Chemopreventive Phytochemicals Research Articles

Xenohormesis mechanisms underlying chemopreventive effects of some dietary phytochemicals

A wide variety of phytochemicals present in our diet, including fruits, vegetables, and spices, have been shown to possess a broad range of health-beneficial properties. The cytoprotective and restorative effects of dietary phytochemicals are likely to result from the modulation of several distinct cellular signal transduction pathways. Many dietary phytochemicals that are synthesized as secondary metabolites function as toxins, that is, "phytoalexins," and hence protect plants against insects and other damaging organisms and stresses. However, at the relatively low doses consumed by humans and other mammals, these same toxic plant-derived chemicals, as mild stressors, activate adaptive cellular response signaling, conferring stress resistance and other health benefits. This phenomenon has been referred to as xenohormesis. This review highlights the xenohormesis mechanisms underlying chemopreventive effects of some dietary chemopreventive phytochemicals, with special focus on the nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) as a key player.

Resveratrol inhibits genistein-induced multi-drug resistance protein 2 (MRP2) expression in HepG2 cells

The interactions between various dietary cancer chemopreventive phytochemicals in drug transporter functions are not well studied. In this study, the effects of genistein and resveratrol on the multidrug resistance protein 2 (MRP2) expression and the underlying molecular mechanisms were investigated using HepG2-C3 cells that are stably transfected with a construct containing human MRP2 promoter region conjugated with luciferase reporter gene. A 3-fold induction of MRP2 luciferase activity was observed after genistein (50μM) treatment to HepG2-C3 cells, but was diminished by the resveratrol (50μM) cotreatment. This observation was further validated by Western blot analysis and RT-PCR analysis as resveratrol also inhibited genistein-induced MRP2 protein synthesis and mRNA expression. Immunofluorescence study revealed that genistein-induced formation of MRP2 vacuoles was dramatically reduced by resveratrol. The binding affinity between retinoid X receptor alpha (RXRα) and MRP2 promoter was examined by DNA–protein pull-down assay. The results showed that resveratrol inhibited the genistein-induced binding of RXRα to the promoter sequence of MRP2 gene, and this mechanism could potentially contribute to the inhibition of genistein-induced MRP2 expression by resveratrol. Taken together, our present study suggests that naturally occurring phytochemicals can potentially interfere with each other’s regulatory function on the cancer chemoprevention-related genes through a competitive mechanism.

Molecular Pathways for Cancer Chemoprevention by Dietary Phytochemicals

Interest in dietary phytochemicals for potential cancer chemoprevention has increased substantially. Screening dietary compounds for chemopreventive activity however, requires a systematic and wide-ranging approach to encompass the complexity of carcinogenesis. We present some of the molecular pathways that underpin the broad biological processes involved in carcinogenesis. Oxidative stress, inflammation, and the evasion of apoptosis are important biological mechanisms by which carcinogenesis occurs. Subsequently, antioxidant, anti-inflammatory, and pro-apoptotic activity represent important activities for preventing, suppressing, or reversing the development of carcinogenesis. Ultimately, these mechanisms of action may provide a useful basis for screening novel phytochemicals for chemopreventive activity. In this review, we identify the important molecular processes that may be targeted in routine screenings of dietary phytochemicals to ultimately select the most effective potential candidates for cancer chemoprevention.

Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene

BackgroundActivation of nuclear factor erythroid 2-related factor (Nrf2), which belongs to the basic leucine zipper transcription factor family, is a strategy for cancer chemopreventive phytochemicals. It is an important regulator of genes induced by oxidative stress, such as glutathione S-transferases, heme oxygenase-1 and peroxiredoxin 1, by activating the antioxidant response element (ARE). We hypothesized that (1) the citrus coumarin auraptene may suppress premalignant mammary lesions via activation of Nrf2/ARE, and (2) that Nrf2 knockout (KO) mice would be more susceptible to mammary carcinogenesis.MethodsPremalignant lesions and mammary carcinomas were induced by medroxyprogesterone acetate and 7,12-dimethylbenz[a]anthracene treatment. The 10-week pre-malignant study was performed in which 8 groups of 10 each female wild-type (WT) and KO mice were fed either control diet or diets containing auraptene (500 ppm). A carcinogenesis study was also conducted in KO vs. WT mice (n = 30-34). Comparisons between groups were evaluated using ANOVA and Kaplan-Meier Survival statistics, and the Mann-Whitney U-test.ResultsAll mice treated with carcinogen exhibited premalignant lesions but there were no differences by genotype or diet. In the KO mice, there was a dramatic increase in mammary carcinoma growth rate, size, and weight. Although there was no difference in overall survival, the KO mice had significantly lower mammary tumor-free survival. Also, in the KO mammary carcinomas, the active forms of NF-κB and β-catenin were increased ~2-fold whereas no differences in oxidized proteins were observed. Many other tumors were observed, including lymphomas. Interestingly, the incidences of lung adenomas in the KO mice were significantly higher than in the WT mice.ConclusionsWe report, for the first time, that there was no apparent difference in the formation of premalignant lesions, but rather, the KO mice exhibited rapid, aggressive mammary carcinoma progression.

Lifestyle Related Causes of Cancer and Chemoprevention through Phytonutrients

Cancer is a leading cause of death worldwide. There are a lot of cancer causing agents which are divided as physical carcinogens, chemical carcinogens and biological carcinogens. But most of the carcinogens or causes of cancer are related to our lifestyle like diet, habit, occupation, radiation and some infection, etc. Chemoprevention is highly necessary to prevent cancer related preterm death. For this besides avoiding the causes of cancer we should concentrate ourselves on our diet. Because, numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents and recently attention has been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals. In this study, we tried to describe lifestyle related causes of cancer and the molecular basis of cancer prevention through the phytochemicals.

Chemoprevention of Colorectal Carcinogenesis by Natural Anti-Inflammatory Agents

Accumulating epidemiological, clinical, and experimental evidence demonstrates that chronic inflammation plays a critical role in multistep oncogenesis. While long-term users of selective cycloxygenase (COX)-2 inhibitors (- coxibs) and non-steroidal anti-inflammatory drugs (NSAIDs) exert a reduced risk of development of certain types of cancer, including colorectal cancer (CRC), the adverse gastrointestinal and cardiovascular side effects associated with these drugs have limited their daily use for cancer chemoprevention. The role of various proinflammatory mediators during carcinogenesis and their promise as potential targets for chemoprevention of inflammation-associated carcinogenesis has been recently highlighted. A variety of chemopreventive phytochemicals and phytonutrients are able to alter or correct undesired cellular functions caused by abnormal pro-inflammatory signal transmissions that are mediated by NF-kappaB, etc. Modulation of cellular signaling involved in chronic inflammatory responses, induced by anti-inflammatory agents, hence provides a rational and practical strategy in molecular target-based cancer chemoprevention. This short review will focus on the role of chronic inflammation in colorectal oncogenesis and introduce dietary cancer chemopreventive agents with anti-inflammatory activity. Keywords: Colon carcinogenesis, inflammation, chemoprevension, flavonoid, carotenoid

Isothiocyanates: A Chemical Class of Potential Nutraceuticals

Isothiocyanates comprise the most promising class of chemopreventive phytochemicals. They are encountered at substantial amounts in cruciferous vegetables where they exist in the form of glucosinolates. Epidemiological studies have linked consumption of isothiocyanates to low cancer incidence at a number of sites. Furthermore, laboratory studies in animal models of cancer have established that various isothiocyanates can effectively antagonise the carcinogenicity of chemicals. A principal mechanism of action of these chemicals is to modulate the metabolism of chemical carcinogens so as to favour their metabolic detoxification. In this mini review we discuss the ability of isothiocyanates to influence carcinogen-metabolising enzyme systems, such as cytochromes P450 and conjugation systems, at dietary levels of exposure.

