Dietary Phytochemicals in Chemoprevention of Cancer

Curr. Med. Chem. – Immun., Endoc. & Metab. Agents, 2005, 5, 61-72

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Dietary Phytochemicals in Chemoprevention of Cancer M. Russo, I. Tedesco, G. Iacomino, R. Palumbo, G. Galano and G. L. Russo* Institute of Food Sciences, National Research Council, 83100 Avellino, Italy Abstract: Regular consumption of fruit and vegetables is associated with reduced risks of cancer, cardiovascular disease and other aging-related diseases. Convincing evidence exists suggesting that an increased fruit, vegetables, and grains consumption is a relatively easy and practical strategy to significantly reduce the incidence of chronic diseases. Cancer chemoprevention intends to interrupt the carcinogenesis process, which includes initiation, promotion and progression of otherwise normal cells to reduce cancer. Despite the failure of β-carotene clinical trial to prevent lung cancer, the development of diet-derived constituents represents one of the major goal in cancer chemoprevention. A key question is whether a purified phytochemical has the same protective effects as does the whole food or mixture of foods in which the phytochemical is present. Putative chemopreventive agents are identified on the basis of epidemiological and in vitro and in vivo studies. All these compounds present tumor-suppressing properties in animal models of carcinogenesis, and they interfere with cellular processes involved in tumor formation, such as suppression of NF-kB and AP1 activation, induction of apoptosis, downregulation of β-catenin expression and activation of ARE/EpRE-dependent gene expression. Phase I clinical trials have been completed only for few of these phytochemicals, and pilot phase II-III trials are planned. In this review, we will begin by describing the different methodological approaches in studying chemopreventive agents, followed by the description of the mechanisms by which these compounds act. Finally, we will review more in details data concerning well-known and promising chemopreventive phytochemicals.

Key Words: Phytochemicals; cancer; chemoprevention; resveratrol; quercetin; curcumin; EGCG; genistein. CHEMOPREVENTION: PECTIVE

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HISTORICAL

PERS-

When Dr. Michael Sporn coined first the term “chemoprevention” referring to the possibility that natural forms of vitamin A could prevent the development and progression of epithelial cancer [1], he, probably, did not imagine the impact that this new approach chemoprevention would have had in cancer research. A recent search on PubMed limited to the last five years revealed more than 1600 review articles on “chemoprevention” and several thousands research articles published on this topic. As Dr. Sporn recently pointed out, a more modern and complete definition of chemoprevention includes the use of natural or pharmacological agents to suppress, arrest or reverse carcinogenesis at its early stages [2]. Chemoprevention can be divided into three main areas: 1) primary prevention in high-risk healthy individuals; 2) cancer prevention in individuals that already had developed pre-malignant lesions; 3) prevention of secondary forms of cancers in patients already treated for a primary cancer [3]. The final goal of all these different aspects of chemoprevention is the attainment of clinical evidence for cancer reduction. Since now, identification of “good” chemopreventive agents crossed a winding road. The clearest and most compelling evidence that a molecule possess a preventing activity, regards tamoxifen in breast cancer. Tamoxifen is *Address correspondence to this author at the Istituto Scienze dell’Alimentazione, Via Roma 52 A/C, 83100 Avellino, Italy; Tel: +39 0825 299431; Fax: +39 0825 781585; E-mail: [email protected] 1568-0134/05 $50.00+.00

