Note: This page contains sample records for the topic anticancer agent podophyllotoxin from Science.gov.
While these samples are representative of the content of Science.gov,
they are not comprehensive nor are they the most current set.
We encourage you to perform a real-time search of Science.gov
to obtain the most current and comprehensive results.
Last update: November 12, 2013.
1

[Carboxyl nanodiamond as intracellular transporters of anticancer drug--podophyllotoxin].  

PubMed

The purpose of this study is to investigate the intracellular transporters effect and the cytotoxicity of carboxyl nanodiamond (CND) - podophyllotoxin (PPT). Nanodiamond (ND) was treated with mixed carboxylic acid and finally got 64 nm CND by centrifugation, and then it was reacted with PPT to form CND-PPT. UV spectrophotometry was used to calculate the content of PPT in CND-PPT, the particle size distribution and zeta potential were measured by Dynamic laser scattering instrument. CND, PPT, CND-PPT and CND + PPT (physical mixture of CND and PPT) were characterized by Fourier transform infrared spectroscopy, at the same time, thermal analysis and element analysis were used to estimate the content of the PPT in CND-PPT. The affect of CND, PPT, CND-PPT on HeLa cell was measured with MTT assay. The results showed that content of PPT combined with CND accounted for about 10%. MTT assay showed that CND has low cytotoxicity and CND-PPT can increase the water soluble of PPT. As a conclusion, CND as a hydrophilic pharmaceutical carrier combined with PPT is able to increase the water solubility of PPT, at low concentration, CND-PPT can enhance the antitumor activity in comparison with PPT, so CND can be used as a potential anticancer drug carrier. PMID:23600157

Sun, Tao-Li; Wang, Bin; Peng, Yan; Ni, Jing-Man

2013-01-01

2

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

PubMed

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

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

2012-02-09

3

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

PubMed Central

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

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

2011-01-01

4

Synthesis and anticancer activity of dichloroplatinum(II) complexes of podophyllotoxin.  

PubMed

A series of dichloroplatinum(II) complexes of podophyllotoxin (PPT) were prepared, and their cytotoxicity against sensitive (A-549, HeLa, HCT-8, Hep-G2, K562) and resistant (ADM/K562) cell lines were evaluated. Complex cis-[4?-O-(2?,3?-diaminopropanoyl)-podophyllotoxin] dichloride platinum(II) (12) displayed most potent cytotoxicity with IC50 value in the range 0.071-2.98 ?M. Complex 12 induces cell cycle arrest in the G2/M phase, and inhibits the formation of microtubules in HeLa cells. Furthermore, this complex exhibits potent DNA cleavage capabilities. PMID:23711918

Liu, Xuan; Zhang, Lin-Lin; Xu, Xiao-Hui; Hui, Lin; Zhang, Jin-Bang; Chen, Shi-Wu

2013-05-09

5

A synthetic podophyllotoxin derivative exerts anti-cancer effects by inducing mitotic arrest and pro-apoptotic ER stress in lung cancer preclinical models.  

PubMed

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

2013-04-30

6

Synthesis and biological evaluation of a series of podophyllotoxins derivatives as a class of potent antitubulin agents.  

PubMed

A series of eight novel podophyllotoxin derivatives were designed, synthesized and evaluated for biological activities. The antiproliferative activities were tested against a panel of human cancer cell lines (K562, SGC, Hela and HepG) and the inhibition of tubulin polymerization was also evaluated. Compound 8e displayed significant antiproliferative activities for all four cell lines and strong levels of tubulin polymerization inhibition effect. Combined with cell apoptosis and cell cycle analysis, it demonstrated that compound 3e that effectively interfere with tubulin dynamics prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually dose dependent apoptosis. All experimental measurements were also supported by molecular docking simulations of colchicine binding site, which revealed the governing forces for the binding behavior and a good relationship with anti-tubulin activity and antiproliferative activities. The synthesis and biological studies provided an interesting new class of antitubulin agents for development of lead compounds and also a direction for further structure modification to obtain more potent anti-cancer drugs. PMID:23022053

Liu, Yingqian; Wei, Dongfeng; Zhao, Yonglong; Cheng, Weidong; Lu, Yan; Ma, Yaqiong; Li, Xin; Han, Chao; Wei, Yanxia; Cao, Huiming; Zhao, Chunyan

2012-09-13

7

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.

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

2010-01-01

8

Synthetic and Application Perspectives of Azapodophyllotoxins: Alternative Scaffolds of Podophyllotoxin  

PubMed Central

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

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

2012-01-01

9

ANTICANCER AGENTS FROM UNIQUE NATURAL PRODUCTS SOURCES  

Technology Transfer Automated Retrieval System (TEKTRAN)

Anticancer Agents from Unique Natural Products Sources is a consortium of researchers from academia and industry organized in1995 in response to a request for proposals by the National Cancer Institute to establish National Cooperative Drug Discovery Groups (NCDDGs). The goal of the consortium is t...

10

Phase I Clinical Trials with Anticancer Agents  

Microsoft Academic Search

\\u000a Although the term “phase I” is used to describe numerous trial designs, the overarching goal of a phase I study is to determine\\u000a the optimal dose and\\/or schedule of a therapy for evaluation in the phase II setting. Phase I trials typically test different\\u000a doses of an anticancer agent(s) in various neoplastic diseases, with safety evaluation as a main objective.

Stephen Leong; Justin Call; Alex A. Adjei; Wells Messersmith

11

Radiation recall with anticancer agents.  

PubMed

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

Burris, Howard A; Hurtig, Jane

2010-11-02

12

Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents  

PubMed Central

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

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

2013-01-01

13

Biological evaluation and molecular modelling study of podophyllotoxin derivatives as potent inhibitors of tubulin polymerization.  

PubMed

Microtubules are considered as important targets of anticancer therapy. Podophyllotoxin and its structural derivative are major microtubule-interfering agents with potent anticancer activity. In this study, we reported the anticancer effects of 10 representative podophyllotoxin derivatives on a panel of four human cancer cell lines. Deoxypodophyllotoxin (6b) and ?-apopicropodophyllotoxin (6g) elicited strong antiproliferative effects (IC??) at a range of 0.0073-0.14 ?M. Direct tubulin depolymerization assay in vitro was also performed. Results showed that that the two compounds can inhibit microtubule polymerization. Experimental measurements were also supported by molecular dynamic simulations, which showed that the two active compounds formed interactions with the colchicine-binding site of the tubulin protein. Our results helped us understand the nature of tubulin binding and determine the core design of a new series of potent inhibitors of tubulin polymerization. PMID:23786349

Ma, Yaqiong; Fang, Senbiao; Li, Huanhuan; Han, Chao; Lu, Yan; Zhao, Yonglong; Liu, Yingqian; Zhao, Chunyan

2013-07-01

14

Quantitative measure of cytotoxicity of anticancer drugs and other agents  

Microsoft Academic Search

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

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

2008-01-01

15

Vitamin D as a promising anticancer agent.  

PubMed

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

2011-04-01

16

Vitamin D as a promising anticancer agent  

PubMed Central

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

Chakraborti, Chandra Kanti

2011-01-01

17

Synthesis and Quantitative Structure-Activity Relationship (QSAR) Study of Novel Isoxazoline and Oxime Derivatives of Podophyllotoxin as Insecticidal Agents.  

PubMed

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

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

2012-08-21

18

Concept and Clinical Evaluation of Carrier-Mediated Anticancer Agents  

Microsoft Academic Search

Major advances in the use of carrier vehicles delivering pharmacologic agents and enzymes to sites of disease have occurredoverthepast10years.Thisreviewfocusesonthe concepts and clinical evaluation of carrier-mediated anti- cancer agents that are administered i.v. or orally. The pri- mary types of carrier-mediated anticancer agents are nanoparticles,nanosomes,whicharenanoparticle-sizedli- posomes, and conjugated agents. Nanosomes are further subdivided into stabilized and nonstabilized or conven- tional nanosomes.

WILLIAM C. ZAMBONI; UNC Lineberger

19

Benzimidazole derivatives as potential anticancer agents.  

PubMed

Benzimidazole ring system is found in many bioactive heterocyclic compounds because of their diverse biological and clinical applications. Furthermore, benzimidazole derivatives are structural isosters of naturally occurring nucleotides, thus they can interact with biological macromolecules such as proteins, enzymes and receptors. This review discusses the benzimidazole derivatives which possess anticancer activity of medicinal efficacy. PMID:23190032

El Rashedy, Ahmed A; Aboul-Enein, Hassan Y

2013-03-01

20

Monitoring of occupational exposure to cytostatic anticancer agents  

Microsoft Academic Search

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

Marja Sorsa; Diana Anderson

1996-01-01

21

Recent progress in drug delivery systems for anticancer agents  

Microsoft Academic Search

Recent progress in understanding the molecular basis of cancer brought out new materials such as oligonucleotides, genes,\\u000a peptides and proteins as a source of new anticancer agents. Due to their macromolecular properties, however, new strategies\\u000a of delivery for them are required to achieve their full therapeutic efficacy in clinical setting. Development of improved\\u000a dosage forms of currently marketed anticancer drugs

Chong-Kook Kim; Soo-Jeong Lim

2002-01-01

22

Pharmaceutical development of anticancer agents derived from marine sources.  

PubMed

The marine ecosystem is more and more acknowledged as a source of potential anticancer agents. After the identification of a potential substance several hurdles have to be overcome before a marine candidate can enter the clinic. Amongst these are the establishment of a method which ensures sufficient supply and, which is the focus of this review, the development of a clinically useful pharmaceutical formulation. General issues with respect to the pharmaceutical development of marine anticancer agents will be discussed, which will be illustrated by highlighting aspects of the pharmaceutical development and clinical use of some representative compounds. PMID:11142687

Nuijen, B; Bouma, M; Manada, C; Jimeno, J M; Schellens, J H; Bult, A; Beijnen, J H

2000-11-01

23

Nanovectors for anticancer agents based on superparamagnetic iron oxide nanoparticles  

PubMed Central

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

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

2007-01-01

24

Extending nature's leads: the anticancer agent ellipticine.  

PubMed

The natural plant product ellipticine was isolated in 1959 from the Australian evergreen tree of the Apocynaceae family. This compound was found to be an extremely promising anticancer drug. The planar polycyclic structure was found to interact with DNA through intercalation, exhibiting a high DNA binding affinity (10(6) M(-1)). The presence of protonatable ring nitrogens distinguished ellipticine from other simple intercalators. Both monocationic and uncharged species were found to be present under physiological conditions. The positive charge stabilized the binding of ellipticine to nucleic acids, while the more lipophilic uncharged compound was shown to readily penetrate membrane barriers. The structural nature of these compounds offers a plausible basis for the implication of multiple modes of action, including DNA binding, interactions with membrane barriers, oxidative bioactivation and modification of enzyme function; most notably that of topoisomerase II and telomerase. Pharmacologically, a number of toxic side effects have been shown to be problematic, but the amenability of ellipticine towards systematic structural modification has permitted the extensive application of rational drug design. A number of successful ellipticine analogs have been designed and synthesized with improved toxicities and anticancer activities. More recently the synthetic focus has broadened to include the design of hybrid compounds, as well as drug delivery conjugates. Considerable research efforts have been directed towards gaining a greater understanding of the mechanism of action of these drugs that will aid further in the optimization of drug design. PMID:15032720

Garbett, Nichola C; Graves, David E

2004-03-01

25

New anticancer agents mimicking protein recognition motifs.  

PubMed

The novel tetrasubstituted pyrrole derivatives 8g, 8h, and 8i showed selective cytotoxicity against M14 melanoma cells at low micromolar concentration. Structure-activity relationships (SARs) indicated the presence of three aromatic substituents on the pyrrole core as necessary for biological activity. Computational studies strongly suggest that the peculiar 3D orientation of these substituents is able to reproduce the hydrophobic side chains in LxxLL-like protein recognition motifs. Biological results showed altered p53 expression and nuclear translocation in cells sensitive to the compounds, suggesting p53 involvement in their anticancer mechanism of action. Unfortunately, because of poor solubility of the active analogues, it was not possible to perform further investigation by NMR techniques. Pharmacophore models were generated and used to perform 3D searches in molecular databases. Results indicated that two compounds share the same pharmacological profile and the same pharmacophoric features with our new derivatives, and one of them inhibited MDM2-MDM4 heterodimer formation. PMID:23879262

Persico, Marco; Ramunno, Anna; Maglio, Vita; Franceschelli, Silvia; Esposito, Chiara; Carotenuto, Alfonso; Brancaccio, Diego; De Pasquale, Valeria; Pavone, Luigi Michele; Varra, Michela; Orteca, Nausicaa; Novellino, Ettore; Fattorusso, Caterina

2013-08-19

26

Novel benzimidazole derivatives as expected anticancer agents.  

PubMed

A series of 1-(1H-benzimidazol-2-yl)-3-(substituted)-2-propen-1-one and its 1-methyl analogues 2c-h were synthesized and cyclized with different reagents such as ethyl cyanoacetate, thiourea, hydroxylamine hydrochloride, guanidinium sulfate, methylhydrazine, phenylhydrazine and/or hydrogen peroxide in different reactions to produce pyridones 3a,b, pyrimidinethione 4a,b, isoxazole 5a,b, aminopyrimidine 6a,b, pyrazoline 7i-k and epoxy derivative 8, respectively. Acetohydrazide 10 reacted with formic acid, acetic anhydride, carbon disulfide and/or thiosemicarbazide to yield compounds 11-19. Also compound 21a,b was condensed with different monosaccharides to yield the corresponding N-glycoside Schiff's bases derivatives 22a-h, which upon treatment with acetic anhydride afforded 23a-h derivatives. The anticancer activity of some of the newly synthesized compounds was evaluated against HEPG2 (human liver carcinoma cell line) and PC12 (pheochromocytoma of the rat adrenal medulla) cells. Benzimidazole-2-isoxazole 5a derivative exhibited high potency against HEPG2 and PC12 cells. Benzimidazole chalcones 2c,e, benzimidazole mercaptoacetohydrazide 14 and benzimidazole thiosemicarbazide 15a,b derivatives gave high potency against PC12 cells. PMID:21796934

Nofal, Zienab M; Soliman, Elsyed A; Abd El-Karim, Somaia S; El Zahar, Magdy I; Srour, Aladdin M; Sethumadhavan, Shalini; Maher, Timothy J

27

Design and synthesis of fluoroacylshikonin as an anticancer agent.  

PubMed

A series of shikonin derivatives, selectively acylated by various fluorinated carboxylic acids at the side chain of shikonin, were synthesized and their anticancer activity evaluated, in which eight compounds are reported for the first time. Among all the compounds tested, compound showed the most potent anticancer activity against B16-F10 (malignant melanoma cells), MG63 (human osteosarcoma cells), and A549 (lung cancer cells) with IC50 0.39 ± 0.01, 0.72 ± 0.04 and 0.58 ± 0.02 µmol/L. Docking simulation of compound was carried out to position into a tubulin active site to determine the probable binding conformation. All the results suggested that compound may be a potential anticancer agent. Chirality 25:757-762, 2013. © 2013 Wiley Periodicals, Inc. PMID:23908135

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

2013-08-01

28

Effect of major nutrients on podophyllotoxin production in Podophyllum hexandrum suspension cultures  

Microsoft Academic Search

The effect of major medium ingredients (sugar, nitrogen source and phosphate) in Podophyllum hexandrum suspension cultures was investigated in order to increase the production of podophyllotoxin, the raw material in the synthesis of anticancer drugs. Amongst B5, Eriksson, MS, Nitsch, Street and White's medium, MS medium resulted in high growth and podophyllotoxin accumulation. The optimum level of nitrogen was found

S. Chattopadhyay; R. S. Mehra; A. K. Srivastava; S. S. Bhojwani; V. S. Bisaria

2003-01-01

29

Titanium and vanadium complexes as anticancer agents.  

PubMed

A series of complexes containing titanium and vanadium as a metal centers have shown to possess a wide spectrum of antitumor properties. These series belong to the non-platinum metal antitumor agents that appear to offer a different alternative for cancer chemotherapy which do not follow mechanism of action of the platinum complexes. The antitumor activity of both titanocene and vanadocene complexes has been established against various animal and xenografted human tumors. The exact mechanism of action for these compounds has not been determined, the target is unknown and even the exact chemical nature of the formulated solutions is still unknown. It has been proposed that these species interact with DNA, inhibiting the cell cycle. However, the antitumor mechanism of the titanocenes is most likely a complex pathway, probably involving a number of different biological molecules related to the transport and delivery of Ti species into cancer cells, and, after hydrolysis, subsequent interaction with nucleic acids and/or proteins and/or other potential coordinating constituents present in the intracellular environment. The tendency to hydrolyze seems to be one of the hypotheses for the tumor-inhibiting potency of the titanocene dihalides. Vanadium compounds exert preventive effects against chemical carcinogenesis on animals, by modifying, mainly, various xenobiotic enzymes, inhibiting, thus, carcinogen-derived active metabolites. The anticarcinogenic effects of vanadium, in combination to its low toxicity, established also, by its administration in humans, suggest vanadium as a candidate antineoplastic agent against human cancer. New complexes being more potent and less toxic favor this perspective. The use of these species as chemotherapeutic agents remains relatively unexplored and waits for future investigation. Research proceeded during the recent decades, enriched our knowledge on the chemical and biochemical properties, as well as the mechanisms of systemic, cellular and molecular antitumor effects of titanium and vanadium compounds. PMID:19538167

Kostova, Irena

2009-10-01

30

Current development of mTOR inhibitors as anticancer agents  

Microsoft Academic Search

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

Sandrine Faivre; Guido Kroemer; Eric Raymond

2006-01-01

31

Application of anticancer agent embolism in Miles’ operation  

Microsoft Academic Search

Summary  Presented in this paper is a report of the prospective studies on rectal cancer. By using the method of anticancer agent gelatin\\u000a sponge to form embolism and by ligating the bilateral arteria ilica internal, we performed Miles’ operation on 64 cases of\\u000a rectal cancer. Only 24 cases in the control group had Miles’ operation. The amount of blood transfused during

Liu Fei-long; Yie Qi-fa; Yang Chuan-yuan; Zhao Cui-lang; Dai Zhi-ben

1995-01-01

32

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

Microsoft Academic Search

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

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

2009-01-01

33

Chromatin modifying agents - the cutting edge of anticancer therapy.  

PubMed

Chromatin modifying compounds are emerging as the next generation of anticancer therapies. By altering gene expression they could be able to correct uncontrolled proliferation and, in certain cases, aberrant apoptotic pathways, which are hallmarks of malignant cells. The modulation of gene expression is regulated via chromatin remodelling processes that include DNA methylation and chromatin modifications. The identification of aberrant methylation of genes and dysregulated histone acetylation status in cancer cells provides a basis for novel epigenetic therapies. Currently available chromatin modifying agents, a group that includes DNA methyltransferase and histone deacetylase inhibitors, exert anticancer effects by reactivating tumour suppressor genes, inhibiting proliferation and inducing apoptosis. It is anticipated that massive parallel sequencing will identify new epigenetic targets for drug development. PMID:21664485

Kwa, Faith A A; Balcerczyk, Aneta; Licciardi, Paul; El-Osta, Assam; Karagiannis, Tom C

2011-06-01

34

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

PubMed

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

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

2010-12-28

35

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

PubMed

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

2013-07-27

36

Quantitative measure of cytotoxicity of anticancer drugs and other agents.  

PubMed

Many anticancer drugs act on cancer cells to promote apoptosis, which includes impairment of cellular respiration (mitochondrial O(2) consumption). Other agents also inhibit cellular respiration, sometimes irreversibly. To investigate the sensitivity of cancer cells to cytotoxins, including anticancer drugs, we compare the profiles of cellular O(2) consumption in the absence and presence of these agents. Oxygen measurements are made at 37 degrees C, using glucose as a substrate, with [O(2)] obtained from the phosphorescence decay rate of a palladium phosphor. The rate of respiration k is defined as -d[O(2)]/dt in a sealed container. Different toxins produce different profiles of impaired respiration, implying different mechanisms for the drug-induced mitochondrial dysfunction. The decrease in the average value of k over a fixed time period, I, is proposed as a characteristic value to assess mitochondrial injury. The value of I depends on the nature of the toxin, its concentration, and the exposure time as well as on the cell type. Results for several cell types and 10 cytotoxins are presented here. PMID:18602881

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

2008-06-18

37

Efficient NQO1 Substrates are Potent and Selective Anticancer Agents.  

PubMed

A major goal of personalized medicine in oncology is the identification of drugs with predictable efficacy based on a specific trait of the cancer cell, as has been demonstrated with gleevec (presence of Bcr-Abl protein), herceptin (Her2 overexpression), and iressa (presence of a specific EGFR mutation). This is a challenging task, as it requires identifying a cellular component that is altered in cancer, but not normal cells, and discovering a compound that specifically interacts with it. The enzyme NQO1 is a potential target for personalized medicine, as it is overexpressed in many solid tumors. In normal cells NQO1 is inducibly expressed, and its major role is to detoxify quinones via bioreduction; however, certain quinones become more toxic after reduction by NQO1, and these compounds have potential as selective anticancer agents. Several quinones of this type have been reported, including mitomycin C, RH1, EO9, streptonigrin, ?-lapachone, and deoxynyboquinone (DNQ). However, no unified picture has emerged from these studies, and the key question regarding the relationship between NQO1 processing and anticancer activity remains unanswered. Here, we directly compare these quinones as substrates for NQO1 in vitro, and for their ability to kill cancer cells in culture in an NQO1-dependent manner. We show that DNQ is a superior NQO1 substrate, and we use computationally guided design to create DNQ analogues that have a spectrum of activities with NQO1. Assessment of these compounds definitively establishes a strong relationship between in vitro NQO1 processing and induction of cancer cell death and suggests these compounds are outstanding candidates for selective anticancer therapy. PMID:23937670

Parkinson, Elizabeth I; Bair, Joseph S; Cismesia, Megan; Hergenrother, Paul J

2013-08-22

38

Current status on development of steroids as anticancer agents.  

PubMed

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

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

2013-05-30

39

Discovery of Natural Product Anticancer Agents from Biodiverse Organisms  

PubMed Central

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

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

2010-01-01

40

Immunomodulating tellurium compounds as anti-cancer agents.  

PubMed

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

Sredni, Benjamin

2011-12-21

41

Clinically relevant drug interactions between anticancer drugs and psychotropic agents.  

PubMed

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

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

2011-01-01

42

Synthesis and evaluation of novel podophyllotoxin analogs.  

PubMed

Because prior studies have shown inconsistency between structure-activity relationships for podophyllotoxin derivatives as topoisomerase II inhibitors and cytotoxic agents, eight novel podophyllotoxin analogs were synthesized to further explore the effects of structural variations on both A and D rings on activity. The new compounds contain a 4,5-dimethoxy substituted A ring and opened D-ring variants and were prepared by appropriate functional and stereochemical operations at the methylenedioxy group, C7, C8, and C8'. Four compounds (15, 18, 21 and 22) demonstrated noticeable inhibitory activity against A549, DU145, KB and KBvin tumor cells, and the most active compound 18 showed IC(50) values less than 10 ?g/mL. PMID:22658864

Li, Jie; Hua, Hui Ming; Tang, Yan Bo; Zhang, Shipeng; Ohkoshi, Emika; Lee, Kuo-Hsiung; Xiao, Zhi yan

2012-05-15

43

Semi-synthesis and biological evaluation of 1,2,3-triazole-based podophyllotoxin congeners as potent antitumor agents inducing apoptosis in HepG2 cells.  

PubMed

A series of 4?-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin congeners were synthesized by employing click chemistry and further evaluated for their antitumor activity by MTT assay. Among them, six congeners (10, 11, 12, 13, 22, and 24) exhibited approximately 100-fold more potent inhibitory activity against four tumor cell lines (HepG2, MKN-45, NCI-H1993, and B16) than etoposide as positive control. Docking studies on binding in the ATPase domain of topoisomerase II revealed perfect docking of four congeners in the active site. Furthermore, the podophyllotoxin congeners 10, 11, 12, and 13 induced cell cycle arrest of HepG2 cells at the G(2) /M phase in a concentration-dependent manner, assessed by flow cytometric analysis, highlighting that they exert their antitumor activity via HepG2 cell apoptosis. PMID:22949330

Chen, Jinying; Ma, Liang; Zhang, Ronghong; Tang, Jie; Lai, Huijun; Wang, Jun; Wang, Guangcheng; Xu, Qinyuan; Chen, Tao; Peng, Fei; Qiu, Jingxiang; Liang, Xiaolin; Cao, Dong; Ran, Yan; Peng, Aihua; Wei, Yuquan; Chen, Lijuan

2012-09-05

44

Insight into dihalogenation of E-ring of podophyllotoxins, and their acyloxyation derivatives at the C4 position as insecticidal agents.  

PubMed

Unexpected sequential E-ring dihalogenation of podophyllotoxin analogues is reported. It demonstrated that a chlorine/bromine atom was prior introduced at the C2' position of podophyllotoxin, and the corresponding free rotation of E-ring around the C1-C1' bond of 2'-chloro or 2'-bromopodophyllotoxin was restricted. When 2'-chloro or 2'-bromopodophyllotoxin reacted with N-chlorosuccinimide (NCS), the chlorine atom was regioselectively introduced at their C6' position on the E-ring. Whereas 2'-chloro or 2'-bromopodophyllotoxin reacted with NBS, the bromine atom was regioselectively introduced at their C5 position on the B-ring. When 2'-chloropodophyllotoxin reacted with different carboxylic acids in the presence of BF3·Et2O, the steric effect of its E-ring for stereoselective synthesis of 4?-acyloxy-2'-chloropodophyllotoxin derivatives was observed. The insecticidal activity of 2'(2',6')-(di)halogen-substituted podophyllotoxin derivatives were evaluated with Mythimna separata Walker. PMID:24018192

Che, Zhiping; Yu, Xiang; Fan, Lingling; Xu, Hui

2013-08-17

45

Genistein and its synthetic analogs as anticancer agents.  

PubMed

Genistein, one of the predominant isoflavones derived from soybeans, has been shown beneficial effects in cancer prevention and treatment. There is an accumulating body of experimental evidences suggesting that genistein affects cancer progression by increasing apoptosis, inducing cell cycle arrest,modulating intracellular signaling pathways, and inhibiting invasion and metastasis of cancer cells. During last decade, many researchers have conducted extensive studies by synthesizing amounts of structurally-modified derivatives based on the isoflavone skeleton of genistein to enhance its anticancer activity, some analogs of which possess more potent activities of the prevention and/or treatment of various cancers. In this review, we summarized the current knowledge regarding anticancer effects,structure-activity relationships and action mechanisms of genistein and its synthesized analogs, which would be beneficial to the rational design of new genistein derivatives as anticancer drugs. PMID:22043996

Li, Qing-Shan; Li, Cui-Yun; Li, Zi-Lin; Zhu, Hai-Liang

2012-03-01

46

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

PubMed Central

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

Vickers, Andrew J.

2008-01-01

47

Differential Toxicities of Anticancer Agents among DNA Repair and Checkpoint Mutants of Saccharomyces cerevisiae1  

Microsoft Academic Search

Most cytotoxic anticancer agents damage DNA directly, interfere with DNA metabolism or chromosome segregation, and are particularly toxic in dividing cells. Although a considerable amount of information on the mechanisms of action of these agents is available, the molecular bases for selective tumor cell killing by chemotherapy are largely unknown. Many genetic alterations found in sporadic and hereditary cancers affect

Julian A. Simon; Philippe Szankasi; Di K. Nguyen; Catherine Ludlow; Heather M. Dunstan; Christopher J. Roberts; Elizabeth L. Jensen; Leland H. Hartwell; Stephen H. Friend

2000-01-01

48

[Apoptosis-reactivating agents for targeted anticancer therapy].  

PubMed

The current knowledge on molecular mechanisms of apoptosis is presented focusing on the key elements of the extrinsic death receptor pathway as well as the intrinsic mitochondrial pathway. Disregulation of apoptotic pathways is considered as a key factor in the survival of cancer cells in response to conventional chemotherapeutic drugs or radiation therapy. Substances that selectively reactivate apoptosis in malignant cells are the promising candidate anticancer drugs, which have now entered various phases of clinical trials. The up-to-date techniques allowing for non-invasive in vivo visualization of apoptotic cells with special reference to therapy-induced cell death are briefly surveyed. PMID:23789342

Fil'chenkov, A A

49

Erlotinib hydro-chloride: an anti-cancer agent  

PubMed Central

In the cation of the title compound, C22H24N3O4 +·Cl?, an active ingredient of the anti­cancer drug also known as Tarceva, the quinazoline ring system is planar within 0.044?(3)?Å. The dihedral angle formed by the mean planes of the two six-membered quinazoline rings is 3.2?(1)°. Both N-bound H atoms participate in N—H?Cl bonds, which link the ions into infinite chains running along the b axis. C—H?O inter­actions involving neighboring cations provide additional stabilization of these aggregates.

Selvanayagam, S.; Sridhar, B.; Ravikumar, K.

2008-01-01

50

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

PubMed

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

2009-11-01

51

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.

Lei, Xiaoguang; Danishefsky, Samuel J.

2011-01-01

52

Progress in the development and acquisition of anticancer agents from marine sources  

Microsoft Academic Search

represent landmarks in the history of medicine. Almost 60% of drugs approved for cancer treatment are of natural origin. Vincristine, irinotecan, etoposide, taxanes and camptothecines are all examples of plant-derived compounds. Dactinomicine, anthracyclines, mitomycin and bleomycin are anticancer agents derived from microbial sources (1). Although marine compounds are under-represented in current pharmacopoeia, it is anticipated that the aquatic environment will

M. L. Amador; J. Jimeno; L. Paz-Ares; H. Cortes-Funes; M. Hidalgo

2003-01-01

53

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

Microsoft Academic Search

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

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

2005-01-01

54

Thioredoxin Reductase as a Potential Molecular Target for Anticancer Agents That Induce Oxidative Stress  

Microsoft Academic Search

Redox-sensitive signaling factors regulate multiple cellular processes, including proliferation, cell cycle, and prosurvival signaling cascades, suggesting their potential as molecular targets for anticancer agents. It is logical to set constraints that a molecular target should meet at least one of the following criteria: (1) inhibition of prosurvival signaling pathways; (2) inhibition of cell cycle progression; or (3) enhancement of the

DeeDee K. Smart; Karen L. Ortiz; David Mattson; C. Matthew Bradbury; Kheem S. Bisht; Leah K. Sieck; Martin W. Brechbiel; David Gius

2004-01-01

55

Synthesis of novel steroid derivatives derived from dehydroepiandrosterone as potential anticancer agents.  

PubMed

A series of dehydroepiandrosterone derivatives containing dihydrazone unit was synthesized via a convenient condensation procedure, and which were evaluated for their potential anticancer activities. The preliminary assays indicated that some of the newly synthesized compounds exhibited good antitumor activities against human hepatocellular liver carcinoma (HepG2), heptoma (Huh-7), gastric cancer (BGC-823) and breast adenocarcinoma (MCF-7) cell lines compared with 5-fluorouracil (5-FU), which might be considered as promising lead scaffold for further design and synthesis of potential anticancer agents. PMID:23547874

Ke, Shaoyong; Wei, Yanhong; Shi, Liqiao; Yang, Qingyu; Yang, Ziwen

2013-10-01

56

Synthesis and cytotoxicity studies of novel Triazolo-benzoxazepine as new anticancer agents.  

PubMed

Cancer continues to be one of the biggest threats to the human civilization because there is no cure of it. Small heterocyclic molecule with low molecular weight and novel structural feature is therapeutically highly demanding. These molecules have the capability to disrupt signaling pathways leading to anticancer activities. Therefore, the search for new anticancer agents continues to draw attention to the research community. In this study, a small triazolo-benzoxazepine scaffolds was synthesized using a one-pot four-step synthetic methodology involving click reaction. Small libraries of 12 compounds were successfully synthesized and screened them against different cancer cell lines. Low micromolar anticancer activity was recorded using MTT assay, and further confirmation of cell death was obtained by phase contrast, fluorescent, and confocal images. PMID:23672315

Banerji, Biswadip; Pramanik, Sumit Kumar; Sanphui, Priyankar; Nikhar, Sameer; Biswas, Subhas C

2013-08-26

57

Chemical Diversity of Metabolites from Fungi, Cyanobacteria, and Plants Relative to FDA-Approved Anticancer Agents.  

PubMed

A collaborative project has been undertaken to explore filamentous fungi, cyanobacteria, and tropical plants for anti-cancer drug leads. Through principal component analysis, the chemical space covered by compounds isolated and characterized from these three sources over the last four years was compared to each other and to the chemical space of selected FDA-approved anticancer drugs. Using literature precedence, nine molecular descriptors were examined: molecular weight, number of chiral centers, number of rotatable bonds, number of acceptor atoms for H-bonds (N,O,F), number of donor atoms for H-bonds (N and O), topological polar surface area using N,O polar contributions, Moriguchi octanol-water partition coefficient, number of nitrogen atoms, and number of oxygen atoms. Four principal components explained 87% of the variation found among 343 bioactive natural products and 96 FDA-approved anticancer drugs. Across the four dimensions, fungal, cyanobacterial and plant isolates occupied both similar and distinct areas of chemical space that collectively aligned well with FDA-approved anticancer agents. Thus, examining three separate re-sources for anticancer drug leads yields compounds that probe chemical space in a complementary fashion. PMID:22993669

El-Elimat, Tamam; Zhang, Xiaoli; Jarjoura, David; Moy, Franklin J; Orjala, Jimmy; Kinghorn, A Douglas; Pearce, Cedric J; Oberlies, Nicholas H

2012-07-12

58

[Clinical pharmacology of anticancer agents [Part 5] Antimetabolites (2)].  

PubMed

III Purine antagonists Biosynthesis of guanine nucleotides has been reported to be up regulated in tumor cells. In guanine nucleotide synthesis, there are 2 rate-limiting enzymes, i.e. inosine monophosphate dehydrogenase for de novo synthesis and hypoxanthine guanine phosphoribosyltransferase for the salvage pathway. Therefore, agents acting on these 2 enzymes to inhibit guanine nucleotide synthesis could be expected to have a superior effect on tumor proliferation. The main antitumor agents belonging to this class are thiopurines [including 6-mercaptopurine (6 MP), 6-thioguanine (6 TG) and 6-thioinosine (TIR)], thiazofurin (TZF), and arabinofuranosylfluoroadenine (F-ara-A). In the activation of 6MP to its ribotide. PRPP is the rate limiting factor. After the ribotide is produced, it is metabolized to another active form by enzymes catalyzing purine nucleotide metabolism. The antitumor effect of TZF is enhanced by the combination of TZF with allopurinol, which increases the plasma hypoxanthine level and subsequently inhibits recovery of the reduced guanine nucleotide pool by TZF. F-ara-A induces DNA strand damage as well as inhibiting DNA synthesis and is expected to have a significant antitumor effect on slowly growing tumors. These agents are mainly effective for treating hematological malignancies. IV Antifolic agents Among the antifolates, methotrexate (MTX) is the most useful drug for both hematologic malignancies and solid tumors. MTX primarily inhibits one-carbon transfer through the inhibition of dihydrofolate reductase and thus blocks the biosynthesis of both purine and pyrimidine nucleotides. Formyl polyglutamate synthetase catalyzes folate to its polyglutamate, both the active and retention forms. It is also important as an activating enzyme as well as being a target of MTX. MTX directly inhibits thymidylate synthetase, which could be the main target during high-dose therapy. High-dose MTX therapy with leucovorin (LV) rescue is effective even for tumors which are resistant to conventional treatment. During clinical use, not only MTX levels but also those of its inactive metabolites [7-hydroxy-MTX and 2, 4-diamino-N10-methylpteroic acid(DAMPA)] should be monitored. High-dose MTX therapy with LV rescue requires precise monitoring and LV rescue should be continued until the MTX level falls below 5 x 10(-8) M. MTX is also known as the safest drug which can be directly administered to into the central nervous system. Many other antifolates are under development, among which trimetrexate might be the most promising. Studies on antimetabolites have developed side by side with research on nucleotide tumor cell metabolism, which has produced a number of the antitumor agents now available for cancer chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1543370

Nakamura, T; Ueda, T; Uchida, M

1992-03-01

59

Unconventional Anticancer Agents: A Systematic Review of Clinical Trials  

PubMed Central

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

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

2006-01-01

60

Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure  

Microsoft Academic Search

Summary An analysis of the growth inhibitory potency of 122 anticancer agents available from the National Cancer Institute anticancer drug screen is presented. Methods of singular value decomposi- tion (SVD) were applied to determine the matrix of distances between all compounds. These SVD-derived dissimilarity dis- tances were used to cluster compounds that exhibit similar tumor growth inhibitory activity patterns against

Ozlem Keskin; Ivet Bahar; Robert L. Jernigan; John A. Beutler; Robert H. Shoemaker; Edward A. Sausville; David G. Covell

2000-01-01

61

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

PubMed Central

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

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

2006-01-01

62

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

NASA Astrophysics Data System (ADS)

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.

2010-03-01

63

MR22388, a novel anti-cancer agent with a strong FLT-3 ITD kinase affinity.  

