therapy. PMID:23701547

Dalla Via, Lisa; García-Argáez, Aida N; Martínez-Vázquez, Mariano; Grancara, Silvia; Martinis, Pamela; Toninello, Antonio



Detection of Alkylating Agents using Electrical and Mechanical Means  

NASA Astrophysics Data System (ADS)

Alkylating agents are reactive molecules having at least one polar bond between a carbon atom and a good leaving group. These often simple molecules are frequently used in organic synthesis, as sterilizing agents in agriculture and even as anticancer agents in medicine. Unfortunately, for over a century, some of the highly reactive alkylating agents are also being used as blister chemical warfare agents. Being relatively simple to make, the risk is that these will be applied by terrorists as poor people warfare agents. The detection and identification of such alkylating agents is not a simple task because of their high reactivity and simple structure of the reactive site. Here we report on new approaches to the detection and identification of such alkylating agents using electrical (organic field effect transistors) and mechanical (microcantilevers) means.

Gerchikov, Yulia; Borzin, Elena; Gannot, Yair; Shemesh, Ariel; Meltzman, Shai; Hertzog-Ronen, Carmit; Tal, Shay; Stolyarova, Sara; Nemirovsky, Yael; Tessler, Nir; Eichen, Yoav




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


Mechanism Based Anticancer Drugs that Degrade Sp Transcription Factors  

E-print Network

Curcumin is the active component of tumeric, and this polyphenolic compound has been extensively investigated as an anticancer drug that modulates multiple pathways and genes. We demonstrated that curcumin inhibited 253JB-V and KU7 bladder cancer...

Chadalapaka, Gayathri



Cellular responses against DNA damaged by platinum anticancer drugs  

E-print Network

The anticancer activity of platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin is mediated by their ability to attack DNA such that generated adducts trigger numerous cellular responses. A better understanding ...

Jung, Yongwon, 1977-



Investigations into the Mechanisms of Cell Death: The Common Link between Anticancer Nanotherapeutics and Nanotoxicology  

NASA Astrophysics Data System (ADS)

Nanotoxicology and anticancer nanotherapeutics are essentially two sides of the same coin. The nanotoxicology discipline deals with the nanoparticle (NP)-induced toxicity and mechanisms of cell death in healthy cells, whereas anticancer agents delivered via nano-based approaches aim to induce cell death in abnormally proliferating cancer cells. The objectives of the studies presented herein were two-fold; to (a) systematically study the physico-chemical properties and cell death mechanisms of model NPs and (b) utilize the knowledge gained from cell death-nanotoxicity studies in developing a potentially novel anticancer nanotherapeutic agent. For the first objective, the effect of a distinguishing characteristic, i.e., surface carbon coating on the matched pairs of carbon-coated and non-coated copper and nickel NPs (Cu, C-Cu, Ni and C-Ni) on the physico-chemical properties and toxicity in A549 alveolar epithelial cells were evaluated. The effect of carbon coating on particle size, zeta potential, oxidation state, cellular uptake, release of soluble metal and concentration dependent toxicity of Cu and Ni NPs was systematically evaluated. A significant effect of carbon coating was observed on the physico-chemical properties, interaction with cellular membranes, and overall toxicity of the NPs. C-Cu NPs, compared to Cu NPs, showed four-fold lower release of soluble copper, ten-fold higher cellular uptake and protection against surface oxidation. In toxicity assays, C-Cu NPs induced higher mitochondrial damage than Cu NPs whereas Cu NPs were associated with a significant damage to plasma membrane integrity. Nickel and carbon coated nickel NPs were less toxic compared to Cu and C-Cu NPs. Thus, by studying the effect of carbon coating, correlations between physico-chemical properties and toxicity of NPs were established. The second objective was focused on utilizing nano-based approaches for the intracellular delivery of an anticancer agent, Cytochrome c (Cyt c), to breast cancer cells for inducing apoptosis. Cytochrome c is an endogenous mitochondrial protein and upon its release to cytosol, leads to apoptotic cell death. Although the mechanism by which Cyt c induces apoptosis theoretically makes it an attractive anti-cancer therapeutic agent, the lack of physicochemical characteristics required for successful cell permeation requires the use of delivery systems such as nanocarriers to facilitate its intracellular delivery. Cytochrome c, being a protein, is susceptible to changes in structural integrity and aggregation which might occur upon exposure to organic solvents and high shear/stress conditions, often used during nanoparticle preparation. Furthermore, successful delivery to cell cytosol requires endosomal release. Therefore, to deliver Cyt c intracellularly, while maintaining conditions for its stability, entrapment was performed using a film hydration method with 1,2-dioleoyl-3-trimethylammonium-propane and cholesterol (DOTAP-Chol) liposomes. It was shown that modulation of hydration buffer pH from 7 to 8.5 increased entrapment of Cyt c in DOTAP-Chol liposomes from 2% to 30%. The optimized formulation showed apoptotic activity in MDA-MB-231 cells. It was also shown that no aggregation, secondary and heme crevice structure change and deamidation was observed for Cyt c released from optimized formulation and that released Cyt c retained apoptotic activity after storage of formulation for twenty eight days at 4 °C.

