Modulation of inflammatory signaling pathways by phytochemicals in ovarian cancer

Inflammation has been suggested to be involved in cancer development and progression. Many clinical and experimental studies have shown that inflammation could contribute to ovarian carcinogenesis through activation of the NF-κB and AP-1 pathways by chronic inflammatory mediators. Phytochemicals, which are natural compounds derived from fruits and vegetables, have shown anti-inflammatory and anti-cancer effects. Due to their relatively low toxicity and easy accessibility, phytochemicals have been investigated for their chemopreventive potential against various cancers. In this review, we discuss the role of phytochemicals in preventing ovarian cancer through anti-inflammatory mechanisms.     

Effects of phytochemicals on ionization radiation-mediated carcinogenesis and cancer therapy

Ionizing radiation (IR)-induced cellular damage is implicated in carcinogenesis as well as therapy of cancer. Advances in radiation therapy have led to the decrease in dosage and localizing the effects to the tumor; however, the development of radioresistance in cancer cells and radiation toxicity to normal tissues are still the major concerns. The development of radioresistance involves several mechanisms, including the activation of mitogenic and survival signaling, induction of DNA repair, and changes in redox signaling and epigenetic regulation. The current strategy of combining radiation with standard cytotoxic chemotherapeutic agents can potentially lead to unwanted side effects due to both agents. Thus agents are needed that could improve the efficacy of radiation killing of cancer cells and prevent the damage to normal cells and tissues caused by the direct and bystander effects of radiation, without have its own systemic toxicity. Chemopreventive phytochemicals, usually non-toxic agents with both cancer preventive and therapeutic activities, could rightly fit in this approach. In this regard, naturally occurring compounds, including curcumin, parthenolide, genistein, gossypol, ellagic acid, withaferin, plumbagin and resveratrol, have shown considerable potential. These agents suppress the radiation-induced activation of receptor tyrosine kinases and nuclear factor-κB signaling, can modify cell survival and DNA repair efficacy, and may potentiate ceramide signaling. These radiosensitizing and counter radioresistance mechanisms of phytochemicals in cancer cells are also associated with changes in epigenetic gene regulation. Because radioresistance involves multiple mechanisms, more studies are needed to discover novel phytochemicals having multiple mechanisms of radiosensitization and to overcome radioresistance of cancer cells. Pre-clinical studies are needed to address the appropriate dosage, timing, and duration of the application of phytochemicals with radiation to justify clinical trials. Nonetheless, some phytochemicals in combination with IR may play a significant role in enhancing the therapeutic index of cancer treatment.     

Targeting signal transduction pathways by chemopreventive agents

Cancer is a dynamic process that involves many complex factors, which may explain why a "magic bullet" cure for cancer has not been found. Death rates are still rising for many types of cancers, which possibly contributes to the increased interest in chemoprevention as an alternative approach to the control of cancer. This strategy for cancer control is based on the presumption that because cancer develops through a multi-step process, each step may be a prospective target for reversing or suppressing the process. Thus, the design and development of chemopreventive agents that act on specific and/or multiple molecular and cellular targets is gaining support as a rational approach to control cancer. Nutritional or dietary factors have attracted a great deal of interest because of their perceived ability to act as highly effective chemopreventive agents. They are professed as being generally safe and may have efficacy as chemopreventive agents by preventing or reversing premalignant lesions and/or reducing second primary tumor incidence. Many of these dietary compounds appear to act on multiple target signaling pathways. Some of the most interesting and well documented are resveratrol and components of tea, including EGCG, theaflavins and caffeine. This review will focus on recent work regarding three well-accepted cellular/molecular mechanisms that may at least partially explain the effectiveness of selected food factors, including those indicated above, as chemopreventive anti-promotion agents. These food compounds may act by: (1) inducing apoptosis in cancer cells; (2) inhibiting neoplastic transformation through the inhibition of AP-1 and/or NF-kappaB activation; and/or (3) suppressing COX-2 overexpression in cancer cells.     