PubMed

This work describes the study of the mechanism of action and spectrum of activity of MR22388, a novel anti-cancer agent belonging to the tripentone series. MR22388 is highly cytotoxic (within the nanomolar range) against numerous cancer cell lines and studies of its cytotoxicity mechanisms show that it is a weak inhibitor of the polymerization of tubulin and that it induces apoptosis via the MAP kinase pathways. Further MR22388 is a very strong inhibitor of several kinases including the tyrosine kinase FLT3-ITD. FLT3-ITD is a mutated form of the tyrosine kinase receptor (RTK) FLT3, resulting in the constitutive activation of the kinase, occurring in about 25% of normal karyotypes' Acute Myeloid Leukemia (AML) and is linked to a bad prognosis. Consecutively, MR22388 appears as a novel promising anticancer lead agent especially for AML therapy. PMID:23268332

Rochais, Christophe; Cresteil, Thierry; Perri, Vittoria; Jouanne, Marie; Lesnard, Aurélien; Rault, Sylvain; Dallemagne, Patrick

2012-12-23

64

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)

2010-03-11

65

Pharmacokinetic Drug–Drug Interaction of the Novel Anticancer Agent E7070 and Acenocoumarol  

Microsoft Academic Search

E7070 is a novel sulfonamide anticancer agent that arrests cancer cells at the G1\\/S boundary of the cell cycle. Three patients receiving chronic therapy with the oral anticoagulant acenocoumarol experienced bleeding and\\/or a prolonged prothrombin time after treatment with E7070 at a dose of 700?mg\\/m2 given as a 1-h infusion. In vitro studies have shown that E7070 has the potential

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

2004-01-01

66

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

Microsoft Academic Search

Mitoxantrone (MH2X), an anthraquinone-type anti-cancer agent used clinically in the treatment of human malignancies, is oxidatively activated by the peroxidase\\/H2O2 enzyme system. In contrast to the enzymatic mechanisms of drug oxidation, the chemical transformations of MH2X are not well described. In this study, MH2X metabolites, produced by the horseradish, lacto- or lignin peroxidase (respectively HRP, LPO and LIP)\\/H2O2 system, were

Thomas B. Brück; Dieter W. Brück

2011-01-01

67

Hydrolysis Process of the Anticancer Agents Novel Non-classical trans-Platinum( ) with Aliphatic Amines  

Microsoft Academic Search

The hydrolysis process of the anticancer agents novel non-classical trans- platinum( ) with aliphatic amines and the influence of solvent models therein have been studied by ? using hybrid density functional theory (B3LYP). In this study, the stepwise hydrolysis, trans- (PtCl2(Am)(isopropylamine)) + 2H2O ? trans-(Pt(Am)(isopropylamine)(OH2)2) 2+ + 2Cl?, was explored. Implicit solvent effects were incorporated through polarized continuum models. The

68

Bacterial biosynthesis and maturation of the didemnin anticancer agents  

PubMed Central

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

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

2012-01-01

69

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

PubMed Central

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

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

2012-01-01

70

Lysosomotropic properties of weakly basic anticancer agents promote cancer cell selectivity in vitro.  

PubMed

Drug distribution in cells is a fundamentally important, yet often overlooked, variable in drug efficacy. Many weakly basic anticancer agents accumulate extensively in the acidic lysosomes of normal cells through ion trapping. Lysosomal trapping reduces the activity of anticancer drugs, since anticancer drug targets are often localized in the cell cytosol or nucleus. Some cancer cells have defective acidification of lysosomes, which causes a redistribution of trapped drugs from the lysosomes to the cytosol. We have previously established that such differences in drug localization between normal and cancer cells can contribute to the apparent selectivity of weakly basic drugs to cancer cells in vitro. In this work, we tested whether this intracellular distribution-based drug selectivity could be optimized based on the acid dissociation constant (pKa) of the drug, which is one of the determinants of lysosomal sequestration capacity. We synthesized seven weakly basic structural analogs of the Hsp90 inhibitor geldanamycin (GDA) with pKa values ranging from 5 to 12. The selectivity of each analog was expressed by taking ratios of anti-proliferative IC(50) values of the inhibitors in normal fibroblasts to the IC(50) values in human leukemic HL-60 cells. Similar selectivity assessments were performed in a pair of cancer cell lines that differed in lysosomal pH as a result of siRNA-mediated alteration of vacuolar proton ATPase subunit expression. Optimal selectivity was observed for analogs with pKa values near 8. Similar trends were observed with commercial anticancer agents with varying weakly basic pKa values. These evaluations advance our understanding of how weakly basic properties can be optimized to achieve maximum anticancer drug selectivity towards cancer cells with defective lysosomal acidification in vitro. Additional in vivo studies are needed to examine the utility of this approach for enhancing selectivity. PMID:23145164

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

2012-11-07

71

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

PubMed Central

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

Zhou, Hong-Yu; Huang, Shi-Le

2011-01-01

72

Medical applications of nanoparticles in biological imaging, cell labeling, antimicrobial agents, and anticancer nanodrugs.  

PubMed

This article reviews the applications of nanotechnology in the fields of medical and life sciences. Nanoparticles have shown promising applications from diagnosis to treatment of various types of diseases including cancer. In this review, we discuss the applications of nanostructured materials such as nanoparticles, quantum dots, nanorods, nanowires, and carbon nanotubes in diagnostics, biomarkers, cell labeling, contrast agents for biological imaging, antimicrobial agents, drug delivery systems, and anticancer nanodrugs for treatment of cancer and other infectious diseases. The adverse affects of nanoparticles on human skin from daily use in cosmetics and general toxicology of nanoscale materials are also reviewed. PMID:21870454

Singh, Ravina; Nalwa, Hari Singh

2011-08-01

73

Gambogic acid is a novel anti-cancer agent that inhibits cell proliferation, angiogenesis and metastasis.  

PubMed

Gambogic acid (GA) is a caged xanthone that is derived from Garcinia hanburyi and functions as a strong apoptotic inducer in many types of cancer cells. The distinct effectiveness of GA has led to its characterization as a novel anti-cancer agent. There is an increasing number of research studies focused on elucidating the molecular mechanisms of GA-induced anti-cancer effects, and several critical signaling pathways have been reported to be influenced by GA treatment. In this review, we summarize the multiple functional effects of GA administration in cancer cells including the induction of apoptosis, the inhibition of proliferation and the prevention of cancer metastasis and tumor angiogenesis. PMID:22339063

Wang, Xu; Chen, Wantao

2012-10-01

74

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.

Ezoe, Sachiko

2012-01-01

75

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

PubMed Central

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

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

2011-01-01

76

[Effect of intrabladder instillation of various anticancer agents on carcinogenesis in rat bladder].  

PubMed

After administration of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to 6-week-old, female F344 rats, various anticancer agents and immunotherapeutic agents were injected into the bladder and their effects were investigated. Injection of adriamycin and mitomycin C (MMC) into the bladder a total of 12 times, 4 weeks after administration of BBN markedly promoted carcinogenesis of the bladder. Injection of bleomycin, cis-dichlorodiamine platinum (CDDP) and picibanil into the bladder a total of 12 times, 4 weeks after administration of BBN did not promote carcinogenesis and CDDP exhibited a tendency to inhibit carcinogenesis. Injection of MMC, CA (cytarabine) and MMC + CA into the bladder a total of 12 times, 4 weeks after administration of BBN indicated that CA has the potential to inhibit the bladder carcinogenesis-promoting effect of MMC. Injection of CDDP and MMC into the bladder a total of 12 times, 20 weeks after administration of BBN inhibited proliferation of bladder carcinoma. Additionally, administration each of CDDP and MMC alone exhibited a carcinogenic effect on the bladder. The above-described results show that considerable care should be taken and that long-term observation of course is required with the use of anticancer agents such as ADM and MMC. PMID:3149447

Okamura, T

1988-11-01

77

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

PubMed

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

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

2011-11-01

78

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.

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

2013-01-01

79

Benzimidazole bearing oxadiazole and triazolo-thiadiazoles nucleus: design and synthesis as anticancer agents.  

PubMed

Two new series of benzimidazole bearing oxadiazole[1-(1H-benzo[d]imidazol-2-yl)-3-(5-substituted-1,3,4-oxadiazol-2-yl)propan-1-ones (4a-l)] and triazolo-thiadiazoles[1-(1H-benzo[d]imidazol-2-yl)-3-(6-(substituted)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)propan-1-one (7a-e)] have been synthesized successfully from 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanehydrazide (3) with an aim to produce promising anticancer agents. In vitro anticancer activities of synthesized compounds were screened at the National Cancer Institute (NCI), USA, according to their applied protocol against full NCI 60 human cell lines panel; results showed good to remarkable anticancer activity. Among them, compound (4j, NCS: 761980) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 ?M) with GI(50) values ranging from 0.49 to 48.0 ?M and found superior for the non-small cell lung cancer cell lines like HOP-92 (GI(50) 0.49, TGI 19.9,LC(50) >100 and Log(10)GI(50) -6.30, Log(10)TGI -4.70, Log(10)LC(50) >-4.00). PMID:22840417

Husain, Asif; Rashid, Mohd; Mishra, Ravinesh; Parveen, Shama; Shin, Dong-Soo; Kumar, Deepak

2012-07-17

80

Synthesis and evaluation as potential anticancer agents of novel tetracyclic indenoquinoline derivatives.  

PubMed

We report the synthesis and evaluation as potential anticancer agents of a series of tetracyclic indenoquinolines. The compounds, which are obtained through the photoisomerization of Diels-Alder adducts formed between purpurogallin derivatives and nitrosobenzene, have in vitro antiproliferative activities in the ?M to nM range against breast (MCF-7), lung epithelial (A-549), and cervical (HeLa) adenocarcinoma cells. The cytotoxicities of several of the novel tetracycles are comparable to or better than that of camptothecin. A strong correlation between the activity of the compounds and their aromaticity and planarity was observed, suggesting a mode of action similar to that of topoisomerase poisons. PMID:23357037

Chakrabarty, Shubhashis; Croft, Michael S; Marko, Melissa G; Moyna, Guillermo

2013-01-03

81

Anticancer effects of metformin and its potential use as a therapeutic agent for breast cancer.  

PubMed

Metformin is an orally available, biguanide derivative that is widely used in the treatment of Type 2 diabetes. Recent preclinical data have demonstrated that it can also act as an anticancer agent by activation of AMPK and subsequent inhibition of mTOR. Metformin is currently being investigated in several Phase II/III clinical trials. This article will review the current evidence for its mechanism of action, efficacy in preclinical and clinical models, and toxicity. Ongoing and planned studies evaluating the impact of metformin on breast cancer outcomes are also discussed. PMID:21675836

Guppy, Amy; Jamal-Hanjani, Mariam; Pickering, Lisa

2011-06-01

82

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

NASA Astrophysics Data System (ADS)

Poly(lactide-co-glycolide) (PLA50GA50) is a biodegradable and biocompatible polymer. It offers tremendous potential as a basis for drug delivery, either as drug delivery system alone or in conjugate with a medical device. The PLA50GA50 is the material of choice for relatively shorter-duration applications, while the homopolymer PLA (poly-L-lactide) and PGA (polyglycolide) are preferred for longer term delivery of drugs. This paper discusses the degradation properties of poly(lactide-co-glycolide) (PLA50GA50) at inherent viscosity of 0.89 dL/g as preliminary studies for anticancer agent delivery.

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

2010-03-01

83

Genome-Wide Identification of Genes Conferring Resistance to the Anticancer Agents Cisplatin, Oxaliplatin, and Mitomycin C  

Microsoft Academic Search

Cisplatin is a crucial agent in the treatment of many solid tumors, yet many tumors have either acquired or intrinsic resistance to the drug. We have used the homozygous diploid deletion pool of Saccharomyces cerevi- siae, containing 4728 strains with individual deletion of all nonessential genes, to systematically identify genes that when deleted confer sensitivity to the anticancer agents cisplatin,

H. Irene Wu; James A. Brown; Mary J. Dorie; Laura Lazzeroni; J. Martin Brown

2004-01-01

84

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

Microsoft Academic Search

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

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

2007-01-01

85

Systemic use of tumor necrosis factor alpha as an anticancer agent  

PubMed Central

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

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

2011-01-01

86

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

PubMed

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

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

2013-01-22

87

Potential use of Folate-appended Methyl-?-Cyclodextrin as an Anticancer Agent  

PubMed Central

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

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

2013-01-01

88

Analysis of Food and Drug Administration-approved anticancer agents in the NCI60 panel of human tumor cell lines.  

PubMed

Since the early 1990s the Developmental Therapeutics Program of the National Cancer Institute (NCI) has utilized a panel of 60 human tumor cell lines (NCI60) representing 9 tissue types to screen for potential new anticancer agents. To date, about 100,000 compounds and 50,000 natural product extracts have been screened. Early in this program it was discovered that the pattern of growth inhibition in these cell lines was similar for compounds of similar mechanism. The development of the COMPARE algorithm provided a means by which investigators, starting with a compound of interest, could identify other compounds whose pattern of growth inhibition was similar. With extensive molecular characterization of these cell lines, COMPARE and other user-defined algorithms have been used to link patterns of molecular expression and drug sensitivity. We describe here the results of screening current Food and Drug Administration (FDA)-approved anticancer agents in the NCI60 screen, with an emphasis on those agents that target signal transduction. We analyzed results from agents with mechanisms of action presumed to be similar; we also carried out a hierarchical clustering of all of these agents. The addition of data from recently approved anticancer agents will increase the utility of the NCI60 databases to the cancer research community. These data are freely accessible to the public on the DTP website (http://dtp.cancer.gov/). The FDA-approved anticancer agents are themselves available from the NCI as a plated set of compounds for research use. PMID:20442306

Holbeck, Susan L; Collins, Jerry M; Doroshow, James H

2010-05-04

89

Effects of anticancer agents on cell viability, proliferative activity and cytokine production of peripheral blood mononuclear cells  

PubMed Central

We investigated the effects of anticancer agents on peripheral blood mononuclear cells for the purpose of providing data to support new translational chemoimmunotherapy regimens. Peripheral-blood mononuclear cells were treated with one of four anticancer agents (5-fluorouracil, irinotecan, cisplatin, and gemcitabine) for 2 h, after which cell viability was determined. For assessment of effects of each drug on proliferation and cytokine production, cells were stimulated with phytohemagglutinin for 48 h. As a result, the anticancer agents did not affect cell viability. Cell proliferation was unaffected by 5-fluorouracil and irinotecan but inhibited by cisplatin and gemcitabine. Treatment with gemcitabine enhanced the production of IFN-? and decreased the number of regulatory T cells. gemcitabine treatment increased IFN-? production among CD4 T cells but not among CD8 T cells. The results indicated that GEM had immunoregulatory properties that might support immune response against cancer. This finding has implications for designing chemoimmunotherapy strategies.

Sakai, Hiromi; Kokura, Satoshi; Ishikawa, Takeshi; Tsuchiya, Reiko; Okajima, Manabu; Matsuyama, Tatsuzou; Adachi, Satoko; Katada, Kazuhiro; Kamada, Kazuhiro; Uchiyama, Kazuhiko; Handa, Osamu; Takagi, Tomohisa; Yagi, Nobuaki; Naito, Yuji; Yoshikawa, Toshikazu

2013-01-01

90

New perspective for an old antidiabetic drug: metformin as anticancer agent.  

PubMed

Metformin, an inexpensive, well-tolerated oral agent that is commonly used in the first-line treatment for type 2 diabetes, has become the focus of intense research as a potential anticancer agent. This research reflects a convergence of epidemiologic, clinical, and preclinical evidence, suggesting that metformin may lower cancer risk in diabetics and improve outcomes of many common cancers. Notably, metformin mediates an approximately 30 % reduction in the lifetime risk of cancer in diabetic patients. There is growing recognition that metformin may act (1) directly on cancer cells, primarily by impacting mitochondrial respiration leading to the activation of the AMP-activated protein kinase (AMPK), which controls energy homeostasis in cells, but also through other mechanisms or (2) indirectly on the host metabolism, largely through AMPK-mediated reduction in hepatic gluconeogenesis, leading to reduced circulating insulin levels and decreased insulin/IGF-1 receptor-mediated activation of the PI3K pathway. Support for this comes from the observation that metformin inhibits cancer cell growth in vitro and delays the onset of tobacco carcinogen-induced lung cancer in mice and that metformin and its analog phenformin delay spontaneous tumor development cancer-prone transgenic mice. The potential for both direct antitumor effects and indirect host-mediated effects has sparked enormous interest, but has led to added challenges in translating preclinical findings to the clinical setting. Nonetheless, the accumulation of evidence has been sufficient to justify initiation of clinical trials of metformin as an anticancer agent in the clinical setting, including a large-scale adjuvant study in breast cancer, with additional studies planned. PMID:24114491

Leone, Alessandra; Di Gennaro, Elena; Bruzzese, Francesca; Avallone, Antonio; Budillon, Alfredo

2014-01-01

91

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.

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

2012-01-01

92

Synthesis, evaluation and molecular modeling of cyclic tetrapeptide histone deacetylase inhibitors as anticancer agents.  

PubMed

Histone deacetylase inhibitors (HDACIs) are a promising class of anticancer agents. To examine whether a slight change in the recognition domain could alter their inhibitory activity, we synthesized a series of cyclo(-L-Am7(S2Py)-Aib-L-Phe(n-Me)-D-Pro)derivatives and evaluated their HDAC inhibitory and anticancer activities. The peptides exhibited potent HDAC inhibitory activity and inhibited three human cancer cell lines with IC?? in the micromolar range. Docking and molecular dynamics simulation were conducted to explore the interaction mechanisms of class I and II HDACs with these inhibitors. It revealed that the zinc ion in the active site coordinated five atoms of HDACs and the sulfur atom of the inhibitor. The metal binding domains of these compounds interacted with HDAC2, and the surface recognition domains of these compounds interacted with HDAC4 through hydrogen bonding. The hydrophobic interactions also provided favorable contributions to stabilize the complexes. The results obtained from this study would be helpful for us to design some novel cyclic tetrapeptides that may act as potent HDACIs. PMID:22253009

Huang, Dawei; Li, Xiaohui; Sun, Lei; Xiu, Zhilong; Nishino, Norikazu

2012-01-17

93

Pruritus to anticancer agents targeting the EGFR, BRAF, and CTLA-4.  

PubMed

In the past decade, the expanded use of targeted anticancer drugs has significantly prolonged survival in patients treated for a variety of cancers. Despite their increased specificity, agents such as epidermal growth factor receptor inhibitors (EGFRIs), BRAF inhibitors, and targeted immunotherapies have commonly been associated with a number of dermatologic adverse events, often necessitating treatment modifications and negatively impacting patients' quality of life. Although toxicities such as rash and xerosis are frequently discussed, symptomatic pruritus, or itch, has emerged as an important, and frequently neglected, event. The present study reviews the incidence and clinical presentation of pruritus with the EFGRIs, and with two novel anti-melanoma drugs, vemurafenib and ipilimumab, with a focus on the putative underlying pathophysiology, and current management strategies. PMID:23551370

Fischer, Alyssa; Rosen, Alyx C; Ensslin, Courtney J; Wu, Shenhong; Lacouture, Mario E

94

Synthesis and biological evaluation of novel anthranilamide derivatives as anticancer agents.  

PubMed

A new series of anthranilamide derivatives were synthesized and evaluated for their antiproliferative activities against human colon carcinoma cell lines (HCT 116) and human breast adenocarcinoma cell lines (MDA-MB-231) in vitro. The bioassay results indicated that compounds 7a-7d, 11a, and 11b with flexible linkers showed promising antiproliferative activity against both cell lines. Among the compounds synthesized, 7c showed the most significant antiproliferative activity. Flow cytometric analysis indicated that 7c inhibited HCT 116 and MDA-MB-231 cell growth by inducing apoptosis in a dose-dependent manner and suppressed HCT 116 cell proliferation by G1 and S phase arrest. Compound 7c may serve as a lead candidate in the development of novel anticancer agents. PMID:24071576

Liu, J Z; Liang, W; Wang, Y Y; Zhao, G S

2013-08-01

95

Synthesis and in vitro antitumor activity of substituted quinazoline and quinoxaline derivatives: search for anticancer agent.  

PubMed

The synthesis of some 2-furano-4(3H)-quinazolinones, diamides (open ring quinazolines), quinoxalines and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Among the synthesize compounds, seventeen 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, 3-(2-chloro benzylideneamine)-2-(furan-2-yl) quinazoline-4(3h)-one 21 was found to be the most active candidate of the series at five dose level screening against Ovarian OVCAR-4 and Non-small cell lung cancer NCI-H522 with GI50 1.82 & 2.14 ?M respectively. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for quinazoline, diamides and quinoxaline derivatives. PMID:21458891

Noolvi, Malleshappa N; Patel, Harun M; Bhardwaj, Varun; Chauhan, Ankit

2011-03-15

96

Synthesis and biological evaluation of 2-amino-1-thiazolyl imidazoles as orally active anticancer agents.  

PubMed

Designed from a high throughput screened hit compound, novel 2-amino-1-thiazolyl imidazoles were synthesized and demonstrated cytotoxicity against human cancer cells. 1-(4-Phenylthiazol-2-yl)-4-(thiophen-2-yl)-1H-imidazol-2-amine (compound 2), a 2-amino-1-thiazolyl imidazole, inhibited tubulin polymerization, interacted with the colchicine-binding sites of tubulins, and caused cell cycle arrest at the G(2)/M phase in human gastric cancer cells. Disruption of the microtubule structure in cancer cells by compound 2 was also observed. Compound 2 concentration-dependently inhibited the proliferation of cancer cells in histocultured human gastric and colorectal tumors. Given orally, compound 2 prolonged the lifespans of leukemia mice intraperitoneally inoculated with the murine P388 leukemic cells. We report 2-amino-1-thiazolyl imidazoles as a novel class of orally active microtubule-destabilizing anticancer agents. PMID:20890633

Li, Wen-Tai; Hwang, Der-Ren; Song, Jen-Shin; Chen, Ching-Ping; Chen, Tung-Wei; Lin, Chi-Hung; Chuu, Jiunn-Jye; Lien, Tzu-Wen; Hsu, Tsu-An; Huang, Chen-Lung; Tseng, Huan-Yi; Lin, Chu-Chung; Lin, Heng-Liang; Chang, Chung-Ming; Chao, Yu-Sheng; Chen, Chiung-Tong

2010-10-02

97

Berberine as a promising safe anti-cancer agent - is there a role for mitochondria?  

PubMed

Metabolic regulation is largely dependent on mitochondria, which play an important role in energy homeostasis. Imbalance between energy intake and expenditure leads to mitochondrial dysfunction, characterized by a reduced ratio of energy production (ATP production) to respiration. Due to the role of mitochondrial factors/events in several apoptotic pathways, the possibility of targeting that organelle in the tumor cell, leading to its elimination is very attractive, although the safety issue is problematic. Berberine, a benzyl-tetra isoquinoline alkaloid extracted from plants of the Berberidaceae family, has been extensively used for many centuries, especially in the traditional Chinese and Native American medicine. Several evidences suggest that berberine possesses several therapeutic uses, including anti-tumoral activity. The present review supplies evidence that berberine is a safe anti-cancer agent, exerting several effects on mitochondria, including inhibition of mitochondrial Complex I and interaction with the adenine nucleotide translocator which can explain several of the described effects on tumor cells. PMID:21269266

Diogo, Catia V; Machado, Nuno G; Barbosa, Inês A; Serafim, Teresa L; Burgeiro, Ana; Oliveira, Paulo J

2011-06-01

98

Impacts and predictors of cytotoxic anticancer agents in different breast cancer subtypes.  

PubMed

Breast cancer is not a single entity. This study therefore aimed to identify differences in the impacts of anticancer agents and predictive factors between different breast cancer subtypes. A total of 234 patients with luminal (n = 109), luminal-HER2 (L-H, n = 29), HER-2 (n = 35), or triple negative (TN, n = 61) breast cancer subtypes were treated with standard neoadjuvant chemotherapy consisting of an anthracycline and/or taxane. Pathological response and prognosis were examined in each subtype. Expression levels of estrogen and progesterone receptors, HER-2, nuclear grade, MIB-1, p53, topoisomerase IIalpha (topoIIalpha), cytokeratin (CK) 5/6, and epidermal growth factor receptor (EGFR) were examined in association with quasipathological complete response (QpCR). QpCR rates were 9.1% (10/109) in luminal, 45% (13/29) in L-H, 37% (13/35) in HER2, and 54.1% (33/61) in TN. Non-QpCR patients showed significantly poorer 3-year disease-free survival than QpCR patients in TN, but not in patients with other subtypes. No factors were associated with QpCR in luminal patients. Patients with higher nuclear grade were more likely to achieve QpCR in L-H. The proliferative markers MIB-1 and topoIlalpha had opposite impacts on pathological response in HER-2 and TN. The QpCR rate was significantly higher in TN lacking CK5/6 and/or EGFR expression, defined as nonbasal subtype, compared with basal subtype (p = 0.049). Cytotoxic anticancer agents were associated with different responses in different breast cancer subtypes. Identifying basal-type cancer and further subdivision of nonbasal types is important for treating TN patients. PMID:23193913

Ishikawa, Takashi; Shimizu, Daisuke; Yamada, Akimitsu; Sasaki, Takeshi; Morita, Satoshi; Tanabe, Mikiko; Kawachi, Kae; Nozawa, Akinori; Chishima, Takashi; Kimura, Mariko; Ichikawa, Yasushi; Endo, Itaru

2012-01-01

99

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

PubMed

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

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

2013-05-26

100

Telomerase activity and telomere length in human tumor cells with acquired resistance to anticancer agents.  

PubMed

Telomeres and telomerase are targets for anticancer drug development and specific inhibitors are currently under clinical investigation. However, it has been reported that standard cytotoxic agents can affect telomere length and telomerase activity suggesting that they also have of a role in drug resistance. in this study, telomere lengths and telomerase activity as well as drug efflux pump expression, glutathione (GSH) levels and polyadenosine-ribose polymerase (PARP) cleavage were assessed in a panel of human tumor cell lines made resistant to vindesine, gemcitabine and cisplatin. these included two lung cancer cell lines resistant to vindesine (LXFL 529L/Vind, LXFA 526L/Vind), a renal cancer cell line (RXF944L/Gem) and an ovarian cancer cell line (AG6000) resistant to gemcitabine, and one resistant to cisplatin (ADDP). The resistant clones were compared to their parental lines and evaluated for cross resistance to other cytotoxic agents. Several drug specific resistance patterns were found, and various complex patterns of cross resistance emerged from some cell lines, but these mechanisms of resistance could not be related to drug efflux pump expression, GSH levels or pARp cleavage. However, all displayed changes in telomerase activity and/or telomere length. Our studies present evidence that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics. PMID:19933046

Smith, V; Dai, F; Spitz, M; Peters, G J; Fiebig, H H; Hussain, A; Burger, A M

2009-11-01

101

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

PubMed

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

2014-01-01

102

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

PubMed

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

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

103

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

PubMed Central

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

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

2011-01-01

104

Review. Acridine orange could be an innovative anticancer agent under photon energy.  

PubMed

Acridine orange (AO) was extracted as a dye from coal tar over a hundred years ago. It has various unique biological activities and has been shown to be a useful fluorescent dye specific for DNA and RNA, a pH indicator, photosensitizer, antitumor and antimalarial drug, and detector of bacteria and parasites. It has recently been found that AO accumulates in musculoskeletal sarcomas and that after illumination of the tumors with visible light or irradiation with low-dose X-rays, the dye rapidly exerts selective cytocidal effect against the sarcoma cells. Therefore, surgery combined with photo- (PDT) or radiodynamic therapy (RDT) with AO (AO-PDT and -RDT) has been applied to human musculoskeletal sarcomas. The results of a clinical study on the outcome of this therapeutic strategy revealed that it yielded better local control and remarkably better limb function than wide resectional surgery. Based on our experimental studies, it was clarified that AO accumulates in acidic organelles or structures, especially lysosomes, depending on the acidity. An enormous number of protons are produced in cancer from lactate or CO2 under hypoxic conditions, which are moved into the extracellular fluid or lysosomes to maintain the intracellularfluid pH. Therefore, AO shows marked accumulation in the acidic lysosomes of cancer cells. Photon energy from visible light or X-rays excites the AO accumulated in lysosomes; the excited AO emits fluorescence and forms activated oxygen from intra-cytoplasmic oxygen. The activated oxygen destroys lysosomes, with the released lysosomal enzymes causing rapid death of the cancer cells. On the other hand, normal cells can exclude AO quickly because they are not acidic. Thus, AO-PDT and AO-RDT exhibit strong and selective cytocidal effect against malignant tumors. In conclusion, we believe that AO-PDT and AO-RDT exhibit selective anticancer cell activity and that AO excited by photon energy has excellent potential as an anticancer agent. PMID:17436568

Kusuzaki, Katsuyuki; Murata, Hiroaki; Matsubara, Takao; Satonaka, Haruhiko; Wakabayashi, Toru; Matsumine, Akihiko; Uchida, Atsumasa

105

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

PubMed Central

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

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

2012-01-01

106

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

PubMed Central

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

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

1995-01-01

107

Fanconi anemia D2 protein confers chemoresistance in response to the anticancer agent, irofulven.  

PubMed

The Fanconi anemia-BRCA pathway of genes are frequently mutated or epigenetically repressed in human cancer. The proteins of this pathway play pivotal roles in DNA damage signaling and repair. Irofulven is one of a new class of anticancer agents that are analogues of mushroom-derived illudin toxins. Preclinical studies and clinical trials have shown that irofulven is effective against several tumor cell types. The exact nature of irofulven-induced DNA damage is not completely understood. Previously, we have shown that irofulven activates ATM and its targets, NBS1, SMC1, CHK2, and p53. In this study, we hypothesize that irofulven induces DNA double-strand breaks and FANCD2 may play an important role in modulating cellular responses and chemosensitivity in response to irofulven treatment. By using cells that are proficient or deficient for FANCD2, ATR, or ATM, we showed that irofulven induces FANCD2 monoubiquitination and nuclear foci formation. ATR is important in mediating irofulven-induced FANCD2 monoubiquitination. Furthermore, we showed that FANCD2 plays a critical role in maintaining chromosome integrity and modulating chemosensitivity in response to irofulven-induced DNA damage. Therefore, this study suggests that it might be clinically significant to target irofulven therapy to cancers defective for proteins of the Fanconi anemia-BRCA pathway. PMID:17172419

Wang, Yutian; Wiltshire, Timothy; Senft, Jamie; Wenger, Sharon L; Reed, Eddie; Wang, Weixin

2006-12-01

108

BRCA1 contributes to cell cycle arrest and chemoresistance in response to the anticancer agent irofulven.  

PubMed

Tumor suppressor gene BRCA1 is frequently mutated in familial breast and ovarian cancer. BRCA1 plays pivotal roles in maintaining genomic stability by interacting with numerous proteins in cell cycle control and DNA repair. Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114, NSC 683863) is one of a new class of anticancer agents that are analogs of mushroom-derived illudin toxins. Preclinical studies and clinical trials have demonstrated that irofulven is effective against several tumor cell types. The exact nature of irofulven-induced DNA damage is not completely understood. We demonstrated previously that irofulven activates ATM and its targets, NBS1, SMC1, CHK2, and p53. In this study, we hypothesize that irofulven induces DNA double-strand breaks and that BRCA1 may affect chemosensitivity by controlling cell cycle checkpoints, DNA repair, and genomic stability in response to irofulven treatment. We observed that irofulven induces the formation of chromosome breaks and radials and the activation and foci formation of gamma-H2AX, BRCA1, and RAD51. We also provided evidence that irofulven induces the generation of DNA double-strand breaks. By using BRCA1-deficient or -proficient cells, we demonstrated that in response to irofulven, BRCA1 contributes to the control of S and G(2)/M cell cycle arrest and is critical for repairing DNA double-strand breaks and for RAD51-dependent homologous recombination. Furthermore, we found that BRCA1 deficiency results in increased chromosome damage and chemosensitivity after irofulven treatment. PMID:17229870

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

2007-01-17

109

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

PubMed

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

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

2013-02-01

110

Synthesis and biological evaluation of ursolic acid-triazolyl derivatives as potential anti-cancer agents.  

PubMed

A series of ursolic acid-1-phenyl-1H-[1,2,3]triazol-4-ylmethylester congeners have been designed and synthesized in an attempt to develop potent antitumor agents. A regioselective approach using Huisgen 1,3-dipolar cycloaddition reaction of ursolic acid-alkyne derivative with various aromatic azides was employed to target an array of triazolyl derivatives in an efficient manner. Their structures were confirmed by using (1)H NMR, (13)C NMR, IR and MS analysis. All the compounds were evaluated for anti-cancer activity against a panel of four human cancer cell lines including A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2) using sulforhodamine-B assay. The pharmacological results showed that most of the compounds displayed high level of antitumor activities against the tested cancer cell lines compared with ursolic acid. Compounds 7b, 7g, 7p and 7r were found to be the most potent compounds in this study. PMID:23811086

Rashid, Showkat; Dar, Bilal Ahmad; Majeed, Rabiya; Hamid, Abid; Bhat, Bilal Ahmad

2013-06-07

111

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

PubMed Central

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

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

2011-01-01

112

Mitochondrial complex II, a novel target for anti-cancer agents.  

PubMed

With the arrival of the third millennium, in spite of unprecedented progress in molecular medicine, cancer remains as untamed as ever. The complexity of tumours, dictating the potential response of cancer cells to anti-cancer agents, has been recently highlighted in a landmark paper by Weinberg and Hanahan on hallmarks of cancer [1]. Together with the recently published papers on the complexity of tumours in patients and even within the same tumour (see below), the cure for this pathology seems to be an elusive goal. Indisputably, the strategy ought to be changed, searching for targets that are generally invariant across the landscape of neoplastic diseases. One such target appears to be the mitochondrial complex II (CII) of the electron transfer chain, a recent focus of research. We document and highlight this particularly intriguing target in this review paper and give examples of drugs that use CII as their molecular target. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease. PMID:23142170

Kluckova, Katarina; Bezawork-Geleta, Ayanachew; Rohlena, Jakub; Dong, Lanfeng; Neuzil, Jiri

2012-11-06

113

Antigen shedding may improve efficiencies for delivery of antibody-based anticancer agents in solid tumors  

PubMed Central

Recombinant immunotoxins (RIT) are targeted anti-cancer agents that are composed of a targeting antibody fragment and a protein toxin fragment. SS1P is a RIT that targets mesothelin on the surface of cancer cells and is being evaluated in patients with mesothelioma. Mesothelin, like many other target antigens, is shed from the cell surface. However, whether antigen shedding positively or negatively affects the delivery of RIT remains unknown. In this study, we used experimental data with SS1P to develop a mathematical model that describes the relationship between tumor volume changes and the dose level of the administered RIT, while accounting for the potential effects of antigen shedding. We found that antigen shedding is a favorable biological process for targeted therapy of solid tumors. Shed antigens acted as a protective reservoir of RIT and buffered against the well-known binding site barrier effect, promoting a more uniform distribution of RIT in the tumor. In addition, our model reproduced the decrease in tumor size upon RIT treatment in animal experiments. Our findings therefore can be used to study the delivery efficacy of RITs and also antibody drug conjugates currently in clinical trials.

Pak, Youngshang; Zhang, Yujian; Pastan, Ira; Lee, Byungkook

2012-01-01

114

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

PubMed

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

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

2012-07-04

115

The anticancer agent prodigiosin induces p21 WAF1\\/CIP1 expression via transforming growth factor-beta receptor pathway  

Microsoft Academic Search

The anticancer agent prodigiosin has been shown to act as an efficient immunosuppressant, eliciting cell cycle arrest at non-cytotoxic concentrations, and potent proapoptotic and antimetastatic effects at higher concentrations. Gene expression profiling of MCF-7 cells after treatment with a non-cytotoxic concentration of prodigiosin showed that expression of the p21WAF1\\/CIP1 gene, a negative cell cycle regulator was induced. In this study,

Vanessa Soto-Cerrato; Francesc Viñals; James R. Lambert; Ricardo Pérez-Tomás

2007-01-01

116

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

Microsoft Academic Search

A new anthracycline derivative, SM5887, in combination with commonly used anticancer agents was evaluated against T-cell leukemia MOLT-3 and human osteosarcoma MG-63 cell lines in culture. MOLT-3 and MG-63 cells were incubated with various concentrations of 13-hydroxy SM5887 (SM5887-OH, the active metabolite of SM5887) and other drugs for 3 and 4 days, respectively. Cell growth inhibition was determined by MTT

Tatsuya Takagi; Yasuo Yazawa I; Kenichi Suzuki; Yasuo Yamauchi; Yasuhiko Kano

1996-01-01

117

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

Microsoft Academic Search

Dushinsky et al. left a great gift to human beings with the discovery of 5-fluorouracil (5-FU). Approximately 50 years have elapsed from that discovery to the development of S-1 (TS-1w). The concept of developing an anticancer agent that simultaneously possesses both efficacy- enhancing and adverse reaction-reducing effects could be achieved only with a three- component combination drug. S-1 is an

Tetsuhiko Shirasaka

2008-01-01

118

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

PubMed Central

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

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

2009-01-01

119

Biotransformation of podophyllotoxin to picropodophyllin by microbes.  

PubMed

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

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

1998-01-01

120

Recent developments of steroid sulfatase inhibitors as anti-cancer agents.  

PubMed

The steroid sulfatase (STS) enzyme plays a pivotal role in the formation of biologically active steroid hormones. Its involvement in the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, is an important step in the formation of estradiol and androstenediol, both of which are estrogenic steroids that can stimulate tumor growth. Consequently, as STS is widely distributed throughout the entire body, it has a substantial influence on hormone-dependent cancer mitogenesis. It is a useful prognostic marker of disease as a significant majority of breast tumors over-express the enzyme and there are indications of STS having a role in prostate cancer. This knowledge has led to the development of potent STS inhibitors for use as anti-cancer agents. There are now several steroidal and non-steroidal STS inhibitors available. New in vivo models, using ovariectomized female nude mice, have been developed to pre-clinically test these inhibitors. These studies have demonstrated the excellent efficacy and effect of STS inhibitors on breast carcinoma development. Recently, 667 COUMATE, an irreversible type of inhibitor which utilizes a phenol sulfamate ester as its active pharmacophore, has completed a Phase I clinical trial in postmenopausal women with breast cancer. These studies have indicated the potential clinical benefit for the use of STS inhibitors. Most pre-clinical and clinical studies have focused on breast cancer as the target for STS inhibition. However, there are other hormone-dependent malignancies, such as endometrial and prostate cancer, that could in the future be treated with these new potent STS inhibitors. PMID:18855575

Foster, Paul A; Reed, Michael J; Purohit, Atul

2008-10-01

121

Intraarterial infusion chemotherapy for metastatic liver tumors using multiple anti-cancer agents suspended in a lipid contrast medium.  

