Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 11, Issue 3, 2011

The reputation of garlic (Allium Sativum) as an effective remedy for tumours extends back to the Egyptian Codex Ebers of 1550 B.C. Half a century ago, Weisberger and Pensky (1958). have reported the tumour inhibitory property of a sulfhydryl-blocking agent in Garlic [1]. During the past 25 years, numerous studies of several organosulfur compounds extracted from garlic (Table 1) have demonstrated their biological effects in preventing and/or controlling cancer. Allicin is a transient compound responsible for the typical odour of garlic that readily decomposes into several organosulfur compounds. Diallyl trisulfide (DATS) is the most abundant in fresh garlic oil whereas commercial garlic oil products have primarily diallyl disulfide (DADS) [2]. However, after consumption of raw garlic, allicin is decomposed in stomach acid into several compounds mainly DADS that was also detected in human breath without other organosulfur volatiles [3,4]. Moreover, incubation with whole blood at 37°C, demonstrated longer bioavailability for DADS (Half-life, 60 min) compared with DATS (Half-life, 4 min) and ajoene (Half-life, 1 min) [3,5]. Several epidemiological studies have demonstrated the benefit of garlic consumption in reducing risk of several human malignancies including colorectal, esophageal, gastric and prostate cancer. The Iowa women's health case/control (212/3500) study has shown 48% lower risk of colon cancer for the highest intake in comparison with no intake of garlic [6]. The multicentre Italian case/control (1016/1159) study has reported 40% lower risk of stomach cancer for the highest intake of raw garlic compared to the lowest intake [7]. The Chinese case/control (152/234) study has identified protective effect of high garlic intake against esophageal cancer in a high epidemic area in the Jiangsu province [8]. The English case/control (328/328) study has established a lower risk for prostate cancer with high intake of garlic among men before the age of 75 years [9], that was confirmed in a larger European case/control (1294/1451) study [10]. The Shanghai case/control (291/414) study has found significantly decreased risk for laryngeal cancer with high garlic consumption [11]. Several bioactive garlic organosulfur components have demonstrated profound anticancer effects in preventing carcinogenesis, stopping tumour growth, inducing cancer cell death as comprehensively illustrated in this issue. The numerous in vitro cell line experiments and in vivo animal model studies reviewed in the manuscripts of this thematic issue have clearly determined the various biological and molecular mechanisms responsible for the anticancer activity of these garlic organosulfur compounds. Druesne-Pecollo and Latino-Martel provided comprehensive evidence from numerous in vitro and in vivo studies confirming the efficacy of garlic organosulfur compounds in inhibiting histone deacetylase activity in several types of tumour suggesting a prominent role in cancer control and prevention. Tsubura et al. demonstrated the various mechanisms of action of DADS in exerting anticancer activity in breast cancer cells in both in vitro and in vivo studies arguing the case for its role in the prevention and control of breast cancer. Diedrich et al. illustrated the molecular targets for the anticancer biological activity of garlic organosulfur compounds including several metabolic, transporter or repair enzymes that are pivotal for malignant cell proliferation, metastases and survival. Kaschula et al. reported the unique anticancer biological actrivity of several synthetic E- and Z-ajoene analogues in human cancer cells. More significantly, some garlic organosulfur compounds have been shown to enhance the efficacy of several routinely used chemotherapeutic drugs against drug-resistant human malignant cells. Ajoene has been shown to enhance the efficacy of both cytarabine and fludarabine in human resistant leukaemia KG1a cells [12,13]. Also, DAS has been shown to attenuate the resistance of human leukaemia K562 cells to vinblastin and vincristine by significant reduction of p-glycoprotein-mediated multidrug resistance [14]. Two pilot clinical studies of garlic compounds have demonstrated their clinical benefits in cancer patients. The topical application of ajoene has induced significant clinical response with reduction in tumour size in 17 out of 21 patients with skin basal cell carcinoma [15]. The daily dose of 0.2g garlic extract/kg body weight for one month has significantly lowered the mass of prostate and the international prostate score values in 27 patients with benign prostate Hyperplasia as well as the total and free prostate-specific antigen (PSA) in 9 patients with prostate cancer [16]. These garlic organosulfur compounds are promising candidates for cancer treatment with proven pre-clinical anticancer biological activities through well-established molecular mechanisms and preliminary clinical efficacy in small number of patients. Further pre-clinical animal and pilot clinical studies to establish their bioavailability, pharmacokinetics and tolerance are warranted to exploit their clinical role as supplement to improve the current chemotherapy outcome in patients suffering from several human malignancies.....