currently the only agent approved by FDA (Food and Drug Administration) in United States for the prevention of breast cancer in women at high-risk of oestrogen-receptor-positive tumors based on a 49% reduction in invasive breast cancer in the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial [4, 5]. In this study, 13,338 women at increased risk for cancer development were treated with 20 mg of tamoxifen daily versus placebo for five years. The decision to test tamoxifen as potential chemopreventive agents derived from several in vitro, molecular studies indicating that tamoxifen acts as a selective oestrogenreceptor modulator (SERM), able to bind and inhibit oestrogen receptors in one organ (such as breast), and activate the same receptors in other organs (bone and uterus) [2, 5-8]. In addition, tamoxifen was able: 1. to prevent breast cancer in rats [9-11]; 2) to show an excellent safety profile when used in the adjuvant treatment of breast cancer [12]; 3) to possess minimal toxic effects; 4) to have beneficial effects on the maintain bone mineral density [5]; 5) to reduce the risk of developing a contralateral breast cancer in women with a history of breast cancer [12]. Actually, another SERM, raloxifene, is under consideration as breast cancer chemopreventer, based on its ability to prevent osteoporosis in postmenopausal women [13]. The hope is that raloxifene might reduce breast cancer risk without the increase in endometrial cancer risk caused by tamoxifen. The STAR (Study of Tamoxifen and Raloxifene) trial is currently in progress (19,000 eligible women received either tamoxifen at 20 mg daily or raloxifene at 60 mg daily for 5 years) with the first data expected by 2006 [4]. The other side of the coin is represented by the ATBC Cancer Prevention Study, where 29,133 male smokers, ages 50-69, were treated daily with β-carotene, vitamin E, both β© 2005 Bentham Science Publishers Ltd.

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carotene and vitamin E, or placebo. The alarming results obtained after 5-8 years of follow-up, caused the immediate end of the trial since β-carotene supplementation was associated with an increased risk of lung cancer development [14-17]. However, it must be mentioned that analysis of the secondary endpoints of the same study indicated that αtocopherol supplementation reduced of 32% and 41% prostate cancer incidence and mortality, respectively [14]. The ATBC Cancer Prevention Study was thought and realized on the basis of strong epidemiological data suggesting that consumption of large quantities of fruit and vegetables, food where β-carotene is abundantly present, was associated with a decreased risk of developing cancer (reviewed in [18]). The lesson deriving from this failure is that a chemopreventive approach based only on epidemiological data linking dietary habits and risk of developing cancer is not sufficient to justify a large and costly clinical trial. As we will discuss later in this review, the road to develop and evaluate potential chemopreventive agents includes the collection of experimental data obtained on cell culture and animal models. Searching the Literature, many compounds, both naturally occurring and/or obtained by chemical synthesis, possess potential chemopreventive activity in inhibiting carcinogenesis in different experimental models. These include vitamins and minerals, phytochemicals and synthetic compounds. The present review will focus on the chemopreventive activity of selected phytochemicals present in food. DIETARY CHEMOPREVENTIVE AGENTS Many dietary compounds have been identified as potential chemopreventive agents. These include vitamins, minerals, carotenoids, and the large class of phytochemicals (polyphenols, isothiocyanates, organosulfur compounds) (Table 1). These compounds can be divided into two main groups: cancer-blocking and cancer-suppressing agents. The former prevents carcinogens to hit their cellular targets by several mechanisms including enhancing carcinogen detoxification, modifying carcinogen uptake and metabolism, scavenging ROS (reactive oxygen species) and other oxidative species, enhancing DNA repair. The latter inhibits cancer promotion and progression after formation of preneoplastic cells occurred [19-21]. The final fate of potential carcinogens, whether from exogenous or endogenous sources, depends largely on their interaction with the metabolism system in the human body. (reviewed in [22]). Metabolizing enzymes catalyse two major biotransformation reactions: phase 1 reactions that add or expose functional groups to xenobiotics such as –OH, SH, NH 2 or –COOH, and phase 2 reactions that involve the conjugation of large water soluble biomolecules (glucuronidation, sulfation, acetylation, methylation, and conjugation with glutathione) to the xenobiotics. For these reactions to occur, a functional group must be present on either the parent compound or its phase 1 product. These two groups of enzymes are also known as activating enzymes and detoxifying enzymes, respectively, based on the biological consequences of enzymatic reactions. The cytochrome P450 family, a group of important monooxygenase enzymes,

