Prevention of prostate cancer through custom tailoring of chemopreventive regimen

One practical way to control cancer is through chemoprevention, which refers to the administration of synthetic or naturally occurring agents to block, reverse or delay the process of carcinogenesis. For a variety of reasons, the most important of which is human acceptance, for chemopreventive intervention naturally occurring diet-based agents are preferred over synthetic agents. For a long time, the prevailing mantra of cancer chemoprevention has been: "Find effective agents with acceptable or no toxicity and use them in preventing cancer in relatively healthy people or individuals at high risk for developing cancer". In pursuing this goal many naturally occurring phytochemicals capable of affording protection against carcinogenesis in preclinical settings in experimental animals have been described. However, clinical trials of single agents have yielded disappointing results. Since carcinogenesis is a multistage phenomenon in which many normal cellular pathways become aberrant, it is unlikely that one agent could prove effective in preventing cancer. This review underscores the need to build an armamentarium of naturally occurring chemopreventive substances that could prevent or slow down the development and progression of prostate cancer. Thus, the new effective approach for cancer prevention "building a customized mechanism-based chemoprevention cocktail of naturally occurring substances" is advocated.     

The role of human adult stem cells and cell-cell communication in cancer chemoprevention and chemotherapy strategies

Since carcinogenesis is a multi-stage, multi-mechanism process, involving mutagenic, cell death and epigenetic mechanisms, during the "initiation/promotion/and progression" phases, chemoprevention must be based on understanding the underlying mechanism(s) of each phase, In principle, prevention of each of these phases could reduce the risk to cancer. However, because reducing the mutagenic/initiation phase to a zero level is impossible, the most efficacious intervention would be at the promotion phase that requires a sustained exposure to promoting conditions/agents. In addition, assuming the "target" cells for carcinogenesis are the pluri-potent stem cells and their early progenitor or transit cells, chemoprevention strategies for inhibiting the promotion of these two types of pre-malignant "initiated" cells will require different kinds of agents. A hypothesis will be proposed that involves adult stem cells, which express Oct-4 gene and lack gap junctional intercellular communication (GJIC-) or the early progenitor cells which express GJIC+ and are partially-differentiated, if initiated, will be promoted by agents that either inhibit secreted negative growth regulators or by inhibitors of GJIC. Consequently, anti-tumor promoting chemopreventing agents to each of these two types of initiated cells must have different mechanisms of action and work on different target cells. Assuming stem cells are target cells for carcinogenesis, an alternative method of chemoprevention would be to reduce the stem cell pool. Many classes of anti-tumor promoter chemopreventive agents, such as green tea components, resveratrol, caffeic acid phenethylene ester, either up-regulate GJIC in stem cells or prevent the down regulation of GJIC by tumor promoters in early progenitor cells.     

Chemoprevention strategies in the prostate: an overview

Chemoprevention is the administration of agents (drugs, biologics, and nutrients) to prevent induction, inhibit, or delay the progression of cancers. Prostate cancer is an important target for chemoprevention because of its long latency and high prevalence. The development of rational chemopreventive strategies requires knowledge of the mechanisms of prostate carcinogenesis and identification of agents that interfere with these mechanisms. Because of the long time period for prostate carcinogenesis and the large size of the cohort required for an evaluable study, identification and characterization of early intermediate biomarkers and their validation as surrogate endpoints for cancer incidence are essential for chemopreventive agent development. Finally, suitable populations with appropriate risk factors, including the presence of premalignant lesions and genetic predispositions, need to be well characterized for future chemopreventive interventions.     

Carcinogenesis, cancer therapy and chemoprevention

Carcinogenesis and cancer therapy are two sides of the same coin, such that the same cytotoxic agent can cause cancer and be used to treat cancer. This review links carcinogenesis, chemoprevention and cancer therapy in one process driven by cytotoxic agents (carcinoagents) that select either for or against cells with oncogenic alterations. By unifying therapy and cancer promotion and by distinguishing nononcogenic and oncogenic mechanisms of resistance, I discuss anticancer- and chemopreventive agent-induced carcinogenesis and tumor progression and, vice versa, carcinogens as anticancer drugs, anticancer drugs as chemopreventive agents and exploiting oncogene-addiction and drug resistance for chemoprevention and cancer therapy.     