Absorption and metabolism of flavonoids

The benefits of flavonoids as chemopreventive dietary or dietary supplemental agents are still only "potential." Much has been learned about possible mechanisms of action of these agents, but whether they can reach their multiple intended sites of action, particularly in humans, is largely unknown. The biological fate of the flavonoids, including their dietary glycoside forms, is highly complex, dependent on a large number of processes. This review is intended to bring some order into this complex area and deals with the fate of the naturally occurring glycosides, their enzymatic hydrolysis, as well as the resulting aglycones. The impact of membrane transporters as well as metabolic enzymes on the cellular availability of these phytochemicals is examined. A reevaluation of the concept of oral bioavailability applied to the dietary flavonoids is presented.     

Phytochemicals Attenuating Aberrant Activation of ��-Catenin in Cancer Cells

Phytochemicals are a rich source of chemoprevention agents but their effects on modulating the Wnt/β-catenin signaling pathway have remained largely uninvestigated. Aberrantly activated Wnt signaling can result in the abnormal stabilization of β-catenin, a key causative step in a broad spectrum of cancers. Here we report the modulation of lithium chloride-activated canonical Wnt/β-catenin signaling by phytochemicals that have antioxidant, anti-inflammatory or chemopreventive properties. The compounds were first screened with a cervical cancer-derived stable Wnt signaling reporter HeLa cell line. Positive hits were subsequently evaluated for β-catenin degradation, suppression of β-catenin nuclear localization and down-regulation of downstream oncogenic targets of Wnt/β-catenin pathway. Our study shows a novel degradation path of β-catenin protein in HeLa cells by Avenanthramide 2p (a polyphenol) and Triptolide (a diterpene triepoxide), respectively from oats and a Chinese medicinal plant. The findings present Avenanthramide 2p as a potential chemopreventive dietary compound that merits further study using in vivo models of cancers; they also provide a new perspective on the mechanism of action of Triptolide.     

Potential toxicity of flavonoids and other dietary phenolics: significance for their chemopreventive and anticancer properties

Flavonoids, including isoflavones, are natural components in our diet and, with the burgeoning interest in alternative medicine, are increasingly being ingested by the general population. Plant phenolics, which form moieties on flavonoid rings, such as gallic acid, are also widely consumed. Several beneficial properties have been attributed to these dietary compounds, including antioxidant, anti-inflammatory, and anticarcinogenic effects. Flavonoid preparations are marketed as herbal medicines or dietary supplements for a variety of alleged nontoxic therapeutic effects. However, they have yet to pass controlled clinical trials for efficacy, and their potential for toxicity is an understudied field of research. This review summarizes the current knowledge regarding potential dietary flavonoid/phenolic-induced toxicity concerns, including their pro-oxidant activity, mitochondrial toxicity (potential apoptosis-inducing properties), and interactions with drug-metabolizing enzymes. Their chemopreventive activity in animal in vivo experiments may result from their ability to inhibit phase I and induce phase II carcinogen metabolizing enzymes that initiate carcinogenesis. They also inhibit the promotion stage of carcinogenesis by inhibiting oxygen radical-forming enzymes or enzymes that contribute to DNA synthesis or act as ATP mimics and inhibit protein kinases that contribute to proliferative signal transduction. Finally, they may prevent tumor development by inducing tumor cell apoptosis by inhibiting DNA topoisomerase II and p53 downregulation or by causing mitochondrial toxicity, which initiates mitochondrial apoptosis. While most flavonoids/phenolics are considered safe, flavonoid/phenolic therapy or chemopreventive use needs to be assessed as there have been reports of toxic flavonoid-drug interactions, liver failure, contact dermatitis, hemolytic anemia, and estrogenic-related concerns such as male reproductive health and breast cancer associated with dietary flavonoid/phenolic consumption or exposures.     