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metabolises many xenobiotics, catalyzes many types of reactions, is widely distributed among tissues, exists in multiple forms and its levels can be increased by exposure to chemicals in food, water or air. Cytochrome P450 converted products become chemically more reactive and thereby can potentially interact with DNA and proteins causing aberrant mutations and/or alteration of signaling pathways. The other side of the coin is represented by the detoxifying phase 2 enzymes, generally categorized in four major families: UDPglucuronosyltransferase; sulfotranaferases; glutathione Stransferase (GST), N-acetyltransferases. These enzymes compete with the activating cytochrome P450 enzymes by eliminating reactive electrophiles via reduction to make them less reactive, or via conjugation with endogenous substrates. The dynamic equilibrium between carcinogen-activating enzymes and detoxifying enzymes might be fundamental to determine the cell fate after exposure to carcinogens [23]. According to Dr. G. Kelloff [24, 25] chemopreventive agents act on signal transduction regulation at different levels: modulate hormone/growth factor activity, inhibit oncogene activity and activate tumor suppressor genes, induce terminal differentiation, activate apoptosis, restore immuno response, inhibit angiogenesis, decrease inflammation, scavenge ROS. In the following sections, the principal molecular mechanisms underlying the chemopreventive activity of phytochemicals will be reviewed. MAP Kinase Pathways and NF-κB Although the amount of data accumulated during then past decade on the molecular mechanisms underlying phytochemicals activity in cancer prevention, the picture derived from all these efforts is still incomplete and confusing. In general, many of these compounds interfere with the mitogen-activated protein kinase (MAPK)dependent signal pathways that control cell growth and proliferation. Abnormal regulation of MAPK family members, and/or their downstream effectors, at transcriptional level, correlates with defects that lead to cancerogenesis. MAPK includes a large family of proline-directed serine/ threonine kinases that convert extracellular signals into intracellular pathways via activation of a phosphorylation cascade [26-29]. ERK (extracellular signal-regulated protein kinase), JNK (c-Jun N-terminal kinase) and p38 are the three main MAPK signal transduction pathways so far identified and studied [30-32], each of them including at lest three kinases acting in concert: a MAPK kinase kinase that phosphorylates and activates a MAPK kinase that, in turn, phosphorylates and activates MAPK leading to modulation of gene expression. ERK pathway is generally seen as mitogen sensitive, while p38 and JNK are activated following stress-like stimuli [32]. MAPKs converge downstream activating different important transcription factors, including nuclear factor κB (NF-κB) and activator protein 1 (AP1). Unregulated activation and/or overexpression of NF-κB have been associated to anti-apoptotic events and malignant cell growth [20, 33, 34]. Many potential, naturally occurring chemopreventive phytochemicals suppress constitutive NF-κB activation in malignant cells or its activation induced by external tumor promoter, such as PMA (phorbol

Dietary Phytochemicals in Chemoprevention of Cancer

Table 1.

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Dietary Chemopreventive Compoundsa

Class of chemicals

Vitamins

Nutrient

Source

Vitamin D

Dairy products

Folic acid

Vegetables

Vitamin A

Vegetables

Vitamin E (α-tocopherol)