Garlic and garlic-derived compounds reduce the development of mammary cancer in animals and suppress the growth of human breast cancer cells in culture. Oil-soluble compounds derived from garlic, such as diallyl disulfide (DADS), are more effective than water-soluble compounds in suppressing breast cancer. Mechanisms of action include the activation of metabolizing enzymes that detoxify carcinogens, the suppression of DNA adduct formation, the inhibition of the production of reactive oxygen species, the regulation of cell-cycle arrest and the induction of apoptosis. Selenium-enriched garlic or organoselenium compounds provide more potent protection against mammary carcinogenesis in rats and greater inhibition of breast cancer cells in culture than natural garlic or the respective organosulfur analogues. DADS synergizes the effect of eicosapentaenoic acid, a breast cancer suppressor, and antagonizes the effect of linoleic acid, a breast cancer enhancer. Moreover, garlic extract reduces the side effects caused by anti-cancer agents. Thus, garlic and garlic-derived compounds are promising candidates for breast cancer control.

Preclinical studies have shown that fresh garlic extracts, aged garlic, garlic oil and specific organosulfur compounds generated by processing garlic could alter carcinogen metabolism, inhibit tumor cell growth through induction of cell cycle arrest or apoptosis, or angiogenesis. In particular, recent studies have suggested that anticarcinogenic effects of certain garlic compounds may implicate at least in part a modulation of histone acetylation, a process involved in the regulation of gene expression, resulting from the inhibition of histone deacetylase activity. The aim of this review is to describe the available data on sulfur compounds from garlic and histone acetylation and to discuss their potential for cancer prevention. Available data indicate that garlic compounds could inhibit histone deacetylase activity and induce histone hyperacetylation both in vitro as well as in vivo. Sparse studies provide evidence of involvement of histone acetylation in modulation of gene expression by diallyl disulfide and allyl mercaptan. These effects were observed at high concentrations. Further investigations are needed to determine if the HDAC inhibitory effects of garlic organosulfur compounds play a role in primary cancer prevention at doses achievable by human diet.

The ability of garlic preparations to inhibit cancer cell-growth has been attributed to a group of structurally-related organosulfur compounds found in the crushed clove. Historically, interest has centred on three such compounds as allicin, diallyl disulfide and diallyl trisulfide, with less interest on E- and Z-ajoene. A recently developed synthetic route from our laboratory for preparing ajoene analogues allows access to derivatives containing the sulfoxide / vinyl disulfide core whilst varying the terminal end-group functionality. A small library has been synthesized and an advanced lead with p-methoxybenzyl end groups (8) identified. Data on the in vitro anti-proliferation activity of compound (8) is presented here on six cancer cell-lines in comparison with that of Z- and E-ajoene to reveal an enhancement in activity of up to twelvefold. In addition, a modest selectivity is observed for tumour over normal cell-lines of up to threefold. Data on ajoene and its derivatives is presented in the context of chemosensitization in drug-resistance, and ideas on ajoene's mode of action at the molecular level are presented and discussed.