Chemoprevention of tumors: the role of RAR-beta

Chemoprevention can be defined as the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. The knowledge of carcinogenic mechanisms provides the scientific rationale for chemoprevention. Epithelial carcinogenesis proceeds through multiple discernible stages of molecular and cellular alterations. Understanding of the multistep nature of carcinogenesis has evolved through highly controlled animal carcinogenesis studies, and these studies have identified three distinct phases: initiation, promotion and progression. Animal model studies have provided evidence that the development of cancer involves many different factors, including alterations in the structures and functions of different genes. Transitions between successive stages can be enhanced or inhibited in the laboratory by different types of agents, such activities providing the fundamental basis for chemoprevention.     

MicroRNAs as targets for dietary and pharmacological inhibitors of mutagenesis and carcinogenesis

MicroRNAs (miRNAs) have been implicated in many biological processes, cancer, and other diseases. In addition, miRNAs are dysregulated following exposure to toxic and genotoxic agents. Here we review studies evaluating modulation of miRNAs by dietary and pharmacological agents, which could potentially be exploited for inhibition of mutagenesis and carcinogenesis. This review covers natural agents, including vitamins, oligoelements, polyphenols, isoflavones, indoles, isothiocyanates, phospholipids, saponins, anthraquinones and polyunsaturated fatty acids, and synthetic agents, including thiols, nuclear receptor agonists, histone deacetylase inhibitors, antiinflammatory drugs, and selective estrogen receptor modulators. As many as 145 miRNAs, involved in the control of a variety of carcinogenesis mechanisms, were modulated by these agents, either individually or in combination. Most studies used cancer cells in vitro with the goal of modifying their phenotype by changing miRNA expression profiles. In vivo studies evaluated regulation of miRNAs by chemopreventive agents in organs of mice and rats, either untreated or exposed to carcinogens, with the objective of evaluating their safety and efficacy. The tissue specificity of miRNAs could be exploited for the chemoprevention of site-specific cancers, and the study of polymorphic miRNAs is expected to predict the individual response to chemopreventive agents as a tool for developing new prevention strategies.     

Mitochondria: A novel target for the chemoprevention of cancer

The mitochondria have emerged as a novel target for anticancer chemotherapy. This tenet is based on the observations that several conventional and experimental chemotherapeutic agents promote the permeabilization of mitochondrial membranes in cancerous cells to initiate the release of apoptogenic mitochondrial proteins. This ability to engage mitochondrial-mediated apoptosis directly using chemotherapy may be responsible for overcoming aberrant apoptosis regulatory mechanisms commonly encountered in cancerous cells. Interestingly, several putative cancer chemopreventive agents also possess the ability to trigger apoptosis in transformed, premalignant, or malignant cells in vitro via mitochondrial membrane permeabilization. This process may occur through the regulation of Bcl-2 family members, or by the induction of the mitochondrial permeability transition. Thus, by exploiting endogenous mitochondrial-mediated apoptosis-inducing mechanisms, certain chemopreventive agents may be able to block the progression of premalignant cells to malignant cells or the dissemination of malignant cells to distant organ sites as means of modulating carcinogenesis in vivo. This review will examine cancer chemoprevention with respect to apoptosis, carcinogenesis, and the proapoptotic activity of various chemopreventive agents observed in vitro. In doing so, I will construct a paradigm supporting the notion that the mitochondria are a novel target for the chemoprevention of cancer.     

Novel surrogate end-point biomarker to evaluate agents for use in the chemoprevention of reactive oxygen species-associated cancer

Cancer chemoprevention is the use of chemical agents to inhibit, delay or reverse carcinogenesis. We established a novel method to evaluate agents for use in the chemoprevention of reactive oxygen species (ROS)-associated cancer. Induction of renal cell carcinoma in rats by ferric nitrilotriacetate (Fe-NTA) is an established model of ROS-associated cancer. We recently identified the p16INK4A tumor suppressor gene as one of the major target genes in this model, and showed by the use of in situ hybridization that allelic loss of p16IK4A occurs in the increased fraction of renal tubular cells within a few weeks. In the present study, we tested whether diets including green tea powder or a processed grain food are effective chemopreventive agents in this animal model. Consumption of these modified diets led to a significant decrease in the fraction of aneuploid cells after 1 week of repeated Fe-NTA administration. A decrease in renal lipid peroxidation after a single administration of Fe-NTA was also observed. Therefore, intake of green tea or processed grain foods stabilizes p16INK4A in the genome, at least in this model, and might be helpful for the prevention of ROS-associated cancer. This novel method is versatile, and may work as a surrogate end-point biomarker for screening the usefulness of agents for cancer chemoprevention.     