Minocha, Shalini


Anticancer effects of Chinese herbal medicine, science or myth?  

Microsoft Academic Search

Currently there is considerable interest among oncologists to find anticancer drugs in Chinese herbal medicine (CHM). In the\\u000a past, clinical data showed that some herbs possessed anticancer properties, but western scientists have doubted the scientific\\u000a validity of CHM due to the lack of scientific evidence from their perspective. Recently there have been encouraging results,\\u000a from a western perspective, in the

Wen-jing Ruan; Mao-de Lai; Jian-guang Zhou



Canonical and new generation anticancer drugs also target energy metabolism.  


Significant efforts have been made for the development of new anticancer drugs (protein kinase or proteasome inhibitors, monoclonal humanized antibodies) with presumably low or negligible side effects and high specificity. However, an in-depth analysis of the side effects of several currently used canonical (platin-based drugs, taxanes, anthracyclines, etoposides, antimetabolites) and new generation anticancer drugs as the first line of clinical treatment reveals significant perturbation of glycolysis and oxidative phosphorylation. Canonical and new generation drug side effects include decreased (1) intracellular ATP levels, (2) glycolytic/mitochondrial enzyme/transporter activities and/or (3) mitochondrial electrical membrane potentials. Furthermore, the anti-proliferative effects of these drugs are markedly attenuated in tumor rho (0) cells, in which functional mitochondria are absent; in addition, several anticancer drugs directly interact with isolated mitochondria affecting their functions. Therefore, several anticancer drugs also target the energy metabolism, and hence, the documented inhibitory effect of anticancer drugs on cancer growth should also be linked to the blocking of ATP supply pathways. These often overlooked effects of canonical and new generation anticancer drugs emphasize the role of energy metabolism in maintaining cancer cells viable and its targeting as a complementary and successful strategy for cancer treatment. PMID:24792321

Rodríguez-Enríquez, Sara; Gallardo-Pérez, Juan Carlos; Hernández-Reséndiz, Ileana; Marín-Hernández, Alvaro; Pacheco-Velázquez, Silvia C; López-Ramírez, Sayra Y; Rumjanek, Franklin D; Moreno-Sánchez, Rafael



Potential anticancer properties of grape antioxidants.  


Dietary intake of foods rich in antioxidant properties is suggested to be cancer protective. Foods rich in antioxidant properties include grape (Vitis vinifera), one of the world's largest fruit crops and most commonly consumed fruits in the world. The composition and cancer-protective effects of major phenolic antioxidants in grape skin and seed extracts are discussed in this review. Grape skin and seed extracts exert strong free radical scavenging and chelating activities and inhibit lipid oxidation in various food and cell models in vitro. The use of grape antioxidants are promising against a broad range of cancer cells by targeting epidermal growth factor receptor (EGFR) and its downstream pathways, inhibiting over-expression of COX-2 and prostaglandin E2 receptors, or modifying estrogen receptor pathways, resulting in cell cycle arrest and apoptosis. Interestingly, some of these activities were also demonstrated in animal models. However, in vivo studies have demonstrated inconsistent antioxidant efficacy. Nonetheless, a growing body of evidence from human clinical trials has demonstrated that consumption of grape, wine and grape juice exerts many health-promoting and possible anti-cancer effects. Thus, grape skin and seed extracts have great potential in cancer prevention and further investigation into this exciting field is warranted. PMID:22919383

Zhou, Kequan; Raffoul, Julian J



Comparison of phenanthriplatin, a novel monofunctional platinum based anticancer drug candidate, with cisplatin, a classic bifunctional anticancer drug  

E-print Network

Nucleotide excision repair, a DNA repair mechanism, is the major repair pathway responsible for removal of platinum-based anticancer drugs. In this study, 146 bp duplexes were prepared containing either a site-specific ...