Targeting specific cell signaling transduction pathways by dietary and medicinal phytochemicals in cancer chemoprevention

Natural phytochemicals derived from dietary sources or medicinal plants have gained significant recognition in the potential management of several human clinical conditions. Much research has also been geared towards the evaluation of plant extracts as effective prophylactic agents since they can act on specific and/or multiple molecular and cellular targets. Plants have been an abundant source of highly effective phytochemicals which offer great potential in the fight against cancer by inhibiting the process of carcinogenesis through the upregulation of cytoprotective genes that encode for carcinogen detoxifying enzymes and antioxidant enzymes. The mechanistic insight into chemoprevention further includes induction of cell cycle arrest and apoptosis or inhibition of signal transduction pathways mainly the mitogen-activated protein kinases (MAPK), protein kinases C (PKC), phosphoinositide 3-kinase (PI3K), glycogen synthase kinase (GSK) which lead to abnormal cyclooxygenase-2 (COX-2), activator protein-1 (AP-1), nuclear factor-kappaB (NF-κB) and c-myc expression. Effectiveness of chemopreventive agents reflects their ability to counteract certain upstream signals that leads to genotoxic damage, redox imbalances and other forms of cellular stress. Targeting malfunctioning molecules along the disrupted signal transduction pathway in cancer represent a rational strategy in chemoprevention. NF-κB and AP-1 provide mechanistic links between inflammation and cancer, and moreover regulate tumor angiogenesis and invasiveness, indicating that signaling pathways that mediate their activation provide attractive targets for new chemotherapeutic approaches. Thus cell signaling cascades and their interacting factors have become important targets of chemoprevention and phenolic phytochemicals and plant extracts seem to be promising in this endeavor.

Modulation of Aflatoxin B1–Mediated Genotoxicity in Primary Cultures of Human Hepatocytes by Diindolylmethane, Curcumin, and Xanthohumols

This study employed cultured human primary hepatocytes to investigate the ability of the putative chemopreventive phytochemicals curcumin (CUR), 3,3'-diindolylmethane (DIM), isoxanthohumol (IXN), or 8-prenylnaringenin (8PN) to reduce DNA adduct formation of the hepatocarcinogen aflatoxin B1 (AFB). Following 48 h of pretreatment, DIM and 8PN significantly increased AFB-DNA adduct levels, whereas CUR and IXN had no effect. DIM greatly enhanced the transcriptional expression of cytochrome P450 (CYP) 1A1 and CYP1A2 mRNA. Glutathione S-transferase mRNAs were not increased by any of the treatments. In vitro enzyme activity assays demonstrated that 8PN and DIM, but not CUR or IXN, inhibited human CYP1A1, CYP1A2, and CYP3A4 activities. To distinguish between treatment effects on transcription versus direct effects on enzyme activity for DIM, we evaluated the effects of pretreatment alone (transcriptional activation) versus cotreatment alone (enzyme inhibition). The results demonstrated that effects on gene expression, but not catalytic activity, are responsible for the observed effects of DIM on AFB-DNA adduct formation. The increase in AFB-DNA damage following DIM treatment may be explained through its substantial induction of CYP1A2 and/or its downregulation of GSTM1, both of which were significant. The increase in DNA damage by DIM raises potential safety risks for dietary supplements of DIM and its precursor indole-3-carbinol.

Dietary Chemopreventive Phytochemicals: Too Little or Too Much?

There is a large body of evidence that the consumption of fruit and vegetables can decrease the risk of cancer. However, the link between diet and health is extremely complex. Some dietary phytochemicals seem to offer protection in an exposure-related manner and many molecular targets and signaling pathways affected by phytochemicals have been discovered. Although in vitro studies have contributed significantly to our understanding, quite a number use concentrations orders of magnitude greater than those achievable in humans or toxic to normal tissues (exemplified by toxic concentrations of indole-3-carbinol, epigallocatechin-3-gallate, curcumin, and genistein for breast cells). Such studies may produce results that are physiologically irrelevant, thus hindering predictions of efficacy. Here, we argue for careful consideration to be given to the in vitro experimental conditions under which dietary phytochemicals are investigated. Design features, such as the use of appropriate nontoxic concentrations, extended treatment times, three-dimensional cultures, primary tumor cultures, and comparison of susceptibility of various cancer subtypes, should improve our understanding of their molecular targets. This in turn would facilitate predictions as to their potential usefulness in the clinic.