Vegetable oils

Ascorbic acid

Vegetables and Fruits

Calcium

Dairy products, vegetables

Selenium,

Vegetables, fruits, cereal grains, meat, fish

Iron

Red meat

Zinc

Vegetables

Lycopene

Tomatoes

Lutein

Dark green vegetables

β--Carotene

Orange yellow vegetables

Genistein

Soybeans, soy products

Quercetin

Vegetables, fruits

Rutin

Vegetables, fruits

Silymarin

Milk thistle

Catechins

Grapes

Anthocyanins

Vegetables, fruits, black tea

Resveratrol

Grapes, red wine

Curcumin

Turmeric, curry, mustard

Caffeic acid

Fruits, coffee beans, soybeans

Ferulic acid

Fruits, soybeans, rice

(-)-Epigallocatechin-3-gallate

Green tea

Chlorogenic acid

Fruits, coffee beans, soybeans

Allyl isothiocyanate

Brussel sprouts

2-Phenylethyl isothiocyanate

Cabbage

Benzyl isothiocyanate

Garden cress

3-Methylsulfinylpropyl isothiocyanate

Broccoli

Sulforaphane

Broccoli

Diallyl sulfide

Garlic, onion

Allyl mercaptan

Allium vegetables

Allyl methyl trisulfide

Allium vegetables

S-allyl cysteine

Garlic

Indole-3-carbinol

Cruciferous vegetables

Brassinin

Cruciferous vegetables

Minerals

Carotenoids

Flavonoids

Phenolic acids

Isothiocyanates

Organosulfur compounds

Indoles a

Adapted from [19, 22, 200]

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12-myristate 13-acetate) or TNF-α (tumor-necrosis factorα) [20, 35-37]. The other transcription factor triggered by MAPK pathways is AP1 [38-40], consisting of Jun homo or heterodimers whose aberrant activation also drive cells to malignant transformation [38, 41]. ARE/EpRE Signaling Plant phenolic antioxidants, such as caffeic and chlorogenic acid, curcumin [42], and green tea polyphenols [43] (Table 1), represent one of the major class of dietary components characterized by a double function: antioxidant and ability to modulate the expression of several detoxifying enzymes, such as GST, NQO (NADPH:quinone oxidoreductase), and HO1 (heme oxygenase 1) [25, 44, 45], a group of the major inducible detoxifying enzymes. The study of these enzymes led to the discovery of the antioxidant response element/electrophile responsive element (ARE/ EpRE) [46-51], an enhancer sequence, that regulates the cellular response to potential chemopreventive agents present in the diet. More recently, it has been shown that ARE/EpRE regulate transcription of several other genes, including cyclooxygenase 2 (COX2) [52], and apolipoprotein A-I [53]. Different members of the AP1 protein family, such as Jun/Fos heterodimer, failed to show binding activity to the ARE sequence, although the great similarity between the ARE and the AP1 binding site [54-56]. Later, new transcriptional factors, related to nuclear factor E2-related factors 2 (Nrf2), belonging to helix-loop-helix bZIP superfamily were found to be able to heterodimerize and bind to the ARE sequence [57, 58]. Nrf2-null mice presented lower mRNA and protein levels of detoxifying enzymes [5964], and developed a large number of tumors after treatment with carcinogens [61, 65], as well as were deficient in detoxifying aflatoxin B [66]. The interaction between Nrf2 and ARE sequence also involves small proteins (Maf family from musculoaponeurotic-fibrosarcoma virus) that form heterodimers with Nrf2 [67]. Several different pathways are triggered by dietary phytochemicals leading to ARE activation. These include PKC, PI3K, MAPK, JNK pathways (reviewed in [20] and [22]), and are characterized by the ability to interfere with the interaction between Nrf2 and its main negative regulator, Keap 1. Keap 1 is a cytosolic actin-binding protein named Kelch-like ECH-associating protein 1 with a docking activity on Nrf2, and other ZIP proteins. As a consequence, the transcription factors sequestered by Keap 1 are blocked in an inactive form into the cytoplasm [68]. Although the real mechanism of action is still unclear, the Nrf2-Keap 1 heterodimer works as an intracellular sensor against changes in electrophiles or ROS concentrations [68]; for this reason, it would be more appropriate to define ARE as EpRE (Electrophile Response Element). How phytochemicals interfere with this mechanism is still unclear [20]. It can be evoked the capacity of several phase 2 gene inducers (including phytochemicals), to increase ROS, despite their antioxidant nature (discussed in [20]). As summarized in Fig. (1), chemopreventive factors free docked Nrf2 acting via ROS/electrophiles on Keap 1. Free Nrf2 can translocate from the cytoplasm to the nucleus where it activates the

