Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 10, Issue 8, 2010

Multidrug resistance has been felt to be one of the mechanisms by which chemotherapy drugs develop resistance, and hence, failure in cancer drug therapy. Several investigations through the years have been undertaken to identify the genes involved in modulating multidrug resistance. Several drug-resistant proteins and genes have been since discovered, including variants in genes that encode for different drug metabolizing enzymes. Furthermore, of the 48 ATP binding cassette transporters, several have been described to have a role in drug resistance, including ABCB1 (P-glycoprotein, Pgp), ABCG2 (breast cancer resistance protein), and multidrug resistance-associated protein 1 (MRP1). Pgp has historically been the prototype that correlated with resistance of varying cancer cell lines and correlated with the expression of the protein, encoded by MDR-1. However, despite multitude of studies addressing its significance and efforts undertaken to effect its reversal, clinical trials on Pgp inhibition has resulted in failure of overcoming resistance. In this thematic issue, the role of pharmacogenomics in drug metabolism, clinical effects, toxicity, and risks it confers to the development of cancer is actively explored. Lee presents an overview of pharmacogenetics and pharmacogenomics as well as the role gene polymorphisms play especially with regard to the disposition of certain cytotoxic chemotherapy drugs with the goal of ultimately providing pharmacogenetic testing for individualizing treatment regimens for patients. Drug resistance has been described not only in cytotoxic drugs but has been an emerging phenomenon with targeted agents and angiogenesis inhibitors. Tavakoli and Aragon-Ching discusses the mechanisms of drug resistance with the use of angiogenesis inhibitors and explores the pre-clinical and clinical trials that underlie the processes resulting in emergence of resistance to these agents. Lokesh et al. provides a comprehensive review of anti-cancer therapeutic agents approved by the United States Food and Drug Administration within the past decade, as it relates to the role of drug transporters as a mechanism of resistance. In as much as genetic polymorphisms are thought to confer drug resistance, certain drug transporter gene polymorphisms have been shown to be related to risk of developing disease. The impact of a specific ATP binding cassette (ABC) transporter, ABCC11, is explored by Toyoda and Ishikawa, as it relates to the apocrine phenotype, response to chemotherapy, and breast cancer risk. Finally, Robey et al. offers a thoughtprovoking view regarding the status of ABC transporters as it relates to mechanisms of drug resistance and the potential role of drug transporters as therapeutic targets for central nervous system treatment. Furthermore, the authors discuss an in-depth review of the complexity and pitfalls of the P-glycoprotein hypothesis -a long held view that inhibition of the Pgp may cause reversal of drug resistance. Several challenges exist in the quest to overcome the ever present problem of drug resistance. These articles represent a tremendous effort from the contributors to provide a comprehensive review of the field of multidrug resistance and underscore the need for continuing investigation in this field of cancer research.

There is wide interpatient variability in drug response and toxicity to standard doses of most anticancer medications. Genetic polymorphisms in genes encoding metabolic enzymes, receptors and drug transporters targeted by anticancer medications are often found, in part, to be responsible for the observed variability. Approximately 80% of all sequence variations residing in genes is in the form of single nucleotide polymorphisms or SNPs. The location of SNPs can be in the protein coding sequence, regulatory regions or at exon-intron boundaries of genes. Adverse drug reactions resulting from these sequence variations are due to changes in the activity of the encoded protein (in many instances the protein is non-functional) or perturbations in the level of gene expression. The goal of pharmacogenetic testing is to identify genetic polymorphisms that predispose patients to an adverse drug reaction, thereby allowing the health care provider to make informed decisions pertaining to the type of drug, dosage and dosage scheduling to be administered.

Angiogenesis inhibitors have a major role in the treatment of varying cancers today. While originally thought to be independent of resistance, increasing data suggests varying mechanisms that bring about drug resistance, either intrinsically or through adaptation. The role of vascular endothelial growth factor single nucleotide polymorphisms (VEGF SNPs) in terms of therapeutic response and toxicity has increasingly been recognized, as well as its potential for contributing to drug resistance. This review will focus on theories, preclinical models, and clinical trials that help elucidate the mechanisms of resistance and clinical response to angiogenesis inhibitors.

Membrane transporters play a role in determining the absorption, distribution, metabolism and excretion of small molecule anticancer drugs and mediating chemosensitivity and resistance of tumor cells to these drugs. Our understanding of the influence of these transporters on the pharmacokinetics, clinical effectiveness and tolerability has considerably increased in the last decade. We reviewed the interaction of the small molecule anticancer drugs approved in the last decade with the more common membranes transporters, such as ABCB1, ABCG2, and OATP. The drugs were divided into three categories: targeted therapies, cytotoxic agents and hormonal therapies. The literature appears to focus on the interaction of the targeted therapies compared to the remaining two categories. Furthermore, most data stemmed from nonclinical studies with only a few clinical examples where transporters corresponded with systemic exposure, clinical effectiveness, or tolerability. More nonclinical and clinical studies are needed to improve the ability to use the findings from these nonclinical studies to predict clinical outcomes, but the literature appears to be rapidly expanding as our understanding of these transporters grows. Therefore, determining the interaction of membrane transporters with small molecule anticancer drugs can facilitate the development of effective and safe treatments.