Organic sulfur compounds (OSCs) derived from plants, fungi or bacteria can serve as chemopreventive and/or chemotherapeutic agents and have been attracting medical and research interest as a promising source for novel anti-cancer agents. Garlic, which has long been used as a medicinal plant in different cultures due to its multiple beneficial effects, contains a consistent number of OSCs, the majority of which are currently under investigation for their biological activities. Experimental animal and laboratory studies have shown strong evidence that garlic OSCs may affect cancer cells by promoting early mitotic arrest followed by apoptotic cell death without affecting healthy cells. The ability of OSCs to hinder cancer cell proliferation and viability tightly correlates with the length of the sulfur chain. Current data support a mechanism of mitotic arrest of cancer cells due to the alteration of the microtubule network, possibly as a consequence of the high reactivity of sulfur atoms against the thiol groups of different cellular macromolecules controlling crucial regulatory functions. Taken together, these findings indicate a promising potential for the use of garlic-derived sulfur compounds in chemoprevention and chemotherapy.

Altered cellular metabolism is a hallmark of tumorigenesis. Described first in 1924 by Otto Warburg, a cancer cell undergoes complete metabolic reprogramming to attain nutrient self-sufficiency for proliferation and survival. Interplay between diverse signalling cascades confers this metabolic advantage. In this review we focus on signalling molecules that regulate this altered metabolic paradigm in a cancer cell with emphasis on small molecule mediated intervention for attenuation of growth and progression of tumor.

Previous cancer chemoprevention studies from our laboratories and by other investigators have demonstrated that the extract of red beetroot (Beta vulgaris L.), the FDA approved red food color E162, can be effective in suppressing the development of multiorgan tumors in experimental animals. To further explore this finding, we have compared the cytotoxic effect of the red beetroot extract with anticancer drug, doxorubicin (adriamycin) in the androgen-independent human prostate cancer cells (PC-3) and in the wellestablished estrogen receptor-positive human breast cancer cells (MCF-7). This red colored anticancer antibiotic was selected for comparative cytotoxic study because its chemical structure with a planar configuration of an aromatic chromophore attached to a sugar molecule is remarkably similar to that of betanin, the beetroot extract constituent primarily responsible for its red color. Both doxorubicin and the beetroot extract exhibited a dose-dependent cytotoxic effect in the two cancer cell lines tested. Although the cytotoxicity of the beetroot extract was significantly lower when compared to doxorubicin, it continued to decrease the growth rate of the PC-3 cells (3.7% in 3 days vs. 12.5% in 7 days) when tested at the concentration of 29 μg/ml. In contrast, doxorubicin, at the same concentration level, completely inhibited the growth of the PC-3 cells in three days. Similarly, comparative studies in the normal human skin FC and liver HC cell lines showed that the beetroot extract had significantly lower cytotoxic effect than doxorubicin (8.6% vs. 100%, respectively, at 29 μg/ml concentration of each, three-day test period). The results suggest that betanin, the major betacyanin constituent, may play an important role in the cytotoxicity exhibited by the red beetroot extract. Further studies are needed to evaluate the chemopreventive potentials of the beetroot extract when used alone or in combination with doxorubicin to mitigate the toxic side-effects of the latter.

Tumors with mutations in the gene encoding the serine-threonine protein kinase BRAF are dependent on the MAPK signaling pathway for their growth, what offers an opportunity to test oncogene-targeted therapy. Mutations at the position V600 of BRAF were described in approximately 8% of all solid tumors, including 50% of melanomas, 30 to 70% of papillary thyroid carcinomas and 5 to 8% of colorectal adenocarcinomas. Specific BRAF kinase inhibitors are undergoing rapid clinical development and promising data on efficacy have been demonstrated in activated mutant BRAF V600 melanomas. This review article will address: (a) preclinical data on the antitumor activity of BRAF inhibitors in cell lines/ in vivo models and their opposing functions as inhibitors or activators of the MAPK pathway, depending on the cellular context; (b) drug development from non-selective RAF inhibitors to selective BRAF inhibitors, such as PLX4032 and GSK2118436, with emphasis in the clinical efficacy and toxicity of these agents; and (c) possible mechanisms of resistance to BRAF inhibitors and strategies to overcome its development in BRAF mutant tumors.