PubMed

An ethiodized oil, Lipiodol (Lipiodol Ultra-Fluid, Laboratoire Guerbet, Paris, France), when injected into the hepatic artery, is selectively retained by liver tumors. Thus, anti-cancer agents suspended in Lipiodol can be delivered specifically to liver tumors. Before clinical trials of this new drug delivery system were begun, the movements of drugs suspended in Lipiodol were examined in vitro. It was found that 5-fluorouracil, doxorubicin, and mitomycin C were continuously released from oil phase to water phase, and when these three drugs were collectively suspended in Lipiodol, each was released independently. During clinical investigations, 42 patients with unresectable metastatic liver tumors were treated with intraarterial infusions of anti-cancer drugs in Lipiodol. As a result, the administration of a combination of anti-cancer agents suspended in Lipiodol was shown to be effective in controlling metastatic liver tumors. It was concluded that such a method could be applied to a variety of metastatic liver tumors with different drug sensitivities. PMID:2553236

Taniguchi, H; Takahashi, T; Yamaguchi, T; Sawai, K

1989-11-15

122

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

PubMed Central

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

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

2012-01-01

123

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

PubMed

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

Brück, Thomas B; Brück, Dieter W

2010-09-29

124

Hydrazides/Hydrazones as Antimicrobial and Anticancer Agents in The New Millennium.  

PubMed

Hydrazide/hydrazone derivatives are of quite interest for medicinal chemists because of their vast spectrum of biological activity. Literature reports reveal that the hydrazide derivatives have been extensively studied for their biological profile during the past decade. The aim of the present work is to collect literature reports focusing the antimicrobial and anticancer study of different hydrazide/hydrazone derivatives carried out during the past decade which will serve as a valuable source of information for the researchers working in the field of antimicrobial and anticancer research. PMID:23621636

Kumar, Pradeep; Narasimhan, Balasubramanian

2013-04-25

125

Hydrazides/hydrazones as antimicrobial and anticancer agents in the new millennium.  

PubMed

Hydrazide/hydrazone derivatives are of quite interest for medicinal chemists because of their vast spectrum of biological activity. Literature reports reveal that the hydrazide derivatives have been extensively studied for their biological profile during the past decade. The aim of the present work is to collect literature reports focusing the antimicrobial and anticancer study of different hydrazide/hydrazone derivatives carried out during the past decade which will serve as a valuable source of information for the researchers working in the field of antimicrobial and anticancer research. PMID:23621689

Kumar, Pradeep; Narasimhan, Balasubramanian

2013-06-01

126

The Thioredoxin System Mediates Redox-Induced Cell Death in Human Colon Cancer Cells: Implications for the Mechanism of Action of Anticancer Agents  

Microsoft Academic Search

Anticancer agents act, at least in part, by inducing reactive oxygen and nitrogen species (RONS). We examined the redox effect on SW480 and HT-29 colon cancer cells of four anticancer compounds, arsenic trioxide, phosphoaspirin, phosphosulindac, and nitric oxide-donating aspirin (NO- ASA). All compounds inhibited the growth of both cell lines (IC50, 10-90 Mmol\\/L) and induced RONS detected by a general

Yu Sun; Basil Rigas

127

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.

Bhattacharya, Arup

2011-01-01

128

Dual Extraction of Essential Oil and Podophyllotoxin from Juniperus virginiana  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

129

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.

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

2011-01-01

130

2H-chromene derivatives bearing thiazolidine-2,4-dione, rhodanine or hydantoin moieties as potential anticancer agents.  

PubMed

A variety of (Z)-[(2H-chromen-3-yl)methylene]azolidinones 6a-t bearing thiazolidine-2,4-dione, rhodanine or hydantoin scaffolds were designed and synthesized as potential anticancer agents. Inhibitory effect of synthesized compounds 6a-t on the viability of cancer and non-cancer cells was assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) reduction assay. The SAR study revealed that the N-substitution of azolidinone moiety cannot improve the activity but S/NH replacement (thiazolidine-2,4-dione/hydantoin) and S/O alteration (rhodanine/thiazolidine-2,4-dione) enable us to modulate the growth inhibition activity against various cell lines. Moreover, 6-bromo and 2-methyl substituents on chromene ring had positive effects on growth inhibitory activity depending on the tumor cell lines. Among the synthesized compounds, hydantoin derivative 6o with a 6-bromo-2-methyl-2H-chromene substructure showed the best profile of cytotoxicity comparable to that of cisplatin as standard anticancer agent. PMID:23202485

Azizmohammadi, Mohammad; Khoobi, Mehdi; Ramazani, Ali; Emami, Saeed; Zarrin, Abdolhossein; Firuzi, Omidreza; Miri, Ramin; Shafiee, Abbas

2012-11-02

131

Potential use of cetrimonium bromide as an apoptosis-promoting anticancer agent for head and neck cancer.  

PubMed

A potential therapeutic agent for human head and neck cancer (HNC), cetrimonium bromide (CTAB), was identified through a cell-based phenotype-driven high-throughput screen (HTS) of 2000 biologically active or clinically used compounds, followed by in vitro and in vivo characterization of its antitumor efficacy. The preliminary and secondary screens were performed on FaDu (hypopharyngeal squamous cancer) and GM05757 (primary normal fibroblasts), respectively. Potential hit compounds were further evaluated for their anticancer specificity and efficacy in combination with standard therapeutics on a panel of normal and cancer cell lines. Mechanism of action, in vivo antitumor efficacy, and potential lead compound optimizations were also investigated. In vitro, CTAB interacted additively with gamma radiation and cisplatin, two standard HNC therapeutic agents. CTAB exhibited anticancer cytotoxicity against several HNC cell lines, with minimal effects on normal fibroblasts; a selectivity that exploits cancer-specific metabolic aberrations. The central mode of cytotoxicity was mitochondria-mediated apoptosis via inhibition of H(+)-ATP synthase activity and mitochondrial membrane potential depolarization, which in turn was associated with reduced intracellular ATP levels, caspase activation, elevated sub-G(1) cell population, and chromatin condensation. In vivo, CTAB ablated tumor-forming capacity of FaDu cells and delayed growth of established tumors. Thus, using an HTS approach, CTAB was identified as a potential apoptogenic quaternary ammonium compound possessing in vitro and in vivo efficacy against HNC models. PMID:19654225

Ito, Emma; Yip, Kenneth W; Katz, David; Fonseca, Sonali B; Hedley, David W; Chow, Sue; Xu, G Wei; Wood, Tabitha E; Bastianutto, Carlo; Schimmer, Aaron D; Kelley, Shana O; Liu, Fei-Fei

2009-08-04

132

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

PubMed

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

Kosani?, Marijana; Manojlovi?, Nedeljko; Jankovi?, Slobodan; Stanojkovi?, Tatjana; Rankovi?, Branislav

2012-12-05

133

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

PubMed

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

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

2013-05-01

134

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)

2009-11-25

135

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.

Deng, Yuxia; Zhang, Haijun

2013-01-01

136

Anthracenedione Derivatives as Anticancer Agents Isolated from Secondary Metabolites of the Mangrove Endophytic Fungi  

PubMed Central

In this article, we report anticancer activity of 14 anthracenedione derivatives separated from the secondary metabolites of the mangrove endophytic fungi Halorosellinia sp. (No. 1403) and Guignardia sp. (No. 4382). Some of them inhibited potently the growth of KB and KBv200 cells, among which compound 6 displayed strong cytotoxicity with IC50 values of 3.17 and 3.21 ?M to KB and KBv200 cells, respectively. Furthermore, we demonstrate that the mechanism involved in the apoptosis induced by compound 6 is probably related to mitochondrial dysfunction. Additionally, the structure-activity relationships of these compounds are discussed.

Zhang, Jian-ye; Tao, Li-yang; Liang, Yong-ju; Chen, Li-ming; Mi, Yan-jun; Zheng, Li-sheng; Wang, Fang; She, Zhi-gang; Lin, Yong-cheng; To, Kenneth Kin Wah; Fu, Li-wu

2010-01-01

137

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

PubMed

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

2013-03-21

138

Characterization of a gene cluster responsible for the biosynthesis of anticancer agent FK228 in Chromobacterium violaceum No. 968.  

PubMed

A gene cluster responsible for the biosynthesis of anticancer agent FK228 has been identified, cloned, and partially characterized in Chromobacterium violaceum no. 968. First, a genome-scanning approach was applied to identify three distinctive C. violaceum no. 968 genomic DNA clones that code for portions of nonribosomal peptide synthetase and polyketide synthase. Next, a gene replacement system developed originally for Pseudomonas aeruginosa was adapted to inactivate the genomic DNA-associated candidate natural product biosynthetic genes in vivo with high efficiency. Inactivation of a nonribosomal peptide synthetase-encoding gene completely abolished FK228 production in mutant strains. Subsequently, the entire FK228 biosynthetic gene cluster was cloned and sequenced. This gene cluster is predicted to encompass a 36.4-kb DNA region that includes 14 genes. The products of nine biosynthetic genes are proposed to constitute an unusual hybrid nonribosomal peptide synthetase-polyketide synthase-nonribosomal peptide synthetase assembly line including accessory activities for the biosynthesis of FK228. In particular, a putative flavin adenine dinucleotide-dependent pyridine nucleotide-disulfide oxidoreductase is proposed to catalyze disulfide bond formation between two sulfhydryl groups of cysteine residues as the final step in FK228 biosynthesis. Acquisition of the FK228 biosynthetic gene cluster and acclimation of an efficient genetic system should enable genetic engineering of the FK228 biosynthetic pathway in C. violaceum no. 968 for the generation of structural analogs as anticancer drug candidates. PMID:17400765

Cheng, Yi-Qiang; Yang, Min; Matter, Andrea M

2007-03-30

139

Characterization of a Gene Cluster Responsible for the Biosynthesis of Anticancer Agent FK228 in Chromobacterium violaceum No. 968?  

PubMed Central

A gene cluster responsible for the biosynthesis of anticancer agent FK228 has been identified, cloned, and partially characterized in Chromobacterium violaceum no. 968. First, a genome-scanning approach was applied to identify three distinctive C. violaceum no. 968 genomic DNA clones that code for portions of nonribosomal peptide synthetase and polyketide synthase. Next, a gene replacement system developed originally for Pseudomonas aeruginosa was adapted to inactivate the genomic DNA-associated candidate natural product biosynthetic genes in vivo with high efficiency. Inactivation of a nonribosomal peptide synthetase-encoding gene completely abolished FK228 production in mutant strains. Subsequently, the entire FK228 biosynthetic gene cluster was cloned and sequenced. This gene cluster is predicted to encompass a 36.4-kb DNA region that includes 14 genes. The products of nine biosynthetic genes are proposed to constitute an unusual hybrid nonribosomal peptide synthetase-polyketide synthase-nonribosomal peptide synthetase assembly line including accessory activities for the biosynthesis of FK228. In particular, a putative flavin adenine dinucleotide-dependent pyridine nucleotide-disulfide oxidoreductase is proposed to catalyze disulfide bond formation between two sulfhydryl groups of cysteine residues as the final step in FK228 biosynthesis. Acquisition of the FK228 biosynthetic gene cluster and acclimation of an efficient genetic system should enable genetic engineering of the FK228 biosynthetic pathway in C. violaceum no. 968 for the generation of structural analogs as anticancer drug candidates.

Cheng, Yi-Qiang; Yang, Min; Matter, Andrea M.

2007-01-01

140

Preclinical Assessment of Vernonia amygdalina Leaf Extracts as DNA Damaging Anti-cancer Agent in the Management of Breast Cancer  

PubMed Central

Breast cancer is the leading cause of death among women between 40 and 55 years of age and is the second overall cause of death among women. Fortunately, the mortality rate from breast cancer has decreased in recent years due to an increased emphasis on early detection and more effective treatments. Despite early detection, conventional and chemotherapeutic methods of treatment, about 7% of women still died every year. Hence, the aim of the present study was to assess the therapeutic efficacy of vernonia amygdalina (VA) leaf extracts as anti-cancer agent against human breast cancer in vitro using the MTT [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and alkaline single cell gel electrophoresis (Comet) assays, respectively. In this experiment, human breast adenocarcinoma (MCF-7) cells were treated with different doses of VA leaf extracts for 48 hours. Data obtained from the MTT assay showed that VA significantly ((P < 0.05) reduced the viability of MCF-7 cells in a dose-dependent manner upon 48 hours of exposure. Data generated from the comet assay also indicated a slight dose-dependent increase in DNA damage in MCF-7 cells associated with VA treatment. We observed a slight increase in comet tail-length, tail arm and tail moment, as well as in percentages of DNA cleavage at all doses tested, showing an evidence that VA-induced minimal genotoxic damage in MCF-7 cells. Taken together, our findings suggest that VA treatment moderately (P < 0.05) reduces cellular viability and induces minimal DNA damage in MCF-7 cells. These findings provide evidence that VA extracts represent a DNA-damaging anti-cancer agent against breast cancer and its mechanisms of action functions, at least in part, through minimal DNA damage and moderate toxicity in tumors cells.

Yedjou, Clement; Izevbigie, Ernest; Tchounwou, Paul

2008-01-01

141

Preclinical assessment of vernonia amygdalina leaf extracts as DNA damaging anti-cancer agent in the management of breast cancer.  

PubMed

Breast cancer is the leading cause of death among women between 40 and 55 years of age and is the second overall cause of death among women. Fortunately, the mortality rate from breast cancer has decreased in recent years due to an increased emphasis on early detection and more effective treatments. Despite early detection, conventional and chemotherapeutic methods of treatment, about 7% of women still died every year. Hence, the aim of the present study was to assess the therapeutic efficacy of vernonia amygdalina (VA) leaf extracts as anti-cancer agent against human breast cancer in vitro using the MTT [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide[ and alkaline single cell gel electrophoresis (Comet) assays, respectively. In this experiment, human breast adenocarcinoma (MCF-7) cells were treated with different doses of VA leaf extracts for 48 hours. Data obtained from the MTT assay showed that VA significantly ((P < 0.05) reduced the viability of MCF-7 cells in a dose-dependent manner upon 48 hours of exposure. Data generated from the comet assay also indicated a slight dose-dependent increase in DNA damage in MCF-7 cells associated with VA treatment. We observed a slight increase in comet tail-length, tail arm and tail moment, as well as in percentages of DNA cleavage at all doses tested, showing an evidence that VA-induced minimal genotoxic damage in MCF-7 cells. Taken together, our findings suggest that VA treatment moderately (P < 0.05) reduces cellular viability and induces minimal DNA damage in MCF-7 cells. These findings provide evidence that VA extracts represent a DNA-damaging anti-cancer agent against breast cancer and its mechanisms of action functions, at least in part, through minimal DNA damage and moderate toxicity in tumors cells. PMID:19151427

Yedjou, Clement; Izevbigie, Ernest; Tchounwou, Paul

2008-12-01

142

Indole3-carbinol as a chemopreventive and anti-cancer agent  

Microsoft Academic Search

During the course of oncogenesis and tumor progression, cancer cells constitutively upregulate signaling pathways relevant to cell proliferation and survival as a strategy to overcome genomic instability and acquire resistance phenotype to chemotherapeutic agents. In light of this clinical and molecular heterogeneity of human cancers, it is desirable to concomitantly target these genetic abnormalities by using an agent with pleiotropic

Jing-Ru Weng; Chen-Hsun Tsai; Samuel K. Kulp; Ching-Shih Chen

2008-01-01

143

The Anticancer Agent Adriamycin Can be Actively Cytotoxic without Entering Cells  

NASA Astrophysics Data System (ADS)

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

Tritton, Thomas R.; Yee, Gene

1982-07-01

144

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

PubMed

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

Kryshchyshyn, Anna; Atamanyuk, Dmytro; Lesyk, Roman

2012-05-03

145

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

PubMed Central

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

Kryshchyshyn, Anna; Atamanyuk, Dmytro; Lesyk, Roman

2012-01-01

146

BPR0C305, an orally active microtubule-disrupting anticancer agent.  

PubMed

BPR0C305 is a novel N-substituted indolyl glyoxylamide previously reported with in-vitro cytotoxic activity against a panel of human cancer cells including P-gp-expressing multiple drug-resistant cell sublines. The present study further examined the underlying molecular mechanism of anticancer action and evaluated the in-vivo antitumor activities of BPR0C305. BPR0C305 is a novel synthetic small indole derivative that demonstrates in-vitro activities against human cancer cell growth by inhibiting tubulin polymerization, disrupting cellular microtubule assembly, and causing cell cycle arrest at the G2/M phase. It is also orally active against leukemia and solid tumor growths in mouse models. Findings of these pharmacological and pharmacokinetic studies suggest that BPR0C305 is a promising lead compound for further preclinical developments. PMID:24025560

Li, Wen-Tai; Yeh, Teng-Kuang; Song, Jen-Shin; Yang, Yung-Ning; Chen, Tung-Wei; Lin, Chi-Hung; Chen, Ching-Ping; Shen, Chien-Chang; Hsieh, Chih-Chien; Lin, Heng-Liang; Chao, Yu-Sheng; Chen, Chiung-Tong

2013-11-01

147

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

PubMed

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

2013-08-21

148

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

PubMed

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 LD(50) of HN-2 (20mg/kg) percutaneously, decreased WBC count from 24h onwards. Liver glutathione (GSH) level decreased prominently and the maximum depletion was observed on 7th day post-HN-2 administration. Oxidised glutathione (GSSG) level increased significantly at 24h post-administration and subsequently showed a progressive decrease. Hepatic malondialdehyde (MDA) level and percent DNA damage increased progressively following HN-2 administration. The spleen weight decreased progressively and reached a minimum on 3-4 days with subsequent increase. The antidotes were administered repeatedly for 4 and 8 days after percutaneous administration of single sublethal dose (0.5 and 0.25 LD(50)) of HN-2. Treatment with DRDE-07, DRDE-30 and DRDE-35 significantly protected the changes in spleen weight, WBC count, GSH, GSSG, MDA and DNA damage following HN-2 administration (0.5 and 0.25 LD(50)). There was no alteration in the transaminases (AST and ALT), and alkaline phosphatase (ALP) activities, neither with HN-2 nor with antidotes. The present study shows that HN-2 is highly toxic by percutaneous route and DRDE-07, DRDE-30 and DRDE-35 can partially protect it. PMID:19397960

Sharma, Manoj; Vijayaraghavan, R; Gautam, Anshoo

2009-05-03

149

Dinitroazetidines are a novel class of anticancer agents and hypoxia-activated radiation sensitizers developed from highly energetic materials.  

PubMed

In an effort to develop cancer therapies that maximize cytotoxicity, while minimizing unwanted side effects, we studied a series of novel compounds based on the highly energetic heterocyclic scaffold, dinitroazetidine. In this study, we report the preclinical validation of 1-bromoacetyl-3,3-dinitroazetidine (ABDNAZ), a representative lead compound currently in a phase I clinical trial in patients with cancer. In tumor cell culture, ABDNAZ generated reactive free radicals in a concentration- and time-dependent manner, modulating intracellular redox status and triggering apoptosis. When administered to mice as a single agent, ABDNAZ exhibited greater cytotoxicity than cisplatin or tirapazamine under hypoxic conditions. However, compared with cisplatin, ABDNAZ was better tolerated at submaximal doses, yielding significant tumor growth inhibition in the absence of systemic toxicity. Similarly, when combined with radiation, ABDNAZ accentuated antitumor efficacy along with the therapeutic index. Toxicity studies indicated that ABDNAZ was not myelosuppressive and no dose-limiting toxicity was apparent following daily administration for 14 days. Taken together, our findings offer preclinical proof-of-concept for ABDNAZ as a promising new anticancer agent with a favorable toxicity profile, either as a chemotherapeutic agent or a radiosensitizer. PMID:22589277

Ning, Shoucheng; Bednarski, Mark; Oronsky, Bryan; Scicinski, Jan; Saul, Gordon; Knox, Susan J

2012-05-15

150

Hypersensitivity reactions to anticancer agents: Data mining of the public version of the FDA adverse event reporting system, AERS  

PubMed Central

Background Previously, adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) database were reviewed to confirm platinum agent-associated hypersensitivity reactions. The present study was performed to confirm whether the database could suggest the hypersensitivity reactions caused by anticancer agents, paclitaxel, docetaxel, procarbazine, asparaginase, teniposide, and etoposide. Methods After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving candidate agents were analyzed. The National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 was applied to evaluate the susceptibility to hypersensitivity reactions, and standardized official pharmacovigilance tools were used for quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Results Based on 1,644,220 AERs from 2004 to 2009, the signals were detected for paclitaxel-associated mild, severe, and lethal hypersensitivity reactions, and docetaxel-associated lethal reactions. However, the total number of adverse events occurring with procarbazine, asparaginase, teniposide, or etoposide was not large enough to detect signals. Conclusions The FDA's adverse event reporting system, AERS, and the data mining methods used herein are useful for confirming drug-associated adverse events, but the number of co-occurrences is an important factor in signal detection.

2011-01-01

151

Podophyllotoxin directly binds a hinge domain in E2 of HPV and inhibits an E2/E7 interaction in vitro.  

PubMed

Podophyllotoxin (PT), a strong cytotoxic agent from berberidaceae, has been known to inhibit tubulin polymerization. Although PT has been used for developing anticancer drugs as one of seed compounds, clinical treatment by itself has been unsuccessful because of the side effects, except one example in the treatments of warts. In this study, we screened peptides binding to PT with T7 phage display clonings in order to obtain more information about molecular mechanism of the action. A selected phage clone has a specific amino acid sequence to be SVPSRRRPDGRTHRSSRG. A homology search by protein database BLAST showed that this sequence had a similarity to a hinge domain (HD) of E2 protein in human papillomavirus (HPV) type 1a which is known to cause plantar warts. Surface plasmon resonance (SPR) analysis showed that PT bound to a recombinant HPV 1a E2 protein giving a K(D)=24.1microM which has compared with those of other domains of E2 protein. Also we demonstrated whether PT inhibited HD interaction or not. E7 protein of HPV has been known to be an oncoprotein and was reported to interact with HD of E2 protein. We demonstrated that an E2/E7 interaction was inhibited by the addition of PT in this report. And we showed the bindings of PT to other types of HPV. Our results suggest that PT is potential as a tool for clarifying the molecular mechanism of HPV. PMID:18396405

Saitoh, Takeki; Kuramochi, Kouji; Imai, Takahiko; Takata, Kei-ichi; Takehara, Masahide; Kobayashi, Susumu; Sakaguchi, Kengo; Sugawara, Fumio

2008-03-25

152

Intercalating agents with covalent bond forming capability. A novel type of potential anticancer agents. 2. Derivatives of chrysophanol and emodin.  

PubMed

Fifty-one new C-methyl-modified derivatives of the anthraquinones chrysophanol and emodin or their various methyl ethers were prepared for structure-activity relationship studies of anticancer activity against mouse leukemia L1210 and human leukemia HL-60 cells. Representative compounds were spectrophotometrically studied for their capacity to interact with natural and denatured DNA. In general, those anthraquinones bearing an amino function interact with DNA. 1,8-Dimethoxyanthraquinones are incapable of intercalating into DNA. 1- or 8-Monohydroxymono-methoxyanthraquinones, however, interact with DNA to some extent. No straightforward correlation is apparent between the DNA-affinity data of the compounds studied spectrophotometrically and their cytotoxic effects. Cytotoxic potencies of these compounds on cell growth inhibition during a 72-h period are inversely correlated to their potencies when inhibiting [3H]TdR incorporation into DNA during the initial 30 min of exposure. Surprisingly, some compounds that showed more cytotoxicity did not inhibit initial TdR incorporation (0-30 min), while some others that strongly inhibited TdR incorporation initially did not exhibit cytotoxicity in 72 h. The results suggest that the cytotoxicity produced by these compounds is time dependent and is not a direct result of initial inhibition of DNA replication. PMID:2738893

Koyama, M; Takahashi, K; Chou, T C; Darzynkiewicz, Z; Kapuscinski, J; Kelly, T R; Watanabe, K A

1989-07-01

153

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

NASA Astrophysics Data System (ADS)

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

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

154

Synthesis, cytotoxicity, and pro-apoptosis activity of etodolac hydrazide derivatives as anticancer agents.  

PubMed

Etodolac hydrazide and a novel series of etodolac hydrazide-hydrazones 3-15 and etodolac 4-thiazolidinones 16-26 were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, (1)H NMR, (13)C NMR, HREI-MS) methods. Some selected compounds were determined at one dose toward the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI, Bethesda, USA). 2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetic acid[(4-chlorophenyl)methylene]hydrazide 9 demonstrated the most marked effect on the prostate cancer cell line PC-3, with 58.24% growth inhibition at 10(-5) M (10 µM). Using the MTT colorimetric method, compound 9 was evaluated in vitro against the prostate cell line PC-3 and the rat fibroblast cell line L-929, for cell viability and growth inhibition at different doses. Compound 9 exhibited anticancer activity with an IC(50) value of 54 µM (22.842 µg/mL) against the PC-3 cells and did not display any cytotoxicity toward the L-929 rat fibroblasts, compared to etodolac. In addition, this compound was evaluated for caspase-3 and Bcl-2 activation in the apoptosis pathway, which plays a key role in the treatment of cancer. PMID:23609809

Ç?kla, Pelin; Özsavc?, Derya; Bingöl-Özakp?nar, Özlem; ?ener, Azize; Çevik, Özge; Özba?-Turan, Suna; Akbu?a, Jülide; ?ahin, Fikrettin; Küçükgüzel, ? Güniz

2013-04-22

155

Synthesis and evaluation of polymeric gold glyco-conjugates as anti-cancer agents.  

PubMed

The antitumor activity of organo-gold compounds is a focus of research from the past two decades. A variety of gold stabilizing ligands such as vitamins and xanthanes have been prepared and explored for their 'chelating effect' as well as for their antitumor activity. Dithiocarbamates (DTC) compounds and their metallic conjugates have been well explored for their antiproliferative activities. In this study, glycopolymer based DTC-conjugates are prepared by reversible addition-fragmentation chain transfer polymerization (RAFT) and subsequently modified with gold(I) phosphine. These polymer-DTC derivatives and their gold compounds are tested for their in vitro toxicity in both normal and cancer cell lines. The Au(I) phosphine conjugated cationic glycopolymers of 10 kDa and 30 kDa are evaluated for their cytotoxicity profiles using MTT assay. Au(I) compounds are well-known for their mitochondrial toxicity, hence hypoxic cell lines bearing unusually enlarged mitochondria are subjected to these anticancer compounds. It is concluded that these polymeric DTC derivatives and their gold conjugates indeed show higher accumulation as well as cytotoxicity to cancer cells under hypoxic conditions in comparison to the normoxic ones. Hypoxic MCF-7 cells showed significant sensitivity toward the low molecular weight (10 kDa) glycopolymer-Au(I) complexes. PMID:23631753

Ahmed, Marya; Mamba, Saul; Yang, Xiao-Hong; Darkwa, James; Kumar, Piyush; Narain, Ravin

2013-05-16

156

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

PubMed Central

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

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

2012-01-01

157

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

PubMed

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

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

2012-10-25

158

Synthesis and bioactivity evaluation of new 6-aryl-5-cyano thiouracils as potential antimicrobial and anticancer agents.  

PubMed

Several novel 6-aryl-5-cyano thiouracil derivatives were synthesized and explored for their activities as antibacterial, antifungal and anticancer agents. The antimicrobial evaluation revealed that compounds 7b and 7c possessed superior antibacterial activity against the Gram positive bacteria S. aureus and B. subtilis compared to the reference drug amoxicillin. Moreover, compound 4i was found to be a broad spectrum antimicrobial agent and it also exhibited the highest antifungal activity against C. albicans, even higher than the reference drug amphotericin B (MIC = 2.34, 3.00 ?g/mL respectively). Selected compounds were tested for in vitro cytotoxicity at a single 10(-5) M concentration in accordance to the NCI (USA) protocol. The preliminary screening results showed that most of the compounds had limited cytotoxic activity against renal cancer UO-31 and/or A498 cell lines. Nevertheless, compounds 6d and 6i displayed potent growth inhibitory effect toward non-small cell lung cancer HOP-92 and leukemia MOLT-4 cell lines, respectively. PMID:22902882

Taher, Azza Taher; Abou-Seri, Sahar Mahmoud

2012-08-17

159

Recent advances in the development of 1,8-naphthalimide based DNA targeting binders, anticancer and fluorescent cellular imaging agents.  

PubMed

The development of functional 1,8-naphthalimide derivatives as DNA targeting, anticancer and cellular imaging agents is a fast growing area and has resulted in several such derivatives entering into clinical trials. This review gives an overview of the many discoveries and the progression of the use of 1,8-naphthalimides as such agents and their applications to date; focusing mainly on mono-, bis-naphthalimide based structures, and their various derivatives (e.g. amines, polyamine conjugates, heterocyclic, oligonucleotide and peptide based, and those based on metal complexes). Their cytotoxicity, mode of action and cell-selectivity are discussed and compared. The rich photophysical properties of the naphthalimides (which are highly dependent on the nature and the substitution pattern of the aryl ring) make them prime candidates as probes as the changes in spectroscopic properties such as absorption, dichroism, and fluorescence can all be used to monitor their binding to biomolecules. This also makes them useful species for monitoring their uptake and location within cells without the use of co-staining. The photochemical properties of the compounds have also been exploited, for example, for photocleavage of nucleic acids and for the destruction of tumour cells. PMID:23325367

Banerjee, Swagata; Veale, Emma B; Phelan, Caroline M; Murphy, Samantha A; Tocci, Gillian M; Gillespie, Lisa J; Frimannsson, Daniel O; Kelly, John M; Gunnlaugsson, Thorfinnur

2013-01-17

160

Improving the design of phase II trials of cytostatic anticancer agents.  

PubMed

This paper examines the design of phase II trials in oncology and recommends departing from the traditional uncontrolled trial design. Entrance into phase II clinical evaluation represents a key milestone in the development of any new cancer therapy. As novel molecular-targeted therapies are introduced, whose primary action is to slow the growth of tumors, it will be important to ensure that the clinical trial design will effectively capture any clinical benefit of these agents. The objective of a phase II trial should, in addition to identifying active therapies, be extended to identifying those that are likely to be successful in pivotal trials. It is therefore necessary to quantify the likelihood of either incorrectly halting the development of an active agent or continuing development of an ineffective agent. We believe only randomized studies with comparative intent and including a concurrent active control, can reliably assess these risks corresponding to significance and power. Given that the objective of phase II studies is to identify promising treatments, it is important not be constrained by conventional levels of significance. This paper will review the various approaches to phase II trial design in oncology and provide a framework for fully powered randomized trials of a moderate size. For example, a randomized trial of just 100 patients could lead to the termination of development of 90% of inactive agents whereas at least 80% of agents with a meaningful and realistic increase in progression-free survival would be identified for confirmatory study. We believe randomized studies with progression-free survival endpoints are the most powerful and economical method of determining the clinical activity of new cytostatic agents. PMID:16843736

Stone, Andrew; Wheeler, Catherine; Barge, Alan

2006-07-14

161

Modulation of the anti-cancer efficacy of microtubule-targeting agents by cellular growth conditions.  

PubMed

Mitotic spindle-disrupting agents target and disrupt microtubule dynamics. These agents include clinically important chemotherapies, including taxanes (paclitaxel (Taxol), docetaxel (Taxotere)) and vinca alkaloids (vincristine (Oncovin), vinblastine). Taxanes are a standard component of treatment for many malignancies, often in conjunction with other cytotoxic agents. However, the optimal sequencing of these treatments and whether efficacy may be influenced by in vitro cellular growth conditions remain incompletely investigated. Yet such preclinical investigations may guide clinical decision making. We therefore studied the effect of cell density on rapid killing by paclitaxel and vincristine. Breast, ovarian and prostate cancer cells were sensitive to rapid killing by either agent when grown at low density, but were markedly resistant when grown at high density, i.e. nearly confluent. The resistance of densely growing cells to rapid killing by these drugs translated to increased clonogenic survival. Pretreatment of densely growing cancer cells with cisplatin followed by paclitaxel, partially reversed the treatment resistance. Gene ontology associations from microarray analyses of cells grown at low and high density, suggested roles for membrane signal transduction and adhesion, but potentially also DNA damage repair and metabolism. Taken together, the treatment resistance at higher cell density may be associated with a lower proportion of active cycling in cells growing at high density as well as transduction of survival signals induced by increased cell-cell adhesion. Collectively these findings suggest mechanisms by which growth conditions may contribute to resistance to rapid killing by microtubule-disrupting drugs. PMID:20234172

Dorsey, Jay F; Dowling, Melissa L; Kim, Mijin; Voong, Ranh; Solin, Lawrence J; Kao, Gary D

2010-05-15

162

COMMENTARY Anticancer Agents Targeting Signaling Molecules and Cancer Cell Environment: Challenges for Drug Development?  

Microsoft Academic Search

The focus of drug development has moved from cytotoxic compounds identified by screening to therapies that act at spe- cific molecular targets. Although some of these agents may cause visible tumor reduction and may be adequately evaluated by standard oncology drug development methods, other novel therapies may not be amenable to our current practices. Conse- quently, our concepts of drug

Karen A. Gelmon; Elizabeth A. Eisenhauer; Adrian L. Harris; Mark J. Ratain; Paul Workman

1999-01-01

163

Potential use of alexidine dihydrochloride as an apoptosis-promoting anticancer agent.  

PubMed

Despite advances in surgery, radiation, and chemotherapy, novel therapeutics are needed for head and neck cancer treatment. The objective of this current study was to evaluate alexidine dihydrochloride as a novel compound lead for head and neck cancers. Using a tetrazolium-based assay, the dose required to reduce cell viability by 50% (ED50) was found to be approximately 1.8 micromol/L in FaDu (human hypopharyngeal squamous cancer) and approximately 2.6 micromol/L in C666-1 (human undifferentiated nasopharyngeal cancer) cells. In contrast, the ED50 values were much higher in untransformed cells, specifically at approximately 8.8 micromol/L in GM05757 (primary normal human fibroblast), approximately 8.9 micromol/L in HNEpC (primary normal human nasal epithelial), and approximately 19.6 micromol/L in NIH/3T3 (mouse embryonic fibroblast) cells. Alexidine dihydrochloride did not interfere with the activities of cisplatin, 5-fluorouracil, or radiation, and interacted in a less-than-additive manner. DNA content analyses and Hoechst 33342 staining revealed that this compound induced apoptosis. Alexidine dihydrochloride-induced mitochondrial damage was visualized using transmission electron microscopy. Mitochondrial membrane potential (DeltaPsiM) depolarization was detectable after only 3 hours of treatment, and was followed by cytosolic Ca2+ increase along with loss of membrane integrity/cell death. Caspase-2 and caspase-9 activities were detectable at 12 hours, caspase-8 at 24 hours, and caspase-3 at 48 hours. FaDu cell clonogenic survival was reduced to < 5% with 1 micromol/L alexidine dihydrochloride, and, correspondingly, this compound decreased the in vivo tumor-forming potential of FaDu cells. Thus, we have identified alexidine dihydrochloride as the first bisbiguanide compound with anticancer specificity. PMID:16985057

Yip, Kenneth W; Ito, Emma; Mao, Xinliang; Au, P Y Billie; Hedley, David W; Mocanu, Joseph D; Bastianutto, Carlo; Schimmer, Aaron; Liu, Fei-Fei

2006-09-01

164

Spectroscopic investigations on the interactions of potent platinum(II) anticancer agents with bovine serum albumin.  

PubMed

The interactions of three platinum(II)-based anticancer complexes [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)](2+), [(5,6-dimethyl-1,10-phenanthroline)(1R,2R-diaminocyclohexane)platinum(II)](2+), and [(5,6-dimethyl-1,10-phenanthroline)(1,2-diaminoethane)platinum(II)](2+) (56MEEN) with BSA have been examined by circular dichroism (CD), fluorescence and (1)H pulsed gradient spin-echo (PGSE) diffusion NMR spectroscopy. The number of association constants and sites differed depending upon the spectroscopic method. This may be because each technique monitors different types of interaction/s and/or as a consequence of the different concentration ranges required for each technique. The titration of BSA with the achiral 56MEEN as monitored by CD indicates a reduction in the ?-helical nature of the albumin, with the association constant calculated to be ~5?×?10(6) M(-1) for one site. Due to the chiral nature of the other two complexes, their association with albumin was not monitored using CD but was examined using fluorescence and PGSE diffusion NMR. Titration of BSA with any of the three metal complexes resulted in quenching of fluorescence, with the number of association sites calculated to be ~1.1, with an association constant of ~2?×?10(5) M(-1). PGSE diffusion NMR provided insights into interactions occurring with the BSA in its entirety, rather than with individual regions. Metal complex binding sites were estimated (~10 equivalent) from the diffusion data, with the average association constant for all sites ~10(2)-10(3)M(-1). These experiments highlight the information that can be elucidated from complementary spectroscopic techniques and demonstrate the usefulness of PGSE diffusion NMR in monitoring multiple weak binding sites, which is of great importance in studying drug-biomolecule interactions. PMID:23667391

Krause-Heuer, Anwen M; Price, William S; Aldrich-Wright, Janice R

2012-05-11

165

New pyrazolopyrimidine inhibitors of protein kinase d as potent anticancer agents for prostate cancer cells.  