Understanding the molecular mechanisms of cancer prevention by dietary phytochemicals:From experimental models to clinical trials

Chemoprevention is one of the cancer prevention approaches wherein natural/synthetic agent(s) are prescribed with the aim to delay or disrupt multiple pathways and processes involved at multiple steps, i.e., initiation, promotion, and progression of cancer. Amongst environmental chemopreventive compounds, diet/beverage-derived components are under evaluation, because of their long history of exposure to humans, high tolerability, low toxicity, and reported biological activities. This compilation briefly covers and compares the available evidence on chemopreventive efficacy and probable mechanism of chemoprevention by selected dietary phytochemicals(capsaicin, curcumin, diallyl sulphide, genistein, green/black tea polyphenols, indoles, lycopene, phenethyl isocyanate, resveratrol, retinoids and tocopherols) in experimental systems and clinical trials. All the dietary phytochemicals covered in this review have demonstrated chemopreventive efficacy against spontaneous or carcinogen-induced experimental tumors and/or associated biomarkers and processes in rodents at several organ sites. The observed anti-initiating, anti-promoting and anti-progression activity of dietary phytochemicals in carcinogen-induced experimental models involve phytochemical-mediated redox changes, modulation of enzymes and signaling kinases resulting to effects on multiple genes and cell signaling pathways. Results from clinical trials using these compounds have not shown them to be chemopreventive. This may be due to our:(1) inability to reproduce the exposure conditions, i.e., levels, complexity, other host and lifestyle factors; and(2) lack of understanding about the mechanisms of action and agent-mediated toxicity in several organs and physiological processes in the host. Current research efforts in addressing the issues of exposure conditions, bioavailability, toxicity and the mode of action of dietary phytochemicals may help address the reason for observed mismatch that may ultimately lead to identification of new chemopreventive agents for protection against broad spectrum of exposures.     

Overview of mechanisms of cancer chemopreventive agents

Epidemiological data provide evidence that it is possible to prevent cancer and other chronic diseases, some of which share common pathogenetic mechanisms, such as DNA damage, oxidative stress, and chronic inflammation. An obvious approach is avoidance of exposure to recognized risk factors. As complementary strategies, it is possible to render the organism more resistant to mutagens/carcinogens and/or to inhibit progression of the disease by administering chemopreventive agents. In a primary prevention setting, addressed to apparently healthy individuals, it is possible to inhibit mutation and cancer initiation by triggering protective mechanisms either in the extracellular environment or inside cells, e.g., by modifying transmembrane transport, modulating metabolism, blocking reactive species, inhibiting cell replication, maintaining DNA structure, modulating DNA metabolism and repair, and controlling gene expression. Tumor promotion can be counteracted by inhibiting genotoxic effects, favoring antioxidant and anti-inflammatory activity, inhibiting proteases and cell proliferation, inducing cell differentiation, modulating apoptosis and signal transduction pathways, and protecting intercellular communications. In a secondary prevention setting, when a premalignant lesion has been detected, it is possible to inhibit tumor progression via the same mechanisms, and in addition by affecting the hormonal status and the immune system in various ways, and by inhibiting tumor angiogenesis. Although tertiary prevention, addressed to cancer patients after therapy, is outside the classical definition of chemoprevention, it exploits similar mechanisms. It is also possible to affect cell-adhesion molecules, to activate antimetastasis genes, and to inhibit proteases involved in basement membrane degradation.     