Li, Meiyi, S.M. Massachusetts Institute of Technology



Biological Agents  


... Statistics Training Publications Newsroom Small Business Anti-Retaliation Biological Agents Safety and Health Topics A-Z Index What's New Biological agents include bacteria, viruses, fungi, other microorganisms and ...


Anticancer activity of botanical alkyl hydroquinones attributed to topoisomerase II poisoning  

SciTech Connect

Cytotoxic alkyl hydroquinone compounds have been isolated from many plants. We previously isolated 3 structurally similar cytotoxic alkyl hydroquinone compounds from the sap of the lacquer tree Rhus succedanea L. belonging to the sumac family, which have a long history of medicinal use in Asia. Each has an unsaturated alkyl chain attached to the 2-position of a hydroquinone ring. One of these isolates, 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. We found that HQ17(3) was a topoisomerase (Topo) II poison. It irreversibly inhibited Topo II{alpha} activity through the accumulation of Topo II-DNA cleavable complexes. A cell-based assay showed that HQ17(3) inhibited the growth of leukemia HL-60 cells with an EC{sub 50} of 0.9 {mu}M, inhibited the topoisomerase-II-deficient cells HL-60/MX2 with an EC{sub 50} of 9.6 {mu}M, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 {mu}M. These results suggest that Topo II is the cellular drug target. In HL-60 cells, HQ17(3) promptly inhibited DNA synthesis, induced chromosomal breakage, and led to cell death with an EC{sub 50} about one-tenth that of hydroquinone. Pretreatment of the cells with N-acetylcysteine could not attenuate the cytotoxicity and DNA damage induced by HQ17(3). However, N-acetylcysteine did significantly reduce the cytotoxicity of hydroquinone. In F344 rats, intraperitoneal injection of HQ17(3) for 28 days induced no clinical signs of toxicity. These results indicated that HQ17(3) is a potential anticancer agent, and its structural features could be a model for anticancer drug design.

Huang, C.-P. [Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan (China); Fang, W.-H.; Lin, L.-I. [Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan (China); Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan (China); Chiou, Robin Y. [Department of Food Science, National Chiayi University, Chiayi, Taiwan (China); Kan, L.-S. [Institute of Chemistry, Academia Sinica, Taipei, Taiwan (China); Chi, N.-H.; Chen, Y.-R.; Lin, T.-Y. [Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan (China); Lin, S.-B. [Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan (China); Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan (China)], E-mail:



The Anticancer Effect of Fucoidan in PC-3 Prostate Cancer Cells  

PubMed Central

Fucoidan, a sulfated polysaccharide, has a variety of biological activities, such as anti-cancer, anti-angiogenic and anti-inflammatory. However, the mechanisms of action of fucoidan as an anti-cancer agent have not been fully elucidated. The present study examined the anti-cancer effect of fucoidan obtained from Undaria pinnatifida in PC-3 cells, human prostate cancer cells. Fucoidan induced the apoptosis of PC-3 cells by activating both intrinsic and extrinsic pathways. The induction of apoptosis was accompanied by the activation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK1/2 MAPK) and the inactivation of p38 MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt. In addition, fucoidan also induced the up-regulation of p21Cip1/Waf and down-regulation of E2F-1 cell-cycle-related proteins. Furthermore, in the Wnt/?-catenin pathway, fucoidan activated GSK-3? that resulted in the decrease of ?-catenin level, followed by the decrease of c-myc and cyclin D1 expressions, target genes of ?-catenin in PC-3 cells. These results suggested that fucoidan treatment could induce intrinsic and extrinsic apoptosis pathways via the activation of ERK1/2 MAPK, the inactivation of p38 MAPK and PI3K/Akt signaling pathway, and the down-regulation of Wnt/?-catenin signaling pathway in PC-3 prostate cancer cells. These data support that fucoidan might have potential for the treatment of prostate cancer. PMID:23966032