PubMed

The emergence of protein kinase D (PKD) as a potential therapeutic target for several diseases including cancer has triggered the search for potent, selective, and cell-permeable small molecule inhibitors. In this study, we describe the identification, in vitro characterization, structure-activity analysis, and biological evaluation of a novel PKD inhibitory scaffold exemplified by 1-naphthyl PP1 (1-NA-PP1). 1-NA-PP1 and IKK-16 were identified as pan-PKD inhibitors in a small-scale targeted kinase inhibitor library assay. Both screening hits inhibited PKD isoforms at about 100 nM and were ATP-competitive inhibitors. Analysis of several related kinases indicated that 1-NA-PP1 was highly selective for PKD as compared to IKK-16. SAR analysis showed that 1-NA-PP1 was considerably more potent and showed distinct substituent effects at the pyrazolopyrimidine core. 1-NA-PP1 was cell-active, and potently blocked prostate cancer cell proliferation by inducing G2/M arrest. It also potently blocked the migration and invasion of prostate cancer cells, demonstrating promising anticancer activities on multiple fronts. Overexpression of PKD1 or PKD3 almost completely reversed the growth arrest and the inhibition of tumor cell invasion caused by 1-NA-PP1, indicating that its anti-proliferative and anti-invasive activities were mediated through the inhibition of PKD. Interestingly, a 12-fold increase in sensitivity to 1-NA-PP1 could be achieved by engineering a gatekeeper mutation in the active site of PKD1, suggesting that 1-NA-PP1 could be paired with the analog-sensitive PKD1(M659G) for dissecting PKD-specific functions and signaling pathways in various biological systems. PMID:24086585

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

2013-09-23

166

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

PubMed

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

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

2009-12-06

167

A modified HSP70 inhibitor shows broad activity as an anticancer agent  

PubMed Central

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

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

2013-01-01

168

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

PubMed Central

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

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

2013-01-01

169

The thioredoxin system mediates redox-induced cell death in human colon cancer cells: Implications for the mechanism of action of anticancer agents  

PubMed Central

Anticancer agents act, at least in part, by inducing reactive oxygen and nitrogen species (RONS). We examined the redox effect on SW480 and HT-29 colon cancer cells of four anticancer compounds, arsenic trioxide, phospho-aspirin, phospho-sulindac and nitric oxide-donating aspirin (NO-ASA). All compounds inhibited the growth of both cell lines (IC50s 10–90 ?M) and induced RONS detected by a general RONS molecular probe. NO-ASA, which induced at least four individual RONS (NO, H2O2, superoxide anion and peroxynitirte) induced apoptotic and necrotic cell death that was RONS-mediated (cell death paralleled RONS levels and was abrogated by N-acetyl cysteine, but not by diphenylene iodonium, which displayed prooxidant activity and enhanced cell death). NF-?B and MAPKs were modulated by RONS. Thioredoxin-1 (Trx-1), an oxidoreductase involved in redox-regulation, was heavily oxidized in response to RONS and mediated the growth inhibitory effect of the anticancer agents; knocking-down trx-1 expression by siRNA abrogated cell death induced by them. These compounds also inhibited the activity of thioredoxin reductase that reduces oxidized Trx-1, whereas the thioredoxin reductase inhibitor aurothiomalate synergized with NO-ASA in the induction of cell death. Our findings indicate that the Trx system mediates to a large extent redox-induced cell death in response to anticancer agents. This mechanism of action may be shared by more anticancer agents and deserves further assessment as a candidate mechanism for the pharmacological control of cancer.

Sun, Yu; Rigas, Basil

2013-01-01

170

The thioredoxin system mediates redox-induced cell death in human colon cancer cells: implications for the mechanism of action of anticancer agents.  

PubMed

Anticancer agents act, at least in part, by inducing reactive oxygen and nitrogen species (RONS). We examined the redox effect on SW480 and HT-29 colon cancer cells of four anticancer compounds, arsenic trioxide, phosphoaspirin, phosphosulindac, and nitric oxide-donating aspirin (NO-ASA). All compounds inhibited the growth of both cell lines (IC(50), 10-90 micromol/L) and induced RONS detected by a general RONS molecular probe. NO-ASA, which induced at least four individual RONS (NO, H(2)O(2), superoxide anion, and peroxynitirte), induced apoptotic and necrotic cell death that was RONS-mediated (cell death paralleled RONS levels and was abrogated by N-acetyl cysteine but not by diphenylene iodonium, which displayed prooxidant activity and enhanced cell death). Nuclear factor-kappaB and mitogen-activated protein kinases were modulated by RONS. Thioredoxin-1 (Trx-1), an oxidoreductase involved in redox regulation, was heavily oxidized in response to RONS and mediated the growth inhibitory effect of the anticancer agents; knocking-down trx-1 expression by small interfering RNA abrogated cell death induced by them. These compounds also inhibited the activity of Trx reductase that reduces oxidized Trx-1, whereas the Trx reductase inhibitor aurothiomalate synergized with NO-ASA in the induction of cell death. Our findings indicate that the Trx system mediates to a large extent redox-induced cell death in response to anticancer agents. This mechanism of action may be shared by more anticancer agents and deserves further assessment as a candidate mechanism for the pharmacologic control of cancer. PMID:18922898

Sun, Yu; Rigas, Basil

2008-10-15

171

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

PubMed

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

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

2013-04-16

172

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

PubMed Central

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

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

2012-01-01

173

Glucosylation of cyclodextrin-complexed podophyllotoxin by cell cultures of Linum flavum L  

Microsoft Academic Search

The glucosylation of the cytotoxic lignan podophyllotoxin by cell cultures derived from Linum flavum was investigated. Four cyclodextrins: ß-cyclodextrin, ?-cyclodextrin, dimethyl-ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin were used to improve the solubility of podophyllotoxin by complexation. Dimethyl-ß-cyclodextrin met our needs the best and the solubility of podophyllotoxin could be enhanced from 0.15 to 1.92 mM, using a podophyllotoxin\\/cyclodextrin ratio of 1:1. Growth parameters

Wim van Uden; Holidi Oeij; Herman J. Woerdenbag; Niesko Pras

1993-01-01

174

Potential antagonism of tubulin-binding anticancer agents in combination therapies.  

PubMed

ZD6126 is a vascular targeting agent, developed for the treatment of solid tumors. In vivo, ZD6126 is rapidly converted into the tubulin-binding agent N-acetylcolchinol. We have previously reported that in vitro N-acetylcolchinol disrupts microtubules and induces rapid changes in endothelial cell morphology, which in a tumor would lead to a rapid loss of tumor vessel integrity and subsequent extensive tumor necrosis. The aim of this study was to investigate the effect of cytotoxic antineoplastic drugs-cisplatin, doxorubicin, vincristine, paclitaxel, and docetaxel-on endothelial cell response to N-acetylcolchinol. We found that cisplatin and doxorubicin did not interfere with the ability of N-acetylcolchinol to cause morphologic changes in human umbilical vein endothelial cells, whereas vincristine showed additive effects. In contrast, the microtubule-stabilizing agents paclitaxel (1-10 micromol/L) and docetaxel (0.1-1 micromol/L) prevented the morphologic changes induced by N-acetylcolchinol in human umbilical vein endothelial cells. The effect was observed when cells were exposed to paclitaxel and N-acetylcolchinol together or when paclitaxel was given shortly before N-acetylcolchinol. Paclitaxel and N-acetylcolchinol interacted at the level of microtubule organization, as shown in immunofluorescence analysis of the cytoskeleton. The protective effect was reversible because 4 hours after paclitaxel wash out, cells recovered the sensitivity to N-acetylcolchinol. In vivo, pretreatment of mice with paclitaxel inhibited the vascular targeting activity of ZD6126 on newly formed vessels in the Matrigel plug assay and ZD6126-induced necrosis in tumors. These findings indicate that paclitaxel, depending on the timing and schedule of administration, can affect the vascular targeting activity of ZD6126, which may have an effect on the optimal scheduling of therapies based on the combined use of microtubule-stabilizing and microtubule-destabilizing agents. PMID:15814654

Taraboletti, Giulia; Micheletti, Gianluca; Dossi, Romina; Borsotti, Patrizia; Martinelli, Michele; Fiordaliso, Fabio; Ryan, Anderson J; Giavazzi, Raffaella

2005-04-01

175

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

PubMed

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

2010-04-11

176

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

PubMed

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 product (FPP) under various conditions. High recovery (99.57%) of API was found after three freeze-thaw cycle processes of fluorapacin FPP. Susceptibility of fluorapacin to oxidative degradation was studied by treating fluorapacin and FPP in 30% hydrogen peroxide aqueous solution, and the result verified the oxidative stability of fluorapacin. However, treatment of this drug candidate under strong light (4500 Lx+/-500 Lx) for 10 days showed substantial effect on the recovery of fluorapacin, especially from fluorapacin FPP. Strong acid (1.0M, HCl) did not affect the recovery of fluorapacin while strong basic condition (1.0M, NaOH) accelerated the disproportionation of fluorapacin to its related substances A and B. The stability of fluorapacin in its aqueous media at a pH range of 2.0-10.0 for up to 6h was further investigated, and 4.0-8.0 was found to be the most stable pH range. Fluorapacin and FPP were exposed to the elevated temperatures of 40 and 60 degrees C for 10 days without obvious impact on their stability. The thermal stability of fluorapacin API and FPP under constant humidity with light protection was also thoroughly investigated under accelerated (40+/-2 degrees C, RH 75+/-5%, 6 months) and long-term (25+/-2 degrees C, RH 60+/-10%, 24 months) conditions. There was no significant change except minor color change of fluorapacin FPP. Therefore, fluorapacin has excellent stability as a potential drug candidate for further clinical development investigation. PMID:18678459

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

2008-07-03

177

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

PubMed

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

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

2013-02-18

178

Compatibility and stability of the novel anti-cancer agent C1311 in infusion devices and its in vitro biocompatibility.  

PubMed

C1311 is the lead compound from the imidazoacridinones, a novel group of rationally designed anti-cancer agents. The compound is pharmaceutically formulated as a lyophilized product containing 100 mg C1311 (anhydrous free base) per dosage unit and requires reconstitution before intravenous administration. The aim of this study was to determine the stability of C1311 in the reconstituted solution and infusion solution and its compatibility with infusion devices. Moreover, the buffer capacity and haemolytic potential of C1311 infusion solutions, which exhibit a relatively low pH of 2-3, were evaluated in vitro. C1311 was shown to be stable in the reconstituted solution for at least 48 h and for at least 96 h after subsequent dilution in 0.9% sodium chloride and 5% dextrose. In vitro infusion simulation studies showed C1311 infusion solutions to be compatible with a low-density polyethylene administration set. Furthermore, the buffer capacity and haemolysis studies showed no indications for haemolysis or potential for vascular irritation upon continuous infusion of C1311. In conclusion, C1311 lyophilized product is adequately stable and compatible after reconstitution and in infusion fluids to be used in the clinic and is not expected to cause formulation-associated side effects in the intended administration schedule in the forthcoming Phase I clinical study. PMID:16460599

den Brok, Monique W J; Nuijen, Bastiaan; Harms, Remko; Buluran, Josie N; Harvey, Michael D; Grieshaber, Charles K; Beijnen, Jos H

2005-03-01

179

Advances in the chemistry and pharmacology of ecteinascidins, a promising new class of anti-cancer agents.  

PubMed

Ecteinascidins are marine natural products consisting of two or three linked tetrahydroisoquinoline subunits and an active carbinolamine functional group. Their potent antiproliferative activity against a variety of tumor cells has made them attractive candidates for development as anticancer agents. The lead compound, ecteinascidin 743 (ET 743), is currently in phase II clinical trials but the low amounts present in its natural source, the tunicate Ecteinascidia turbinata, made it necessary to develop efficient synthetic procedures. Recent improvements on the original synthesis are reviewed as well as new strategies starting from readily available cyanosafracin B. ET 743 is known to bind to the minor groove of DNA giving rise to a covalent adduct with the exocyclic amino group at position 2 of a guanine in a fashion similar to saframycin antibiotics. Some of the resulting complexes have been studied by a variety of biochemical and spectroscopic methods and also by computer simulations. The rules for sequence specificity have been well established (preferred targets are RGC and YGG, where R and Y stand for purine and pyrimidine, respectively), and it has been shown that binding of ET 743 to DNA is accompanied by minor groove widening and DNA bending towards the major groove. Although the precise target for antitumor action remains to be unambiguously defined, a role in affecting the transcriptional regulation of some inducible genes is rapidly emerging. PMID:12678757

Manzanares, I; Cuevas, C; García-Nieto, R; Marco, E; Gago, F

2001-11-01

180

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

PubMed

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

2003-10-01

181

Insights into the Reactivity of Gold-Dithiocarbamato Anticancer Agents toward Model Biomolecules by Using Multinuclear NMR Spectroscopy.  

PubMed

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

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

2013-09-03

182

The alpha-fetoprotein-derived growth inhibitory peptide 8-mer fragment: review of a novel anticancer agent.  

PubMed

This review describes the antigrowth and anticancer activities of the alpha-fetoprotein (AFP)-derived growth inhibitory peptide (GIP) 8-mer fragment. The 8-amino acid peptide (GIP-8) comprises the carboxy-terminal portion of a 34-amino acid peptide (GIP-34) previously identified as an occult epitopic segment of the full-length human AFP molecule. The GIP-8 segment has been chemically synthesized, purified, characterized, and bioassayed. The purified 8-mer segment was characterized as a random coil (disordered) structure extending from a C-terminal beta-hairpin that forms a horseshoe-shaped partially cyclic octapeptide; this structure can be formulated into a fully cyclic form by the addition of asparagine or glutamine residues. The pharmacophore of the octo- and nanopeptide forms is largely composed of a PXXP motif known to interact with Src-3 (SH3) domains of serine/theronine kinases. The GIP-8 has been shown to be growth-suppressive largely in estradiol (E2)-dependent neonatal and tumor-cell proliferation models and to inhibit tumor-cell adhesion to extracellular matrices. The 8-mer GIP displays antigrowth properties in immature mouse uterine cells and anticancer cell proliferation traits in estrogen receptor positive (ER(+)), but not (ER()) negative breast tumor cells. Even though its mechanism of action has not been fully elucidated, GIP-8 has been shown by computer modeling to dock with the extracellular loops of G-coupled seven transmembrane helical-like receptors, which could possibly interfere with signal transduction through MAP kinase pathways. It was apparent that the GIP-8 derived from the 34-mer GIP fragment of HAFP represented an E2-sensitive growth inhibitory motif, which allows the participation in cellular events, such as receptor binding, contact inhibition, extracellular matrix adhesion, angiogenesis, and T-cell activation. Thus, it was proposed that the 8-mer fragment derived from GIP could potentially serve as a lead compound for targeted cancer therapeutic agents of the biologic-response modifier type. PMID:17627416

Mizejewski, Gerald J

2007-02-01

183

Characterisation of cytotoxicity and DNA damage induced by the topoisomerase II-directed bisdioxopiperazine anti-cancer agent ICRF-187 (dexrazoxane) in yeast and mammalian cells  

Microsoft Academic Search

BACKGROUND: Bisdioxopiperazine anti-cancer agents are inhibitors of eukaryotic DNA topoisomerase II, sequestering this protein as a non-covalent protein clamp on DNA. It has been suggested that such complexes on DNA represents a novel form of DNA damage to cells. In this report, we characterise the cytotoxicity and DNA damage induced by the bisdioxopiperazine ICRF-187 by a combination of genetic and

Lars H Jensen; Marielle Dejligbjerg; Lasse T Hansen; Morten Grauslund; Peter B Jensen; Maxwell Sehested

2004-01-01

184

Analysis of metastatic spread and growth of tumor cells in mice with depressed natural killer activity by anti-asialo GMl antibody or anticancer agents  

Microsoft Academic Search

Summary The mechanism of artificial and spontaneous metastases of tumor was analyzed in B16 melanoma cells and C57BL\\/6 mice by using anti-asialo GM1 antibody and anticancer agents. Single administrations of 500 µg anti-asialo GM1 antibody resulted in significantly decreased NK activity in spleen cells of C57BL\\/6 mice, lasting 10 days from the day following administration. Treatment with anti-asialo GM1 antibody

N. Saijo; A. Ozaki; Y. Beppu; K. Takahashi; J. Fujita; Y. Sasaki; H. Nomori; M. Kimata; E. Shimizu; A. Hoshi

1984-01-01

185

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

Microsoft Academic Search

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”,

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

2012-01-01

186

Encapsulation of magnetotactic bacteria for targeted and controlled delivery of anticancer agents for tumor therapy.  

PubMed

We showed that magnetotactic bacteria (MTB) have great potentials to be used as microcarriers for targeted delivery of therapeutic agents. Indeed, magnetotaxis inherent in MTB can be exploited to direct them towards a tumor while being propelled by their own flagellated molecular motors. Nonetheless, although the thrust propelling force above 4 pN of the MC-1 MTB showed to be superior compared to other technologies for displacement in the microvasculature, MTB becomes much less efficient when travelling in larger blood vessels due to higher blood flow. In the latter case, a new technique developed by our group and referred to as Magnetic Resonance Navigation (MRN), has been successfully applied in larger vessels using synthetic microcarriers nut proved to be less efficient in the microvasculature due mainly to technological constraints. These findings called for the need to integrate both approaches by encapsulating MTB in special MRN-compatible microcarriers to be release in the vicinity of microvascular networks where they becomes more effective for targeting purposes in tumoral lesions. In this study Magnetococcus strain MC-1 were encapsulated in giant vesicles. The survival of the encapsulated bacteria was monitored. The release of bacteria from giant vesicles was also studied in different time intervals and conditions. PMID:22255868

Afkhami, Fatemeh; Taherkhani, Samira; Mohammadi, Mahmood; Martel, Sylvain

2011-01-01

187

Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent.  

PubMed

CGP 41251 was originally identified as an inhibitor of protein kinase C (PKC), inhibiting mainly the conventional PKC subtypes, and subsequently shown to inhibit the vascular endothelial growth factor (VEGF) receptor kinase insert domain-containing receptor, which is involved in angiogenesis. CGP 41251 inhibits reversibly intracellular PKC activity, induction of c-fos and the corresponding activation of the mitogen-activated protein kinase induced by either tumor promoting phorbol esters, platelet-derived growth factor, or basic fibroblast growth factor, but not by the epidermal growth factor. CGP 41251 inhibited the ligand-induced autophosphorylation of the receptors for platelet-derived growth factor, stem cell factor, and VEGF (kinase insert domain-containing receptor) that correlated with the inhibition of the mitogen-activated protein kinase activation, but did not affect the ligand-induced autophosphorylation of the receptors for insulin, insulin-like growth factor-I, or epidermal growth factor. CGP 41251 showed broad antiproliferative activity against various tumor and normal cell lines in vitro, and is able to reverse the p-glycoprotein-mediated multidrug resistance of tumor cells in vitro. CGP 41251 showed in vivo antitumor activity as single agent and inhibited angiogenesis in vivo. Thus, CGP 41251 may suppress tumor growth by inhibiting tumor angiogenesis (via its effects on the VEGF receptor tyrosine kinases) in addition to directly inhibiting tumor cell proliferation (via its effects on PKCs). PMID:10454207

Fabbro, D; Buchdunger, E; Wood, J; Mestan, J; Hofmann, F; Ferrari, S; Mett, H; O'Reilly, T; Meyer, T

188

Salmonella choleraesuis as an anticancer agent in a syngeneic model of orthotopic hepatocellular carcinoma.  

PubMed

Some anaerobic and facultative anaerobic bacteria represent novel therapeutic agents that have been recently applied in cancer therapy. Previously, we found that Salmonella choleraesuis in combination with cisplatin could retard tumor growth in the murine subsutaneous hepatocellular carcinoma (HCC) model. In this regard, we investigated the antitumor activity of S. choleraesuis in the ML-1 orthotopic tumor model. Systemically administered S. choleraesuis accumulated within not only subcutaneous but also orthotopic tumors for at least 30 days, forming tumor-to-normal tissue ratios exceeding 1,000-10,000 to 1. The antitumor effects of S. choleraesuis were evaluated in mice bearing subcutaneous and orthotopic ML-1 tumors. Compared with the control treatment, S. choleraesuis significantly prolonged the animal survival, reduced the tumor size, as well as upregulated interferon (IFN)-gamma and induced IFN-inducible chemokines CXCL10 (IP-10) productions. Furthermore, immunohistochemical staining of the tumors revealed decreased intratumoral microvessel density, increased infiltration of neutrophils, CD4(+) and CD8(+) T cells, and induced cell death in tumor microenvironment. In conclusion, these results suggest that tumor-targeted therapy using S. choleraesuis, which exerts tumoricidal and antiangiogenic activities, represents a potential strategy for the treatment of HCC. PMID:17960612

Lee, Che-Hsin; Wu, Chao-Liang; Shiau, Ai-Li

2008-02-15

189

Covalently combining carbon nanotubes with anticancer agent: preparation and antitumor activity.  

PubMed

A multiwalled carbon nanotube (MWNT)-based drug delivery system was developed by covalently combining carbon nanotubes with the antitumor agent 10-hydroxycamptothecin (HCPT) using hydrophilic diaminotriethylene glycol as the spacer between nanotube and drug moieties. The surface functionalizations of the nanotube were carried out by enrichment of carboxylic groups with optimized oxidization treatment, followed by covalently linking hydrophilic diaminotriethylene glycol via amidation reaction, and then HCPT was chemically attached to carbon nanotubes through a cleavable ester linkage. It is demonstrated that the obtained MWNT-HCPT conjugates are superior in antitumor activity both in vitro and in vivo to clinical HCPT formulation. In vivo single photon emission computed tomography (SPECT) imaging and ex vivo gamma scintillation counting analyses reveal that MWNT-HCPT conjugates have relatively long blood circulation and high drug accumulation in the tumor site. These properties together with the enhanced cell uptake and multivalent presentation of HCPT on a single nanotube benefit substantially the antitumor effects and would boost significantly the applications of carbon nanotubes in the biomedicine field. PMID:19702292

Wu, Wei; Li, Rutian; Bian, Xiaochen; Zhu, Zhenshu; Ding, Dan; Li, Xiaolin; Jia, Zhijun; Jiang, Xiqun; Hu, Yiqiao

2009-09-22

190

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

PubMed

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

2013-01-01

191

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

NASA Astrophysics Data System (ADS)

A new nano dimensional heterobimetallic Cu-Sn containing complex as a potential drug candidate was designed, synthesized and characterized by analytical and spectral methods. The electronic absorption and electron paramagnetic resonance parameters of the complex revealed that the Cu(II) ion exhibits a square pyramidal geometry with the two pyrazole nitrogen atoms, the amine nitrogen atom and the carboxylate oxygen of the phenyl glycine chloride ligand located at the equatorial sites and the coordinated chloride ion occupying an apical position. 119Sn NMR spectral data showed a hexa-coordinated environment around the Sn(IV) metal ion. TEM, AFM and XRD measurements illustrate that the complex could induce the condensation of CT-DNA to a particulate nanostructure. The interaction of the Cu-Sn complex with CT-DNA was investigated by UV-vis absorption and emission spectroscopy, as well as cyclic voltammetric measurements. The results indicated that the complex interacts with DNA through an electrostatic mode of binding with an intrinsic binding constant Kb = 8.42 × 104 M - 1. The Cu-Sn complex exhibits effective cleavage of pBR322 plasmid DNA by an oxidative cleavage mechanism, monitored at different concentrations both in the absence and in the presence of reducing agents.

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

2010-05-01

192

Pharmaceutical development of a lyophilised dosage form for the investigational anticancer agent Imexon using dimethyl sulfoxide as solubilising and stabilising agent.  

PubMed

Imexon is a member of the class of 2-cyanoaziridine derivatives, which have been of interest as immunomodulators and anticancer agents since the late 1970s. For the scheduled phase I clinical trials a stable, sterile, injectable pharmaceutical dosage form containing 100 mg Imexon was required. Despite adequate solubility, its instability in aqueous media seriously hampered the pharmaceutical development of Imexon. In this study we describe the successful use of the organic solvent dimethyl sulfoxide (DMSO) as a formulation vehicle for Imexon. DMSO is shown to provide the stability required for Imexon during manufacturing and to be a suitable vehicle for lyophilisation, which was employed to gain sufficient shelf-life for the final product. The relatively low vapour pressure of DMSO, which would theoretically result in extremely slow sublimation during lyophilisation, was shown not to limit the successful lyophilisation of Imexon from DMSO at a concentration of 25 mg/mL. The lyophilisation cycle developed for Imexon resulted in residual DMSO contents of 4.6 +/- 0.6% in the lyophilised product, limiting the amount of DMSO administered to the patient to well below the 50 mg/day acceptable in pharmaceutical products as stated in ICH guidelines. Imexon 100 mg/vial lyophilised product was shown stable for at least 12 months of storage at -20 degrees C and +5 +/- 3 degrees C in the dark. PMID:15793808

den Brok, Monique W J; Nuijen, Bastiaan; Lutz, Christiane; Opitz, Hans-Georg; Beijnen, Jos H

2005-05-01

193

Discovery of water-soluble anticancer agents (edotides) from a vegetable found in Benin City, Nigeria.  

PubMed

Cancer claims the lives of more than six million people each year in the world. About 1,268,000 new cancer cases, and 553,400 deaths were reported in the United States in 2001. Current treatment approaches have yielded significant progress in the fight against cancer, but the incidence of developing certain types of cancer continues to rise. This is especially true in the African-American communities. African Americans are about 33% more likely to die of cancer than are whites and more than twice likely to die of cancer as are Asian-Islander, American-Indians, and Hispanics. This increase coupled with the harsh side effects of some of the cancer chemotherapies have led to the search for more natural biological products, especially those derived from plant products, currently known as herbal medicine. There is a need for a continued search for novel natural products that may be used as cancer chemopreventive and/or chemotherapeutic agents. The objective of this study was to evaluate the effect(s) of a novel water-soluble leaf extract of Vernonia amygdalina (VA) on human breast cancer cell DNA synthesis. MCF-7 cell line, considered a suitable model, was used in this study. Treatment of cells with physiologically relevant concentrations of water-soluble VA extract potently inhibited DNA synthesis in a concentration-dependent fashion both in the absence and presence of serum. Fractions of VA extract separated using preparative reverse-phase chromatography also inhibited DNA synthesis (P < 0.005). These results suggest that VA vegetable, if incorporated in the diet, may prevent or delay the on-set of breast cancer. PMID:12626774

Izevbigie, Ernest B

2003-03-01

194

The triphenyltin(VI) complexes of NSAIDs and derivatives. Synthesis, crystal structure and antiproliferative activity. Potent anticancer agents.  

PubMed

The novel triphenyltin(IV) esters of flufenamic acid (1), Hflu, [Ph(3)Sn(flu)] (2), and of [2-(2,3-dichlorophenylamino)benzoic acid] (3), Hdcpa, [Ph(3)Sn(dcpa)] (4) have been structurally characterized by means of vibrational and (1)H, (13)C NMR spectroscopic studies. The crystal and molecular structures of [SnPh(3)(dcpa)(DMSO)] 4a are described. The molecular structure of 4a reveals that the Sn atom has a distorted trigonal bipyramidal coordination geometry with equatorial phenyl groups and the carboxylate and dimethylsulfoxide oxygen atoms occupying axial positions. The crystal structure of 4a is self-assembled by C-H-? and ?-? stacking interactions. The in vitro cytotoxic activity of 1-4 and of the related non-steroidal anti-inflammatory drugs, NSAIDs, [2-(2,6-dimethylphenylamino)benzoic acid], Hdmpa (5), [Ph(3)Sn(dmpa)] (6), [2-(2,3-dimethylphenylamino)benzoic acid], mefenamic acid, Hmef (7) and [Ph(3)Sn(mef)] (8) has been evaluated against the cancer cell lines MCF-7, T-24, A-549 and L-929. The ligands exhibited very poor cytotoxic activity against the four cancer cell lines. Complex 6 exhibits the highest activity and selectivity against A-549 and MCF-7 cancer cell lines and complex 8 the highest activity and selectivity against T-24 cancer cell line. The cytotoxic results indicate that coupling of Hdmpa and Hmef with R(3)Sn(IV) metal center results in complexes with important biological properties and remarkable cytotoxic activity, since they display IC(50) values in a ?? range better to that of the antitumor drug cis-platin. Complexes 6 and 8 are considered as excellent antitumor compounds and the results of this study represent the discovery of triphenyltin(IV) esters as a potential novel class of anticancer agents. PMID:21194618

Dokorou, Vaso; Primikiri, Alexandra; Kovala-Demertzi, Dimitra

2010-10-16

195

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.

CARROLL, CANDACE E.; LIANG, YAYUN; BENAKANAKERE, INDIRA; BESCH-WILLIFORD, CYNTHIA; HYDER, SALMAN M.

2013-01-01

196

The anticancer agent prodigiosin induces p21WAF1/CIP1 expression via transforming growth factor-beta receptor pathway.  

PubMed

The anticancer agent prodigiosin has been shown to act as an efficient immunosuppressant, eliciting cell cycle arrest at non-cytotoxic concentrations, and potent proapoptotic and antimetastatic effects at higher concentrations. Gene expression profiling of MCF-7 cells after treatment with a non-cytotoxic concentration of prodigiosin showed that expression of the p21WAF1/CIP1 gene, a negative cell cycle regulator was induced. In this study, we show that prodigiosin induces p21 expression leading to cell cycle blockade. Subsequently, we attempted to elucidate the molecular mechanisms involved in prodigiosin-mediated p21 gene expression. We demonstrate that prodigiosin induces p21 in a p53-independent manner as prodigiosin induced p21 in cells with both mutated and dominant negative p53. Conversely, the transforming growth factor-beta (TGF-beta) pathway has been found to be necessary for p21 induction. Prodigiosin-mediated p21 expression was blocked by SB431542, a TGF-beta receptor inhibitor. Nevertheless, this pathway alone is not enough to induce p21 expression. The TGF-beta family member (nonsteroidal anti-inflammatory drug)-activated gene 1/growth differentiation factor 15 (NAG-1) may activate this pathway, as it has previously been suggested to signal through the TGF-beta pathway and is overexpressed in response to prodigiosin treatment. We show that NAG-1 colocalizes with TGF-beta receptor type I, suggesting a possible interaction between them. Taken together, these results suggest the TGF-beta pathway is required for induction of p21 expression after prodigiosin treatment of MCF-7 cells. PMID:17765876

Soto-Cerrato, Vanessa; Viñals, Francesc; Lambert, James R; Pérez-Tomás, Ricardo

2007-07-18

197

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

PubMed

Podophyllotoxin (POD) is a naturally occurring lignan with pronounced antineoplastic and antiviral properties. POD binds to tubulin and prevents the formation of mitotic spindle. Although cases of overdose or accidental ingestion are quite often, no specific therapy is currently available to treat the POD intoxication. In the current investigation, the protective effects and mechanisms of curcumin (CUR) on podophyllotoxin toxicity were evaluated in vitro and in vivo. The results showed that CUR could protect POD-induced cytotoxicity by recovering the G2/M arrest and decrease the changes of membrane potential and microtubule structure in Vero cells. A significant decrease of mortality rates was observed in Swiss mice treated by intragastrical administration of POD+CUR as compared with POD alone. The POD+CUR group also exhibited decreases in plasma transaminases, alkaline phosphatase, lactate dehydrogenase, plasma urea, creatinine and malondialdehyde level but elevated superoxide dismutase and glutathione levels as compared to the POD group. Histological examination of the liver and kidney demonstrated less morphological changes in the treatment of POD+CUR as compared with POD alone. The mechanism of the protective effects might be due to the competitive binding of CUR with POD in the same colchicines binding site as revealed by the tubulin polymerization assay and the molecular docking analysis, and the antioxidant activity against the oxidative stress induced by POD. In summary, both in vitro and in vivo data indicated the promising role of CUR as a protective agent against the POD poisoning. PMID:23088858

Li, Juan; Dai, Cai-Xia; Sun, Hua; Jin, Lu; Guo, Chong-Yi; Cao, Wei; Wu, Jie; Tian, Hai-Yan; Luo, Cheng; Ye, Wen-Cai; Jiang, Ren-Wang

2012-10-23

198

Synthesis and evaluation of 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines as Bcl-2 inhibitory anticancer agents.  

PubMed

A series of substituted 3-(benzylthio)-5-(1H-indol-3-yl)-4H-1,2,4-triazol-4-amines has been synthesised and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents. Synthesis of the target compounds was readily accomplished in good yields through a cyclisation reaction between indole-3-carboxylic acid hydrazide and carbon disulfide under basic conditions, followed by S-benzylation. Active compounds, such as the nitrobenzyl analogue 6c, were found to exhibit sub-micromolar IC50 values in Bcl-2 expressing human cancer cell lines. Molecular modelling and ELISA studies further implicated anti-apoptotic Bcl-2 as a candidate molecular target underpinning anticancer activity. PMID:23474389

Hamdy, Rania; Ziedan, Noha; Ali, Samia; El-Sadek, Mohamed; Lashin, Elsaid; Brancale, Andrea; Jones, Arwyn T; Westwell, Andrew D

2013-02-14

199

Synthesis and cytotoxic activity on human cancer cells of carbamate derivatives of 4?-(1,2,3-triazol-1-yl)podophyllotoxin.  

PubMed

Carbamate derivatives of 4?-(1,2,3-triazol-1-yl)podophyllotoxin were synthesized by means of click chemistry, and their cytotoxicities against human cancer cell lines HL-60, A-549, HeLa, and HCT-8 were evaluated. Some compounds were more potent than the anticancer drug etoposide. 4'-O-Demethyl-4?-[(4-hydroxymethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin cyclopentyl carbamate, the most potent compound, induced cell cycle arrest in the G2/M phase accompanied by apoptosis in A-549 cells. Furthermore, this compound inhibited the formation of microtubules in A-549 cells and caused the inhibition of DNA topoisomerase-II. PMID:23711769

Liu, Jian-Fei; Sang, Chun-Yan; Xu, Xiao-Hui; Zhang, Lin-Lin; Yang, Xuan; Hui, Lin; Zhang, Jin-Bang; Chen, Shi-Wu

2013-04-09

200

Bioprospecting for podophyllotoxin in the Big Horn Mountains, Wyoming  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

201

Pharmacokinetics and pharmacodynamics of phase II drug metabolizing/antioxidant enzymes gene response by anticancer agent sulforaphane in rat lymphocytes.  

PubMed

This study assesses the pharmacokinetics (PK) and pharmacodynamics (PD) of Nrf2-mediated increased expression of phase II drug metabolizing enzymes (DME) and antioxidant enzymes which represents an important component of cancer chemoprevention in rat lymphocytes following intravenous (iv) administration of an anticancer phytochemical sulforaphane (SFN). 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 each 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 and converted to cDNA, 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. 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-fold) over the time zero were seen for HO-1, Nrf2, and NQO1, and significant increases (>5-fold) for GSTT1, GPx1, and Maf. PK-PD analyses using GastroPlus and the bootstrap method provided reasonable fitting for the PK and PD profiles and parameter estimates. 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 iv 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

2012-09-11

202

Mutation of the p53 gene in human astrocytic tumours correlates with increased resistance to DNA-damaging agents but not to anti-microtubule anti-cancer agents.  

PubMed Central

Astrocytic tumours often become resistant to a variety of chemotherapeutic agents in advanced stages and frequently possess mutations in the p53 tumour-suppressor gene. Previous studies using established cell lines to investigate the relation between mutated p53 genes and altered resistance to anti-cancer agents brought inconsistent results. In this report, we examined the status of the p53 gene in 56 astrocytic tumour specimens by single-strand conformation polymorphism and their in vitro chemosensitivity to 30 different kinds of anti-cancer agents. The chemosensitivity was determined by drug-induced cell death using flow cytometry. We found that the mutated p53 gene correlated with increased resistance to DNA-damaging agents but the sensitivity to anti-microtubule agents was independent of the mutation, suggesting a clinical significance of the status of p53 gene in astrocytic tumours and a rational application of anti-microtubule agents to the patients with p53-mutated astrocytic tumours.

Iwadate, Y.; Tagawa, M.; Fujimoto, S.; Hirose, M.; Namba, H.; Sueyoshi, K.; Sakiyama, S.; Yamaura, A.

1998-01-01

203

Enediyne-lexitropsin DNA-targeted anticancer agents. Physicochemical and cytotoxic properties in human neoplastic cells in vitro, and intracellular distribution.  

PubMed

Two series of hybrids of a dynemicin A model and DNA minor groove binding lexitropsins were synthesized and their cytotoxic activities were investigated in a panel of human normal and malignant cell lines using a colorimetric assay. Adriamycin was used as a control. Several of the agents demonstrated cytotoxic activity, the extent of which varied with tumor type. IC50s of the hybrids ranged from approximately 14-48 microM following 96 h incubation in the presence of test compound. Intracellular distribution studies were facilitated through endogenous fluorescence of the compounds. Evidence of nuclear uptake of the hybrid agents was demonstrated by confocal laser scanning microscopy. The results warrant further development of DNA-targeted enediyne-lexitropsin hybrids as potential anticancer agents. PMID:9154109

Xie, Y; Miller, G G; Cubitt, S A; Soderlind, K J; Allalunis-Turner, M J; Lown, J W

1997-04-01

204

Design, synthesis and biological evaluation of a novel series of anthrapyrazoles linked with netropsin-like oligopyrrole carboxamides as anticancer agents  

PubMed Central

Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. Combilexin molecules, which combine DNA minor groove binding and intercalating functionalities, have the potential for increased DNA binding affinity and increased selectivity due to their dual mode of DNA binding. This study describes the synthesis of DNA minor groove binder netropsin analogs containing either one or two N-methylpyrrole carboxamide groups linked to DNA-intercalating anthrapyrazoles. Those hybrid molecules which had both two N-methylpyrrole groups and terminal (dimethylamino)alkyl side chains displayed submicromolar cytotoxicity towards K562 human leukemia cells. The combilexins were also evaluated for DNA binding by measuring the increase in DNA melting temperature, for DNA topoisomerase II?-mediated double strand cleavage of DNA, for inhibition of DNA topoisomerase II? decatenation activity, and for inhibition of DNA topoisomerase I relaxation of DNA. Several of the compounds stabilized the DNA-topoisomerase II? covalent complex indicating that they acted as topoisomerase II? poisons. Some of the combilexins had higher affinity for DNA than their parent anthrapyrazoles. In conclusion, a novel group of compounds combining DNA intercalating anthrapyrazole groups and minor groove binding netropsin analogs have been designed, synthesized and biologically evaluated as possible novel anticancer agents.

Zhang, Rui; Wu, Xing; Guziec, Lynn J.; Guziec, Frank S.; Chee, Gaik-Lean; Yalowich, Jack C.; Hasinoff, Brian B.

2010-01-01

205

PEG–Anticancer Drugs  

Microsoft Academic Search

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

Francesca Cateni; Marina Zacchigna

206

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

PubMed

A series of novel 1,2,3-triazole-dithiocarbamate hybrids were designed, synthesized and evaluated for anticancer activity against four selected human tumor cell lines (MGC-803, MCF-7, PC-3, EC-109). Majority of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 3a and 3c showed excellent broad spectrum anticancer activity with IC50 values ranging from 0.73 to 11.61 ?M and 0.49-12.45 ?M, respectively. Particularly, compound 3a was more potent than 5-fluorouracil against all tested human cancer cell lines. Flow cytometry analysis demonstrated that treatment of MGC-803 with 3c led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death after 12 h. PMID:23353743

Duan, Ying-Chao; Ma, Yong-Cheng; Zhang, En; Shi, Xiao-Jing; Wang, Meng-Meng; Ye, Xian-Wei; Liu, Hong-Min

2013-01-04

207

Synthesis of the peptaibol framework of the anticancer agent culicinin D: stereochemical assignment of the AHMOD moiety.  