Hop proanthocyanidins induce apoptosis, protein carbonylation, and cytoskeleton disorganization in human colorectal adenocarcinoma cells via reactive oxygen species

Proanthocyanidins (PCs) have been shown to suppress the growth of diverse human cancer cells and are considered as promising additions to the arsenal of chemopreventive phytochemicals. An oligomeric mixture of PCs from hops ( Humulus lupulus) significantly decreased cell viability of human colon cancer HT-29 cells in a dose-dependent manner. Hop PCs, at 50 or 100 μg/ml, exhibited apoptosis-inducing properties as shown by the increase in caspase-3 activity. Increased levels of intracellular reactive oxygen species (ROS) was accompanied by an augmented accumulation of protein carbonyls. Mass spectrometry-based proteomic analysis in combination with 2-alkenal-specific immunochemical detection identified β-actin and protein disulfide isomerase as major putative targets of acrolein adduction. Incubation of HT-29 cells with hop PCs resulted in morphological changes that indicated disruption of the actin cytoskeleton. PC-mediated hydrogen peroxide (H 2O 2) formation in the cell culture media was also quantified; but, the measured H 2O 2 levels would not explain the observed changes in the oxidative modifications of actin. These findings suggest new modes of action for proanthocyandins as anticarcinogenic agents in human colon cancer cells, namely, promotion of protein oxidative modifications and cytoskeleton derangement.

Preclinical Assays for Identifying Cancer Chemopreventive Phytochemicals

Dietary factors influence carcinogenesis in a variety of tissues. The consumption of fruits and vegetables is associated with a decreased risk of several types of epithelial malignancies. In addition, there are interrelationships between diet, environmental factors, and genetics that can affect cancer risk. Potential chemopreventive agents against cancer development can be found among nutritive and/or nonnutritive compounds in inedible and edible plants. To identify potential cancer chemopreventive agents, scientists are evaluating hundreds of phytochemicals for the prevention of cancer. This short review article describes in vitro and in vivo assays reported to identify potential cancer preventive compounds from plants.

Nrf2 as a Master Redox Switch in Turning on the Cellular Signaling Involved in the Induction of Cytoprotective Genes by Some Chemopreventive Phytochemicals

A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities. Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5'-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed. This review highlights the cytoprotective gene expression induced by some representative dietary chemopreventive phytochemicals with the Nrf2-Keap1 system as a prime molecular target.

NF-kappa B and Nrf2 as potential chemopreventive targets of some anti-inflammatory and antioxidative phytonutrients with anti-inflammatory and antioxidative activities.

Chemoprevention refers to the use of defined non-toxic chemical regimens to inhibit, reverse or retard the process of multi-stage carcinogenesis that involves multiple signal transduction events. A new horizon in chemoprevention research is the recent discovery of molecular links between inflammation and cancer. Components of the cell signaling network, especially those that converge on the ubiquitous eukaryotic redox-sensitive transcription factor, nuclear factor-kappa B (NF-kappa B), have been implicated in the pathogenesis of many inflammation-associated disorders. A wide variety of chemopreventive and chemoprotective phytochemicals and phytonutrients can alter or correct undesired cellular functions caused by abnormal pro-inflammatory signal transmissions, mediated by NF-kappaB. Modulation of cellular signaling involved in chronic inflammatory responses, induced by anti-inflammatory agents, hence provides a rational and pragmatic strategy in molecular target-based chemoprevention and cytoprotection. Induction of phase-2 detoxifying or antioxidant genes represents an important cellular defence in response to oxidative and electrophilic insults. Nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) plays a crucial role in regulating phase-2 detoxifying/antioxidant gene induction. Many antioxidants derived from dietary and medicinal plants have been found to activate this particular redox-sensitive transcription factor, thereby potentiating the cellular antioxidant or detoxification capacity.