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transcription of detoxifying enzyme genes. However, this pathway is complicated by the presence of different, independent phosphorylating events. Serine-40 in Nrf2 is phosphorylated by atypical PKC isoforms [69-71], and this phosphorylation seems to be necessary for Nrf2 to release Keap 1, but it is not required for Nrf2 nuclear functions [69, 70]. More controversial is the role of MAPK in Nrf2 activation. Several important studies (reviewed in [22]) demonstrated that MAPK is strongly involved in this pathway. However, MAPK might not directly phosphorylate Nrf2. In fact, although the use of MAPK inhibitors reduces Nrf2 translocation from the cytoplasm to the nucleus, and its nuclear accumulation [72, 73], Nrf2 point mutations in the conserved consensus MAPK phosphorylation sites show enzymatic activities similar to wild-type with respect to the interaction with the Keap 1 and the transactivation of ARE/EpRE mediated reporter activity [73]. TGF-β Pathway A different pathway involved in the activity of chemopreventive agents is the TGF-β serine–threonine kinase signaling pathway. TGF-β acts as negative regulator of cell proliferation; in fact, loss of function of its receptor is involved in the genesis of several forms of cancer [74-76]. TGF-β receptor activates SMAD pathway, a complex group of factors (SMAD2–SMAD3–SMAD4 complexes) that upon phosphorylation and subsequent nuclear translocation, bind co-activators and co-repressors modulating gene transcription. Similarly to TGF-β receptor, mutations that inactivate SMADs are also implicated in tumor formation (reviewed in [2]). Therefore, chemopreventive agents able to restore TGFβ receptor and SMADs functions are thought as potential chemopreventers. A link between NF-κB and TGF-β pathway is represented by SMAD7 that suppresses TGF-β signaling. Several cytokines involved in the inflammatory process promoting carcinogenesis activate NF-κB and STAT1 that, in turn, upregulate SMAD7 [77-79]. β-Catenin Pathway Finally, β-catenin, a component of the cell–cell adhesion machinery, has been proposed as a potential phytochemical target in chemoprevention (reviewed in [20]). The molecule represents a key element in cytoskeleton formation linking E-cadherin to actin filaments [80]. The involvement of βcatenin in tumorigenesis depends on its nuclear activity as transcription factor [81]. In normal conditions, cytoplasmic, β-catenin is rapidly degraded by ubiquitin-mediated proteasomal degradation [82-84]. When stabilized following several proliferating stimuli, such as WNT signaling and other growth factors, β-catenin translocates to the nucleus and activates transcription of genes involved in cell cycle control and proliferation (reviewed in [20]). Apoptosis and Cancer Chemoprevention Apoptosis plays a central homeostatic role by which genetically damaged cells are eliminated from the organism. Apoptosis of pre-malignant or malignant cells represents a protective mechanism against tumor formation and development since it removes from the body genetically



Fig. (1). A simplified model of two types of cellular response to phytochemicals. The scheme on the right represents the signaling pathways leading to Nrf2-dependent gene expression of phase 2 detoxifying enzymes. On the left, the two main apoptotic pathways (intrinsic and extrinsic) triggered by phytochemicals are schematically reported (see text for details).