PubMed

The postulated structure of the potent anticancer peptaibol culicinin D has been synthesized using Fmoc-based solid-phase peptide synthesis (SPPS). Comparison of the (1)H NMR data for the reported structure of culicinin D with the data obtained for the two synthetic polypeptides epimeric at C-6 in the AHMOD unit established the C-6 stereochemistry of the AHMOD residue in the natural product to be (R). PMID:23126283

Hung, Kuo-yuan; Harris, Paul W R; Brimble, Margaret A

2012-11-05

208

Synthesis and Spectroscopic Study of Anticancer agent A-007 Prodrugs and Progress Towards the Synthesis of Tetramic acid Antibiotics  

Microsoft Academic Search

4, 4'-Dihydroxybenzophenone-2, 4-dinitrophenylhydrazone (A-007) has recently completed a phase-I clinical trial, and objective responses were seen in advanced breast cancer, lung cancer, ovarian cancer, melanoma, skin cancer and non-Hodgkin's lymphoma. Despite the promising results in the clinical trials, the major disadvantage to using A-007 as a broad-scale therapeutic is its poor water solubility. To make use of this promising anticancer

Sarada Sagiraju

2008-01-01

209

Current challenges for the early clinical development of anticancer drugs in the era of molecularly targeted agents  

Microsoft Academic Search

The emergence of molecularly targeted agents in oncology has not only revolutionized the care of cancer patients, but also\\u000a changed the daily practice of medical oncologists. Molecularly targeted agents indeed often differ from traditional cytotoxic\\u000a agents by their administration schedules and routes, their toxicity profiles, and\\/or the assessment of their antitumor activity.\\u000a In addition, the observation that molecularly targeted agents

Christophe Le Tourneau; Véronique Diéras; Patricia Tresca; Wulfran Cacheux; Xavier Paoletti

2010-01-01

210

Next generation sequencing in predicting gene function in podophyllotoxin biosynthesis.  

PubMed

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

2012-11-16

211

Non-DNA-binding platinum anticancer agents: Cytotoxic activities of platinum-phosphato complexes towards human ovarian cancer cells  

PubMed Central

DNA is believed to be the molecular target for the cytotoxic activities of platinum (Pt) anticancer drugs. We report here a class of platinum(II)- and platinum(IV)-pyrophosphato complexes that exhibit cytotoxicity comparable with and, in some cases, better than cisplatin in ovarian cell lines (A2780, A2780/C30, and CHO), yet they do not show any evidence of covalent binding to DNA. Moreover, some of these compounds are quite effective in cisplatin- and carboplatin-resistant cell line A2780/C30. The lack of DNA binding was demonstrated by the absence of a detectable Pt signal by atomic absorption spectroscopy using isolated DNA from human ovarian cells treated with a platinum(II)-pyrophosphato complex, (trans-1,2-cyclohexanediamine)(dihydrogen pyrophosphato) platinum(II), (pyrodach-2) and from NMR experiments using a variety of nucleotides including single- and double-stranded DNA. Furthermore, pyrodach-2 exhibited reduced cellular accumulations compared with cisplatin in cisplatin- and carboplatin-resistant human ovarian cells, yet the IC50 value for the pyrophosphato complex was much less than that of cisplatin. Moreover, unlike cisplatin, pyrodach-2 treated cells overexpressed fas and fas-related transcription factors and some proapoptotic genes such as Bak and Bax. Data presented in this report collectively indicate that pyrodach-2 follows different cytotoxic mechanisms than does cisplatin. Unlike cisplatin, pyrodach-2 does not undergo aquation during 1 week and is quite soluble and stable in aqueous solutions. Results presented in this article represent a clear paradigm shift not only in expanding the molecular targets for Pt anticancer drugs but also in strategic development for more effective anticancer drugs.

Bose, Rathindra N.; Maurmann, Leila; Mishur, Robert J.; Yasui, Linda; Gupta, Shefalika; Grayburn, W. Scott; Hofstetter, Heike; Salley, Tara

2008-01-01

212

OT-404, multi-targeted anti-cancer agent affecting tumor proliferation, chemo-resistance, and angiogenesis.  

PubMed

There is a need for a comprehensive anti-cancer strategy that simultaneously targets abnormal proliferation, angiogenesis rates, and development of chemotherapy resistance. We have identified a small molecule, OT-404, that effectively inhibited proliferation and angiogenesis of either chemo-sensitive or -resistant human cancer cells and enhanced cancer cell sensitivity to different chemotherapy. In vivo studies of human tumor xenografts in nude mice showed that OT-404, used alone or encapsulated into nanoparticles, inhibited the growth of doxorubicin-resistant breast cancer MCF-7 by more than 80%, and by 95% when combined with doxorubicin. These findings provide evidence for the potential of OT-404 in cancer management. PMID:23348692

Rebbaa, Abdelhadi; Patil, Ghanshyam; Yalcin, Murat; Sudha, Thangirala; Mousa, Shaker A

2013-01-21

213

The root bark of Paeonia moutan is a potential anticancer agent in human oral squamous cell carcinoma cells.  

PubMed

Currently there is growing use of complementary and alternative anticancer medicines worldwide, and considerable interest in finding anticancer drugs among Chinese medicinal herbs. The aim of this study was to determine the antitumor activity of the root bark of Paeonia moutan (RBPM) in human squamous cell carcinoma (OSCC) cells. Cell lines derived from human oral squamous cell carcinoma (HSC2, 3, 4, SAS) were tested with different concentrations of RBPM (1-100 ?g/ml) using a series of in vitro assay systems. RBPM at a concentration of 100 ?g/ml inhibited monolayer and anchorage-independent growth, and interrupted coordinated migration. RBPM activated the phosphorylation of extracellular signal-regulated kinase (ERK) and serine/threonine kinase AKT in 30 min; then, at a later stage (after 6 hours) exhibited potent cytostatic, pro-apoptotic effects through the down-regulation of the expression of cyclin-dependent kinase 4 and its partner cyclin D1, and poly(ADP-ribose) polymerase cleavage. We found direct evidence that RBPM induces apoptotic cell death via DNA fragmentation. Taken together, the antitumor activity of RBPM was demonstrated through antiproliferative and apoptotic effects. PMID:22753719

Li, Chunnan; Yazawa, Kazunaga; Kondo, Seiji; Mukudai, Yoshiki; Sato, Daisuke; Kurihara, Yuji; Kamatani, Takaaki; Shintani, Satoru

2012-07-01

214

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

PubMed

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

2012-05-02

215

Anticancer effects of free polyunsaturated fatty acids in an oily lymphographic agent following intrahepatic arterial administration to a rabbit bearing VX-2 tumor.  

PubMed

The anti-hepatic cancer effects of three free polyunsaturated fatty acids (linoleic, alpha-linolenic, and gamma-linolenic acids) dissolved in an oily lymphographic agent, Lipiodol Ultra-Fluid (Lipiodol), following intrahepatic arterial administration were examined using a rabbit liver cancer model, VX-2. The tumor was inoculated into the subcapsular parenchyma of the liver of rabbits, and Lipiodol alone or Lipiodol containing each one of the free fatty acids was administered into the hepatic artery 14 days after inoculation. The rabbits were sacrificed 7 days after administration. Lipiodol containing one of the fatty acids selectively remained in the tumor area. Although VX-2 tumor grew extensively in both the untreated group and the group that received Lipiodol alone, growth of VX-2 tumor was greatly suppressed in the group that received Lipiodol containing the free fatty acid. Pathological observation also showed that Lipiodol containing the free fatty acid had an anticancer effect on VX-2 tumor growing in the liver of rabbits. Average survival days in the group treated with Lipiodol containing gamma-linolenic acid were significantly prolonged compared with those in the control groups. Although growth rates of the tumor at the death of rabbits were large in the control groups, VX-2 tumor shrank at death of five rabbits of six in the group treated with Lipiodol containing gamma-linolenic acid. These results suggest that the intrahepatic arterial administration of Lipiodol containing the free fatty acids is an effective method of delivery of these fatty acids as anticancer agents. PMID:1309442

Hayashi, Y; Fukushima, S; Kishimoto, S; Kawaguchi, T; Numata, M; Isoda, Y; Hirano, J; Nakano, M

1992-01-15

216

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

PubMed

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

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

2013-10-08

217

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: gilbertopardo@infomed.sld.cu [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)

2011-06-15

218

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

PubMed

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

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

2005-10-01

219

Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT4  

Microsoft Academic Search

The mechanism by which aplidine, a marine natural product in early clinical development as an anticancer agent, induces cell growth inhibition and apoptosis has been investigated in the human leukemia cell line MOLT-4. This cell line is characterized not only by the ability to secrete VEGF, but also for the presence on its surface of the VEGF receptor-1 (VEGFR-1). Previous

M Broggini; S V Marchini; E Galliera; P Borsotti; G Taraboletti; E Erba; M Sironi; J Jimeno; G T Faircloth; R Giavazzi; M D’Incalci

2003-01-01

220

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

PubMed

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

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

2012-01-01

221

Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1  

PubMed Central

AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione], a prodrug with two dimethylamino N-oxide groups, is converted to the topoisomerase II inhibitor AQ4 [1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione] by reduction of the N-oxides to dimethylamino substituents. Earlier studies showed that several drug-metabolizing cytochrome P450 (P450) enzymes can catalyze this reductive reaction under hypoxic conditions comparable with those in solid tumors. CYP2S1 and CYP2W1, two extrahepatic P450 enzymes identified from the human genome whose functions are unknown, are expressed in hypoxic tumor cells at much higher levels than in normal tissue. Here, we demonstrate that CYP2S1, contrary to a published report (Mol Pharmacol 76:1031–1043, 2009), is efficiently reduced by NADPH–P450 reductase. Most importantly, both CYP2S1 and CYP2W1 are better catalysts for the reductive activation of AQ4N to AQ4 than all previously examined P450 enzymes. The overexpression of CYP2S1 and CYP2W1 in tumor tissues, together with their high catalytic activities for AQ4N activation, suggests that they may be exploited for the localized activation of anticancer prodrugs.

Nishida, Clinton R.; Lee, Melody

2010-01-01

222

Efficient hypoxic activation of the anticancer agent AQ4N by CYP2S1 and CYP2W1.  

PubMed

AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione], a prodrug with two dimethylamino N-oxide groups, is converted to the topoisomerase II inhibitor AQ4 [1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione] by reduction of the N-oxides to dimethylamino substituents. Earlier studies showed that several drug-metabolizing cytochrome P450 (P450) enzymes can catalyze this reductive reaction under hypoxic conditions comparable with those in solid tumors. CYP2S1 and CYP2W1, two extrahepatic P450 enzymes identified from the human genome whose functions are unknown, are expressed in hypoxic tumor cells at much higher levels than in normal tissue. Here, we demonstrate that CYP2S1, contrary to a published report (Mol Pharmacol 76:1031-1043, 2009), is efficiently reduced by NADPH-P450 reductase. Most importantly, both CYP2S1 and CYP2W1 are better catalysts for the reductive activation of AQ4N to AQ4 than all previously examined P450 enzymes. The overexpression of CYP2S1 and CYP2W1 in tumor tissues, together with their high catalytic activities for AQ4N activation, suggests that they may be exploited for the localized activation of anticancer prodrugs. PMID:20566689

Nishida, Clinton R; Lee, Melody; de Montellano, Paul R Ortiz

2010-06-21

223

Synthesis and characterization of RGD-fatty acid amphiphilic micelles as targeted delivery carriers for anticancer agents.  

PubMed

Novel amphiphilic conjugates consisting of an Arg-Gly-Asp (RGD) peptide binding motif and aliphatic fatty acids of varying chain length (C10-C18) were synthesized and evaluated for their ability to form micelles and bind specifically to alphaVbeta3 integrin over-expressing tumor cells. The aphilphiles were characterized by IR, proton NMR and mass spectrometry. The size and zeta potential of the resultant micelles were ranged from 178 to 450 nm and - 13.5 to 39.6 mV, respectively. The critical micellar concentration (CMC), drug loading efficiency and tumor cell binding of these amphiphiles were determined. The CMC values, determined by pyrene fluorescent probe method, ranged from 0.02 to 0.12 mM for C14-RGD, C16-RGD and C18-RGD. The C18-RGD micelles with lowest CMC were found to increase the solubility of taxol, a model anticancer drug, by 87%. C18-RGD amphiphiles also exhibited significantly higher (12.1 +/- 1.14%, P < 0.05) binding to alphaVbeta3 integrin over-expressing human breast cancer cells (HTB-129) when compared to normal human epidermal keratinocyte (NHEK) cells (6.68 +/- 0.34). The results from this study demonstrated the feasibility of designing RGD-fatty acid amphiphiles as micellar drug delivery carriers to target to cancer cells. PMID:17365273

Shen, Steve I; Kotamraj, Phanidhara R; Bhattacharya, Shiladitya; Li, Xiaoling; Jasti, Bhaskara R

2007-01-01

224

Discovery of P3971 an Orally Efficacious Novel Anticancer Agent Targeting HIF-1? and STAT3 Pathways.  

PubMed

Hypoxia-inducible factor-1? (HIF-1?) and signal transducer and activator of transcription 3 (STAT3) are transcription factors and are activated in response to hypoxia. Both HIF-1? and STAT3 regulate various aspects of cancer biology such as cell survival, proliferation, angiogenesis etc. and are constitutively expressed in a wide range of human cancers. In the last decade, over expression of HIF-1? and STAT3 has been demonstrated in many common human cancers, thereby emerging as highly compelling anticancer targets for drug discovery. We herein report the design and synthesis of new imidazopyridine based potent dual inhibitors of HIF-1? and STAT3 pathways. The lead compound of this series P3971 has been identified as a potent inhibitor of HIF-1? (200 nM) and STAT3 (350 nM) with significant antiproliferative activity against various cancer cell lines. Moreover, P3971 was also found to be orally efficacious in HCT116 (colon cancer) and H460 (lung cancer) xenograft mice models. PMID:24102269

Godse, Pallavi; Kumar, Pramod; Yewalkar, Nilambari; Deore, Vijaykumar; Lohar, Manoj; Mundada, Ramswaroop; Padgaonkar, Amol; Manohar, Sonal; Joshi, Asavari; Bhatia, Dimple; Desai, Nikesh; Damre, Anagha; Bhonde, Mandar; Joshi, Kalpana; Sharma, Rajiv; Kumar, Sanjay

2013-11-01

225

Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents.  

PubMed

The main difficulty in the development of ATP antagonist kinase inhibitors is target specificity, since the ATP-binding motif is present in many proteins. We introduce a strategy that has allowed us to identify compounds from a kinase inhibitor library that block the cyclin-dependent kinases responsible for regulating transcription, i.e., CDK7 and especially CDK9. The screening cascade employs cellular phenotypic assays based on mitotic index and nuclear p53 protein accumulation. This permitted us to classify compounds into transcriptional, cell cycle, and mitotic inhibitor groups. We describe the characterization of the transcriptional inhibitor class in terms of kinase inhibition profile, cellular mode of action, and selectivity for transformed cells. A structural selectivity rationale was used to optimize potency and biopharmaceutical properties and led to the development of a transcriptional inhibitor, 3,4-dimethyl-5-[2-(4-piperazin-1-yl-phenylamino)-pyrimidin-4-yl]-3H-thiazol-2-one, with anticancer activity in animal models. PMID:21035734

Wang, Shudong; Griffiths, Gary; Midgley, Carol A; Barnett, Anna L; Cooper, Michael; Grabarek, Joanna; Ingram, Laura; Jackson, Wayne; Kontopidis, George; McClue, Steven J; McInnes, Campbell; McLachlan, Janice; Meades, Christopher; Mezna, Mokdad; Stuart, Iain; Thomas, Mark P; Zheleva, Daniella I; Lane, David P; Jackson, Robert C; Glover, David M; Blake, David G; Fischer, Peter M

2010-10-29

226

Synthesis of some new 1,3,5-trisubstituted pyrazolines bearing benzene sulfonamide as anticancer and anti-inflammatory agents.  

PubMed

Thirteen new 2-pyrazoline derivatives bearing benzenesulfonamide moiety (2a-m) were synthesized by condensing appropriate chalcones with 4-hydrazinonbenzenesulfonamide hydrochloride and tested for anticancer and anti-inflammatory actions. According to the protocol of the National Cancer Institute (NCI) in vitro disease-oriented human cells screening panel assay compounds 2b, 2c, 2e, 2f and 2g exhibited considerable antitumor activities against the entire tested tumor cell lines and showed effective growth inhibition GI(50) (MG-MID) values of 2.63, 2.57, 6.61, 3.31 and 2.57?M, respectively, beside a cyclostatic activity TGI (MG-MID) 9.54, 8.51, 24.0, 19.9 and 8.71?M, respectively. Two compounds 2g and 2k showed more potent anti-inflammatory activity than celecoxib at 5h in carrageenan-induced rat paw edema bioassay. These compounds (2g and 2k) proved to have superior gastrointestinal safety profiles as compared to celecoxib, when tested for their ulcerogenic effects. Compounds 2g and 2k showed no inhibition against the enzymatic activity of bovine COX-2 (in vitro). PMID:21664130

Bashir, Rafia; Ovais, Syed; Yaseen, Shafiya; Hamid, Hinna; Alam, M S; Samim, Mohammad; Singh, Surender; Javed, Kalim

2011-05-27

227

Biosynthesis of podophyllotoxin in Linum album cell cultures  

Microsoft Academic Search

.   Cell cultures of Linum album Kotschy ex Boiss. (Linaceae) showing high accumulation of the lignan podophyllotoxin (PTOX) were established. Enzymological\\u000a studies revealed highest activities of phenylalanine ammonia-lyase, cinnamyl alcohol dehydrogenase, 4-hydroxycinnamate:CoA\\u000a ligase and cinnamoyl-CoA:NADP oxidoreductase immediately prior to PTOX accumulation. To investigate PTOX biosynthesis, feeding\\u000a experiments were performed with [2-13C]3?,4?-dimethoxycinnamic acid, [2-13C]3?,4?-methylenedioxycinnamic acid (MDCA), [2-13C]3?,4?,5?-trimethoxycinnamic acid, [2-13C]sinapic acid, [2-13C]-

Véronique Seidel; Jörg Windhövel; Graham Eaton; Wilhelm A. Alfermann; Randolph R. Arroo; Manuel Medarde; Maike Petersen; Jack G. Woolley

2002-01-01

228

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

PubMed

In cancer chemotherapy, metal-based complexes have been recognized as the most promising means of inhibiting cancer growth due to the successful application of cis-platin and its derivatives above many of the existing organic anticancer agents. The limitations in their rational design can be traced to the complexity of the mechanism of their operations, lack of proper knowledge of their targets and lack of force fields in docking packages to appropriately define the metal centre of the organometallic complexes. In this paper, some of the promising anticancer complexes of Ru(II) such as the rapta-based complexes formulated as [Ru(?6-p-cymene)L2(pta)] and those with unusual ligands are considered. CatB and kinases which have been experimentally confirmed as possible targets of the complexes are also predicted by the three methods as one of the most targeted receptors while TopII and HDAC7 are predicted by two and one of the methods as best targets. The interesting features of the binding of the complexes show that some of the complexes preferentially target specific macromolecules than the others, which is an indication of their specificity and possibility of their therapeutic combination without severe side effects that may come from competition for the same target. Also, introduction of unusual ligands is found to significantly improve the activities of most of the complexes studied. Strong correlations are observed for the predicted binding sites and the orientation of the complexes within the binding site by the three methods of docking. However there are disparities in the ranking of the complexes by the three method of docking, especially that of Glide. PMID:23529035

Adeniyi, Adebayo A; Ajibade, Peter A

2013-03-25

229

Anticancer Chemotherapy.  

National Technical Information Service (NTIS)

Despite troubled beginnings, anticancer chemotherapy has made significant contribution to the control of cancer in man, particularly within the last two decades. Early conceptual observations awakened the scientific community to the potentials of cancer c...

R. E. Weller

1988-01-01

230

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

PubMed

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

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

2006-04-01

231

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

Microsoft Academic Search

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

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

2004-01-01

232

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

PubMed

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

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

2010-08-30

233

The Efficacy of Topoisomerase II-Targeted Anticancer Agents Reflects the Persistence of Drug-Induced Cleavage Complexes in Cells†  

PubMed Central

Genistein, a widely consumed bioflavonoid with chemopreventative properties in adults, and etoposide, a commonly prescribed anticancer drug, are well-characterized topoisomerase II poisons. Although both compounds display similar potencies against human topoisomerase II? and ? in vitro and induce comparable levels of DNA cleavage complexes in cultured human cells, their cytotoxic and genotoxic effects differ significantly. As determined by assays that monitored viability or the phosphorylation of histone H2AX, etoposide was much more toxic in CEM cells than genistein. Further studies that characterized the simultaneous treatment of cells with genistein and etoposide indicate that the differential actions of the two compounds are not related to the effects of genistein on cellular processes outside of its activity against topoisomerase II. Rather, they appear to result from a longer persistence of cleavage complexes induced by etoposide as compared to genistein. Parallel in vitro studies with purified type II enzymes led to similar conclusions regarding cleavage complex persistence. Isoform-specific differences were observed in vitro and in cells treated with etoposide. To this point, the t1/2 of etoposide-induced DNA cleavage complexes formed with topoisomerase II? in CEM cells was ?5 times longer than those formed with topoisomerase II?. The cytotoxicity of etoposide following four treatment-recovery cycles was similar to that induced by continuous exposure to the drug over an equivalent time period. Taken together, these findings suggest that it may be possible to preferentially target topoisomerase II? with etoposide by employing a schedule that utilizes pulsed drug treatment-recovery cycles.

Bandele, Omari J.; Osheroff, Neil

2009-01-01

234

Structure activity relationship of arylidene pyrrolo and pyrido [2,1-b] Quinazolones as cytotoxic agents: synthesis, SAR studies, biological evaluation and docking studies.  

PubMed

Tubulin is the one of the most useful and strategic molecular targets for anticancer drugs. Agents that bind in Colchicine-binding site of tubulin include Phenstatin, Combretastatin A-4, Colchicine, Steganacin, Podophyllotoxin and certain other synthetic analogues of these compounds. Arylidene pyrollo and pyrido [2,1- b] quinazolones (isoindigatone and its synthetic analogues) have been earlier reported to be tubulin inhibitors evidenced by tubulin polymerization assay. The present study is an extension of the library of the isoindigatone and its synthetic analogues to generate the structure activity relationship. The study explores the role of the arylidene ring and also provides some intresting observations such as the placement of bicyclic ring such as naphylidene for potential activity. Some of the important interactions of KNH- 3 and KNH-11 with the amino acid residues of active site of Tubulin have also been observed by molecular modeling. PMID:23061561

Mangla, Veenu; Nepali, Kunal; Singh, Gagandip; Singh, Jagjeet; Guru, Santosh; Gupta, Manish Kumar; Mahajan, Priya; Saxena, Ajit Kumar; Lal Dhar, Kanaya

2013-08-01

235

Sulfur-substituted naphthalimides as photoactivatable anticancer agents: DNA interaction, fluorescence imaging, and phototoxic effects in cultured tumor cells  

Microsoft Academic Search

A series of sulfur-substituted naphthalimides (1–5) was prepared and investigated as antitumor drugs. Initial DNA interaction studies (by the fluorescence quenching method, UV\\/vis and CD spectroscopy, thermal denaturation, topoisomerase Western blot analysis, and DNA photocleavage experiments) expectedly suggested the DNA and topoisomerase as main targets of the agents. Fluorescence spectroscopic and microscopic experiments indicated a significant sensitivity of the emission

Ingo Ott; Yufang Xu; Jianwen Liu; Malte Kokoschka; Melanie Harlos; William S. Sheldrick; Xuhong Qian

2008-01-01

236

Novel 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: Promising anticancer agents  

Microsoft Academic Search

A series of 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives was synthesized and 13 of them were selected by the National Cancer Institute (NCI) and evaluated for their in vitro anticancer activity. Seven of the investigated compounds, 3i, 3j, 3k, 3o, 3p, 3q, and 3r, displayed high anticancer activity in the primary assay. These compounds have been selected for a full anticancer screening against a

Ahmed S. Aboraia; Hamdy M. Abdel-Rahman; Nadia M. Mahfouz; Mahmoud A. EL-Gendy

2006-01-01

237

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

Microsoft Academic Search

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

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

2002-01-01

238

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

PubMed

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

2012-02-01

239

Structural simplification of bioactive natural products with multicomponent synthesis: Dihydropyridopyrazole analogues of podophyllotoxin  

Microsoft Academic Search

A three-component condensation of 5-amino-3-methylpyrazole, tetronic acid, and various aromatic, heteroaromatic, and aliphatic aldehydes leads to the formation of dihydropyridopyrazole analogues of a cytotoxic lignan podophyllotoxin. This new heterocyclic scaffold-based library allows a drastic reduction of the structural complexity of the natural product with the retention of its potent cytotoxic properties. Similarly to podophyllotoxin, the presented analogues induce apoptosis in

Igor V. Magedov; Madhuri Manpadi; Elena Rozhkova; Nikolai M. Przheval’skii; Snezna Rogelj; Scott T. Shors; Wim F. A. Steelant; Severine Van slambrouck; Alexander Kornienko

2007-01-01

240

Management of Metabolic Effects Associated With Anticancer Agents Targeting the PI3K-Akt-mTOR Pathway  

PubMed Central

Agents inhibiting the phosphoinositide 3–kinase–Akt–mammalian target of rapamycin (PAM) pathway are currently in various stages of clinical development in oncology, ranging from some in early-phase evaluations to others that have already received regulatory approval for treatment in advanced cancers. The administration of PAM pathway inhibitors has been associated with metabolic toxicities of hyperlipidemia and hyperglycemia. The PAM Task Force of the National Cancer Institute Investigational Drug Steering Committee convened an interdisciplinary expert panel to review the pathophysiology of hyperlipidemia and hyperglycemia induced by PAM pathway inhibitors, summarize the incidence of these metabolic toxicities induced by such agents in the current literature, advise on clinical trial screening and monitoring criteria, and provide management guidance and therapeutic goals on occurrence of these toxicities. The overarching aim of this consensus report is to raise awareness of these metabolic adverse events to enable their early recognition, regular monitoring, and timely intervention in clinical trials. Hyperglycemia and hyperlipidemia are generally not acutely toxic and most often reversible with therapeutic intervention. Dose modifications or discontinuation of PAM pathway inhibitors should only be considered in situations of severe events or if progressive metabolic derangement persists after therapeutic interventions have been attempted for a sufficient duration. Specialty consultation should be sought to aid clinical trial planning and the management of these metabolic adverse events.

Busaidy, Naifa L.; Farooki, Azeez; Dowlati, Afshin; Perentesis, John P.; Dancey, Janet E.; Doyle, Laurence A.; Brell, Joanna M.; Siu, Lillian L.

2012-01-01

241

Synthesis and SAR of [1,2,4]triazolo[1,5-a]pyrimidines, a class of anticancer agents with a unique mechanism of tubulin inhibition.  

PubMed

The synthesis and SAR of a series of triazolopyrimidines as anticancer agents are described. Treatment of 5-chloro-6-(trifluorophenyl)-N-fluoroalkyl [1,2,4]triazolo[1,5-a]pyrimidin-7-amine with an alcohol, a thiol, or an alkylamine provided the corresponding final compounds. A clear SAR requirement has been established for optimal activity. A (1S)-2,2,2-trifluoro-1-methylethylamino group or an achiral 2,2,2-trifluoroethylamino group is required at the 5-position to achieve high potency. On the phenyl ring, both fluoro atoms, at the positions ortho to the triazolopyrimidine core, are needed for optimal activity. At the position para to the triazolopyrimidine core, on the phenyl ring, the best activity is achieved with an oxygen linkage followed by a three-methylene unit, and an alkylamino or a hydroxy group. The mechanism of action for this series of triazolopyrimidines was shown to be unique in that they promoted tubulin polymerization in vitro, but did not bind competitively with paclitaxel.1 Instead, they inhibit the binding of vincas to tubulin. Selected compounds were studied further, and it was shown that these compounds were able to overcome resistance attributed to several multidrug resistance transporter proteins. Lead compounds were shown to inhibit tumor growth in several nude mouse xenograft models, with high potency and efficacy, when dosed either orally or intravenously. PMID:17228873

Zhang, Nan; Ayral-Kaloustian, Semiramis; Nguyen, Thai; Afragola, Jay; Hernandez, Richard; Lucas, Judy; Gibbons, James; Beyer, Carl

2007-01-25

242

Potential of xanthones from tropical fruit mangosteen as anti-cancer agents: caspase-dependent apoptosis induction in vitro and in mice.  

PubMed

The pericarp of mangosteen (Garcinia mangostana L.) is rich in various xanthones that are known to possess unique biological activities. In this work, we characterized the anti-proliferative and cytotoxic activities of mangosteen xanthones both in vitro and in mice. In vitro analysis with a human colorectal adenocarcinoma cell line, COLO 205, showed that mangosteen xanthones not only inhibit the proliferation of target cells but also induce their death by apoptosis that involves the activation of the caspase cascade. In vivo analysis using a mouse subcutaneous tumor model with COLO 205 cells showed that, at relatively low doses, the growth of tumors was repressed upon intratumoral administration of mangosteen xanthones. When a higher dose of mangosteen xanthones was administered, the size of tumors was reduced gradually, and, in some mice, the disappearance of tumors was seen. Histopathological evaluation and biochemical analysis of tumors that received mangosteen xanthones indicate the induction of apoptosis in tumors, which resulted in the repression of their growth and the reduction of their sizes. These results demonstrate the potential of mangosteen xanthones to serve as anti-cancer agents for the chemotherapy of cancer. PMID:20101528

Watanapokasin, Ramida; Jarinthanan, Faongchat; Jerusalmi, Alan; Suksamrarn, Sunit; Nakamura, Yukio; Sukseree, Supawadee; Uthaisang-Tanethpongtamb, Wanlaya; Ratananukul, Piniti; Sano, Takeshi

2010-01-26

243

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

PubMed Central

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

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

2012-01-01

244

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

PubMed

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

2011-07-06

245

Supramolecular chiro-biomedical assays and enantioselective HPLC analyses for evaluation of profens as non-steroidal anti-inflammatory drugs, potential anticancer agents and common xenobiotics.  

PubMed

The permanent world-wide increase in therapeutic administration of racemic profens as easy available non-prescribed analgesic drugs and a common first-choice anti-inflammatory agents was recently linked with renewed interest in their beneficial use, also as enantiopure formulations, to treat and/or prevent a variety of human malignancies including its four major types as colorectal, breast, lung, and prostate cancer. This underlies the continuous need of selecting perfectly suited chiral separation methods of profens capable to determine nanolevels of a distomer in presence of the eutomer in a variety of complex biological and environmental media. Thus, current improvements for direct enantiomeric separations of profens by well defined supramolecular-based chiral HPLC and recently developed monolithic, combinatorial, bimodal and polymeric chiral stationary phases employing a modern supramolecular chirality concepts has been outlined in this review. The use of diverse supramolecular approaches for chiral HPLC as an easy accessible tool enabling fast development of nanoscale enantioselective, high-throughput and gradient screening procedures for in situ monitoring of stereoselective ADME properties of profens in range of anticancer drug discovery technologies has been also addressed. PMID:18673249

Ali, Imran; Hussain, Iqbal; Saleem, Kishwar; Aboul-Enein, Hassan Y; Bazylak, Grzegorz

2008-06-01

246

Polymer conjugates as anticancer nanomedicines  

Microsoft Academic Search

The transfer of polymer–protein conjugates into routine clinical use, and the clinical development of polymer–anticancer-drug conjugates, both as single agents and as components of combination therapy, is establishing polymer therapeutics as one of the first classes of anticancer nanomedicines. There is growing optimism that ever more sophisticated polymer-based vectors will be a signficant addition to the armoury currently used for

Ruth Duncan

2006-01-01

247

Anticancer Drug Development  

Microsoft Academic Search

Around the world, tremendous resources are being invested in prevention, diagnosis, and treatment of cancer. Cancer is the\\u000a second leading cause of death in Europe and North America. Discovery and development of anticancer agents are the key focus\\u000a of several pharmaceutical companies as well as non-profit government and non-government organizations, like the National Cancer\\u000a Institute (NCI) in the United States,

Ajit S. Narang; Divyakant S. Desai

248

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

PubMed

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

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

2012-09-05

249

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

PubMed

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

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

2010-05-07

250

PT-ACRAMTU, A Platinum-Acridine Anticancer Agent, Lengthens and Aggregates, but does not Stiffen or Soften DNA.  

PubMed

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

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

2013-05-01

251

Disaccharide esters screened for inhibition of tumor necrosis factor-alpha release are new anti-cancer agents.  

PubMed

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine playing a part in various pathological states. Non-toxic inhibitors of TNF-alpha release are thought to be promising agents for cancer prevention. We found that the acetone fraction of the tobacco leaf surface lipid containing glucose esters and sucrose esters inhibited both TNF-alpha release from BALB/3T3 and KATO III cells induced by okadaic acid and tumor promotion by okadaic acid on mouse skin initiated with 7,12-dimethylbenz(a)anthracene (DMBA). Next, we investigated the inhibition of TNF-alpha release with synthetic disaccharide esters, such as 6,6'-di-O-alkanoyl-alpha, alpha-trehaloses (6,6'-diester-trehaloses), 4,4'-di-O-alkanoyl-alpha, alpha-trehaloses (4,4'-diester-trehaloses) and 6,6'-diamino-6,6'-dideoxy-N,N'-dialkanoyl-alpha, alpha-trehaloses (6,6'-diamide-trehaloses) bearing fatty acids of various chain lengths, and n-dodecyl-beta-D-maltoside as a disaccharide monoester. 6,6'-Diester-trehaloses and 4,4'-diester-trehaloses of C8 to C12 fatty acids, 6,6'-diamide-trehaloses of C8 to C14 fatty acids, and n-dodecyl-beta-D-maltoside all inhibited TNF-alpha release in a dose-dependent manner. The IC50 values are 7.4-14.8 microM for 6,6'-diester-trehaloses (C8 to C12), 14.6-21.6 microM 4,4'-diester-trehaloses (C8 to C12), 2.9-15.0 microM for 6,6'-diamide-trehaloses (C8 to C14) and 23 microM for dodecyl-beta-D-maltoside. Both 6,6'-di-O-octanoyl-alpha, alpha-trehalose (C8, designated as SS555) and n-dodecyl-beta-D-maltoside (C12) inhibited tumor promotion by okadaic acid on mouse skin initiated with DMBA. Percentages of tumor-bearing mice in week 15 of tumor promotion were reduced from 60.0 to 13.3 with SS555, and to 46.7 with n-dodecyl-beta-D-maltoside. Moreover, SS555 inhibited TNF-alpha gene expression mediated through inhibition of AP-1 activation, but not NF-kappa B activation. This paper reports that diester-trehaloses of C8 to C12 fatty acids and mimics of disaccharide monoesters such as n-dodecyl-beta-D-maltoside appear to be potential cancer-preventive agents of a new type. PMID:10429660

Okabe, S; Suganuma, M; Tada, Y; Ochiai, Y; Sueoka, E; Kohya, H; Shibata, A; Takahashi, M; Mizutani, M; Matsuzaki, T; Fujiki, H

1999-06-01

252

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

NASA Astrophysics Data System (ADS)

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

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

2013-02-01

253

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

PubMed Central

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

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

2012-01-01

254

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

PubMed

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

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

2012-08-17

255

Mitochondria-mediated apoptosis operating irrespective of multidrug resistance in breast cancer cells by the anticancer agent prodigiosin.  

PubMed

Prodigiosin (PG) is a red pigment produced by Serratia marcescens with pro-apoptotic activity in haematopoietic and gastrointestinal cancer cell lines, but no marked toxicity in non-malignant cells. Breast cancer is the most frequent malignancy among women in the European Union and better therapies are needed, especially for metastatic tumors. Moreover, multidrug resistance is a common phenomenon that appears during chemotherapy, necessitating more aggressive treatment as prognosis worsens. In this work, we extend our experiments on PG-induced apoptosis to breast cancer cells. PG was potently cytotoxic in both estrogen receptor positive (MCF-7) and negative (MDA-MB-231) breast cancer cell lines. Cytochrome c release, activation of caspases-9, -8 and -7 and cleavage of poly (ADP-ribose) polymerase protein typified the apoptotic event and caspase inhibition revealed that PG acts via the mitochondrial pathway. In a multidrug-resistant subline of MCF-7 cells that over-expresses the breast cancer resistance protein, the cytotoxic activity of PG was slightly reduced. However, flow-cytometry analysis of PG accumulation and efflux in MCF-7 sublines showed that PG is not a substrate for this resistance protein. These results suggest that PG is an interesting and potent new pro-apoptotic agent for the treatment of breast cancer even when multidrug resistance transporter molecules are present. PMID:15345324

Soto-Cerrato, Vanessa; Llagostera, Esther; Montaner, Beatriz; Scheffer, George L; Perez-Tomas, Ricardo

2004-10-01

256

Design, synthesis and potent cytotoxic activity of novel podophyllotoxin derivatives.  

PubMed

Twenty new acyl thiourea derivatives of podophyllotoxin and 4'-demethylepipodophyllotoxin were prepared and screened for their cytotoxicity against four human tumor cell lines, A-549, DU-145, KB, and KBvin. With IC50 values of 0.098-1.13 ?M, compounds 13b, 13c, and 13o displayed much better cytotoxic activity than the control etoposide. Most importantly, 13b and 13o exhibited promising cytotoxicity against the drug resistant tumor cell line KBvin with IC50 values of 0.098 and 0.13 ?M, respectively, while etoposide lost activity completely. Structure-activity relationship (SAR) correlations of the new derivatives have been established. Compounds 13b and 13o merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates. PMID:23490151

Li, Wen-Qun; Wang, Xu-Li; Qian, Keduo; Liu, Ying-Qian; Wang, Chih-Ya; Yang, Liu; Tian, Jin; Morris-Natschke, Susan L; Zhou, Xing-Wen; Lee, Kuo-Hsiung

2013-02-17

257

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

PubMed

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

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

2011-02-24

258

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

PubMed

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

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

2011-08-10

259

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.