Anthocyanins Induce the Activation of Phase II Enzymes through the Antioxidant Response Element Pathway against Oxidative Stress-Induced Apoptosis

Reactive oxygen species (ROS)-induced cell damage is inevitable and severe and is involved in numerous diseases, including cancer. Reducing oxidative stress is one of the strategies of chemoprevention. Anthocyanins are naturally occurring flavonoids that show multiple benefits. We first pointed out the effects of anthocyanins in the contributions to activation of phase II antioxidant and detoxifying enzymes, chemopreventive potency, and involved transcriptional regulation. Our results obtained in rat liver Clone 9 cells showed that treatment of anthocyanins leads to positive effects on elevating the antioxidant capacity, including activated expression of glutathione-related enzymes (glutathione reductase, glutathione peroxidase, and glutathione S-transferase) and recruited GSH content. In addition, the activity of NAD(P)H: quinone oxidoreductase (NQO1) was also promoted under the treatment of anthocyanin. This influential functions as the defense system against programmed cell death induced by H2O2. The capacity for induction of luciferase expression by anthocyanins in cells transfected with rat nqo1-promoter constructed plasmid was further investigated; we found that the molecular mechanism is related to the activation of antioxidant response element (ARE) upstream of genes that are involved in antioxidation and detoxification. Our data suggest that natural anthocyanins are recommended as chemopreventive phytochemicals and could stimulate the antioxidant system to resist oxidant-induced injury. And, more important, the promoting effect of anthocyanins on ARE-regulated phase II enzyme expression seems to be a critical point in modulating the defense system against oxidative stress.

Tumor angiogenesis – A potential target in cancer chemoprevention

Tumor angiogenesis is critically important for the growth of solid tumors as tumors remain in dormant phase for a long time in the absence of the initiation of blood vessel formation. Tumors can grow up to ∼2 mm size without requirement of blood supply as diffusion is sufficient at this level to support the removal of wastes from and supply of nutrients to tumor cells. Therefore, angiogenesis process could be an important target to suppress tumor growth and metastasis. Angiogenesis is required at almost every step of tumor progression and metastasis, and tumor vasculature has been identified as strong prognostic marker for tumor grading. Endothelial cells are the main players of angiogenesis process and could be peculiar target for antiangiogenic therapy because they are non-transformed and easily accessible to achievable concentrations of antiangiogenic agents, and also are unlikely to acquire drug resistance. Several antiangiogenic strategies have been developed to inhibit tumor growth by targeting different components of tumor angiogenesis. Chemopreventive agents have been shown to target and inhibit different aspects and components of angiogenesis process and can be used conveniently as they are mostly non-toxic natural compounds and could be part of our daily diet. However, a risk assessment for the use of antiangiogenic phytochemicals is needed as they can also disrupt normal physiologic angiogenesis such as wound healing and endometrium development processes. This review focuses on how different chemopreventive phytochemicals target various components of angiogenesis, including angiogenic signaling, which usually starts from tumor cells producing angiogenic factors and affecting endothelial cells growth, migration and capillary vessel organization for tumor angiogenesis.

Natural dietary anti-cancer chemopreventive compounds: redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells

Many dietary phytochemicals exhibit health-beneficial effects including prevention of diseases such as cancer, as well as neurological, cardiovascular, inflammatory, and metabolic diseases. Evolutionarily, herbivorous and omnivorous animals have been ingesting plants. This interaction between "animal-plant" ecosystems has resulted in an elaborate system of detoxification and defense mechanisms evolved by animals including humans. Mammalian cells, including human cells, respond to these dietary phytochemicals by "non-classical receptor sensing" mechanisms of electrophilic chemical-stress typified by "thiol-modulated" cellular signaling events primarily leading to the gene expression of pharmacologically beneficial effects, but sometimes unwanted cytotoxicity also. Our laboratory has been studying two groups of dietary phytochemical cancer-chemopreventive compounds (isothiocyanates and polyphenols), which are effective in chemical-induced, as well as genetically-induced, animal carcinogenesis models. These compounds typically generate "cellular stress" and modulate gene expression of phase II detoxifying/antioxidant enzymes. Electrophiles, reactive oxygen species, and reactive nitrogen species are known to act as second messengers in the modulation of many cellular signaling pathways leading to gene expression changes and pharmacological responses. Redox-sensitive transcription factors such as nuclear factor-E2-related factor 2 (Nrf2), AP-1, NF-kappaB, to cite a few examples, sense and transduce changes in the cellular redox status and modulate gene expression responses to oxidative and electrophilic stresses, presumably via sulfhydryl modification of critical cysteine residues found on these proteins and/or other upstream redox-sensitive molecular targets. In the current review, we will explore dietary cancer chemopreventive phytochemicals, discuss the link between oxidative/electrophilic stresses and the redox circuitry, and consider different redox-sensitive transcription factors. We will also discuss the kelch-like erythroid Cap'n'Collar homologue-associated protein 1 (Keap1)-Nrf2 axis in redox signaling of induction of phase II detoxifying/antioxidant defense mechanisms, an important target and preventive strategy for normal cells against carcinogenesis, and the converse inhibition of cell growth/inflammatory signaling pathways that would confer therapeutic intervention in many types of cancers. Finally, we will summarize the Nrf2 paradigm in gene expression, the pharmacotoxicogenomic relevance of redox-sensitive Nrf2, and the redox regulation of cell death mechanisms.