Synergistic chemoprotective mechanisms of dietary phytoestrogens in a select combination against prostate cancer

Combination of dietary phytoestrogens with diverse molecular mechanisms may enhance their anticancer efficacy at physiological concentrations, as evidenced in epidemiological studies. A select combination of three dietary phytoestrogens containing 8.33 μM each of genistein (G), quercetin (Q) and biochanin A (B) was found to be more potent in inhibiting the growth of androgen-responsive prostate cancer cells (LNCaP) as well as DU-145 and PC-3 prostate cancer cells in vitro than either 25 μM of G, B or Q or 12.5+12.5 μM of G+Q, Q+B or G+B. Subsequent mechanistic studies in PC-3 cells indicated that the action of phytoestrogens was mediated both through estrogen receptor (ER)-dependent and ER-independent pathways as potent estrogen antagonist ICI-182780 (ICI, 5 μM) could not completely mask the synergistic anticancer effects, which were sustained appreciably in presence of ICI. G+Q+B combination was significantly more effective than individual compounds or their double combinations in increasing ER-β, bax (mRNA expression); phospho-JNK, bax (protein levels); and in decreasing bcl-2, cyclin E, c-myc (mRNA expression); phospho-AKT, phospho-ERK, bcl-2, proliferating cell nuclear antigen (protein levels) in PC-3 cells. Phytoestrogens also synergistically stimulated caspase-3 activity. Our findings suggest that selectively combining anticancer phytoestrogens could significantly increase the efficacy of individual components resulting in improved efficacy at physiologically achievable concentrations. The combination mechanism of multiple anticancer phytochemicals may be indicative of the potential of some vegetarian diet components to elicit chemopreventive effects against prostate cancer at their physiologically achievable concentrations, in vivo.     

Oleanane triterpenoids in the prevention and therapy of breast cancer: current evidence and future perspectives

Breast cancer is one of the most frequently diagnosed cancers and major cause of death in women in the world. Emerging evidence underscores the value of dietary and non-dietary phytochemicals, including triterpenoids, in the prevention and treatment of breast cancer. Oleanolic acid, an oleanane-type pentacyclic triterpenoid, is present in a large number of dietary and medicinal plants. Oleanolic acid and its derivatives exhibit several promising pharmacological activities, including antioxidant, anti-inflammatory, hepatoprotective, cardioprotective, antipruritic, spasmolytic, antiallergic, antimicrobial and antiviral effects. Numerous studies indicate that oleanolic acid and other oleanane triterpenoids modulate multiple intracellular signaling pathways and exert chemopreventive and antitumor activities in various in vitro and in vivo model systems. A series of novel synthetic oleanane triterpenoids have been prepared by chemical modifications of oleanolic acid and some of these compounds are considered to be the most potent anti-inflammatory and anticarcinogenic triterpenoids. Accumulating studies provide extensive evidence that synthetic oleanane derivatives inhibit proliferation and induce apoptosis of various cancer cells in vitro and demonstrate cancer preventive or antitumor efficacy in animal models of blood, breast, colon, connective tissue, liver, lung, pancreas, prostate and skin cancer. This review critically examines the potential role of oleanolic acid, oleanane triterpenoids and related synthetic compounds in the chemoprevention and treatment of mammary neoplasia. Both in vitro and in vivo studies on these agents and related molecular mechanisms are presented. Several challenges and future directions of research to translate already available impressive preclinical knowledge to clinical practice of breast cancer prevention and therapy are also presented.     

Cell signaling pathways altered by natural chemopreventive agents

Epidemiological studies have indicated a significant difference in the incidence of cancers among ethnic groups, who have different lifestyles and have been exposed to different environmental factors. It has been estimated that more than two-thirds of human cancers, which are contributed by mutations in multiple genes, could be prevented by modification of lifestyle including dietary modification. The consumption of fruits, soybean and vegetables has been associated with reduced risk of several types of cancers. The in vitro and in vivo studies have demonstrated that some dietary components such as isoflavones, indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), curcumin, (-)-epigallocatechin-3-gallate (EGCG), apigenin, etc., have shown inhibitory effects on human and animal cancers, suggesting that they may serve as chemopreventive agents. Experimental studies have also revealed that these components regulate the molecules in the cell signal transduction pathways including NF-kappaB, Akt, MAPK, p53, AR, and ER pathways. By modulating cell signaling pathways, these components, among other mechanisms, activate cell death signals and induce apoptosis in precancerous or cancer cells, resulting in the inhibition of cancer development and/or progression. This article reviews current studies regarding the effects of natural chemopreventive agents on cancer-related cell signaling pathways and provides comprehensive knowledge of the biological and molecular roles of chemopreventive agents in cancer cells.     