1985-01-01

260

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

1998-01-01

261

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

PubMed

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

2011-07-19

262

Genetic activity profiles of anticancer drugs  

Microsoft Academic Search

The results from short-term tests for genetic and related effects, abstracted from the open literature for 36 anticancer drugs, are examined in this review. Data for 27 of these agents are available in the EPA\\/IARC Genetic Activity Profile (GAP) database. Data summaries, including data listings and activity profiles, are presented for nine anticancer drugs added to the GAP database for

Marcus A. Jackson; H. Frank Stack; Michael D. Waters

1996-01-01

263

Proteomic changes induced by podophyllotoxin in human cervical carcinoma HeLa cells.  

PubMed

Podophyllotoxin, a kind of lignan extracted from the Podophyllum plant, has been shown to inhibit the growth of various carcinoma cells. However, the molecular mechanism remains unclear. In this study, the inhibition of cell growth and changes in protein expression induced by podophyllotoxin were investigated in human cervical carcinoma HeLa cells. Our results demonstrate that Podophyllotoxin inhibits HeLa cell growth and induces apoptosis. By using proteomic techniques, seven proteins were found to be significantly regulated by podophyllotoxin compared to the untreated control; among them, four were down-regulated and three were up-regulated. All of the seven proteins were identified with peptide mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) after in-gel trypsin digestion. Five of these proteins are involved in protein metabolism, and the other two play roles in cell communication and signaling transduction pathways. It is suggested that the effect of podophyllotoxin on the growth of tumor cells is significantly related to the metabolism-associated proteins. PMID:23336514

Wang, Bochan; Chen, Lifeng; Zhen, Hong; Zhou, Li; Shi, Ping; Huang, Zhiwei

2013-01-01

264

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

PubMed

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

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

2012-08-09

265

Novobiocin Analogues as Anticancer Agents.  

National Technical Information Service (NTIS)

Novel analogues and derivatives of novobiocin are provided, including compounds having modifications to the amide side chain, coumarin ring, and sugar moieties. The compounds of the present invention are useful as heat shock protein 90 inhibitors, and may...

B. S. Blagg L. Neckers X. M. Yu

2005-01-01

266

Plant-derived anticancer agents  

Microsoft Academic Search

Natural product drugs play a dominant role in pharmaceutical care. This is especially obvious in the case of antitumor drugs, as exemplified by paclitaxel (Taxol®), vincristine (Oncovin®), vinorelbine (Navelbine®), teniposide (Vumon®), and various water-soluble analogs of camptothecin (e.g., Hycamtin®). The most efficient method of discovering drugs such as these (i.e. novel chemical prototypes that may function through unique mechanisms of

John M. Pezzuto

1997-01-01

267

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

PubMed

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

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

2000-02-11

268

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

PubMed

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

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

2002-11-01

269

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

PubMed

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

Paulson, J C; McClure, W O

1975-11-01

270

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

PubMed

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

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

2012-10-09

271

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.

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

2012-01-01

272

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.

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

2013-01-01

273

Alleviation of Podophyllotoxin Toxicity Using Coexisting Flavonoids from Dysosma versipellis.  

PubMed

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

2013-08-21

274

Biosynthesis of podophyllotoxin in Linum album cell cultures.  

PubMed

Cell cultures of Linum album Kotschy ex Boiss. (Linaceae) showing high accumulation of the lignan podophyllotoxin (PTOX) were established. Enzymological studies revealed highest activities of phenylalanine ammonia-lyase, cinnamyl alcohol dehydrogenase, 4-hydroxycinnamate:CoA ligase and cinnamoyl-CoA:NADP oxidoreductase immediately prior to PTOX accumulation. To investigate PTOX biosynthesis, feeding experiments were performed with [2-(13)C]3',4'-dimethoxycinnamic acid, [2-(13)C]3',4'-methylenedioxycinnamic acid (MDCA), [2-(13)C]3',4',5'-trimethoxycinnamic acid, [2-(13)C]sinapic acid, [2-(13)C]- and [2,3-(13)C(2)]ferulic acid. Analysis of the metabolites by HPLC coupled to tandem mass spectrometry revealed incorporation of label from ferulic acid into PTOX and deoxypodophyllotoxin (DOP). In addition, MDCA was also unambiguously incorporated intact into PTOX. These observations suggest that in L. album both ferulic acid and methylenedioxy-substituted cinnamic acid can be incorporated into lignans. Furthermore, it appears that, in this species, the hydroxylation of DOP is a rate-limiting point in the pathway leading to PTOX. Electronic supplementary material to this paper can be obtained by using the Springer LINK server located at http://dx.doi.org/wo.1007/s00425-002-0834-1. PMID:12355164

Seidel, Véronique; Windhövel, Jörg; Eaton, Graham; Alfermann, A Wilhelm; Arroo, Randolph R J; Medarde, Manuel; Petersen, Maike; Woolley, Jack G

2002-07-25

275

Podophyllotoxin induces CREB phosphorylation and CRE-driven gene expression via PKA but not MAPKs  

Microsoft Academic Search

CRE-driven luciferase reporter is commonly used in drug screening systems involving G protein-coupled receptors (GPCRs). In\\u000a a screen campaign designed to search for melanocortin-4 receptor (MC4R) agonists, podophyllotoxin, a microtubules disruptor,\\u000a was found to induce cAMPresponsive element (CRE)-driven reporter expression. MC4R was not involved because podophyllotoxin\\u000a induced CREB activation and CRE-driven transcription in cells not expressing MC4R. Previous studies indicated

Ya Qiong Chen; Xin Xie

2010-01-01

276

Time and dose-dependent modulation of phase 1 and phase 2 gene expression in response to treatment of MCF-7 cells with a natural anti-cancer agent.  

PubMed

Several known anti-cancer agents have been shown to lead to increased expression of phase 2 metabolic enzymes without affecting phase 1 enzymes. Phase 1 cytochrome P450 (CYP) enzymes are relevant in cancer studies in that they are involved in oxidative metabolism, biotransformation and detoxification, whereas phase 2 enzyme catalysis leads to clearance. In this study, we obtained semi-quantitative measurements of cytochrome P450 (phase 1) and phase 2 microsomal epoxide hydrolase (mEH) gene expression levels in response to treatment of MCF-7 breast cancer cells with water-soluble Vernonia amygdalina (V.A.) extract. V.A., a vegetable grown in Nigeria, has potential as an anti-cancer agent. The results of Western blot and RT-PCR analyses show that V.A. extract acts as a monofunctional inducer within exposure times ranging from 2-16 hr and dose ranges from 3-100 microg/ml of V.A. Exposure of cells to low doses of V.A. did not affect expression levels of CYP1A1/1A2 mRNA, but lead to induction of mEH, thus supporting the chemotherapeutic potential of VA. However, in parallel studies, CYP3A4 gene expression was also induced, suggesting potential intermediates which influence drug-drug interactions. These data are useful toward further validating V.A. extract as a potential clinically useful natural anti-cancer agent and provide some support for the concept that modulation in CYP3A4 expression in response to treatment is relevant to prognosis. PMID:14682387

Howard, C B; Stevens, J; Izevbigie, E B; Walker, A; McDaniel, O

2003-11-01

277

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

Microsoft Academic Search

Clioquinol has been shown to have anticancer activity both in vitro and in vivo. The present study compared the cytotoxicity of clioquinol with six analogues using human cancer cell lines. Of the analogues tested, 8-hydroxy-5-nitroquinoline (NQ) was the most toxic, with an IC50 that was five to ten fold lower than that of other congeners. Its activity was enhanced by

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

2011-01-01

278

Anticancer chemotherapy  

SciTech Connect

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

Weller, R.E.

1991-10-01

279

POST-HARVEST AND SCALE-UP EXTRACTION OF AMERICAN MAYAPPLE LEAVES FOR PODOPHYLLOTOXIN PRODUCTION  

Technology Transfer Automated Retrieval System (TEKTRAN)

Leaves of American mayapple, Podophyllum peltatum, are of interest to the pharmaceutical industry as an alternative source of podophyllotoxin. In this study, the effects of post-harvest handling were evaluated by inflicting physical damage to leaves of mayapple to simulate rough handling. The effect...

280

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

281

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

PubMed

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

Casey, Mike; Keaveney, Claire M

2003-12-05

282

Synthesis and biological evaluation of some new 2-pyrazolines bearing benzene sulfonamide moiety as potential anti-inflammatory and anti-cancer agents  

Microsoft Academic Search

Eight novel 2-pyrazolines (2a–h) were synthesized by the reaction of appropriate chalcones\\/flavanones with 4-hydrazinonbenzenesulfonamide hydrochloride and tested for anti-inflammatory and anti-cancer activities. Two compounds 2c and 2e showed good anti-inflammatory activity which is comparable to the reference drug celecoxib in carrageenan-induced rat paw edema bioassay and found safe from the point of view of ulcer induction. Compounds 2c and 2e

Sameena Bano; Kalim Javed; Shamim Ahmad; I. G. Rathish; Surender Singh; M. S. Alam

2011-01-01

283

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

Microsoft Academic Search

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

Yoichi Miyamoto; Tatsuya Od; Hiroshi Maeda

284

Cajanol, a novel anticancer agent from Pigeonpea [ Cajanus cajan (L.) Millsp.] roots, induces apoptosis in human breast cancer cells through a ROS-mediated mitochondrial pathway  

Microsoft Academic Search

Cajanol (5-hydroxy-3-(4-hydroxy-2-methoxyphenyl)-7-methoxychroman-4-one) is an isoflavanone from Pigeonpea [Cajanus cajan (L.) Millsp.] roots. As the most effective phytoalexin in pigeonpea, the cytotoxic activity of cajanol towards cancer cells has not been report as yet. In the present study, the anticancer activity of cajanol towards MCF-7 human breast cancer cells was investigated. In order to explore the underlying mechanism of cell growth

Meng Luo; Xia Liu; Yuangang Zu; Yujie Fu; Su Zhang; Liping Yao; Thomas Efferth

2010-01-01

285

Induction of multidrug resistance in MOLT4 cells by anticancer agents is closely related to increased expression of functional P-glycoprotein and MDR1 mRNA  

Microsoft Academic Search

Purpose: The aim of this study was to investigate the multidrug resistance (MDR) pattern, MDR gene and P-glycoprotein (P-gp) expression, and P-gp function in drug-induced human T-lymphoblastoid leukemia MOLT-4 sublines. Methods: The MDR sublines were developed by exposing the parental MOLT-4 cells to stepwise increasing concentrations of anticancer drugs daunorubicin (DNR), vinblastine (VBL) and doxorubicin (DOX). Degrees of resistance were

Zhen-Li Liu; Kenji Onda; Sachiko Tanaka; Tsugutoshi Toma; Toshihiko Hirano; Kitaro Oka

2002-01-01

286

Synthesis and biological evaluation of novel 4?-(1,3,4-oxadiazole-2-amino)-podophyllotoxin derivatives.  

PubMed

A series of new 4?-(1,3,4-oxadiazole-2-amino)-podophyllotoxin derivatives were designed and synthesized. Their cytotoxicity in vitro against six tumor cell lines (DU-145, SGC-7901, A549, SH-SY5Y, HepG2 and HeLa) were evaluated by standard MTT assay. The pharmacological results showed that most of the newly synthesized podophyllotoxin derivatives displayed potent cytotoxicity against at least one of the tested tumor cells; and among the new derivatives, 11b was more potent than podophyllotoxin against HepG2 and Hela cell lines. Furthermore, 11b exhibited much better selectivity toward the normal cell lines L929 and Vero than etoposide, 5-Fu and podophyllotoxin. The possible antitumor mechanism of 11b is to inhibit the activity of DNA topoisomerase II, result in the S-phase arrest, and then cause apoptotic cell death. PMID:22687745

Ren, Jie; Wu, Lin; Xin, Wen Qun; Chen, Xin; Hu, Kun

2012-05-23

287

Novel Marine Compounds: Anticancer or Genotoxic?  

PubMed Central

In the past several decades, marine organisms have generously gifted to the pharmaceutical industries numerous naturally bioactive compounds with antiviral, antibacterial, antimalarial, anti-inflammatory, antioxidant, and anticancer potentials. But till date only few anticancer drugs (cytarabine, vidarabine) have been commercially developed from marine compounds while several others are currently in different clinical trials. Majority of these compounds were tested in the tumor xenograft models, however, lack of anticancer potential data in the chemical- and/or oncogene-induced pre-initiation animal carcinogenesis models might have cost some of the marine anticancer compounds an early exit from the clinical trials. This review critically discusses importance of preclinical evaluation, failure of human clinical trials with certain potential anticancer agents, the screening tests used, and choice of biomarkers.

Arif, Jamal M.

2004-01-01

288

Reversal of mdr1-mediated multidrug resistance in human leukemia cells by a new spin-labeled derivative of podophyllotoxin.  

PubMed

GP7 (4-[4"-(2", 2", 6", 6"-tetramethyl-l"-piperidinyloxy) amino]-4'-demethyl epipodophyllotoxin) is a promising anticancer drug of the podophyllotoxin class. However, little is known about its anti-multidrug resistance effects. In the present study, we investigated the effects of GP7 on P-glycoprotein (P-gp) overexpression multidrug-resistant human leukemia K562/ADM cells with the comparison of VP-16 and K562 cells. GP7 inhibited the proliferation of K562/ADM cells in a concentration- or time-dependent manner, and the inhibitory effect of GP7 on K562/ADM cells was 1.50-fold higher than that of VP-16. GP7 caused G2/M phase accumulation but VP-16 caused S phase accumulation in K562/ADM and K562 cells. GP7 could induce apoptosis of both K562/ADM and K562 cell lines, but there was no significant difference between GP7- and VP-16-induced apoptotic ratios. GP7 could also induce typical apoptotic morphological changes and internucleosomal DNA fragmentation of K562/ADM and K562 cells, but DNA fragmentation induced by GP7 in K562/ADM cells was weaker than that in K562 cells. When treated with GP7 or VP-16 for 48 h, 128-256 microM GP7 induced more DNA fragmentation than VP-16 did, but 32-64 microM GP7 induced less DNA fragmentation than VP-16 did. GP7 could down-regulate the expression of P-gp in K562/ADM cells but VP-16 could not. Our findings suggest that GP7 may reverse multidrug resistance in human leukemia K562/ADM cells via down-regulation of P-gp expression. PMID:20225656

Qi, She-Ning; Song, Li-Juan; Chen, Yan; Jing, Yuan-Xue

2010-02-01

289

The mechanism of photo-ionization of podophyllotoxin and its derivatives:a laser flash photolysis study  

NASA Astrophysics Data System (ADS)

Podophyllotoxin and its derivatives are very light (UV) sensitive, and can be readily photo-ionized to produce some transient species, such as radical cation, radical anion and superoxide anion radical. The laser flash photolysis of podophyllotoxin and its derivatives has been performed for the first time. The mechanism of photo-ionization has been confirmed and illustrated. In addition, the related reaction rate constants and molar extinction coefficients of the transient species have been determined.

Wang, S.-L.; Yao, S.-D.; Mei, W.; Zhang, Y.-L.; Zhang, M.-W.; Zhang, Z.-C.

1998-12-01

290

Increased podophyllotoxin production in Podophyllum hexandrum cell suspension cultures after feeding coniferyl alcohol as a ?-cyclodextrin complex  

Microsoft Academic Search

Cell suspension cultures, derived from roots of Podophyllum hexandrum Royle (Berberidaceae), accumulate podophyllotoxin. In this study the use of ß-cyclodextrin in feeding the poorly water-soluble precursor coniferyl alcohol to these cultures is described. By complexation with ß-cyclodextrin, a solution of 3 mM coniferyl alcohol could be fed, resulting in enhanced podophyllotoxin accumulation. The same concentration of non-complexed suspended coniferyl alcohol

Herman J. Woerdenbag; Wim van Uden; Henderik W. Frijlink; Coenraad F. Lerk; Niesko Pras; Theo M. Malingré

1990-01-01

291

Selective anticancer effects of 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine, a lipophilic prodrug of 5-fluoro-2'-deoxyuridine, dissolved in an oily lymphographic agent on hepatic cancer of rabbits bearing VX-2 tumor.  

PubMed

3',5'-Dioctanoyl-5-fluoro-2'-deoxyuridine (FdUrd-C8), one of the lipophilic prodrugs of 5-fluoro-2'-deoxyuridine (FdUrd) was dissolved in an oily lymphographic agent (Lipiodol Ultra-Fluid), which had been studied as a carrier of the anticancer drug for hepatic cancer. The prodrug was administered into the left proper hepatic artery of rabbits bearing VX-2 tumor in the liver in order to examine the anticancer effects and possible adverse effects on nontumorous hepatic cells. Lipiodol or FdUrd-C8*Lipiodol selectively remained in the hepatic cancer area but disappeared from nontumorous parts of the liver 7 days after injection. Tumor growth rates in 1 week of the untreated group, a group given injections of 0.2 ml of Lipiodol alone, and groups given injections of 0.2 ml of Lipiodol containing 30, 50, 70, and 100 mg of FdUrd-C8 were 636, 436, 34.8, 14.9, -2.4, and -10.4% of the size at the time of treatment, respectively. Pathological observation also showed that FdUrd-C8 had a strong anticancer effect on VX-2 tumor growing in the liver of the rabbits. In contrast to the effect on the cancerous cells, that on nontumorous hepatic cells was very slight. In pathological observation, necrosis or degeneration of nontumorous hepatic cells was hardly observed. Plasma glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase levels temporarily rose 1 day after injection but returned to the initial levels within 7 days in all groups. PMID:3028618

Fukushima, S; Kawaguchi, T; Nishida, M; Juni, K; Yamashita, Y; Takahashi, M; Nakano, M

1987-04-01

292

A facile synthesis of some 3-cyano-1,4,6-trisubstituted-2(1 H )-pyridinones and their biological evaluation as anticancer agents  

Microsoft Academic Search

The synthesis of some new 3-cyano-1,4,6-trisubstituted-2(1H)-pyridinones supported with various pharmacophores and functionalities at positin-1 is described. The in vitro anticancer\\u000a activity of 24 of the newly synthesized compounds was evaluated according to the protocol of the NCI in vitro disease-oriented\\u000a human cells screening panel assay. The results revealed that five compounds 4a–c, 7b, and 12b were able to display moderate

Sherif A. F. RostomHassan; Hassan M. Faidallah; Mohammed S. Al-Saadi

293

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

PubMed

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

Bandgar, Babasaheb P; Gawande, Shrikant S

2010-01-11

294

Synthesis and biological evaluation of novel alkyl amide functionalized trifluoromethyl substituted pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents.  

PubMed

A series of novel alkyl amide functionalized trifluoromethyl substituted pyrazolo[3,4-b]pyridine derivatives 5, 6 and 7 were prepared starting from 6-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine 3 via selective N-alkylation, followed by reaction with different primary aliphatic amines, cyclic secondary amines or l-amino acids under different set of conditions. All the synthesized compounds 5, 6 and 7 were screened for anticancer activity against four cancer cell lines such as A549-Lung cancer (CCL-185), MCF7-Breast cancer (HTB-22), DU145-Prostate cancer (HTB-81) and HeLa-Cervical cancer (CCL-2). The compounds 5i and 6e are found to have promising bioactivity at micro molar concentration. PMID:24060486

Chavva, K; Pillalamarri, S; Banda, V; Gautham, S; Gaddamedi, J; Yedla, P; Kumar, C G; Banda, N

2013-09-03

295

Convenient synthesis of fused heterocyclic 1,3,5-triazines from some N-acyl imidates and heterocyclic amines as anticancer and antioxidant agents.  

PubMed

N-Acyl imidates (2), reacting with 5-amino pyrazole (3), 2-aminobenzimidazole (4), 3-amino-1,2,4-triazole (5), 3,5-diamino-1,2,4-triazole (6), and 5-aminotetrazole (7) give pyrazolo[1,5-a][1,3,5]triazine (8), benzo[4,5]imidazo[1,2-a][1,3,5]triazine (9), [1,2,4]triazolo [2,3-a][1,3,5]triazine (10), [1,2,4]tri azolo[2,3-a][1,3,5]triazin-5-ylamine (12), and tetrazolo-[1,5-a][1,3,5]triazine (14) derivatives, respectively. The synthesized compounds were characterized on the basis of IR, (1)H-NMR, (13)C-NMR, and mass spectral data and elemental analyses results. Five of the newly synthesized compounds, 8a, 9a, 10a, 12a, and 14a, were selected by National Cancer Institute and screened for their anticancer activity against three cancer cell lines MCF7, NCI-H460, and SF-268, where 12a exhibited moderate anti-proliferation potential. 12a was, thus, further tested for anticancer activity against 60 human cancer cell lines and showed moderate growth inhibition potency. 12a showed a high growth inhibitory activity against A498 renal cancer cell line. All of the newly synthesized compounds 8-10, 12 and 14 were tested for their antioxidant capacity where they exhibited very high activity, even higher than the widely used reference antioxidants butylated hydroxytoluene and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Compound 12a also showed the highest antioxidant activity. PMID:16041836

Bekircan, Olcay; Küxük, Murat; Kahveci, Bahittin; Kolayli, Sevgi

2005-08-01

296

Synthesis of novel 3,5-diaryl pyrazole derivatives using combinatorial chemistry as inhibitors of tyrosinase as well as potent anticancer, anti-inflammatory agents.  

PubMed

In the present article, we have synthesized a combinatorial library of 3,5-diaryl pyrazole derivatives using 8-(2-(hydroxymethyl)-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-2-phenyl-4H-chromen-4-one (1) and hydrazine hydrate in absolute ethyl alcohol under the refluxed conditions. The structures of the compounds were established by IR, (1)H NMR and mass spectral analysis. All the synthesized compounds were evaluated for their anticancer activity against five cell lines (breast cancer cell line, prostate cancer cell line, promyelocytic leukemia cell line, lung cancer cell line, colon cancer cell line) and anti-inflammatory activity against TNF-alpha and IL-6. Out of 15 compounds screened, 2a and 2d exhibited promising anticancer activity (61-73% at 10 microM concentration) against all selected cell lines and IL-6 inhibition (47% and 42% at 10 microM concentration) as in comparison to standard flavopiridol (72-87% inhibition at 0.5 microM) and dexamethasone (85% inhibition at 1 microM concentration), respectively. Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Out of 15, four 3,5-diaryl pyrazole derivatives exhibiting potent inhibitory activities against both the monophenolase and diphenolase actions of tyrosinase. The IC(50) values of compounds (2a, 2d, 2h and 2l) for monophenolase inhibition were determined to range between 1.5 and 30 microM. Compounds 2a, 2d, 2h and 2l also inhibited diphenolase significantly with IC(50) values of 29.4, 21.5, 2.84 and 19.6 microM, respectively. All four 3,5-diaryl pyrazole derivatives were active as tyrosinase inhibitors (2a, 2d, 2h and 2l), and belonging to competitive inhibitors. Interestingly, they all manifested simple reversible slow-binding inhibition against diphenolase. PMID:20638287

Bandgar, Babasaheb P; Totre, Jalinder V; Gawande, Shrikant S; Khobragade, C N; Warangkar, Suchita C; Kadam, Prasad D

2010-06-19

297

Synthesis and biological evaluation of some new 2-pyrazolines bearing benzene sulfonamide moiety as potential anti-inflammatory and anti-cancer agents.  

PubMed

Eight novel 2-pyrazolines (2a-h) were synthesized by the reaction of appropriate chalcones/flavanones with 4-hydrazinonbenzenesulfonamide hydrochloride and tested for anti-inflammatory and anti-cancer activities. Two compounds 2c and 2e showed good anti-inflammatory activity which is comparable to the reference drug celecoxib in carrageenan-induced rat paw edema bioassay and found safe from the point of view of ulcer induction. Compounds 2c and 2e showed very mild inhibition against the enzymatic activity of ovine COX-1 and COX-2 (in vitro). The compounds 2c and 2f exhibited considerable antitumor activity against tested 60 human tumor cell lines. Specifically, compound 2f exhibited promising anti-proliferative activity with GI(50) values less than 2 ?M particularly against MOLT-4 (1.94), SR (1.28) in leukemia cancer, EKVX (1.88) in non small cell lung cancer, COLO 205 (1.69) in colon cancer. PMID:22019186

Bano, Sameena; Javed, Kalim; Ahmad, Shamim; Rathish, I G; Singh, Surender; Alam, M S

2011-08-16

298

The direct mapping of the uptake of platinum anticancer agents in individual human ovarian adenocarcinoma cells using a hard X-ray microprobe.  

PubMed

Uptake of platinum-based anticancer compounds into individual human ovarian andenocarcinoma cells was measured using an X-ray microprobe. The uptake of cisplatin, a platinum-based compound, in drug-resistant cells is decreased by approximately 50% after 24 h, compared with the uptake of the drug in nonresistant cells over the same time period. The Pt103 derivative of the drug, in contrast, showed an increased uptake by an order of magnitude in resistant cells over the same time period. Increased uptake appears to allow Pt103 to overcome the resistance mechanism developed by the cell. This work additionally shows that the X-ray microprobe is able to directly quantify Pt drug uptake on a subcellular level and can measure the mass of Pt down to a detectable limit of 20 attograms of Pt (2 x 10(-17) grams or 6 x 10(4) Pt atoms) in 1 s. Such exquisite elemental sensitivity combined with high spatial resolution paves the way for quantitative submicron three-dimensional mapping of elemental distributions within individual cells. PMID:12702562

Ilinski, Petr; Lai, Barry; Cai, Zhonghou; Yun, Wenbing; Legnini, Daniel; Talarico, Teresa; Cholewa, Marian; Webster, Lorraine K; Deacon, Glen B; Rainone, Silvina; Phillips, Don R; Stampfl, Anton P J

2003-04-15

299

Carboxylesterase-2 is a highly sensitive target of the antiobesity agent orlistat with profound implications in the activation of anticancer prodrugs.  

PubMed

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

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

2012-12-07

300

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

PubMed

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

2013-01-14

301

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

PubMed

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

Abdel Rahman, Doaa Ezzat

2013-01-01

302

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

PubMed Central

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)](PF6)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 104 M?1. They are also strong binders of human serum albumin having binding constants on the order of 104 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 IC50 values range from 7 – 159 ?M (after 72 h drug incubation). They also have antibacterial activity against Gram-positive strains of pathogenic bacteria with IC50 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; Mbarushimana, P. Canisius; Brock, Alyssa; Didion, Jacob; Woods, Jason; Gonzalez-Sarrias, Antonio; Seeram, Navindra P.

2011-01-01

303

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

PubMed

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

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

2008-12-30

304

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

1988-01-01

305

Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing.  

PubMed

Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC(50) of 0.04 ?M). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2? (FRS2?). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design. PMID:23409720

Ho, H K; Németh, G; Ng, Y R; Pang, E; Szántai-Kis, C; Zsákai, L; Breza, N; Greff, Z; Horváth, Z; Pató, J; Szabadkai, I; Szokol, B; Baska, F; ?rfî, L; Ullrich, A; Kéri, G; Chua, B T

2013-01-01

306

Essential viral and cellular zinc and iron containing metalloproteins as targets for novel antiviral and anticancer agents: implications for prevention and therapy of viral diseases and cancer.  

PubMed

In this review the authors summarize the experimental data on the role of a selected group of metalloproteins, particularly viral (v) and cellular (c) zinc finger proteins (ZFP) and iron containing proteins which are involved in cell proliferation, neovascularization, apoptosis, and viral infection. Furthermore, this review summarizes the data embracing the hypothesis that disruption of certain metalloproteins by novel pharmacological agents is a key factor in controlling viral and proliferative diseases. The primary goal of this review is to show the potential therapeutic applications of ZFP disrupting agents, zinc chelators and iron chelators in the control of viral diseases and cancer. It is known that zinc or iron deficiency, resulting from exposure of culture cells to membrane-permeable Zn2+ or Fe(2+)-chelators, can induced apoptosis in virally transformed cells while normal cells remain unaffected under these conditions. Apoptosis is possibly due to simultaneous inactivation of vZFP, cZFP, and/or iron containing proteins, which are essential for maintenance of cellular and viral structure and which are activated in virally transformed cells. New insights concerning apoptosis, viral metalloproteins, and novel antiviral agents will also be reviewed. From the evidence reviewed, one can infer that development of a variety of drugs that control or neutralize vZFP may lead to a new therapeutic approach directed at controlling and preventing a wide spectrum of viral diseases and cancer. Furthermore, the results suggest that these agents may be useful to prevent transmission of viral diseases. Finally, this review not only points out the limits of our understanding of this system, but also directs scientists to opportunities for future research. PMID:11396187

Fernandez-Pol, J A; Hamilton, P D; Klos, D J

307

Anticancer Effects of Free Polyunsaturated Fatty Acids in an Oily Lymphographic Agent following Intrahepatic Arterial Administration to a Rabbit Bearing VX-2 Tumor  

Microsoft Academic Search

The anti-hepatic cancer effects of three free polyunsaturated fatty acids (linoleic, a-linolenic, and •¿?y-linolenic acids) dissolved in an oily lymphographic agent, Lipiodol Ultra-Fluid (Lipiodol), following intra- hepatic arterial administration were examined using a rabbit liver cancer model, VX-2. The tumor was inoculated into the subcapsular parenchyma of the liver of rabbits, and Lipiodol alone or Lipiodol containing each one of

Yoshiki Hayashi; Shoji Fukushima; Shuichi Kishimoto; Takeo Kawaguchi; Mitsuhiro Â; Yoshihiro Isoda; Jiro Mirano; Masahiro Nakano

308

Combination therapy: Opportunities and challenges for polymer–drug conjugates as anticancer nanomedicines  

Microsoft Academic Search

The discovery of new molecular targets and the subsequent development of novel anticancer agents are opening new possibilities for drug combination therapy as anticancer treatment. Polymer–drug conjugates are well established for the delivery of a single therapeutic agent, but only in very recent years their use has been extended to the delivery of multi-agent therapy. These early studies revealed the

Francesca Greco; María J. Vicent

2009-01-01

309

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

PubMed

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

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

1986-11-01

310

Anticancer activity of polyoxomolybdate.  

PubMed

Anticancer polyoxomolybdates have been investigated for medical application of polyoxometalates as discrete cluster anions of metal oxides. [NH3Pri]6[Mo7O24].3H2O (PM-8) has been recognized as one of significant antitumoral polyoxomolybdates. PM-8 had shown the growth suppression against several tumors, for examples, Co-4, human colon cancer, MX-1, human breast cancer, and OAT, human lung cancer. PM-8 showed the tumor growth suppression for MKN-45 human gastric cancer in tumor bearing mice. PM-8 inhibited the cell growth of AsPC-1 which depended on the dose with showing DNA ladder formation and DNA fragmentation, and positive Hoechst staining indicating apoptosis. The ratio of apoptotic cells on flow cytometry analysis were 35%, and 57% with treatment of PM-8 after 48, and 72 h, respectively. One of the anti-tumor activity of PM-8 result from the activation of apoptotic pathway. It is thought that polyoxomolybdates will be applied as a novel anti-tumor agent especially against cancers which are difficult to be treated clinically. PMID:16860529

Yanagie, H; Ogata, A; Mitsui, S; Hisa, T; Yamase, T; Eriguchi, M

2006-06-30

311

Strategies For The Rapid Construction Of Conditionally-Replicating HSV-1 Vectors Expressing Foreign Genes As Anti-Cancer Therapeutic Agents  

PubMed Central

Conditionally replication-competent Herpes Simplex Virus Type 1 (HSV-1) vectors expressing foreign genes have been developed as experimental therapeutic agents. Traditional methods of virus construction, including growth selection based on thymidine kinase gene expression, and color selection based on a reporter gene expression are often time-consuming and relatively inefficient. This review summarizes the various strategies developed in recent years for the rapid and efficient construction of novel conditionally replication-competent mutant HSV expressing multiple foreign genes. Additionally, two new modifications of existing strategies, which have not been previously reported, are discussed.

Parker, Jacqueline N.; Zheng, Xiaojia; Luckett, William; Markert, James M.; Cassady, Kevin A.

2010-01-01

312

A potential anti-cancer agent: 5-chloro-7-iodo-8-hy-droxy-quinolinium dichlorido(5-chloro-7-iodo-quinolin-8-olato-?2 N,O)palladium(II) dihydrate  

PubMed Central

The title PdII coordination compound, (C9H6ClINO)[PdCl2(C9H4ClINO)]·2H2O, was prepared as a potential anti­cancer agent. Its structure is ionic and consists of a square-planar [PdCl2(CQ)]? complex anion (CQ is 5-chloro-7-iodo­quinolin-8-olate), with the PdII atom surrounded by two chloride ligands in a cis configuration and one N,O-bidentate CQ mol­ecule, a protonated anion of CQ as counter-cation and two non-coordinated water mol­ecules. The water mol­ecules are involved in O—H?O and N—H?O hydrogen bonds, which inter­connect the HCQ+ cations into a chain parallel to [010]. Apart from these inter­actions, the structure is also stabilized by face-to-face ?–? inter­actions [centroid–centroid = 3.546?(3)?Å], which occur between the phenolic parts of the complex anions and cations.

Vranec, Peter; Potocnak, Ivan

2011-01-01

313

Biological Characterization of 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145) as a Selective Sphingosine Kinase-2 Inhibitor and Anticancer Agent  

PubMed Central

In our effort to develop selective sphingosine kinase-2 (SphK2) inhibitors as pharmacological tools, a thiazolidine-2,4-dione analogue, 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145), was synthesized and biologically characterized. Biochemical assay results indicate that K145 is a selective SphK2 inhibitor. Molecular modeling studies also support this notion. In vitro studies using human leukemia U937 cells demonstrated that K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways. K145 also significantly inhibited the growth of U937 tumors in nude mice by both intraperitoneal and oral administration, thus demonstrating its in vivo efficacy as a potential lead anticancer agent. The antitumor activity of K145 was also confirmed in a syngeneic mouse model by implanting murine breast cancer JC cells in BALB/c mice. Collectively, these results strongly encourage further optimization of K145 as a novel lead compound for development of more potent and selective SphK2 inhibitors.

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

2013-01-01

314

Combining anticancer agents photodynamic therapy and LCL85 leads to distinct changes in the sphingolipid profile, autophagy, caspase-3 activation in the absence of cell death, and long-term sensitization.  

PubMed

Two anticancer agents, LCL85 and photodynamic therapy (PDT) were combined to test whether the combination PDT/LCL85 evokes changes in the sphingolipid (SL) profile and promotes cell death. Treatment of SCCVII mouse squamous carcinoma cells using the silicone phthalocyanine Pc 4 for PDT induced increases in the prodeath global ceramides/dihydroceramides (DHceramides), and no changes in the prosurvival sphingosine-1-phosphate (S1P). In contrast, after LCL85, the levels of most ceramides and DHceramides were reduced, whereas the levels of S1P were increased. After PDT/LCL85 the levels of global ceramides and DHceramides, and of S1P, were restored to resting levels. PDT/LCL85 also enhanced the levels of C18-, C20-, and C20:1-ceramide, and C18-DHceramide. Treatment with PDT, with or without LCL85, led to substantial reductions in sphingosine levels. PDT/LCL85 induced enhanced autophagy and caspase-3 activation. None of the treatments affected short-term viability of cells. In contrast, long-term clonogenic survival was reduced not only after PDT or LCL85, but even more after PDT/LCL85. Overall, our data show that short-term exposure to PDT/LCL85 led to distinct signature effects on the SL profile, enhanced autophagy, and caspase-3 activation without cell death. Long-term exposure to PDT/LCL85 enhanced overall cell killing, supporting translational potential of PDT/LCL85. PMID:21545791

Separovic, Duska; Joseph, Nicholas; Breen, Paul; Bielawski, Jacek; Pierce, Jason S; Buren, Eric Van; Bhatti, Gaurav; Saad, Ziad H; Bai, Aiping; Bielawska, Alicja

2011-04-24

315

Phosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside.  

PubMed

The fluorinated pyrimidine family of nucleosides continues to represent major current chemotherapeutic agents for treating solid tumors. We herein report their phosphate prodrugs, ProTides, as promising new derivatives, which partially bypass the dependence of the current drugs on active transport and nucleoside kinase-mediated activation. They are also resistant to metabolic deactivation by phosphorolytic enzymes. We report 39 ProTides of the fluorinated pyrimidine FUDR with variation in the aryl, ester, and amino acid regions. Notably, only certain ProTide motifs are successful in delivering the nucleoside monophosphate into intact cells. We also find that the ProTides retain activity in mycoplasma infected cells, unlike FUDR. Data suggest these compounds to be worthy of further progression. PMID:21892829

McGuigan, Christopher; Murziani, Paola; Slusarczyk, Magdalena; Gonczy, Blanka; Vande Voorde, Johan; Liekens, Sandra; Balzarini, Jan

2011-09-27

316

Discovery and Optimization of a Series of 2-Aryl-4-Amino-5-(3?,4?,5?-trimethoxybenzoyl)Thiazoles as Novel Anticancer Agents  

PubMed Central

A new series of tubulin polymerization inhibitors based on the 2-aryl/heteroaryl-4-amino-5-(3?,4?,5?-trimethoxybenzoyl)thiazole scaffold was synthesized and evaluated for growth inhibition activity on a panel of cancer cell lines, cell cycle effects, and in vivo potency. Structure–activity relationships were elucidated with various substitutions at the 2-position of the thiazole skeleton. Hydrophobic moieties, such as phenyl and 3-thienyl, were well tolerated at this position, and variation of the phenyl substituents had remarkable effects on potency. The most active compound (3b) induced apoptosis through the mitochondrial pathway with activation of caspase-3. We also showed that it has potential antivascular activity since it reduced in vitro endothelial cell migration and disrupted capillary-like tube formation at noncytotoxic concentrations. Furthermore, compound 3b significantly reduced the growth of the HT-29 xenograft in a nude mouse model, suggesting that 3b is a promising new antimitotic agent with clinical potential.

Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Preti, Delia; Tabrizi, Mojgan Aghazadeh; Brancale, Andrea; Fu, Xian-Hua; Li, Jun; Zhang, Su-Zhan; Hamel, Ernest; Bortolozzi, Roberta; Porcu, Elena; Basso, Giuseppe; Viola, Giampietro

2012-01-01

317

BlueBerry Isolate, Pterostilbene, Functions as a Potential Anticancer Stem Cell Agent in Suppressing Irradiation-Mediated Enrichment of Hepatoma Stem Cells  

PubMed Central

For many malignancies, radiation therapy remains the second option only to surgery in terms of its curative potential. However, radiation-induced tumor cell death is limited by a number of factors, including the adverse response of the tumor microenvironment to the treatment and either intrinsic or acquired mechanisms of evasive resistance, and the existence of cancer stem cells (CSCs). In this study, we demonstrated that using different doses of irradiation led to the enrichment of CD133+ Mahlavu cells using flow cytometric method. Subsequently, CD133+ Mahlavu cells enriched by irradiation were characterized for their stemness gene expression, self-renewal, migration/invasion abilities, and radiation resistance. Having established irradiation-enriched CD133+ Mahlavu cells with CSC properties, we evaluated a phytochemical, pterostilbene (PT), found abundantly in blueberries, against irradiation-enriched CSCs. It was shown that PT treatment dose-dependently reduced the enrichment of CD133+ Mahlavu cells upon irradiation; PT treatment also prevented tumor sphere formation, reduced stemness gene expression, and suppressed invasion and migration abilities as well as increasing apoptosis of CD133+ Mahlavu CSCs. Based on our experimental data, pterostilbene could be used to prevent the enrichment of CD133+ hepatoma CSCs and should be considered for future clinical testing as a combined agent for HCC patients.

Lee, Chi-Ming; Su, Yen-Hao; Huynh, Thanh-Tuan; Lee, Wei-Hwa; Chiou, Jeng-Fong; Lin, Yen-Kuang; Hsiao, Michael; Wu, Chih-Hsiung; Lin, Yuh-Feng; Wu, Alexander T. H.; Yeh, Chi-Tai

2013-01-01

318

BlueBerry Isolate, Pterostilbene, Functions as a Potential Anticancer Stem Cell Agent in Suppressing Irradiation-Mediated Enrichment of Hepatoma Stem Cells.  

PubMed

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

2013-06-26

319

Agents.  

PubMed

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

Chambers, David W

2002-01-01

320

Synthesis and antimitotic and tubulin interaction profiles of novel pinacol derivatives of podophyllotoxins.  

PubMed

Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7? (podo) or 7? (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7?-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7?-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series. PMID:22607205

Abad, Andrés; López-Pérez, José L; del Olmo, Esther; García-Fernández, Luis F; Francesch, Andrés; Trigili, Chiara; Barasoain, Isabel; Andreu, José M; Díaz, J Fernando; San Feliciano, Arturo

2012-07-23

321

Novel marine-derived anticancer agents: a phase I clinical, pharmacological, and pharmacodynamic study of dolastatin 10 (NSC 376128) in patients with advanced solid tumors.  

PubMed

Dolastatin (DOLA)-10 is a pentapeptide isolated from the mollusc Dolabella auricularia with clinically promising antitumor activity documented in various in vitro and in vivo tumor models. The objectives of this Phase I study were to determine the maximum tolerated dose, evaluate toxic effects, and document any antitumor activity of this novel agent. Using an electrospray ionization mass spectroscopy system, we also characterized the clinical pharmacokinetics, pharmacodynamics, and metabolism of DOLA-10. The maximum tolerated dose was reached at 300 microg/m2. Granulocytopenia, the dose-limiting toxicity, was documented in 33% of the patients treated at that dose level. There were no episodes of thrombocytopenia or severe anemia (Hgb < 8), and no major nonhematological toxicity was observed. Stabilization of tumor growth was observed in four patients, but no objective responses were seen. Whereas a two-compartment model described the DOLA-10 plasma concentration-time data reasonably well, a three-compartment model consistently performed better. After a rapid distribution phase, DOLA-10 plasma levels declined with mean beta and gamma half-lives of 0.99 and 18.9 h, respectively. Significant interpatient and intrapatient variability in DOLA-10 plasma clearances was observed. The mean area under the concentration-time curve increased proportionally as the dose was escalated, but there was significant overlap between dose levels. The area under the concentration-time curve and the percentage of decline in neutrophils were correlated. A single DOLA-10 metabolite was detected in five patients. Unlike the in vitro studies of DOLA-10, the principal metabolite detected was an N-demethyl derivative, confirmed by mass spectroscopy. In all five subjects, the concentration of this metabolite never exceeded 2% of the simultaneously measured parent drug concentration. The available preclinical, pharmacological, and clinical data suggest that further study of escalated DOLA-10 dosing with cytokine support is warranted. PMID:10778954

Madden, T; Tran, H T; Beck, D; Huie, R; Newman, R A; Pusztai, L; Wright, J J; Abbruzzese, J L

2000-04-01

322

Effects of lentinan alone and in combination with fluoropyrimidine anticancer agent on growth of human oral squamous cell carcinoma in vitro and in vivo.  

PubMed

Chemotherapy has shown little antitumor activity against advanced oral squamous cell carcinoma (OSCC) patients. Therefore, there is an urgent need to develop more effective therapeutic methods for patients with advanced OSCC. Lentinan, beta-(1-->3)-D-glucan, an extract from the edible mushroom, Lentinus edodes, has been reported to show direct antitumor effects and various immunomodulatory effects. S-1 is an oral antineoplastic agent that can induce apoptosis in various types of cancer cells, including OSCC. Hence, combined treatment of cancer cells with Lentinan and S-1 might exert dramatic antitumor effects on OSCC cells. In this study, the response of human OSCC cells to Lentinan alone and in combination with S-1 was examined using nude mouse xenograft models. S-1 (6.9 mg/kg/day, 7 times/week) was administered orally and Lentinan (0.1 mg/kg/day, 2 times/week) was injected into peritumoral tissue for three weeks. Apoptotic cells were detected by a TUNEL method. The gene expression level of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT) was determined using microdissection and RT-PCR, and their protein levels were determined using ELISA. Combined therapy of Lentinan and S-1 markedly exerted antitumor effects on human OSCC xenografts and significantly induced apoptotic cells in tumors treated with Lentinan plus S-1. Microdissection and RT-PCR revealed that the expression of TS and DPD mRNA was down-regulated and that expression of OPRT mRNA was up-regulated in tumors administered the combined treatment. Moreover, ELISA indicated that the protein levels of TS and DPD were down-regulated, and that OPRT was up-regulated in tumors treated with the combined therapy. During the experimental period, no loss of body weight was observed in mice treated with the combined therapy. These findings demonstrate that the combination of Lentinan and S-1 is effective against OSCC and has the potential of being a new therapeutic tool for future treatment of these tumors. PMID:20664931

Harada, Koji; Itashiki, Yasutaka; Takenawa, Takanori; Ueyama, Yoshiya

2010-09-01

323

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.  

PubMed

Heteropentanuclear porphyrazines having the formula [(PtCl(2))(4)LM] where L = tetrakis-2,3-[5,6-di(2-pyridyl)pyrazino]porphyrazinato dianion and M = Zn(II), Mg(II)(H(2)O), 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 [(PtCl(2))(4)LPt]. This latter species has four external N(2(py))PtCl(2) coordination sites which closely resemble cis-platin, (NH(3))(2)PtCl(2), the potent chemotherapeutic anticancer drug, and is able to act as a photosensitizer for the generation of (1)O(2), the cytotoxic agent in photodynamic therapy (PDT). UV-visible spectra and half wave potentials for reduction of [(PtCl(2))(4)LM], [(PtCl(2))(4)LPt], the parallel series of mononuclear [LM] compounds and the pentanuclear [(PdCl(2))(4)LM] compounds were examined in the nonaqueous solvents dimethyl sulfoxide, pyridine, and dimethylformamide. The complete set of available data indicate that external coordination of the PtCl(2) and PdCl(2) 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'Cl(2))(4)LM] (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)O(2) (?(?)), of interest in PDT, were measured for [(PtCl(2))(4)LM] with M = Zn(II), Mg(II)(H(2)O), or Pd(II) and the related macrocycles [(PdCl(2))(4)LM] 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 [(PtCl(2))(4)LZn] and [(PtCl(2))(4)LPd] 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

2012-11-01

324

Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4.  

PubMed

The mechanism by which aplidine, a marine natural product in early clinical development as an anticancer agent, induces cell growth inhibition and apoptosis has been investigated in the human leukemia cell line MOLT-4. This cell line is characterized not only by the ability to secrete VEGF, but also for the presence on its surface of the VEGF receptor-1 (VEGFR-1). Previous studies from our laboratory concerned with evaluating early changes in gene expression induced by aplidine in MOLT-4 cells have shown that the drug decreases the expression of VEGFR-1 (Marchini et al. Proc Am Assoc Cancer Res 2000; 41: 833). Here, we report the ability of aplidine to block the VEGF/VEGFR-1 loop. We found that aplidine blocked VEGF secretion that was temporally followed by a decrease in both VEGF and VEGFR-1 production. Aplidine did not directly affect either VEGF transcription or stabilization of its mRNA. Transfection of MOLT-4 cells with an antisense VEGF cDNA construct, resulted in inhibition of colony formations. One clone, transfected with sense VEGF cDNA, secreting 8-10 times more VEGF than parental cells, was less sensitive to aplidine-induced cytotoxicity and apoptosis than control cells. Moreover, addition of VEGF in the medium decreased the activity of aplidine in MOLT-4 cells. These data demonstrate that aplidine inhibits the growth and induces apoptosis in MOLT-4 cells through the inhibition of VEGF secretion which blocks the VEGF/VEGFR-1 autocrine loop necessary for the growth of these cells. PMID:12529660

Broggini, M; Marchini, S V; Galliera, E; Borsotti, P; Taraboletti, G; Erba, E; Sironi, M; Jimeno, J; Faircloth, G T; Giavazzi, R; D'Incalci, M

2003-01-01

325

Platinum(II) and palladium(II) complexes with (N,N') and (C,N,N')- ligands derived from pyrazole as anticancer and antimalarial agents: synthesis, characterization and in vitro activities.  

PubMed

The study of the reactivity of three 1-(2-dimethylaminoethyl)-1H-pyrazole derivatives of general formula [1-(CH(2))(2)NMe(2)}-3,5-R(2)-pzol] {where pzol represents pyrazole and R=H (1a), Me (1b) or Ph (1c)} with [MCl(2)(DMSO)(2)] (M=Pt or Pd) under different experimental conditions allowed us to isolate and characterize cis-[M{?(2)-N,N'-{[1-(CH(2))(2)NMe(2)}-3,5-R(2)-pzol])}Cl(2)] {MM=PtPt (2a-2c) or Pd (3a-3c)} and two cyclometallated complexes [M{?(3)-C,N,N'-{[1-(CH(2))(2)NMe(2)}-3-(C(5)H(4))-5-Ph-pzol])}Cl] {M=Pt(II) (4c) or Pd(II) (5c)}. Compounds 4c and 5c arise from the orthometallation of the 3-phenyl ring of ligand 1c. Complex 2a has been further characterized by X-ray crystallography. Ligands and complexes were evaluated for their in vitro antimalarial against Plasmodium falciparum and cytotoxic activities against lung (A549) and breast (MDA MB231 and MCF7) cancer cellular lines. Complexes 2a-2c and 5c exhibited only moderate antimalarial activities against two P. falciparum strains (3D7 and W2). Interestingly, cytotoxicity assays revealed that the platinacycle 4c exhibits a higher toxicity than cisplatin in the three human cell lines and that the complex 2a presents a remarkable cytotoxicity and selectivity in lung (IC(50)=3 ?M) versus breast cancer cell lines (IC(50)>20 ?M). Thus, complexes 2c and 4c appear to be promising leads, creating a novel family of anticancer agents. Electrophoretic DNA migration studies in presence of the synthesized compounds have been performed, in order to get further insights into their mechanism of action. PMID:22104300

Quirante, Josefina; Ruiz, Daniel; Gonzalez, Asensio; López, Concepción; Cascante, Marta; Cortés, Roldán; Messeguer, Ramon; Calvis, Carme; Baldomà, Laura; Pascual, Aurélie; Guérardel, Yann; Pradines, Bruno; Font-Bardía, Mercè; Calvet, Teresa; Biot, Christophe

2011-09-22

326

Ferrocene Functionalized Endocrine Modulators as Anticancer Agents  

NASA Astrophysics Data System (ADS)

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

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

327

New styryl sulfones as anticancer agents.  

PubMed

New styryl sulfone compounds have been synthesized and evaluated for their anti-proliferative activity. Among the compounds synthesized, one compound (7k) has shown 51% tumor growth inhibition in mice implanted with HT-29 human carcinoma at 400 mg kg(-1) orally. PMID:14561480

Vedula, Manohar Sharma; Pulipaka, Aravind Babu; Venna, Chandrasekhar; Chintakunta, Vamsee Krishna; Jinnapally, Sreenu; Kattuboina, Venkata Adiseshu; Vallakati, Ravi Krishna; Basetti, Vishnu; Akella, Venkateswarlu; Rajgopal, Sriram; Reka, Ajaya Kumar; Teepireddy, Sravan Kumar; Mamnoor, Prem Kumar; Rajagopalan, Ramanujam; Bulusu, Gopalakrishnan; Khandelwal, Akash; Upreti, Vijay V; Mamidi, Srinivas Rao

2003-09-01

328

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

2012-12-01

329

Sulphonamido-quinoxalines: search for anticancer agent.  

PubMed

A series of new sulphonamido-quinoxaline derivatives 3(a-p) have been prepared which are structurally similar to the High Throughput Screening (HTS) hit identified by Porter and collaborator. The newly synthesized compounds 3b, 3c, 3f, 3i, 3j, 3l, 3n and 3o were further evaluated in the National Cancer Institute for in vitro cytotoxicity assay among them compound 3l showed highest activity against Leukemia RPMI-8226 cell lines (GI50: 1.11 ?M) as compared to other tested compounds. It is to be noted that compound 3l shows significant activity (GI50: 1.11 ?M) compared to the High Throughput Screening (HTS) hit identified by Porter and collaborator (IC50 = 1.3 ?M). Further docking study confirms the c-Met kinase inhibitory mechanism of the synthesized compounds. PMID:23708011

Ingle, Rahul; Marathe, Rajendra; Magar, Dipak; Patel, Harun M; Surana, Sanjay J

2013-04-24

330

Selective anticancer agents suppress aging in Drosophila.  

PubMed

Mutations of the PI3K, TOR, iNOS, and NF-?B genes increase lifespan of model organisms and reduce the risk of some aging-associated diseases. We studied the effects of inhibitors of PI3K (wortmannin), TOR (rapamycin), iNOS (1400W), NF-?B (pyrrolidin dithiocarbamate and QNZ), and the combined effects of inhibitors: PI3K (wortmannin) and TOR (rapamycin), NF-?B (pyrrolidin dithiocarbamates) and PI3K (wortmannin), NF-?B (pyrrolidine dithiocarbamates) and TOR (rapamycin) on Drosophila melanogaster lifespan and quality of life (locomotor activity and fertility). Our data demonstrate that pharmacological inhibition of PI3K, TOR, NF-?B, and iNOS increases lifespan of Drosophila without decreasing quality of life. The greatest lifespan expanding effect was achieved by a combination of rapamycin (5 ?M) and wortmannin (5 ?M) (by 23.4%). The bioinformatic analysis (KEGG, REACTOME.PATH, DOLite, and GO.BP) showed the greatest aging-suppressor activity of rapamycin, consistent with experimental data. PMID:24096697

Danilov, Anton; Shaposhnikov, Mikhail; Plyusnina, Ekaterina; Kogan, Valeria; Fedichev, Peter; Moskalev, Alexey

2013-09-01

331

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

PubMed

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

Takahashi, Masato; Suzuki, Noriyuki; Ishikawa, Tsutomu

2013-03-26

332

Anti-cancer quinazoline derivatives  

US Patent & Trademark Office Database

Quinazoline derivatives of formula: ##STR1## wherein R represents: (1) a straight or branched chain unsaturated hydrocarbon group, or (2) a straight or branched chain saturated or unsaturated hydrocarbon group which is substituted by at least one: heteroatom, the or each heteroatom being halogeno when R is a C.sub.1 hydrocarbon group; or saturated carbocyclic group; or group containing at least one heteroatom, the or each heteroatom being O, N or S when R contains a cyclic group; and n is 0 or an integer of 1-4; X or, when n is an integer of at least 2, each X independently, represents a halogeno, C.sub.1 -C.sub.4 alkyl, aryl or aralkyl group or a group including at least one heteroatom; and Y represents a group of formula: ##STR2## wherein m.gtoreq.1 (poly-L-glutamates); and the pharmaceutically acceptable salts and esters thereof, which are suitable as anti-cancer agents.

1984-05-08

333

4-Des-oxy-4?-[(5-meth-oxy-1H-indol-3-yl)oxalylamino]podophyllotoxin methanol solvate.  

PubMed

The main mol-ecule of the title solvate, C(33)H(30)N(2)O(10)·CH(3)OH, is a new anti-tumor agent, which shows cytotoxicity against MDR cancer cell lines. It has been synthesized by coupling 4?-amino-podophyllotoxin with (5-meth-oxy-1H-indol-3-yl)glyoxyl chloride and structurally characterized. There are two crystallographically independent mol-ecules in the asymmetric unit, which differ in the dihedral angles between the aromatic rings. The dihedral angles between the benzene ring of the benzo[d][1,3]dioxole and the benzene ring of the 5-meth-oxy-1H-indole are 85.08?(3) and 76.88?(3)° and reflect the main conformational difference between the two independent mol-ecules. The asymmetric unit is completed with two methanol solvent mol-ecules, one of which is disordered over two positions, with occupancies close to 0.5. PMID:21581314

Feng, Min; Zhao, Ming; Zhang, Jingze; Yang, Zaixin; Chen, Hong

2008-11-13

334

L-carnitine inhibits apoptotic DNA fragmentation induced by a new spin-labeled derivative of podophyllotoxin via caspase-3 in Raji cells.  

PubMed

L-carnitine (beta-hydroxy-trimethylaminobutyric acid) plays an essential metabolic role that consists of transferring the long chain fatty acids through the mitochondrial barrier, thus allowing their energy-yielding oxidation. GP7 (4-[4''-(2'', 2'', 6'', 6''-tetramethyl-l''-piperidinyloxy) amino] -4'-demethyl-epipodophyllotoxin) is a new spin-labeled derivative of podophyllotoxin semi-synthesized by our university. In this study, we examined the activity of L-carnitine in GP7-induced apoptosis in Burkitt's lymphoma cell line, Raji. GP7 induced time- and dose-dependent apoptotic DNA fragmentation accompanied by caspase-3 activation in Raji cells, and the kinetics of caspase-3 activation induced by GP7 was well correlated with that of apoptotic DNA fragmentation. L-carnitine treatment prevented GP7-induced caspase-3 activation, suppressed caspase-3 cleavage and abrogated GP7-induced apoptotic DNA fragmentation in Raji cells. Our findings suggest that L-carnitine is a potent anti-apoptotic agent to human lymphoma cells and may exert its anti-apoptotic effect via inhibition of caspase-3 activity in GP7-treated Raji cells. PMID:16328043

Qi, She-Ning; Zhang, Zhi-Feng; Wang, Zhen-Yun; Yoshida, Akira; Ueda, Takanori

2006-01-01

335

Cell Death Signaling and Anticancer Therapy  

PubMed Central

For a long time, it was commonly believed that efficient anticancer regimens would either trigger the apoptotic demise of tumor cells or induce a permanent arrest in the G1 phase of the cell cycle, i.e., senescence. The recent discovery that necrosis can occur in a regulated fashion and the increasingly more precise characterization of the underlying molecular mechanisms have raised great interest, as non-apoptotic pathways might be instrumental to circumvent the resistance of cancer cells to conventional, pro-apoptotic therapeutic regimens. Moreover, it has been shown that some anticancer regimens engage lethal signaling cascades that can ignite multiple oncosuppressive mechanisms, including apoptosis, necrosis, and senescence. Among these signaling pathways is mitotic catastrophe, whose role as a bona fide cell death mechanism has recently been reconsidered. Thus, anticancer regimens get ever more sophisticated, and often distinct strategies are combined to maximize efficacy and minimize side effects. In this review, we will discuss the importance of apoptosis, necrosis, and mitotic catastrophe in the response of tumor cells to the most common clinically employed and experimental anticancer agents.

Galluzzi, Lorenzo; Vitale, Ilio; Vacchelli, Erika; Kroemer, Guido

2011-01-01

336

Relationship between podophyllotoxin accumulation and soil nutrients and the influence of Fe(2+) and Mn(2+) on podophyllotoxin biosynthesis in Podophyllum hexandrum tissue culture.  

PubMed

Podophyllotoxin (PDT) and its derivatives, which are isolated from the Podophyllum species, are widely used in the clinical setting. The present study was designed to analyze the correlation between PDT levels in the rhizomes of Podophyllum hexandrum (P. hexandrum) and Dysosma versipellis (D. versipellis) and the nutrients in soil. We also aimed to investigate the influence of Fe(2+) and Mn(2+) on the enzyme activity of phenylalanine ammonia lyase (PAL), cinnamyl alcohol-dehydrogenase (CAD), and deoxypodophyllotoxin 6-hydroylase (DOP6H) and PDT accumulation via P. hexandrum tissue culture. The results showed that PDT accumulation was positively correlated with the [Formula: see text] , [Formula: see text] , Na(+), Fe, and Mn levels and was negatively correlated with the [Formula: see text] and K(+) levels, while the correlation with the Mg(2+), Ca(2+), Cu and Zn levels was not significant. The Fe(2+) and Mn(2+) levels were associated with the increased activity of PAL and CAD at 3-18 days; Fe(2+) enhanced the activity levels by 2.66- and 1.76-fold, respectively, and Mn(2+) was associated with a 1.68- and 1.10-fold increase in activity levels, respectively, compared with the control (CK) at 18 days. DOP6H activity was enhanced by Mn(2+), but it was not significantly affected by Fe(2+). Finally, PDT production was enhanced approximately 60% and 34% by Fe(2+) and Mn(2+), respectively, compared with CK at 16 days. These observations may be useful for the generation of PDT and related lignans via commercial cultivation as well as cell and tissue culture of P. hexandrum and other related plant resources. PMID:23906505

Li, Meng Fei; Li, Wei; Yang, De Long; Zhou, Lan Lan; Li, Tian Tian; Su, Xiao Meng

2013-07-13

337

Synthesis and quantitative structure-activity relationship (QSAR) study of novel 4-acyloxypodophyllotoxin derivatives modified in the A and C rings as insecticidal agents.  

PubMed

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, we have synthesized three series of novel 4-acyloxy compounds derived from podophyllotoxin modified in the A and C rings, which is isolated as the main secondary metabolite from the roots and rhizomes of Podophyllum hexandrum . Their insecticidal activity was preliminarily evaluated against the pre-third-instar larvae of Mythimna separata in vivo. Compound 9g displayed the best promising insecticidal activity. It revealed that cleavage of the 6,7-methylenedioxy group of podophyllotoxin will lead to a less active compound and that the C-4 position of podophyllotoxin was the important modification location. A quantitative structure-activity relationship (QSAR) model was developed by genetic algorithm combined with multiple linear regression (GA-MLR). For this model, the squared correlation coefficient (R(2)) is 0.914, the leave-one-out cross-validation correlation coefficient (Q(2)(LOO)) is 0.881, and the root-mean-square error (RMSE) is 0.024. Five descriptors, BEHm2, Mor14v, Wap, G1v, and RDF020e, are likely to influence the biological activity of these compounds. Among them, two important ones are BEHm2 and Mor14v. This study will pave the way for further design, structural modification, and development of podophyllotoxin derivatives as insecticidal agents. PMID:23278333

He, Shuzhen; Shao, Yonghua; Fan, Lingling; Che, Zhiping; Xu, Hui; Zhi, Xiaoyan; Wang, Juanjuan; Yao, Xiaojun; Qu, Huan

2013-01-10

338

The anti-cancer activities of jasmonates.  

PubMed

Jasmonates, plant stress hormones protecting the plant from microbial pathogens and environmental stresses, were also discovered to have toxic activities toward mammalian cancer cells. Methyl jasmonate (MJ) was found to be the most active anti-cancer derivate among natural jasmonates, exhibiting a specific cell death-induction effect toward several cancer cells. Since that discovery of jasmonates-inducing cancer cell death, the molecular mechanism of action of jasmonates leading to cell death was deciphered. Moreover, in addition to the direct effects of MJ on cancer cell death, it was found to deregulate several genes and affect various intracellular factors and cellular processes, such as sensitization of apoptotic cell death induced by TRAIL, cancer cell migration attenuation, cell cycle arrest, and differentiation. This mini-review summarizes over a decade of research of jasmonates as anti-cancer agents. PMID:23196641

Raviv, Ziv; Cohen, Sharon; Reischer-Pelech, Dortit

2012-11-30

339

Analyses of anticancer drugs by capillary electrophoresis: a review.  

PubMed

Capillary electrophoresis is a fast, inexpensive and low detection limit technique for the analysis of anticancer drugs. It has been used to analyze various anticancer drugs in biological samples, pharmaceutical preparations and environmental matrices. It has also been used to detect various cancer biomarkers in cancer patients. The present article describes the state-of-the art of capillary electrophoresis for the analyses of anticancer drugs. Various drugs discussed belong to several groups such as antimitotic agents, nucleoside analogs, antibiotics, topoisomerase inhibitors and DNA intercalating agents. In addition, efforts have also been made to discuss sample preparation, applications of capillary electrophoresis in genomic research, optimization and future perspectives. Copyright © 2013 John Wiley & Sons, Ltd. PMID:23843248

Ali, Imran; Haque, Ashanul; Wani, Waseem A; Saleem, Kishwar; Al Za'abi, Mohammed

2013-07-11

340

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

PubMed

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

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

2009-05-01

341

Studies on Anticancer Activities of Antimicrobial Peptides  

PubMed Central

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

Hoskin, David W.; Ramamoorthy, Ayyalusamy

2008-01-01

342

[Anticancer activity of oxovanadium compounds].  

PubMed

Cytotoxic and antitumor activity of the biligand vanadyl derivative of L-malic acid (bis(L-malato)oxovanadium(IV) (VO(mal)2) was investigated in comparison with inorganic vanadium(IV) compound--vanadyl sulfate (VOSO4) and also with oxovanadium monocomplex with L-malic acid (VO(mal)) and vanadyl biscomplex with acetylacetonate. In this purpose the effect of vanadyl compounds on growth of normal human skin fibroblasts and tumor cells of different lines: mouse fibrosarcoma (L929), rat pheochromocytome (PC12), human liver carcinoma (HepG2), virus transformated mouse fibroblast (NIN 3T3), virus transformated cells of human kidney (293) were investigated. The results showed that VO(mal)2 was not toxic for normal human skin fibroblasts but considerably inhibited growth of cancer cells in culture. Cytotoxic antitumor effect of vanadium complexes was found to be dependent on incubation time and concentration and on type of cells and nature of ligands of the central group of the complex (VO2+). These studies provide evidence that VO(mal)2 may be considered as a potential antitumor agent due to its low toxicity in non-tumor cells and significant anticancer activity. PMID:23987068

Abakumova, O Iu; Podobed, O V; Beliaeva, N F; Tochilkin, A I

343

Melatonin Anticancer Effects: Review  

PubMed Central

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

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

2013-01-01

344

Melatonin anticancer effects: review.  

PubMed

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

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

2013-01-24

345

Status of non-classical mononuclear platinum anticancer drug development.  

PubMed

Cisplatin has become one of the most commonly used compounds for the treatment of a wide spectrum of human malignancies. Unfortunately, cisplatin has several major drawbacks. Driven by the impressive impact of cisplatin on cancer chemotherapy, great efforts have been made to develop new derivatives with improved pharmacological properties. Among the over 30 platinum agents which have entered clinical trials after the onset of clinical studies with cisplatin in the early 1970s, only carboplatin and oxaliplatin have received worldwide approval so far, nedaplatin, lobaplatin and heptaplatin have gained regionally limited approval. It has become quite evident that mere analogues of cisplatin or carboplatin will not probably offer any substantial clinical advantages over the existing drugs. Consequently, attention turned to the synthesis of non-classical platinum anticancer drugs which were capable of forming a different range of DNA adducts which could display a different spectrum of anticancer activity compared to cisplatin. The status of non-classical bi- and multi-nuclear platinum anticancer drug development has been reviewed. This review will summarize the structural types and structure-activity of non-classical mononuclear platinum anticancer drugs, and discuss their future potential as anticancer agents. PMID:19929810

Zhang, Jinchao; Liu, Dandan; Li, Yaping; Sun, Jing; Wang, Liwei; Zang, Aimin

2009-10-01

346

Activation of K ATP channels increases anticancer drug delivery to brain tumors and survival  

Microsoft Academic Search

Several anticancer drugs are ineffective against brain tumor and do not impact patient survival because they fail to cross the blood-brain tumor barrier (BTB) effective levels. One such agent temozolomide is commonly used in brain tumor patients, which works better when combined with radiation or other anticancer agents. Likewise, trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2\\/neu over

Nagendra S. Ningaraj; Umesh T. Sankpal; Divya Khaitan; Edward A. Meister; Trib Vats

2009-01-01

347

Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells  

Microsoft Academic Search

BACKGROUND: Chloroquine (CQ), the worldwide used anti-malarial drug, has recently being focused as a potential anti-cancer agent as well as a chemosensitizer when used in combination with anti-cancer drugs. It has been shown to inhibit cell growth and\\/or to induce cell death in various types of cancer. 5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice in colorectal cancer, but

Kazuhito Sasaki; Nelson H Tsuno; Eiji Sunami; Giichiro Tsurita; Kazushige Kawai; Yurai Okaji; Takeshi Nishikawa; Yasutaka Shuno; Kumiko Hongo; Masaya Hiyoshi; Manabu Kaneko; Joji Kitayama; Koki Takahashi; Hirokazu Nagawa

2010-01-01

348

Synthesis of Novel 4?-(Acyloxy)-2'(2',6')-(di)halogenopodophyllotoxin Derivatives as Insecticidal Agents.  

PubMed

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, we have prepared three series of novel 4?-(acyloxy)-2'(2',6')-(di)halogenopodophyllotoxin derivatives modified in the C and E rings of podophyllotoxin, which is a naturally occurring aryltetralin lignan isolated from the roots and rhizomes of Podophyllum hexandrum . Their structures were well characterized by (1)H NMR, HRMS, ESI-MS, optical rotation, and mp. The stereochemical configurations of compounds 5s, 6b, 6d, and 7q were unambiguously confirmed by single-crystal X-ray diffraction. Their insecticidal activity was evaluated against the pre-third-instar larvae of oriental armyworm, Mythimna separata Walker, in vivo at a concentration of 1 mg/mL. These derivatives likely displayed the antimolting hormone effect. Among all the derivatives, especially compounds 5a, 5n, 7f, 7n, and 7w exhibited the most potent insecticidal activity with final mortality rates of 70% or so. This suggested that a chlorine or bromine atom introduced at the C2' or C2' and C6' positions on the E ring of podophyllotoxin was necessary for obtaining the potent compounds. This will pave the way for further design, structural modification, and development of podophyllotoxin derivatives as insecticidal agents. PMID:23915199

Che, Zhiping; Yu, Xiang; Zhi, Xiaoyan; Fan, Lingling; Yao, Xiaojun; Xu, Hui

2013-08-15

349

Natural flora and anticancer regime: milestones and roadmap.  

PubMed

Cancer has long been an area of extensive research both at the molecular as well as pharmaceutical level. However, lack of understanding of the underlying molecular signalling and the probable targets of therapeutics is a major concern in successful treatment of cancer. The situation becomes even worse, with the increasing side effects of the existing synthetic commercial drugs. Natural compounds especially those derived from plants have been best explored for their anticancer properties and most of them have been efficient against the known molecular targets of cancer. However, advent of biotechnology and resulting advances in medical arena have let to the increasing knowledge of newer carcinogenic signaling agents which has made the anticancer drug discovery even more demanding. The present review aims to bring forward the molecular mediators of cancer and compiles the plant derived anticancer agents with special emphasis on their clinical status. Since marine arena has proved to be a tremendous source of pharmaceutical agents, this review also focuses on the anticancer potential of marine plants especially algae. This is a comprehensive review covering major aspects of cancer mediation and utilization of marine flora for remediation of this deadly disease. PMID:23293884

Bhatnagar, Ira; Thomas, Noel Vinay; Kim, Se-Kwon

2013-07-01

350

Synthesis and biological evaluation of some novel 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazin-3(2H)-ones as anti-cancer, antimicrobial, and anti-inflammatory agents.  

PubMed

A series of 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazin-3(2H)-ones (2a-j) were synthesized by condensation of the appropriate beta-aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol and tested for anti-cancer, anti-inflammatory, and antimicrobial actions. According to the protocol of the National Cancer Institute (NCI) in vitro disease-oriented human cells screening panel assay, compound 2g showed high activity against HL-60 (TB) (leukemia), SR (leukemia), NCI-H522 (non-small-cell lung cancer), and BT-549 (breast cancer) with a GI(50) value of less than 2 microM. Two compounds (2c and 2f) were found to have promising anti-inflammatory activity, while a fair number of compounds showed good antifungal activity. PMID:20038271

Ahmad, Shamim; Rathish, I G; Bano, Sameena; Alam, M S; Javed, Kalim

2010-04-01

351

Practical guidelines for dose individualization of anticancer targeted drugs.  

PubMed

For drugs such as anticancer agents every effort should be made to minimize inter-patient variability in drug exposure in order to maximize the benefit while maintaining an acceptable risk level of serious adverse effects. Anticancer drugs generally have a preferential route of elimination, either in urine or in bile and feces. In consequence, dose individualization to renal and liver function permits excessive toxicity to be avoided and expected therapeutic benefit to be achieved. However, less is known about the most appropriate starting doses of antineoplastic agents in these individuals. In this review, we discuss trials that have specifically assessed new targeted agents dosing strategies (mainly monoclonal antibodies and tyrosine kinase inhibitors) in the setting of overt biochemical renal and liver dysfunction and we proportionate recommendations and practical guidelines for dose individualization. PMID:23065600

Sáez, María Isabel; Quero, Cristina; Trigo, José Manuel; Muros, Begoña; Alba, Emilio

2012-10-12

352

Anticancer siRNA delivery by new anticancer molecule: a novel combination strategy for cancer cell killing.  

PubMed

The present report describes development of a novel, bifunctional molecule possessing both selective antiproliferative activity and siRNA transfection ability. We synthesized a series of cationic lipo-benzamides and screened for in vitro anticancer activities against a panel of cancer and non-cancer cells. The molecule with a ten carbon chain-length (C10M) significantly inhibited proliferation of cancer cells via arresting the cell cycle predominantly in the G1 phase; but did not affect non-cancerous cells. C10M effectively mediated siRNA delivery in vitro. The combined anticancer effect of the delivery of C10M together with its survivin-targeting siRNA cargo was significantly (p < 0.05) superior to that of agent alone. To our knowledge, this is the first report of a dual-purpose molecule with intrinsic anticancer activity and suitability for use in siRNA delivery. PMID:22926227

Muktapuram, Prathap Reddy; Gara, Rishi Kumar; Sharma, Komal; Rohit, Chilappa; Srinivas, Kolupula; Mishra, Durga Prasad; Bathula, Surendar Reddy

2012-07-27

353

Anticancer activity of small amphipathic ?²,²-amino acid derivatives.  

PubMed

We report the anticancer activity from screening of a series of synthetic ?(2,2)-amino acid derivatives that were prepared to confirm the pharmacophore model of short cationic antimicrobial peptides with high anti-Staphylococcal activity. The most potent derivatives against human Burkitt's lymphoma (Ramos) cells displayed IC(50) values below 8 ?M, and low toxicity against human red blood cells (EC(50) > 200 ?M). A more than 5-fold preference for Ramos cancer cells compared to human lung fibroblasts (MRC-5 cells) was also obtained for the most promising ?(2,2)-amino acid derivative 3-amino-N-(2-aminoethyl)-2,2-bis(naphthalen-2-ylmethyl)propanamide (5c). Screening of 5c at the National Cancer Institute (NCI, USA) confirmed its anticancer potency and revealed a very broad range of anticancer activity with IC(50) values of 0.32-3.89 ?M against 59 different cancer cell lines. Highest potency was obtained against the colon cancer cell lines, a non-small cell lung cancer, a melanoma, and three leukemia cell lines included in the NCI screening panel. The reported ?(2,2)-amino acid derivatives constitute a promising new class of anticancer agents based on their high anticancer potency, ease of synthesis, mode-of-action, and optimized pharmacokinetic properties compared to much larger antimicrobial peptides. PMID:23085771

Hansen, Terkel; Ausbacher, Dominik; Zachariassen, Zack G; Anderssen, Trude; Havelkova, Martina; Strøm, Morten B

2012-10-05

354

Phytosterols as anticancer compounds.  

PubMed

Phytochemicals have been proposed to offer protection against a variety of chronic ailments including cardiovascular diseases, obesity, diabetes, and cancer. As for cancer protection, it has been estimated that diets rich in phytochemicals can significantly reduce cancer risk by as much as 20%. Phytosterols are specific phytochemicals that resemble cholesterol in structure but are found exclusively in plants. Phytosterols are absorbed from the diet in small but significant amounts. Epidemiological data suggest that the phytosterol content of the diet is associated with a reduction in common cancers including cancers of the colon, breast, and prostate. The means by which dietary phytosterols may be achieving these effects is becoming clearer from molecular studies with tumorigenic research models. Phytosterols affect host systems potentially enabling more robust antitumor responses, including the boosting of immune recognition of cancer, influencing hormonal dependent growth of endocrine tumors, and altering sterol biosynthesis. In addition, phytosterols have effects that directly inhibit tumor growth, including the slowing of cell cycle progression, the induction of apoptosis, and the inhibition of tumor metastasis. This review summarizes the current state of knowledge regarding the anticancer effects of phytosterols. PMID:17266177

Bradford, Peter G; Awad, Atif B

2007-02-01

355

Ribonucleases as potential modalities in anticancer therapy  

PubMed Central

Antitumor ribonucleases are small (10–28 kDa) basic proteins. They were found among members of both, ribonuclease A and T1 superfamilies. Their cytotoxic properties are conferred by enzymatic activity, i.e., the ability to catalyze cleavages of phosphodiester bonds in RNA. They bind to negatively charged cell membrane, enter cells by endocytosis and translocate to cytosol where they evade mammalian protein ribonuclease inhibitor and degrade RNA. Here, we discuss structures, functions and mechanisms of antitumor activity of several cytotoxic ribonucleases with particular emphasis to the amphibian Onconase, the only enzyme of this class that reached clinical trials. Onconase is the smallest, very stable, less catalytically efficient and more cytotoxic than most RNase A homologues. Its cytostatic, cytotoxic and anticancer effects were extensively studied. It targets tRNA, rRNA, mRNA as well as the non-coding RNA (microRNAs). Numerous cancer lines are sensitive to Onconase; their treatment with 10 – 100 nM enzyme leads to suppression of cell cycle progression, predominantly through G1, followed by apoptosis or cell senescence. Onconase also has anticancer properties in animal models. Many effects of this enzyme are consistent with the microRNAs, one of its critical targets. Onconase sensitizes cells to a variety of anticancer modalities and this property is of particular interest, suggesting its application as an adjunct to chemotherapy or radiotherapy in treatment of different tumors. Cytotoxic RNases as exemplified by Onconase represent a new class of antitumor agents, with an entirely different mechanism of action than the drugs currently used in the clinic. Further studies on animal models including human tumors grafted on severe combined immunodefficient (SCID) mice and clinical trials are needed to explore clinical potential of cytotoxic RNases.