damaged cells induced to proliferate under uncontrolled mitogenic stimuli. As schematically represented in Fig. (1), the two major pathways active in apoptosis include the death receptor and the mitochondrial pathways. CD95 (Fas/Apo-1) is a member of the TNF/nerve growth factor receptor super-family and is currently recognised as the principal cell surface receptor involved in the signal transduction that induce apoptosis in the immune system and in a variety of tumor cells [85-87]. CD95 mediated apoptosis can be triggered following engagement of the CD95 receptor by a specific ligand, expressed on activated cytotoxic T cells, and by specific anti-CD95 monoclonal antibodies [88]. Stimulation of CD95 with its natural ligand, or agonistic antibodies, leads to clustering of the receptor. This enables the adapter molecule FADD/MORT1 [89] and the death protease caspase-8 [90, 91] to bind the receptor via homophilic death domain and death effector domain interactions, respectively, forming the death-inducing signaling complex (DISC). Recruitment of caspase 8 to the DISC leads to its proteolytic activation [92], which initiates a cascade of caspases leading to apoptosis. The caspases (cystein-type proteases which cleave after an aspartic acid residue) are highly regulated signaling molecules with a central role in apoptosis and, presumably

also in other critical biological processes such as inflammation [93, 94]. Many substrates cleaved by caspases are presumably involved in the final events leading to apoptosis and the last decade of studies have identified some of these [95]. One of the nuclear proteins cleaved during apoptosis is the DNA repair associated enzyme, poly(ADPribose) polymerase (PARP). More recently, other caspase substrates have been identified: they are very interesting because are involved in signal transduction such as protein kinase C delta, MEKK-1, p21-activated kinase 2, focal adhesion kinase, Raf-1 e Akt [96]. METHODS IN CANCER CHEMOPREVENTION Cell Cultures Excellent reviews have been published on the efficacy and importance of cell-based assays in testing chemopreventive agents [25, 97]. Criteria taken in account in choosing the most adequate cell line include sensitivity and relevance to organ system investigated. In addition, cell derived from transgenic mice and/or human cells carrying known mutations in genes that represent biomarkers of a specific stage in the carcinogenesis progression might represent important experimental tools [25]. However, it must be considered all the limits in using in vitro cell lines. The

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agents must be tested over a wide range of concentrations, and attention must be paid to hormesis phenomenon [98]. In addition, caution is needed in culturing cell lines in the presence of phytochemicals in the view of possible errors and artifacts in interpreting the results. In fact, phytochemicals includes phenolic compounds, whose interaction with cell media components might generate reactive species that indirectly cause oxidative damage to cells [99]. In our opinion, cell lines must be used primarily in chemopreventive tests in order to obtain indications on the possible molecular mechanism underlying the biological activity of new phytochemical agents. Animal Models Several in vivo screens in animal models of carcinogenesis that are representative of human cancers have been developed during the past three decades. The information achieved from these studies is important to evaluate doseresponse curve, dosing regimens and combinations with other agents tested [19, 100]. Two of the most used animal models so far employed by the investigators to search for dietary or chemopreventive agents that could suppress human cancers have been the azoxymethane (AOM) rat model, and the Apc/Min mouse model, both largely applied to colorectal tumors. Since rodents do not develop spontaneously colon cancer, the tumors are commonly induced using dimethylhydrazine that is metabolized to AOM and methylazoxymethanol in rats (reviewed in [101]). Similarly to human colon cancers, AOM-induced tumors present mutated K-ras and β-catenin genes [101], and show microsatellite instability, but Apc gene is mutated in only 15% and p53 gene is never mutated [102]. In a typical chemopreventive study, the treatment with the desired agent starts before exposure to AOM, during the initiation phase, during the promotion-progression phase, or through both phases, with the main end point represented by the incidence of colon tumor formation [101]. The other model is referred to a mutant mouse, Min, a dominant mutation that predisposes to multiple intestinal neoplasia [103]. These mutants possess a mutated form of Apc gene, similar to that evidenced in patients with familial adenomatous polyposis. Although this animal model mimics the rapid development of adenomatous polyps that take place in humans with germ-line inactivation of one Apc gene, Kras mutations and p53 inactivation mutations were not detected in Min mice [104, 105]. After discovery of Min mouse, other mice have been obtained carrying different Apc mutations and including other mutated genes, such as Msh2 or Mlh1, responsible for mismatch repair defects [106]. In Table 1 of reference [101], it is reported an exhaustive list of the effects of dietary agents on the tumor number in the small intestine and in the colon of Min mice, and other mutant mice. Dietary treatments are typically begun for the mice by the age of 4–5 weeks, when tumors may already be present, with the primary end point consisting in counting the number of tumors in the small intestine [101]. However, it must be noted that Min mice develop tumors predominantly in the small intestine, not in the colon; in