The role of Sulforaphane in cancer chemoprevention and health benefits: a mini-review

Cancer is a multi-stage process resulting from aberrant signaling pathways driving uncontrolled proliferation of transformed cells. The development and progression of cancer from a premalignant lesion towards a metastatic tumor requires accumulation of mutations in many regulatory genes of the cell. Different chemopreventative approaches have been sought to interfere with initiation and control malignant progression. Here we present research on dietary compounds with evidence of cancer prevention activity that highlights the potential beneficial effect of a diet rich in cruciferous vegetables. The Brassica family of cruciferous vegetables such as broccoli is a rich source of glucosinolates, which are metabolized to isothiocyanate compounds. Amongst a number of related variants of isothiocyanates, sulforaphane (SFN) has surfaced as a particularly potent chemopreventive agent based on its ability to target multiple mechanisms within the cell to control carcinogenesis. Anti-inflammatory, pro-apoptotic and modulation of histones are some of the more important and known mechanisms by which SFN exerts chemoprevention. The effect of SFN on cancer stem cells is another area of interest that has been explored in recent years and may contribute to its chemopreventive properties. In this paper, we briefly review structure, pharmacology and preclinical studies highlighting chemopreventive effects of SFN.     

Curcumin, A Multi-Functional Chemopreventive Agent, Blocks Growth of Colon Cancer Cells by Targeting β-Catenin-Mediated Transactivation and Cell–Cell Adhesion Pathways

Colorectal cancer, the second most frequent diagnosed cancer in the US, causes significant morbidity and mortality in humans. Over the past several years, the molecular and biochemical pathways that influence the development of colon cancer have been extensively characterized. Since the development of colon cancer involves multi-step events, the available drug therapies for colorectal cancer are largely ineffective. The radiotherapy, photodynamic therapy, and chemotherapy are associated with severe side effects and offer no firm expectation for a cure. Thus, there is a constant need for the investigation of other potentially useful options. One of the widely sought approaches is cancer chemoprevention that uses natural agents to reverse or inhibit the malignant transformation of colon cancer cells and to prevent invasion and metastasis. Curcumin (diferuloylmethane), a natural plant product, possesses such chemopreventive activity that targets multiple signalling pathways in the prevention of colon cancer development.     

Anti-Oxidants from Green Tea and Pomegranate for Chemoprevention of Prostate Cancer

Among males, prostate cancer has become the second leading cause of cancer-related deaths in North America, with similar trends in many Western and developing countries. One way to control prostate cancer is through chemoprevention, which refers to the administration of synthetic or naturally occurring agents to block, reverse, or delay the process of carcinogenesis. For a variety of reasons, the most important of which is human acceptance, for chemopreventive intervention, naturally occurring diet-based agents are preferred. Prostate cancer is an ideal candidate disease for chemopreventive intervention, because it grows very slowly, likely for decades, before symptoms arise and a diagnosis is finally established, it has a long latency period, and it is typically diagnosed in men >50 years of age. Most chemopreventive agents are antioxidant in nature. We have been defining the usefulness of dietary anti-oxidants for chemoprevention of prostate and other cancers. It is increasingly appreciated that some of these dietary anti-oxidants are nature’s gift molecules endowed with cancer preventive and therapeutic properties. This review will focus on prostate cancer chemopreventive effects of polyphenolic anti-oxidants derived from green tea and pomegranate. It is a challenge to custom-tailor these gift molecules as cocktails in concentrations that can easily be consumed by humans for delaying prostate and other cancers.     

Chemopreventive agent-induced modulation of death receptors

The goals of chemoprevention of cancer are to inhibit the initiation or suppress the promotion and progression of preneoplastic lesions to invasive cancer through the use specific natural or synthetic agents. Therefore, a more desirable and aggressive approach is to eliminate aberrant clones by inducing apoptosis rather than merely slowing down their proliferation. The increased understanding of apoptosis pathways has directed attention to components of these pathways as potential targets not only for chemotherapeutic but also for chemopreventive agents. Activation of death receptors triggers an extrinsic apoptotic pathway, which plays a critical role in tumor immunosurveillance. An increasing number of previously identified chemopreventive agents were found to induce apoptosis in a variety of premalignant and malignant cell types in vitro and in a few animal models in vivo. Some chemopreventive agents such as non-steroidal anti-inflammatory drugs, tritepenoids, and retinoids increase the expression of death receptors. Thus, understanding the modulation of death receptors by chemopreventive agents and their implications in chemoprevention may provide a rational approach for using such agents alone or in combination with other agents to enhance death receptor-mediated apoptosis as a strategy for effective chemoprevention of cancer.     