Boo, Hye-Jin; Hong, Ji-Young; Kim, Sang-Cheol; Kang, Jung-Il; Kim, Min-Kyoung; Kim, Eun-Ji; Hyun, Jin-Won; Koh, Young-Sang; Yoo, Eun-Sook; Kwon, Jung-Mi; Kang, Hee-Kyoung



Approaches to Improve the Oral Bioavailability and Effects of Novel Anticancer Drugs Berberine and Betulinic Acid  

PubMed Central

Background The poor bioavailability of Berberine (BBR) and Betulinic acid (BA) limits the development of these promising anticancer agents for clinical use. In the current study, BBR and BA in spray dried (SD) mucoadhesive microparticle formulations were prepared. Methods A patented dual channel spray gun technology established in our laboratory was used for both formulations. Gastrointestinal (GI) permeability studies were carried out using Caco-2 cell monolayer grown in in-vitro system. The oral bioavailability and pharmacokinetic profile of SD formulations were studied in Sprague Dawley rats. A549 orthotopic and H1650 metastatic NSCLC models were utilized for the anticancer evaluations. Results Pharmacokinetic studies demonstrated that BBR and BA SD formulations resulted in 3.46 and 3.90 fold respectively, significant increase in plasma Cmax concentrations. AUC levels were increased by 6.98 and 7.41 fold in BBR and BA SD formulations, respectively. Compared to untreated controls groups, 49.8 & 53.4% decrease in the tumor volumes was observed in SD formulation groups of BBR and BA, respectively. Molecular studies done on excised tumor (A549) tissue suggested that BBR in SD form resulted in a significant decrease in the survivin, Bcl-2, cyclin D1, MMP-9, HIF-1?, VEGF and CD31 expressions. Cleaved caspase 3, p53 and TUNEL expressions were increased in SD formulations. The RT-PCR analysis on H1650 tumor tissue suggested that p38, Phospho-JNK, Bax, BAD, cleaved caspase 3&8 mRNA expressions were significantly increased in BA SD formulations. Chronic administration of BBR and BA SD formulations did not show any toxicity. Conclusions Due to significant increase in oral bioavailability and superior anticancer effects, our results suggest that spray drying is a superior alternative formulation approach for oral delivery of BBR and BA. PMID:24614362

Doddapaneni, Ravi; Somagoni, Jaganmohan; Singh, Mandip



ING Proteins as Potential Anticancer Drug Targets  

PubMed Central

Recent emerging evidence suggests that ING family proteins play roles in carcinogenesis both as oncogenes and tumor suppressor genes depending on the family members and on cell status. Previous results from non-physiologic overexpression experiments showed that all five family members induce apoptosis or cell cycle arrest, thus it had been thought until very recently that all of the family members function as tumor suppressor genes. Therefore restoration of ING family proteins in cancer cells has been proposed as a treatment for cancers. However, ING2 knockdown experiments showed unexpected results: ING2 knockdown led to senescence in normal human fibroblast cells and suppressed cancer cell growth. ING2 is also overexpressed in colorectal cancer, and promotes cancer cell invasion through an MMP13 dependent pathway. Additionally, it was reported that ING2 has two isoforms, ING2a and ING2b. Although expression of ING2a predominates compared with ING2b, both isoforms confer resistance against cell cycle arrest or apoptosis to cancer cells, thus knockdown of both isoforms is critical to remove this resistance. Taken together, these results suggest that ING2 can function as an oncogene in some specific types of cancer cells, indicating restoration of this gene in cancer cells could cause cancer progression. Because knockdown of ING2 suppresses cancer cell invasion and induces apoptosis or cell cycle arrest, ING2 may be an anticancer drug target. In this brief review, we discuss possible clinical applications of ING2 with the latest knowledge of molecular targeted therapies. PMID:19442116

Unoki, M.; Kumamoto, K.; Harris, C.C.



Assessment of probiotic potential and anticancer activity of newly isolated vaginal bacterium Lactobacillus plantarum 5BL.  