Some genetic polymorphisms of human ABC transporter genes are reportedly related to the risk of certain diseases and patients' responses to medication. Human ABCC11 functions as an ATP-dependent efflux pump for amphipathic anions. One nonsynonymous SNP 538G>A (Gly180Arg) has been found to greatly affect the function and stability of de novo synthesized ABCC11 (Arg180) variant protein. The SNP variant lacking N-linked glycosylation is recognized as a misfolded protein in the endoplasmic reticulum (ER) and readily undergoes proteasomal degradation. This ER-associated degradation of ABCC11 protein underlies the molecular mechanism of affecting the function of apocrine glands. On the other hand, the wild type (Gly180) of ABCC11 is associated with wettype earwax, axillary osmidrosis, colostrum secretion from the mammary gland, and the potential susceptibility of breast cancer. Furthermore, the wild type of ABCC11 reportedly has ability to efflux cyclic nucleotides and nucleoside-based anticancer drugs. The SNP (538G>A) of the ABCC11 gene is suggested to be a clinical biomarker for prediction of chemotherapeutic efficacy. Major obstacle to the successful chemotherapy of human cancer is development of resistance, and nucleoside-based chemotherapy is often characterized by inter- individual variability. This review provides an overview about the discovery and the genetic polymorphisms in human ABCC11. Furthermore, we focus on the impact of ABCC11 538G>A on the apocrine phenotype, patients' response to nucleoside-based chemotherapy, and the potential risk of breast cancer.

The discovery of the multidrug transporter P-glycoprotein (Pgp) over 35 years ago in drug resistant cells prompted several decades of work attempting to overcome drug resistance by inhibition of drug efflux. Despite convincing laboratory data showing that drug transport can be inhibited in vitro, efforts to translate this discovery to the clinic have not succeeded. Since overexpression of Pgp and related transporters including ABCG2 and members of the ABCC family have been linked with poor outcome, it remains a reasonable hypothesis that this poor outcome is linked to reduction of drug exposure by efflux, and thus to drug resistance. In this review, we will discuss the question of whether ABC transporters mediate drug resistance in cancer through a reduction in drug accumulation in tumors, and whether the “Pgp inhibition hypothesis” might be wrong. The hypothesis, which holds that increased chemotherapy effectiveness can be achieved by inhibiting Pgp-mediated drug efflux has only been validated in model systems. Possible explanations for the failure to validate this clinically include the existence of other factors impacting of drug accumulation and uptake in tumors. Despite these difficulties, a potential role has emerged for drug transporters as therapeutic targets in the central nervous system (CNS). Both lines of investigation point to the need for imaging agents to facilitate the study of drug accumulation in human cancer. This is a critical need for targeted therapies, where an important dose-response relationship is likely to exist, and where drug resistance renders many of the novel targeted agents ineffective in a subset of patients.

The antiproliferative and proapoptotic effects of pomegranate extract (PE), as correlated with its prooxidant activity, were studied. PE exerted greater antiproliferative effects towards cancer, than to normal, cells, isolated from the human oral cavity. In cell-free systems, PE generated hydrogen peroxide (H2O2) in cell culture media and in phosphate buffered saline, with prooxidant activity increasing from acidic to alkaline pH, and oxidized glutathione (GSH) in an alkaline, phosphate buffer. Detection of PE-generated H2O2 was greatly lessened in medium amended with N-acetyl-L-cysteine. Using HSC-2 carcinoma cells as the bioindicator, the cytotoxicity of PE was potentiated towards cells pretreated with the GSH depleter, 1-chloro-2,4-dinitrobenzene, and attenuated in cells cotreated with the H2O2 scavengers, catalase, pyruvate, and divalent cobalt ion. Intracellular GSH was lessened in cells treated with PE; GSH depletion in PE-treated cells was confirmed visually with the fluorescent dye, Cell TrackerTM Green 5-chloromethylfluorescein diacetate. These studies demonstrated that the antiproliferative mechanism of PE was, in part, by induction of oxidative stress. The mode of cell death was by apoptosis, as shown by flow cytometry, activation of casapase-3, and cleavage of PARP. Lessening of caspase-3 activation and of PARP cleavage in cells cotreated with PE and either cobalt or pyruvate, respectively, as compared to PE alone, indicated that apoptosis was through the prooxidant nature of PE.

We sought to determine whether administration of glycerol guaiacolate at an optimal biological dose inhibits human breast cancer cell growth. Human breast cancer MCF-7 and ZR-75-1 cells were treated with glycerol guaiacolate and the therapeutic efficacy and biological activity of this drug was investigated on breast cancer cell growth. MCF-7 cells were injected into the mammary fat pad of overectamized female athymic nude mice. Ten days later, animals were treated with daily intraperitoneal injections of glycerol guaiacolate for six weeks. Tumor size and volume was monitored and immunohistochemical analysis on MUC1, p21 and ki-67 was performed. Glycerol guaiacolate decreased breast cancer cell growth in a dose-dependent manner, decreased cell migration, and caused G1 cell cycle arrest. Our results demonstrate that glycerol guaiacolate inhibits MUC1 protein and mRNA expression levels and significantly increased p21 expression in human breast cancer cells as well as induced PARP cleavage. Similarly, glycerol guaiacolate inhibited breast tumor growth in vivo as well as enhanced p21 expression and decreased breast tumor cell proliferation (ki-67 expression). Collectively, our results demonstrate that glycerol guaiacolate decreased MUC1 expression and enhanced cell growth inhibition by inducing p21 expression in breast cancer cells. These findings suggest that glycerol guaiacolate may provide a novel and effective approach for the treatment of human breast cancer.