Treatment of metastatic castrate resistant prostate cancer (mCRPC) after progression on docetaxel chemotherapy is a challenging clinical scenario with limited availability of treatment options. Re-treatment with docetaxel, either as monotherapy or in combination with other cytotoxics or targeted agents has shown durable responses. However, most docetaxel re-treatment studies have been either retrospective or early phase non-randomised studies which have not formally assessed Quality of life or survival gain with re-treatment. Despite limited evidence for efficacy of mitoxantrone in the second-line, it continues to remain widely used, largely due to lack of available suitable alternatives. Cabazitaxel in combination with prednisolone is the only chemotherapy to have shown a significant survival benefit and receive approval by the U.S. Food and Drug Administration for patients with mCRPC previously treated with a docetaxel-based regimen. Abiraterone acetate has recently demonstrated a significant improvement in survival when compared to placebo in patients with docetaxel-treated mCRPC. This review aims to summarize the current evidence and discuss future strategies for treatment of mCRPC patients following failure of docetaxel chemotherapy.

Mortality-to-incidence ratio in cancer patients is extremely high, positioning cancer as a major cause of death worldwide. Despite hundreds of clinical trials for anti-cancer drugs that are currently in progress, most clinical trials for novel drug treatments fail to pass Phase I. However, previously developed drugs with novel anti-tumor properties offer a viable and cost-effective alternative to fight cancer. Histamine favors the proliferation of normal and malignant cells. Several anti-histamine drugs, including astemizole, can inhibit tumor cell proliferation. Astemizole has gained enormous interest since it also targets important proteins involved in cancer progression, namely, ether a-go-go 1 (Eag1) and Eag-related gene (Erg) potassium channels. Furthermore, Eag1 is thought to be an important marker and a therapeutic target for several different cancers. Astemizole inhibits Eag1 and Erg channel activity, and in cells expressing the Eag1 channel it decreases tumor cell proliferation in vitro and in vivo. It should be noted that some cardiovascular side effects have been reported for astemizole in a few rare cases. Nevertheless, astemizole stands as a very promising anti-cancer tool because it displays several anti-proliferative mechanisms, may serve as the basis to synthesize new anti-cancer agents, and has been previously administered clinically. In this review we will summarize the main findings relating to histamine and anti-histamines in cancer cell proliferation focusing on astemizole targets (Eag1 and Erg channels), and its anti-cancer effects in vitro and in vivo. We will also describe the side effects of astemizole and discuss proposals to overcome such effects in cancer patients. Finally, we will remark on the relevance of developing novel astemizole-related compounds.

The drug design of more effective and less toxic therapeutic agents for multiple myeloma (MM) is mushrooming in parallel to a better understanding of the underlying patho-physiology of this common hematological neoplasm. A decade back, the re-birth of Thalidomide as an anti-neoplastic agent completely transformed the treatment paradigm of patients with MM. Its effectiveness, though, has been jolted by significant adverse effects. IMiDs (immunodulatory compounds) are structural and functional analogs of thalidomide that were specifically designed to enhance immunomodulatory and anticancer properties and better tolerability profiles. Lenalidomide, a second generation IMiD, was created using thalidomide as a template by adding an amino group to the 4th carbon of the phthaloyl ring and removal of a carbonyl group. This novel drug possesses immunomodulatory, antiangiogenic, and direct apoptotic properties among others, which culminate in cancer cell death either through direct interference with key functions of tumor cells or indirectly through modulation of signaling pathways that regulate their interaction to bone marrow stromal cells. While recent preclinical and clinical studies put forward a dual mechanism of action for lenalidomide, involving both a direct tumoricidal activity and immunomodulation, it is presently unclear which mechanism(s) are responsible for clinical activity in patients responding to therapy; mechanisms themselves may also differ depending on the underlying malignancies and their tumor micro-environment. To make this riddle more complex, the relative contribution of each effect towards the eventual anti-tumor activity is very much unexplained. This research review elucidates the mechanistic properties of Lenalidomide - the understanding of which is indispensable to develop rational combination strategies for future management of hematological malignancies.