Numerous bacteria in and on its external parts protect the human body from harmful threats. This study aimed to investigate the potential beneficial effects of the vaginal ecosystem microbiota. A type of bacteria was isolated from vaginal secretions of adolescent and young adult women, cultured on an appropriate specific culture medium, and then molecularly identified through 16S rDNA gene sequencing. Results of 16S rDNA sequencing revealed that the isolate belongs to the Lactobacillus plantarum species. The isolated strain exhibited probiotic properties such as low pH and high bile salt concentration tolerance, antibiotic susceptibility and antimicrobial activity against some pathogenic bacteria. The anticancer effects of the strain on human cancer cell lines (cervical, HeLa; gastric, AGS; colon, HT-29; breast, MCF-7) and on a human normal cell line (human umbilical vein endothelial cells [HUVEC]) were investigated. Toxic side effects were assessed by studying apoptosis in the treated cells. The strain exhibited desirable probiotic properties and remarkable anticancer activity against the tested human cancer cell lines (P???0.05) with no significant cytotoxic effects on HUVEC normal cells (P???0.05). Overall, the isolated strain showed favorable potential as a bioactive therapeutic agent. Therefore, this strain should be subjected to the other required tests to prove its suitability for clinical therapeutic application. PMID:25039934

Nami, Yousef; Abdullah, Norhafizah; Haghshenas, Babak; Radiah, Dayang; Rosli, Rozita; Khosroushahi, Ahmad Yari



Biocompatible nanoparticles intercalated with anticancer drug for target delivery: pharmacokinetic and biodistribution study.  


We have developed new hybrid systems consisting of anticancer drugs such as methotrexate (MTX) or 5-fluorouracil (5-FU) and two-dimensional inorganic delivery carrier like layered double hydroxide (LDH). Such an inorganic vector with biocompatible metal ions can be used to overcome toxicity, immunogenecity and poor integration capacity, which are critical problems caused by conventional viral vectors, cationic liposomes and polymers. Moreover, the intercellular mechanism of LDH nanoparticles is primarily related to clathrin-mediated endocytosis, resultihg in effective delivery and eventually enhancing drug efficacy. In this report, the effect of LDH intercalated with 5-Fu (5-Fu-LDH) was evaluated in whole animal by studying pharmacokinetic behavior and tissue distribution. The results showed that 5-Fu-LDH exhibited favorable blood clearance profiles compared to free 5-Fu, such as sustained drug release, prolonged drug half-life, and increased drug accumulation in target tumor tissue. Furthermore, LDH nanoparticles were rapidly excreted from the body and not accumulated in the organs after administration as 5-Fu-LDH. Therefore, the hybrid system can be promising anticancer chemotherapy agent for tumor targeting with biocompatibility. PMID:20355523

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



Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway.  


In response to some chemotherapeutic agents such as anthracyclines and oxaliplatin, cancer cells undergo immunogenic apoptosis, meaning that their corpses are engulfed by dendritic cells and that tumor cell antigens are presented to tumor-specific CD8(+) T cells, which then control residual tumor cells. One of the peculiarities of immunogenic apoptosis is the early cell surface exposure of calreticulin (CRT), a protein that usually resides in the lumen of the endoplasmic reticulum (ER). When elicited by anthracyclines or oxaliplatin, the CRT exposure pathway is activated by pre-apoptotic ER stress and the phosphorylation of the eukaryotic translation initiation factor eIF2alpha by the kinase PERK, followed by caspase-8-mediated proteolysis of the ER-sessile protein BAP31, activation of the pro-apoptotic proteins Bax and Bak, anterograde transport of CRT from the ER to the Golgi apparatus and exocytosis of CRT-containing vesicles, finally resulting in CRT translocation onto the plasma membrane surface. Interruption of this complex pathway abolishes CRT exposure, annihilates the immunogenicity of apoptosis, and reduces the immune response elicited by anticancer chemotherapies. We speculate that human cancers that are incapable of activating the CRT exposure pathway are refractory to the immune-mediated component of anticancer therapies. PMID:20421432

Zitvogel, Laurence; Kepp, Oliver; Senovilla, Laura; Menger, Laurie; Chaput, Nathalie; Kroemer, Guido



Genetically Engineered Cancer Models, But Not Xenografts, Faithfully Predict Anticancer Drug Exposure in Melanoma Tumors  