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.     

Phytochemicals as anticancer and chemopreventive topoisomerase II poisons

Phytochemicals are a rich source of anticancer drugs and chemopreventive agents. Several of these chemicals appear to exert at least some of their effects through interactions with topoisomerase II, an essential enzyme that regulates DNA supercoiling and removes knots and tangles from the genome. Topoisomerase II-active phytochemicals function by stabilizing covalent protein-cleaved DNA complexes that are intermediates in the catalytic cycle of the enzyme. As a result, these compounds convert topoisomerase II to a cellular toxin that fragments the genome. Because of their mode of action, they are referred to as topoisomerase II poisons as opposed to catalytic inhibitors. The first sections of this article discuss DNA topology, the catalytic cycle of topoisomerase II, and the two mechanisms (interfacial vs. covalent) by which different classes of topoisomerase II poisons alter enzyme activity. Subsequent sections discuss the effects of several phytochemicals on the type II enzyme, including demethyl-epipodophyllotoxins (semisynthetic anticancer drugs) as well as flavones, flavonols, isoflavones, catechins, isothiocyanates, and curcumin (dietary chemopreventive agents). Finally, the leukemogenic potential of topoisomerase II-targeted phytochemicals is described.     

Retinoids as chemopreventive agents

Retinoids are promising agents for cancer chemoprevention. The myriad effects of retinoids on biological processes including development, differentiation, homeostasis, carcinogenesis and apoptosis are mediated through their molecular targets, the retinoid and rexinoid receptors. Tissue specific expression patterns, ligand specificities, receptor numbers, their distinct functions and functional redundancy make retinoid signaling highly complex. The cross-talks of these receptors with cell surface receptors signaling pathways, as well as their interactions with multiple co-activators and co-repressors further add to the complexity of the pleiotropic effects of retinoids. Elucidation of retinoid signaling pathways and indepth understanding of the mechanisms that underlie the anti-proliferative and apoptotic action of retinoids has paved the way for designing synthetic retinoids for effective chemoprevention and therapy of cancer. Development of receptor selective synthetic retinoids is a major focus of molecular retinoid development. Other new avenues encompass identification of novel retinoid regulated genes, orphan-receptor ligands/functions, novel retinoid mechanisms involving receptor-independent apoptosis inducing activity and synergistic combinations with other agents for cancer prevention and therapy. This review focuses on recent advances in the understanding of molecular mechanisms underlying the action of retinoids and retinoid molecular targeting studies designed primarily to develop retinoids with reduced toxicity, while maintaining or enhancing activity in context of chemoprevention. The clinical efficacy of retinoid based chemoprevention trials is discussed.     

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.     

Molecular targets that link dioxin exposure to toxicity phenotypes

Many toxicology studies have elucidated health effects associated with exposure to various chemicals, but few have identified the molecular targets that cause specific endpoints of toxicity. Our understanding of the toxicity of dioxins, a group of chemicals capable of causing toxicity at environmentally relevant levels of exposure, is no exception. Dioxins are unique compared to most chemicals that we are exposed to in the environment because they activate a high affinity receptor, aryl hydrocarbon receptor (AhR), that was identified more than three decades ago. In recent years, several lines of experimental evidence have provided clues for opening the "black box" that contains the molecular mechanisms of dioxin action. These clues have emerged by toxicologists beginning to identify the molecular targets that link AhR signaling to tissue-specific toxicity phenotypes. Endpoints of dioxin toxicity for which downstream molecular targets have begun to be elucidated are observed in developmental or tissue regeneration processes, and include impaired prostate development and hydronephrosis in mouse fetuses and pups, reduced midbrain blood flow and jaw malformation in zebrafish embryos, and impaired fin regeneration in larval and adult zebrafish. Significant progress in identifying molecular targets for dioxin-induced hepatotoxicity in adult mice also has occurred. Misregulation of AhR downstream pathways, such as conversion of arachidonic acid to prostanoids via cyclooxygenase-2, and altered Wnt/β-catenin signaling downregulating Sox9, and signaling by receptors for inflammatory cytokines have been implicated in tissue-specific endpoints of dioxin toxicity. These findings may not only begin to clarify the molecular targets of dioxin action but shed light on new molecular events associated with development and disease.     