Ardelt, Wojciech; Ardelt, Barbara; Darzynkiewicz, Zbigniew

2009-01-01

356

Recent Development of Anticancer Therapeutics Targeting Akt  

PubMed Central

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.

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

2013-01-01

357

In vivo anticancer activity of vanillin semicarbazone  

PubMed Central

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

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

2012-01-01

358

[Peptides: a new class of anticancer drugs].  

PubMed

Peptides are a novel class of anticancer agents embracing two distinct categories: natural antibacterial peptides, which are preferentially bound by cancer cells, and chemically synthesized peptides, which bind specifically to precise molecular targets located on the surface of tumor cells. Antibacterial peptides bind to both cell and mitochondrial membranes. Some of these peptides attach to the cell membrane, resulting in its disorganization. Other antibacterial peptides penetrate cancer cells without causing cell membrane damage, but they disrupt mitochondrial membranes. Thanks to phage and aptamer libraries, it has become possible to obtain synthetic peptides blocking or activating some target proteins found in cancer cells as well as in cells forming the tumor environment. These synthetic peptides can feature anti-angiogenic properties, block enzymes indispensable for sustained tumor growth, and reduce tumor ability to metastasize. In this review the properties of peptides belonging to both categories are discussed and attempts of their application for therapeutic purposes are outlined. PMID:19644153

Smolarczyk, Ryszard; Cicho?, Tomasz; Szala, Stanis?aw

2009-07-22

359

Recent developments in the bioactivity of mono- and diterpenes: anticancer and antimicrobial activity  

Microsoft Academic Search

Secondary plant metabolites, and in particular monoterpenes, have been recognised as potential medicinal agents for centuries.\\u000a As such, terpenes have been the focus of a plethora of scientific studies examining various aspects of their bioactivity.\\u000a In particular, antimicrobial activity and anticancer potential have been studied extensively. Whilst the antimicrobial and\\u000a anticancer activity of terpenes has been demonstrated in vitro, fewer

Sara J. Greay; Katherine A. Hammer

360

The role of metallothioneins in anticancer drug resistance  

Microsoft Academic Search

\\u000a It is an unfortunate reality that many patients with solid tumors initially sensitive to anticancer chemotherapy subsequently\\u000a develop recurrences that resist further treatment with these agents. This problem has fostered research efforts to define\\u000a the mechanisms of resistance and to determine strategies to circumvent them. cis-diamminedichloroplatinum II (cDDP) is widely used in a variety of solid tumors and has dramatically

Robert R. Bahnson; Alakananda Basu; John S. Lazo

361

Mucosal injury from targeted anti-cancer therapy  

Microsoft Academic Search

Background  With the increased use of so-called targeted anti-cancer therapies, there has been a change in toxicities that patients are\\u000a experiencing. As most targeted therapies are given in conjunction with more traditional chemotherapeutic agents, toxicities\\u000a of these combination therapies are also evolving. Whilst we increasingly understand the mechanisms underlying the toxicities\\u000a of chemotherapy and radiotherapy, the addition of targeted treatments requires

Dorothy M. K. Keefe; Rachel J. Gibson

2007-01-01

362

Targeting Anticancer Drugs to Tumor Vasculature Using Cationic Liposomes  

Microsoft Academic Search

Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes\\u000a to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the\\u000a effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor\\u000a vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG),

Amr S. Abu Lila; Tatsuhiro Ishida; Hiroshi Kiwada

2010-01-01

363

Enhancement of the Efficacy of Conventional Anticancer Compounds through the Repression of SNAI Proteins in Aggressive Breast Cancer Cells.  

National Technical Information Service (NTIS)

Our central hypothesis is that combinatorial treatment of SNAI-high breast tumor cells with the SNAI inhibitors will not only diminish their aggressiveness but also make these cells sensitive to the inhibition of some of the conventional anticancer agents...

G. Chaudhuri

2012-01-01

364

Sanguinarine: A Novel Agent Against Prostate Cancer.  

National Technical Information Service (NTIS)

The traditional therapeutic and surgical approaches have not been successful in the management of prostate cancer (CaP). Natural plant-based products have shown promise as anticancer agents. Sanguinarine, a benzophenanthridine alkaloid derived from the ro...

N. Ahmad

2008-01-01

365

Anticancer activity of cardiac glycosides  

PubMed Central

Retrospective clinical data indicate that cardiac glycosides (CGs), notably digoxin, prolong the survival of carcinoma patients treated with conventional chemotherapy. CGs are known to influence the immune response at multiple levels. In addition, recent results suggest that CGs trigger the immunogenic demise of cancer cells, an effect that most likely contributes to their clinical anticancer activity.

Kepp, Oliver; Menger, Laurie; Vacchelli, Erika; Adjemian, Sandy; Martins, Isabelle; Ma, Yuting; Sukkurwala, Abdul Qader; Michaud, Mickael; Galluzzi, Lorenzo; Zitvogel, Laurence; Kroemer, Guido

2012-01-01

366

Semi-synthetic mithramycin SA derivatives with improved anticancer activity.  

PubMed

Mithramycin (MTM) is a potent anti-cancer agent that has recently garnered renewed attention. This manuscript describes the design and development of mithramycin derivatives through a combinational approach of biosynthetic analogue generation followed by synthetic manipulation for further derivatization. Mithramycin SA is a previously discovered analogue produced by the M7W1 mutant strain alongside the improved mithramycin analogues mithramycin SK and mithramycin SDK. Mithramycin SA shows decreased anti-cancer activity compared to mithramycin and has a shorter, two carbon aglycon side chain that is terminated in a carboxylic acid. The aglycon side chain is responsible for an interaction with the DNA-phosphate backbone as mithramycin interacts with its target DNA. It was therefore decided to further functionalize this side chain through reactions with the terminal carboxylic acid in an effort to enhance the interaction with the DNA phosphate backbone and improve the anti-cancer activity. This side chain was modified with a variety of molecules increasing the anti-cancer activity to a comparable level to mithramycin SK. This work shows the ability to transform the previously useless mithramycin SA into a valuable molecule and opens the door to further functionalization and semi-synthetic modification for the development of molecules with increased specificity and/or drug formulation. PMID:23331575

Scott, Daniel; Chen, Jhong-Min; Bae, Younsoo; Rohr, Jürgen

2013-04-04

367

Development and current status of unconventional platinum anticancer complexes.  

PubMed

Cisplatin is routinely employed for the treatment of testicular, ovarian cancer and head/neck tumors. Typical doses administrated to patients are 100 mg/day for up to five days. It is believed that the mechanism of action appears to be the binding of cis-Pt(NH3)(2) unit to DNA at two neighboring guanine bases. In the years following the introduction of cisplatin, the design of new platinum anticancer drugs concentrated mainly on direct cisplatin analogies, which stuck to the set of structure-activity relationships summarized by Clear and Hoeschele in 1973. Lately, some pioneering strategies towards the synthesis of novel platinum anticancer drugs based on the improved understanding of the mechanism of platinum resistance have emerged. Those are based on either changing the coordinated nitrogen ligand or altering the leaving groups. Other strategies have been shifted to discover "non classical" drugs that can act in a way different from cisplatin. Abnormal structures that violate the empirical structure-activity relationships of platinum compounds and multinuclear complexes are examples of these compounds. Several review articles appeared during recent years dealing with the synthesis, preclinical screening, and mechanism of action of platinum-based anticancer drugs. In this review, the progress in the field of anticancer chemistry based on unconventional platinum antitumor agents during the last 10 years will be highlighted. Most of the complexes that illustrate the recent and the previous prominent strategies will be presented. PMID:17305594

Abu-Surrah, Adnan Salim

2007-02-01

368

In Vitro and In Vivo Anticancer Activity of (+)-Spongistatin 1  

PubMed Central

The marine natural product (+)-spongistatin 1 is an extremely potent growth inhibitory agent having activity against a wide variety of cancer cell lines, while exhibiting low cytotoxicity against quiescent human fibroblasts. Consistent with a microtubule-targeting mechanism of action, (+)-spongistatin 1 causes mitotic arrest in DU145 human prostate cancer cells. More importantly, (+)-spongistatin 1 exhibits significant in vivo antitumor activity in the LOX-IMVI human melanoma xenograft model. (+)-Spongistatin 1 is thus an important class of microtubule targeting anticancer agent that warrants further investigation.

Xu, Qunli; Huang, Kuan-Chun; TenDyke, Karen; Marsh, Joanne; Liu, Junke; Qiu, Dayong; Littlefield, Bruce A.; Nomoto, Kenichi; Atasoylu, Onur; Risatti, Christina A.; Sperry, Jeffrey B.; Smith III, Amos B.

2011-01-01

369

In vitro and in vivo anticancer activity of (+)-spongistatin 1.  

PubMed

The marine natural product (+)-spongistatin 1 is an extremely potent growth inhibitory agent having activity against a wide variety of cancer cell lines, while exhibiting low cytotoxicity against quiescent human fibroblasts. Consistent with a microtubule-targeting mechanism of action, (+)-spongistatin 1 causes mitotic arrest in DU145 human prostate cancer cells. More importantly, (+)-spongistatin 1 exhibits significant in vivo antitumor activity in the LOX-IMVI human melanoma xenograft model. (+)-Spongistatin 1 is, thus, an important class of microtubule targeting anticancer agent that warrants further investigation. PMID:21868519

Xu, Qunli; Huang, Kuan-Chun; Tendyke, Karen; Marsh, Joanne; Liu, Junke; Qiu, Dayong; Littlefield, Bruce A; Nomoto, Kenichi; Atasoylu, Onur; Risatti, Christina A; Sperry, Jeffrey B; Smith, Amos B

2011-09-01

370

Anticancer activity of Amauroderma rude.  

PubMed

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

Jiao, Chunwei; Xie, Yi-Zhen; Yang, Xiangling; Li, Haoran; Li, Xiang-Min; Pan, Hong-Hui; Cai, Mian-Hua; Zhong, Hua-Mei; Yang, Burton B

2013-06-20

371

New modulated design and synthesis of quercetin-Cu(II)/Zn(II)-Sn2(IV) scaffold as anticancer agents: in vitro DNA binding profile, DNA cleavage pathway and Topo-I activity.  

PubMed

New molecular topologies quercetin-Cu(II)-Sn2(IV) and Zn(II)-Sn2(IV)1 and 2 were designed and synthesized to act as potential cancer chemotherapeutic agents. Their interaction with CT DNA by UV-vis and fluorescence spectroscopy was evaluated revealing an electrostatic mode of binding. Quercetin complexes are capable of promoting DNA cleavage involving both single and double strand breaks. Complex 1 cleaved pBR322 DNA via an oxidative mechanism while 2 followed a hydrolytic pathway, accessible to the minor groove of the DNA double helix in accordance with molecular docking studies with the DNA duplex of sequence d(CGCGAATTCGCG)2 dodecamer demonstrating that the complex was stabilized by additional electrostatic and hydrogen bonding interactions with the DNA. ROS such as OH?, H2O2 and O2?(-) are the major metabolites responsible for chronic diseases such as cancer, respiratory disorders, HIV, and diabetes etc., therefore eliminating ROS by molecular scaffolds involving SOD enzymatic activity has emerged as a potential way to develop a novel class of drugs. Therefore, in vitro superoxide dismutase activity of redox active complex 1 was evaluated by using a xanthine/xanthine oxidase-NBT assay which showed an IC50 value of 2.26 ?M. Moreover, the cytotoxicity of both the complexes were screened on a panel of human carcinoma cell lines (GI50 values <8.7 ?M) which revealed that 1 has a better prospect of acting as a cancer chemotherapeutic agent, and to elucidate the mechanism of tumor inhibition, Topo-I enzymatic activity was carried out. Furthermore, molecular modeling studies were carried out to understand molecular features important for drug-enzyme interactions which offer new insights into the experimental model observations. PMID:23715526

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

2013-05-29

372

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.

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

2009-01-01

373

Proteomic Approaches in Understanding Action Mechanisms of Metal-Based Anticancer Drugs  

PubMed Central

Medicinal inorganic chemistry has been stimulating largely by the success of the anticancer drug, cisplatin. Various metal complexes are currently used as therapeutic agents (e.g., Pt, Au, and Ru) in the treatment of malignant diseases, including several types of cancers. Understanding the mechanism of action of these metal-based drugs is for the design of more effective drugs. Proteomic approaches combined with other biochemical methods can provide comprehensive understanding of responses that are involved in metal-based anticancer drugs-induced cell death, including insights into cytotoxic effects of metal-based anticancer drugs, correlation of protein alterations to drug targets, and prediction of drug resistance and toxicity. This information, when coupled with clinical data, can provide rational basses for the future design and modification of present used metal-based anticancer drugs.

Wang, Ying; Chiu, Jen-Fu

2008-01-01

374

Designed enediynes: a new class of DNA-cleaving molecules with potent and selective anticancer activity.  

PubMed

The rational design and biological actions of a new class of DNA-cleaving molecules with potent and selective anticancer activity are reported. These relatively simple enediyne-type compounds were designed from basic chemical principles to mimic the actions of the rather complex naturally occurring enediyne anticancer antibiotics, particularly dynemicin A. Equipped with locking and triggering devices, these compounds damage DNA in vitro and in vivo on activation by chemical or biological means. Their damaging effects are manifested in potent anticancer activity with remarkable selectivities. Their mechanism of action involves intracellular unlocking and triggering of a Bergman reaction, leading to highly reactive benzenoid diradicals that cause severe DNA damage. The results of these studies demonstrate the potential of these de novo designed molecules as biotechnology tools and anticancer agents. PMID:1589797

Nicolaou, K C; Dai, W M; Tsay, S C; Estevez, V A; Wrasidlo, W

1992-05-22

375

Clinical Pharmacology and Anticancer Drugs  

Microsoft Academic Search

\\u000a Anticancer drugs are usually aggressive and during treatment result in toxicity, not only in the tumoral cells, but also in\\u000a normal tissues. There exists a large inter-patient variability in human response to chemotherapy, leading to toxicity for\\u000a some patients, lack of efficacy for others, and a satisfactory response in only a fraction of patients. One of the major objectives\\u000a of

Cristina Rodríguez-Antona; Julia Kirchheiner

376

Betulinic acid, a natural compound with potent anticancer effects.  

PubMed

New therapies using novel mechanisms to induce tumor cell death are needed with plants playing a crucial role as a source for potential anticancer compounds. One highly promising class of natural compounds are the triterpenoids with betulinic acid (BetA) as the most prominent representative. In-vitro studies have identified this agent as potently effective against a wide variety of cancer cells, also those derived from therapy-resistant and refractory tumors, whereas it has been found to be relatively nontoxic for healthy cells. In-vivo preclinically applied BetA showed some remarkable anticancer effects and a complete absence of systemic toxicity in rodents. BetA also cooperated with other therapies to induce tumor cell death and several potent derivatives have been discovered. Its antitumor activity has been related to its direct effects on mitochondria where it induces Bax/Bak-independent cytochrome-c release. PMID:20075711

Mullauer, Franziska B; Kessler, Jan H; Medema, Jan Paul

2010-03-01

377

Comparative study of early effects of epipodophyllotoxin derivatives and other cytostatic agents on mastocytoma cultures  

Microsoft Academic Search

SUMMARY The effects of various cytostatic agents (mechloretham- ine, 1-\\/3-D-arabinofuranosylcytosine, 6-mercaptopurine, methotrexate, colchicine, vincristine, a podophyllotoxin derivative, bleomycin, 1,2-bis(3,5-dioxopiperazin-1-yl)pro- pane, the epipodophyllotoxin derivatives 4'-O-demethyl-1- O-(4,6-O-2-thenylidene-ß-D-glucopyranosyl)epipodophyllo- toxin and 4'-O-demethyl-1-O-(4,6-O-ethylidene-\\/3-D-gluco- pyranosyljepipodophyllotoxin, and X-rays) on cell prolifera tion, mitotic index, cellular DNA, RNA, and protein content and on the incorporation of their respective isotope-labeled precursors were studied in cultures of mastocytoma cell line

Alfons Grieder; Richard Maurer; H Stahelin

1977-01-01

378

Anti-Inflammatory Agents for Cancer Therapy  

PubMed Central

Inflammation is closely linked to cancer, and many anti-cancer agents are also used to treat inflammatory diseases, such as rheumatoid arthritis. Moreover, chronic inflammation increases the risk for various cancers, indicating that eliminating inflammation may represent a valid strategy for cancer prevention and therapy. This article explores the relationship between inflammation and cancer with an emphasis on epidemiological evidence, summarizes the current use of anti-inflammatory agents for cancer prevention and therapy, and describes the mechanisms underlying the anti-cancer effects of anti-inflammatory agents. Since monotherapy is generally insufficient for treating cancer, the combined use of anti-inflammatory agents and conventional cancer therapy is also a focal point in discussion. In addition, we also briefly describe future directions that should be explored for anti-cancer anti-inflammatory agents.

Rayburn, Elizabeth R.; Ezell, Scharri J.; Zhang, Ruiwen

2010-01-01

379

Factors affecting podophyllotoxin yield in the ex situ grown Podophyllum hexandrum, an endangered alpine native of the western Himalayas.  

PubMed

This study reports an appreciable yield of podophyllotoxin (PDT) in P. hexandrum plants grown ex situ under polyhouse conditions of a temperate locale. The PDT content of below-ground parts was affected by both plant age and growth period. However, only the effect of plant age on PDT content was significant. Thus, the highest amounts of PDT were recorded in the below-ground parts of 2-year-old plants harvested during the late-growth period (LGP). High total soluble sugars in the below-ground parts during the early growth period (EGP) and the highest nitrate and nitrate reductase in the leaves of 2-year-old plants during the peak-growth period (PGP) indicated higher mobilization and assimilation of starch and nitrate. Probably the surplus carbon and nitrogen gained during the PGP were diverted from aerial parts to below-ground parts during the LGP and in turn contributed to the synthesis of higher amounts of PDT. This study shows that commercial cultivation of P. hexandrum is possible under ex situ temperate conditions. PMID:21625946

Kushwaha, Rekha; Bhattacharya, Amita; Singh, Bikram; Singh, R D

2011-05-29

380

Mesenchymal stem cells for anti-cancer drug delivery.  

PubMed

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

2013-09-01

381

From the sea to anticancer therapy.  

PubMed

Discovery, isolation, characterisation and pre-clinical and clinical trials of plant- or animal-derived drugs displaying pharmacological activities continue to develop and enlarge. Cancer chemotherapy is one of the most promising areas for these drugs. Since a very long time, nature has been an attractive source of potential medicinal agents for human use. The deep sea is becoming a novel and potently appealing source for new drugs, as well as shallow waters. This interest is mainly related to the terrific chemical diversity found in the vast number of plants and animal species, as well as in the microbial world. During the evolution, a rich source of biologically active compounds is developed in the depths of the sea, often reflecting ecological adaptation. Most of them (toxins) are developed to allow survival and flourishing acting against predators and parasites. Recent progress in Scuba diving, hi-tech/biotechnological and procedural advances in structure clarification, organic synthesis and biological assay determined the characterisation and preclinical/clinical evaluation of novel anticancer drugs. The aim of this review is to provide a description of their discovery, mode of action and clinical application. PMID:21756228

Russo, P; Nastrucci, C; Cesario, A

2011-01-01

382

Indigofera suffruticosa: An Alternative Anticancer Therapy  

PubMed Central

Indigofera suffruticosa Mill (Fabeceae) occurs in the Northeast countryside and has intensive popular use in the treatment of infectious, inflammatory and other processes. The main aim of the present work was to investigate the cytotoxic and antitumor effects of aqueous extracts of leaves of I. suffruticosa obtained by infusion and maceration as well as to evaluate the toxicological properties. Aqueous extracts did not exhibit cytotoxicity against HEp-2 (human epidermoid cancer cell) cell lines by MTT method. From the aqueous extract by infusion, the toxicological assay showed low order of toxicity. The antitumor effect of aqueous extracts by infusion (64.53%) and maceration (62.62%) against sarcoma 180 in mice at a dose of 50 mg kg?1 (intraperitoneally), based on low order of toxicity was comparable to the control group, which showed 100% development. Considering the low order of toxicity and that it is highly effective in inhibiting growth of solid tumors, the aqueous extracts of leaves of I. suffruticosa may be used as an alternative anticancer agent.

Vieira, Jeymesson Raphael Cardoso; de Souza, Ivone Antonia; do Nascimento, Silene Carneiro

2007-01-01

383

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

2006-01-01

384

Anticancer activity and mode of action of titanocene C  

Microsoft Academic Search

Summary  Titanocenes constitute a class of metal-based anticancer agents that seem to display a mode of action distinct from that of\\u000a platinum complexes and to be more tolerable with a differing spectrum of activity. In the present study, titanocene C (bis-(N,N-dimethylamino-2(N-methylpyrrolyl)-methyl-cyclopentadienyl)\\u000a titanium(IV) dichloride) was shown to exhibit antiproliferative activity against human tumor cell lines with a mean IC50 value of 48.3?±?32.5 µM.

Ulrike Olszewski; James Claffey; Megan Hogan; Matthias Tacke; Robert Zeillinger; Patrick J. Bednarski; Gerhard Hamilton

2011-01-01

385

Chemical and biological stability of anticancer drugs used in a human tumor clonogenic assay  

Microsoft Academic Search

Human tumor clonogenic assays (HTCA) are being used to evaluate the chemosensitivity of human cancers to both standard and experimental anticancer drugs as well as to predict clinical tumor response and resistance to these agents. To enable us to design and accurately interpret drug assay data we quantitated the chemical and biological stability characteristics of various cell cycle-specific and cell

Ruth Ludwig; David S. Alberts

1984-01-01

386

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

2011-01-01

387

Prooxidant property of green tea polyphenols epicatechin and epigallocatechin-3-gallate: implications for anticancer properties  

Microsoft Academic Search

It is believed that anticancer and apoptosis inducing properties of green tea are mediated by it's polyphenolic constituents particularly catechins. A number of reports have shown that green tea polyphenol (?)-epigallocatechin-3-gallate (EGCG) is among the most effective chemopreventive and apoptosis-inducing agents present in the beverage. Plant polyphenols are naturally occurring antioxidants but they also exhibit prooxidant properties. Over the last

S. Azam; N. Hadi; N. U. Khan; S. M. Hadi

2004-01-01

388

The discovery of a new potential anticancer drug: a case history  

Microsoft Academic Search

DNA minor groove binders (MGB) represent a class of anticancer agents whose DNA sequence specificity was hypothesized to lead to high selectivity of action. Tallimustine (TAM), a benzoyl nitrogen mustard derivative of distamycin A (DST), showed excellent antitumor activity in preclinical tests, but also a severe myelotoxicity. Novel nitrogen mustard, nitrogen half-mustard and sulfur mustard derivatives of DST showing excellent

Paolo Cozzi

2003-01-01

389

Anticancer activity of Nigella sativa (black seed) - a review.  

PubMed

Nigella sativa (N. sativa) seed has been an important nutritional flavoring agent and natural remedy for many ailments for centuries in ancient systems of medicine, e.g. Unani, Ayurveda, Chinese and Arabic Medicines. Many active components have been isolated from N. sativa, including thymoquinone, thymohydroquinone, dithymoquinone, thymol, carvacrol, nigellimine-N-oxide, nigellicine, nigellidine and alpha-hederin. In addition, quite a few pharmacological effects of N. sativa seed, its oil, various extracts and active components have been identified to include immune stimulation, anti-inflammation, hypoglycemic, antihypertensive, antiasthmatic, antimicrobial, antiparasitic, antioxidant and anticancer effects. Only a few authors have reviewed the medicinal properties of N. sativa and given some description of the anticancer effects. A literature search has revealed that a lot more studies have been recently carried out related to the anticancer activities of N. sativa and some of its active compounds, such as thymoquinone and alpha-hederin. Acute and chronic toxicity studies have recently confirmed the safety of N. sativa oil and its most abundant active component, thymoquinone, particularly when given orally. The present work is aimed at summarizing the extremely valuable work done by various investigators on the effects of N. sativa seed, its extracts and active principles against cancer. Those related to the underlying mechanism of action, derivatives of thymoquinone, nano thymoquinone and combinations of thymoquinone with the currently used cytotoxic drugs are of particular interest. We hope this review will encourage interested researchers to conduct further preclinical and clinical studies to evaluate the anticancer activities of N. sativa, its active constituents and their derivatives. PMID:22083982

Randhawa, Mohammad Akram; Alghamdi, Mastour Safar

2011-01-01

390

Development and characterization of molecularly imprinted polymers for the selective enrichment of podophyllotoxin from traditional Chinese medicines.  

PubMed

In the present work, microwave heating initiated precipitation polymerization was developed to prepare podophyllotoxin (PPT) molecularly imprinted polymers (MIPs), resulting in much shorter polymerization time and better particle morphology. Prior to the polymerization, ultraviolet and FTIR spectroscopy were used to study the interactions between PPT and the functional monomers. The synthesized parameters were respectively optimized and the optimal conditions for the efficient adsorption property were template: PPT, 1 mmol; functional monomer: acrylamide, 6 mmol; bi-crosslinker: ethylene glycol dimethacrylate, 20 mmol and divinylbenzene, 20 mmol; porogen: acetonitrile, 40 mL; initiator: azobisisobutyronitrile, 0.01mol L?¹; polymerization temperature: 60°C. FTIR spectroscopy, SEM and thermal analysis were used to characterize the MIPs. The results of the equilibrium rebinding experiments and the competitive adsorption experiments showed that these imprinted polymers exhibited good adsorption ability for the PPT. Scatchard analysis illustrated that two and one types of binding sites were generated in the MIPs and non-imprinted polymers (NIPs), respectively. Using the prepared MIPs as the solid phase extraction (SPE) sorbent, PPT was extracted selectively and efficiently from Dysosma versipellis, Sinopodophyllum hexandrum and Diphylleia sinensis. The regression equation was y=5.873×10?x+17075.659 with the correlation coefficient of 0.9994 in the concentration range of 0.005-0.4 mg mL?¹. After washing and eluting the SPE column with methanol and MeOH/acetic acid solution (v/v, 9:1), the limits of detection were 0.12-0.18 ?g mL?¹ and their recoveries were in the range of 89.5-91.1% with all RSDs lower than 3.7. PMID:21601031

Yuan, Ya; Wang, Yuzhi; Huang, Meidong; Xu, Ran; Zeng, Huan; Nie, Chan; Kong, Jinhuan

2011-04-16

391

[Future directions of anticancer drug development in Japan].  

PubMed

At the 13th Oncology Forum, future directions of anticancer drug development in Japan were discussed. Development of anticancer drugs in the 1990s was based on the concept of total cell kill, but now development of molecular targeted drugs becomes the mainstream. Unfortunately, molecular targeted drugs and antibody agents are mostly foreign products and translational research in Japan is poor as it stands now. As future directions of anticancer drug development, international collaborative development is considered essential, but there are various obstacles to the conduct of international collaborative studies. Companies, medical institutions and regulatory agencies must make collaborative efforts to overcome these obstacles. As future development of anticancer agents in individual cancer regions in Japan is considered, gastric cancer therapy is progressing considerably with the advent of S-1 and in the future, development of multi-agent combination therapy including molecular targeted agents is expected. Much progress in colon cancer therapy has been made owing to accumulation of evidence in recent years. Multi-agent chemotherapy combined with antibody agent, which is advancing overseas, is introduced to Japan. Clinical development of combination therapy with a high therapeutic index, including compounds discovered in Japan, is expected in the future. Although conventionally hormone therapy has been considered as first-line treatment of breast cancer and used in combination with chemotherapy, with the advent of antibody agents in recent years, HER2 sensitivity has greatly affected the algorithm of treatment. Future development of molecular targeted drugs and individualised diagnosis using cDNA array, etc. are likely to advance individualisation of treatment. On the other hand, large-scale clinical trials are required to prove a small difference in adjuvant therapy, etc. and accordingly international studies are becoming indispensable. For urological cancers, molecular targeted drugs have been proved effective in renal cancer and future development of molecular targeted drugs for prostate cancer and testicular tumors is desirable. At that time, elucidation of the mechanism of action of molecular targeted drug and strategic drug development designed to increase its efficacy are expected. As a future direction of anticancer drug development, there are many cancers in whose international collaborative studies Japan can participate. Studies of prostate cancer and renal cell carcinoma can be internationalised while internationalisation of studies in ovarian and pancreatic cancers is essential. Phase III should be performed as international collaborative studies and depending on the type of cancer and drug, collaborative studies in an Asian region are effective. When participating in an international collaborative study, Japan needs to recruit subjects at a speed similar to the rest of the world, but differences in medical environment including clinical trials pose a problem. To solve this problem, it is considered effective not only to pursue the Western environment but also to improve staff such as nurses and CRC. The number of Japanese patients necessary for Phase III studies is individual developmental strategy and needs to be examined by both companies and regulatory agencies. PMID:18281781

Akaza, Hideyuki; Kawai, Koji; Tsuruo, Takashi; Tsukagoshi, Shigeru; Aiba, Keisuke; Shimada, Yasuhiro; Kakeji, Yoshihiro; Ishikawa, Hideki; Ikeda, Tadashi; Nakamura, Seigo; Tamura, Tomohide; Yamamoto, Nobuyuki; Isonishi, Seiji; Hinotsu, Shiro; Hirose, Masaru; Katsura, Jun

2008-02-01

392

[Developing FGFR inhibitors as potential anti-cancer agents].  

PubMed

Fibroblast Growth Factor Receptor (FGFR) family is a sequentially highly related subgroup of membrane proteins consisting of four tyrosine kinase type enzyme: FGFR1, FGFR2, FGFR3 and FGFR4. These are kinases of great interest in a wide spectrum of physiological processes such as tissue repair via controlling cell proliferation. As initiatiors of cell proliferation, in some cases they have leading roles in several types of cancer, eg. breast cancer, pancreas cancer, gastric tumors and multiple myeloma via overexpression and/or mutation. This phenomenon makes them promising targets for drug development in order to develop signal transduction therapies based on small molecule FGFR inhibitors. We have developed two main groups of lead molecules: compounds with benzotiophene and oxindole cores utilizing numerous methods from in silico modelling via in vitro biochemichal assays and testing on relevant cell lines to citotoxicity assays. PMID:23926649

Zsákai, Lilian; Németh, Gábor; Szántai-Kis, Csaba; Greff, Zoltán; Horváth, Zoltán; Szokol, Bálint; Baska, Ferenc; Boon, Tin Chuad; Orfi, Lászlo; Kéri, Györgya

2013-01-01

393

Combination of photodynamic therapy with anti-cancer agents.  

PubMed

Degenerative diseases such as cancer usually involve more than one pathological process. Therefore, attempts to combat such diseases with monotherapeutic approaches may not always do so efficiently. For this reason, the use of combination therapy with modalities that target different disease pathways represents an alternative strategy. Photodynamic therapy (PDT) has already been established as an alternative therapy for the treatment of various types of malignant disorders, including oesophageal, lung and bladder cancer as well as other degenerative diseases. This technique involves the administration of a tumor localizing photosensitizer followed by its activation with light of a specific wavelength. In the presence of tissue oxygen, the photoactive sensitizer triggers a series of photochemical and photobiological processes that may lead to direct cancer cell damage, tumor microvascular occlusion and host immune response. Due to these multiple actions, PDT has increasingly gained recognition as a potential adjuvant for conventional cancer treatments. Several preclinical studies and some clinical trials suggest that the use of PDT in combination with established treatments or with newly-developed modalities may be of benefit as compared to the individual modalities. In this review, we briefly introduce the reader to the main photobiological aspects of PDT, and then discuss the use of PDT in combination with other pharmacological approaches for the treatment of cancer. PMID:18673216

Zuluaga, M-F; Lange, N

2008-01-01

394

Plant anticancer agents, L. cytotoxic triterpenes from Sandoricum koetjape stems.  

PubMed

A new ring-A secotriterpene, koetjapic acid [1], and five known compounds, 3-oxo-olean-12-en-29-oic acid [2] (a novel natural product), katonic acid [3], (-)-alloaromadendrene, (-)-caryophyllene oxide, and (+)-spathulenol, have been isolated and characterized from a cytotoxic Et2O-soluble extract of Sandoricum koetjape stems. Of these compounds, 2 and 3 demonstrated significant cytotoxic activity against cultured P-388 cells (ED50 values of 0.61 and 0.11 microgram/ml, respectively). Significant, albeit less intense, cytotoxicity was also observed with a variety of cultured human cancer cells. The 13C-nmr chemical shifts of these triterpenes were assigned unambiguously using selective INEPT nmr experiments. Aside from compounds 2 and 3, these substances were not toxic with cultured cells. PMID:1517737

Kaneda, N; Pezzuto, J M; Kinghorn, A D; Farnsworth, N R; Santisuk, T; Tuchinda, P; Udchachon, J; Reutrakul, V

1992-05-01

395

Oncolytic Measles Virus Strains as Novel Anticancer Agents  

PubMed Central

Introduction Replication-competent oncolytic measles virus (MV) strains preferentially infect and destroy a wide variety of cancer tissues. Clinical translation of engineered attenuated MV vaccine derivatives is demonstrating the therapeutic potential and negligible pathogenicity of these strains in humans. Areas covered The present review summarizes the mechanisms of MV tumor selectivity and cytopathic activity as well as the current data on the oncolytic efficacy and preclinical testing of MV strains. Investigational strategies to reprogram MV selectivity, escape antiviral immunity and modulate the immune system to enhance viral delivery and tumor oncolysis are also discussed. Expert Opinion Clinical viral kinetic data derived from non-invasive monitoring of reporter transgene expression will guide future protocols to enhance oncolytic MV efficacy. Anti-measles immunity is a major challenge of measles-based therapeutics and various strategies are being investigated to modulate immunity. These include the combination of MV therapy with immunosuppressive drugs such as cyclophosphamide, the use of cell carriers and the introduction of immunomodulatory transgenes and wild-type virulence genes. Available MV retargeting technologies can address safety considerations that may arise as more potent oncolytic MV vectors are being developed.

Msaouel, Pavlos; Opyrchal, Mateusz; Domingo Musibay, Evidio; Galanis, Evanthia

2013-01-01

396

Synthesis of functionalized carboranes as potential anticancer and BNCT agents.  

PubMed

Carboranyl aldehydes react with alpha,beta-unsaturated esters, ketones, and nitriles in the presence of DABCO to provide functionalized carboranyl alcohols in good yields. Acetates of these alcohols undergo a facile isomerization with a variety of nucleophiles and afford structurally interesting carboranes. Biological evaluation of these molecules exhibited impressive antiproliferative activity for brain and breast cancer cells. PMID:17279815

Reddy, Venkata Jaganmohan; Roforth, Matthew M; Tan, Chalet; Reddy, M Venkat Ram

2007-01-22

397

Maitake Mushrooms as an Anti-Cancer Agent  

Microsoft Academic Search

LEARNING OUTCOME: The audience will be able to assess current research and study outcomes on the maitake mushroom; be aware of what forms are presently under development for the lay and healthcare market.Currently intense research is focused on plant-based compounds for cancer prevention and treatment. An area of highly exciting study are the medicinal mushrooms used for millennia within the

S. Asanovic

1996-01-01

398

Plant anticancer agents. XIX Constituents of Aquilaria malaccensis.  

PubMed

The stem bark of the Thai tree Aquilaria malaccensis (Thymelaeaceae) has afforded 1,3-dibehenyl-2-ferulyl glyceride (3), which is novel, and 12-O-n-deca- 2, 4, 6-trienoylphorbol-13-acetate (4). The structures of these cytotoxic compounds were elucidated by their spectral and chemical parameters. PMID:7320738

Gunasekera, S P; Kinghorn, A D; Cordell, G A; Farnsworth, N R

399

Dehydroascorbic acid as an anti-cancer agent.  

PubMed

Three discoveries together point the way to a potential treatment for cancer. In 1982, Poydock and colleagues found that dehydroascorbic acid has the remarkable ability to eliminate the aggressive mouse tumours, L1210, P388, Krebs sarcoma, and Ehrlich carcinoma. In 1993, Jakubowski found that cancer cells (but not normal cells) contain measurable quantities of homocysteine thiolactone. Recently, the author found that dehydroascorbic acid reacts with homocysteine thiolactone converting it to the toxic compound, 3-mercaptopropionaldehyde. Taken together, these findings suggest that rapidly-dividing tumour cells make unusually large amounts of homocysteine thiolactone and that administered dehydroascorbic acid enters the cells and converts the thiolactone to mercaptopropionaldehyde which kills the cancer cells. The effectiveness of dehydroascorbic acid might be further increased by combining it with methionine and/or methotrexate to increase the homocysteine concentration in cancer cells. PMID:18378072

Toohey, John I

2008-04-02

400

Sonodynamic therapy: activation of anticancer agents with ultrasound  

Microsoft Academic Search

VX2 carcinoma was introduced into the right rear thigh of rabbits. The tumors were exposed to ultrasound (US; 1.97 MHz; 1.35 W\\/cm2 ) for ten minutes, 24 hours after intravenous injection of hematoporphyrin (Hp; 20 mg\\/kg). Tumor damaging effects were evaluated by measuring the tumor diameter every three days following treatment. Any effect on the tumor growth caused by US

J. Jeffers; R. Q. Feng; J. B. Fowlkes; D. E. Brenner; C. A. Cain

1991-01-01