PubMed Central

Background. Rodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed. Methods. In this work, we evaluated the plasma and tumor dispositions of an antimelanoma agent, carboplatin, in patients with cutaneous melanoma compared with four different murine melanoma models (one GEMM, one human cell line xenograft, and two OSTs). Results. Using microdialysis to sample carboplatin tumor disposition, we found that OSTs and xenografts were poor predictors of drug exposure in human tumors, whereas the GEMM model exhibited PK parameters similar to those seen in human tumors. Conclusions. The tumor PKs of carboplatin in a GEMM of melanoma more closely resembles the tumor disposition in patients with melanoma than transplanted tumor models. GEMMs show promise in becoming an improved prediction model for intratumoral PKs and response in patients with solid tumors. PMID:22993143

Combest, Austin J.; Roberts, Patrick J.; Dillon, Patrick M.; Sandison, Katie; Hanna, Suzan K.; Ross, Charlene; Habibi, Sohrab; Zamboni, Beth; Muller, Markus; Brunner, Martin; Sharpless, Norman E.



The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity  

PubMed Central

The systematic translation of cancer genomic data into knowledge of tumor biology and therapeutic avenues remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacologic annotation is available1. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number, and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacologic profiles for 24 anticancer drugs across 479 of the lines, this collection allowed identification of genetic, lineage, and gene expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Altogether, our results suggest that large, annotated cell line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of “personalized” therapeutic regimens2. PMID:22460905

Barretina, Jordi; Caponigro, Giordano; Stransky, Nicolas; Venkatesan, Kavitha; Margolin, Adam A.; Kim, Sungjoon; Wilson, Christopher J.; Lehár, Joseph; Kryukov, Gregory V.; Sonkin, Dmitriy; Reddy, Anupama; Liu, Manway; Murray, Lauren; Berger, Michael F.; Monahan, John E.; Morais, Paula; Meltzer, Jodi; Korejwa, Adam; Jané-Valbuena, Judit; Mapa, Felipa A.; Thibault, Joseph; Bric-Furlong, Eva; Raman, Pichai; Shipway, Aaron; Engels, Ingo H.; Cheng, Jill; Yu, Guoying K.; Yu, Jianjun; Aspesi, Peter; de Silva, Melanie; Jagtap, Kalpana; Jones, Michael D.; Wang, Li; Hatton, Charles; Palescandolo, Emanuele; Gupta, Supriya; Mahan, Scott; Sougnez, Carrie; Onofrio, Robert C.; Liefeld, Ted; MacConaill, Laura; Winckler, Wendy; Reich, Michael; Li, Nanxin; Mesirov, Jill P.; Gabriel, Stacey B.; Getz, Gad; Ardlie, Kristin; Chan, Vivien; Myer, Vic E.; Weber, Barbara L.; Porter, Jeff; Warmuth, Markus; Finan, Peter; Harris, Jennifer L.; Meyerson, Matthew; Golub, Todd R.; Morrissey, Michael P.; Sellers, William R.; Schlegel, Robert; Garraway, Levi A.



Exploring CYP1A1 as anticancer target: homology modeling and in silico inhibitor design.  


Microsomal cytochrome P450 family 1 enzymes has great importance in the bioactivation of mutagens. P450 catalyzed reactions involve a wide range of substrates, and this versatality is reflected in a structural diversity, evident in the active sites of available P450 structures. This structure offers a template to study further structure-function relationships of alternative substrates and other cytochrome P450 family 1 members. In this paper, we document a homology model of CYP P450 1A1 from Homo sapiens, developed on the basis of template crystal structure of human microsomal P450 1a2 in complex with inhibitor (PDB Id: 2HI4). Homology modeling is performed at the programs, both in the commercial and public realms. We tried to explore CYP1A1 as a potential target for anticancer chemotherapy. To gain an insight into the binding of ligands with enzyme, protein-ligand complex was developed by including information about the known ligand as spatial restraints and optimizing the mutual interactions between the ligand and the binding site. Active site characterization and the study for involvement of specific aminoacids in binding with ligand, facilitates structure based inhibitor design. This study should prove useful in the design and development of potential novel anticancer agents. PMID:18665399