Modulation of apoptosis-related cell signalling pathways by curcumin as a strategy to inhibit tumor progression

A hallmark of cancer is resistance to apoptosis, with both the loss of proapoptotic signals and the gain of anti-apoptotic mechanisms contributing to tumorigenesis. As inducing apoptosis in malignant cells is one of the most challenging tasks regarding cancer, researchers increasingly focus on natural products to regulate apoptotic signaling pathways. Curcumin, a polyphenolic derivative of turmeric, is a natural compound derived from Curcuma longa, has attracted great interest in the research of cancer during the last half century. Extensive studies revealed that curcumin has chemopreventive properties, which are mainly due to its ability to arrest cell cycle and to induce apoptosis in cancer cells either alone or in combination with chemotherapeutic agents or radiation. The underlying action mechanisms of curcumin are diverse and has not been elucidated so far. By regulating multiple important cellular signalling pathways including NF-κB, TRAIL, PI3 K/Akt, JAK/STAT, Notch-1, JNK, etc., curcumin are known to activate cell death signals and induce apoptosis in pre-cancerous or cancer cells without affecting normal cells, thereby inhibiting tumor progression. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy. This article reviews the main effects of curcumin on the different apoptotic signaling pathways involved in curcumin induced apoptosis in cancer cells via cellular transduction pathways and provides an in depth assessment of its pharmacological activity in the management of tumor progression.     

Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants

Dietary phenolic compounds are known to elicite vital cellular responses such as cell cycle arrest, apoptosis and differentiation by activating a cascade of molecular events. As there is an increasing interest to improve the efficacy of these compounds for use as potential chemopreventive agents, we wanted to understand the impact of phenolic compounds on target genes in prostate cancer. In this study we used human cDNA microarrays with 2400 clones consisting of 17 prosite motifs to characterize alterations in gene expression pattern in response to the phenolic antioxidants ellagic acid (EA) and resveratrol (RE). Over a 48-hr exposure of androgen - sensitive LNCaP cells to EA and RE, a total of 593 and 555 genes respectively, showed more than a two fold difference in expression. A distinct set of genes in both EA-and RE-treated cells may represent the signature profile of phenolic antioxidant-induced gene expression in LNCaP cells. Although extensive similarity was found between effects of EA - and RE - responsive genes in prostate cancer cells, out of 246 genes with overlapping responses, 25 genes showed an opposite effect. Quantitative RT-PCR was used to verify and validate the differential expression of selected genes identified from cDNA microarrays. In-depth analysis of the data from this study provided insight into the alterations in the p53 - responsive genes, p300, Apaf-1, NF-kBp50 and p65 and PPAR families of genes, suggesting the activation of multiple signaling pathways that leads to growth inhibition of LNCaP cells. This is a first study to look for changes in a large number of human genes in response to dietary compounds.     

Select Dietary Phytochemicals Function as Inhibitors of COX-1 but Not COX-2

Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors. Many active dietary factors are reported to suppress carcinogenesis by targeting COX-2. A major question was accordingly raised: why has the lifelong use of phytochemicals that likely inhibit COX-2 presumably not been associated with adverse cardiovascular side effects. To answer this question, we selected a library of dietary-derived phytochemicals and evaluated their potential cardiovascular toxicity in human umbilical vein endothelial cells. Our data indicated that the possibility of cardiovascular toxicity of these dietary phytochemicals was low. Further mechanistic studies revealed that the actions of these phytochemicals were similar to aspirin in that they mainly inhibited COX-1 rather than COX-2, especially at low doses.