Colon cancer prevention with NO-releasing NSAIDs

A seminal advance in the prevention of colon cancer has been the observation that nonsteroidal antiinflammatory drugs (NSAIDs) reduce the incidence of and mortality from colon cancer by about half. Among current efforts to overcome the side effects of NSAIDs, an important limitation for their application as chemopreventive agents, is the synthesis of nitric oxide-releasing NSAIDs. These novel compounds may display greater safety and greater efficacy compared to their parent traditional NSAIDs and thus hold significant promise as chemopreventive agents against human colon cancer. In this review we discuss salient features of their pharmacology, in vitro and animal data pertaining to colon cancer, their mechanisms of action, and assess their potential in the chemoprevention of colon cancer.     

β-catenin-mediated signaling: A novel molecular target for chemoprevention with anti-inflammatory substances

Inflammation is thought to play a role in the pathophysiology of cancer. Accumulating evidence from clinical and laboratory-based studies suggests that substances with anti-inflammatory activities are potential candidates for chemoprevention. Recent advances in cellular and molecular biology of cancer shed light on components of intracellular signaling cascades that can be potential molecular targets of chemoprevention with various anti-inflammatory substances. Although cyclooxygenase-2, a primary enzyme that mediates inflammatory responses, has been well recognized as a molecular target for chemoprevention by both synthetic and natural anti-inflammatory agents, the cellular signaling mechanisms that associate inflammation and cancer are not still clearly illustrated. Recent studies suggest that β-catenin-mediated signaling, which regulates developmental processes, may act as a potential link between inflammation and cancer. This review aims to focus on β-catenin-mediated signaling pathways, particularly in relation to its contribution to carcinogenesis, and the modulation of inappropriately activated β-catenin-mediated signaling by nonsteroidal anti-inflammatory drugs and chemopreventive phytochemicals possessing anti-inflammatory properties.     

beta-Catenin-mediated signaling: a novel molecular target for chemoprevention with anti-inflammatory substances

Inflammation is thought to play a role in the pathophysiology of cancer. Accumulating evidence from clinical and laboratory-based studies suggests that substances with anti-inflammatory activities are potential candidates for chemoprevention. Recent advances in cellular and molecular biology of cancer shed light on components of intracellular signaling cascades that can be potential molecular targets of chemoprevention with various anti-inflammatory substances. Although cyclooxygenase-2, a primary enzyme that mediates inflammatory responses, has been well recognized as a molecular target for chemoprevention by both synthetic and natural anti-inflammatory agents, the cellular signaling mechanisms that associate inflammation and cancer are not still clearly illustrated. Recent studies suggest that beta-catenin-mediated signaling, which regulates developmental processes, may act as a potential link between inflammation and cancer. This review aims to focus on beta-catenin-mediated signaling pathways, particularly in relation to its contribution to carcinogenesis, and the modulation of inappropriately activated beta-catenin-mediated signaling by nonsteroidal anti-inflammatory drugs and chemopreventive phytochemicals possessing anti-inflammatory properties.     

Nonsteroidal anti-inflammatory drugs and the induction of apoptosis in colon cells: Evidence for PHS-dependent and PHS-independent mechanisms

NSAIDs are potent chemopreventive agents for colon cancer. Although their mechanism of action is unknown, it probably relates to their modulation of colon epithelial cell kinetics, i.e. apoptosis and/or cell proliferation. NSAIDs are pleiotropic in their biochemical activities; their best known effect is inhibition of prostaglandin H synthase (PHS), the enzyme catalyzing the biosynthesis of prostaglandins. Current data appear to lead to two conflicting conclusions. One body of data indicates that PHS is important in induction of apoptosis and colon carcinogenesis and that its inhibition by NSAIDs is required for induction of apoptosis and their overall chemopreventive effect. Another set of data indicates that NSAIDs may induce apoptosis and prevent colon cancer without inhibiting the activity of PHS. Both sides of this argument are presented and discussed. This apparent contradiction may be resolved if one accepts that both mechanisms are correct but that they act on different steps of this multistep process.