Sangamwar, Abhay T; Labhsetwar, Leena B; Kuberkar, Sharad V



Synthesis and Biological Evaluation of Novel 3-Alkylpyridine Marine Alkaloid Analogs with Promising Anticancer Activity  

PubMed Central

Cancer continues to be one of the most important health problems worldwide, and the identification of novel drugs and treatments to address this disease is urgent. During recent years, marine organisms have proven to be a promising source of new compounds with action against tumoral cell lines. Here, we describe the synthesis and anticancer activity of eight new 3-alkylpyridine alkaloid (3-APA) analogs in four steps and with good yields. The key step for the synthesis of these compounds is a Williamson etherification under phase-transfer conditions. We investigated the influence of the length of the alkyl chain attached to position 3 of the pyridine ring on the cytotoxicity of these compounds. Biological assays demonstrated that compounds with an alkyl chain of ten carbon atoms (4c and 5c) were the most active against two tumoral cell lines: RKO-AS-45-1 and HeLa. Micronucleus and TUNEL assays showed that both compounds are mutagenic and induce apoptosis. In addition, Compound 5c altered the cellular actin cytoskeleton in RKO-AS-45-1 cells. The results suggest that Compounds 4c and 5c may be novel prototype anticancer agents. PMID:25089949

Goncalves, Alessandra Mirtes Marques Neves; de Lima, Aline Brito; Barbosa, Maria Cristina da Silva; de Camargos, Luiz Fernando; de Oliveira, Julia Teixeira; Barbosa, Camila de Souza; Villar, Jose Augusto Ferreira Perez; Costa, Andre Carvalho; da Silva, Isabella Viana Gomes; Silva, Luciana Maria; Varotti, Fernando de Pilla; dos Santos, Fabio Vieira; Viana, Gustavo Henrique Ribeiro



Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting.  


The anticancer efficacy of the pyruvate analog 3-bromopyruvate has been demonstrated in multiple tumor models. The chief principle underlying the antitumor effects of 3-bromopyruvate is its ability to effectively target the energy metabolism of cancer cells. Biochemically, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been identified as the primary target of 3-bromopyruvate. Its inhibition results in the depletion of intracellular ATP, causing cell death. Several reports have also demonstrated that in addition to GAPDH inhibition, the induction of cellular stress also contributes to 3-bromopyruvate treatment-dependent apoptosis. Furthermore, recent evidence shows that 3-bromopyruvate is taken up selectively by tumor cells via the monocarboxylate transporters (MCTs) that are frequently overexpressed in cancer cells (for the export of lactate produced during aerobic glycolysis). The preferential uptake of 3-bromopyruvate via MCTs facilitates selective targeting of tumor cells while leaving healthy and non-malignant tissue untouched. Taken together, the specificity of molecular (GAPDH) targeting and selective uptake by tumor cells, underscore the potential of 3-bromopyruvate as a potent and promising anticancer agent. In this review, we highlight the mechanistic characteristics of 3-bromopyruvate and discuss its potential for translation into the clinic. PMID:23267123

Ganapathy-Kanniappan, Shanmugasundaram; Kunjithapatham, Rani; Geschwind, Jean-Francois



Structure-activity relationship study of novel anticancer aspirin-based compounds  

PubMed Central

We performed a structure-activity relationship (SAR) study of a novel aspirin (ASA) derivative, which shows strong anticancer activity in vitro and in vivo. A series of ASA-based benzyl esters (ABEs) were synthesized and their inhibitory activity against human colon (HT-29 and SW480) and pancreatic (BxPC-3 and MIA PaCa-2) cancer cell lines was evaluated. The ABEs that we studied largely comprise organic benzyl esters bearing an ASA or acyloxy group (X) at the meta or para position of the benzyl ring and one of four different leaving groups. The nature of the salicyloyl/acyloxy function, the leaving group, and the additional substituents affecting the electron density of the benzyl ring, all were influential determinants of the inhibitory activity on cancer cell growth for each ABE. Positional isomerism also played a significant role in this effect. The mechanism of action of these compounds appears consistent with the notion that they generate either a quinone methide or an m-oxybenzyl zwitterion (or an m-hydroxybenzyl cation), which then reacts with a nucleophile, mediating their biological effect. Our SAR study provides an insight into the biological properties of this