Ins and outs of dietary phytochemicals in cancer chemoprevention

A voluminous number of evidence suggests that an increased consumption of fruit and vegetables is a relatively easy and practical strategy to reduce significantly the incidence of chronic diseases, such as cancer, cardiovascular diseases and other aging-related pathologies. This review will critically discuss the applications of chemical and dietary chemoprevention, intending the protecting effects against cancer of chemically synthesized molecules, or phytochemicals present in the regular diet. The length of chemopreventive treatments requires the administration of low doses of chemopreventive agents, to avoid toxic side effects. This poses the question, here discussed, of the bioavailability of these compounds, usually very modest. Another key issue is whether purified phytochemicals have the same protective effects, as do the whole food or mixture of foods in which these compounds are present. These aspects will be analysed at the light of the “antioxidant hypothesis” in cancer prevention and the “combination chemoprevention”, both referring to the pleiotropic and synergistic effects of compounds present in the diet. Single molecules may evolve in perfect chemopreventive agents, as in the case of tamoxifen, or generate ambiguity. Resveratrol and quercetin represent two paradoxes, discussed here.

Phenolic Phytochemicals Derived from Red Pine (Pinus densiflora) Inhibit the Invasion and Migration of SK‐Hep‐1 Human Hepatocellular Carcinoma Cells

Considerable attention has recently been focused on identifying chemopreventive phytochemicals derived from medicinal plants. Here, we analyzed phenolic phytochemicals from red pine (RP) leaves and found epigallocatechin gallate (EGCG) and epigallocatechin (EGC), and catechin gallate (CG) as their major phenolic phytochemicals. This article also investigated whether RP leaf extract and its phenolic phytochemicals inhibit the invasion of SK-Hep-1 human hepatocellular carcinoma cells (SK-Hep-1 cells). RP suppressed the invasion and the migration of SK-Hep-1 cells. EGCG and CG also inhibited the invasion and migration, with EGC exhibiting a lower efficacy. Matrix metalloproteinases (MMPs), particularly gelatinase-A (MMP-2) and gelatinase-B (MMP-9), degrade components of the basement membrane and are strongly implicated in invasion and metastasis formation of malignant tumors. RP suppressed both MMP-2 and MMP-9 activities. EGCG and CG reduced the activities of MMP-9 and MMP-2 in a dose-dependent manner, with EGC exhibiting a lower efficacy on both MMPs. Our results suggest that RP inhibits tumor invasion and migration, which may be attributed to the effects of EGCG and CG. In particular, EGCG plays a key role in the efficacy of RP against hepatocarcinogenesis.

Intracellular signaling network as a prime chemopreventive target of (–)‐epigallocatechin gallate

Chemoprevention is an attempt to use either naturally occurring or synthetic substances or their mixtures to intervene in the progress of carcinogenesis. Recently, it has been shown that some edible phytochemicals alter gene expression, directly or indirectly, thereby regulating the carcinogenic processes. (-)-Epigallocatechin gallate (EGCG), a principal antioxidant derived from green tea, is one of the most extensively investigated chemopreventive phytochemicals. EGCG has been known to block each stage of carcinogenesis by modulating signal transduction pathways involved in cell proliferation, transformation, inflammation, apoptosis, metastasis and invasion. This review addresses the molecular target-based chemoprevention with EGCG by focusing on the common events mediated by transcription factors, such as NF-kappa B, activator protein-1 and nuclear factor erythroid 2 p45-related factor, and upstream kinases involved in the cellular signaling network.