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addition, this model is more expensive than the AOM rat model [101]. In addition to these model, several other transgenic and gene knockout mice which carry one or more wellcharacterized gene mutations predisposing to carcinogenesis have been developed as appropriate models to study chemoprevention in lymphatic system, skin, lung, liver, cervix, prostate, mammary gland cancers (reviewed in [25, 97]). Most of the studies performed in animal model for chemoprevention suggest that chemopreventive agents “delay” the onset of cancer, but do not “prevent” it. This phenomenon is a reflex of the high dose of carcinogens used to induce tumors in animals. However, when the same carcinogen is administered at low doses, a more prolonged delay in cancer develop can be achieved [2]. Transferring this information from animal models to human cancers might allow a lifetime suppression of malignancy, considering that in humans the latency period for carcinogenesis is 10-20 years [107]. Human Studies As stated in the report of the Chemoprevention Working Group [14], the “gold standard” for in clinical studies regarding cancer prevention are large-scale, randomised, placebo-controlled, double-blinded clinical trials using as endpoint cancer incidence. However, these studies are costly and require many years to be completed. A valid alternative to this approach is represented by clinical trials performed on population and individuals at increased risk of cancer due to the presence of highly penetrant susceptibility genes, such as (Apc, Mlh-1, Msh-2, BCRA1/2), or environmental exposure. Trials performed in high-risk populations (lifetime risk very high, e.g. 80% for FAP) may reach the desired result recurring to relatively small cohorts followed for short period of time. If treatment satisfied the two fundamental parameters of efficacy and safety, it might be subsequently proved in a different population characterized by moderated risk (e.g. 10-20% for current adenoma, inflammatory bowel diseased). Finally, if still positive, the chemopreventive agent might be tested on the general population (e.g. 5-6% overall risk to develop colorectal cancer in US population), although, as risk lowers, ethical issues arise in deciding if and how people must be treated, and a careful benefitversus-risk analysis must be performed (reviewed in [2, 14]). After a potential chemopreventive agent passed the preclinical testing, i. e. resulted safe and effective in animal models, and the mechanisms whereby the agent inhibits carcinogenesis, have been clarified, it is possible to plan human clinical trials. The efficacy and toxicity of a potential preventive molecule are typically assessed in a series of standardized clinical trails, organized in three phases (reviewed in [19]. In phase I trial, a small number of healthy individuals (~ 25, nonrandomized or randomised) are treated with the candidate agent to establish its safety and pharmacokinetic variables, such as absorption, distribution, metabolism and excretion [19]. Phase II trial is required to evaluate the efficacy of the agent in a larger group of subjects (50-200) at high risk of certain cancers (see above). In this phase, potential surrogate endpoint biomarkers


(molecular and/or morphological) can be established to assess clinical sign/symptoms of tumor progression and determine if the treatment with the chemopreventive agent might identify these biomarkers as diagnostic and prognostic markers [19]. If the chemopreventive agent tested is a molecule already tested for clinical use (e. g. NSAIDS for analgesia), phase I is not required. Finally, phase III chemopreventive trials are generally conducted either on population at high risk or in healthy individuals. It recruits from hundreds to thousands of subjects observed for several years, and are usually a randomised and placebo-controlled trial having, as end points, reduction of cancer incidence and replacement of standard care [19]. CHEMOPREVENTIVE ACTIVITY OF SELECTED PHYTOCHEMICALS In the previously mentioned work by Dr. P. Greenwald [19], a comprehensive review of all the ongoing phase I, II and III cancer prevention trials sponsored by The Division of Cancer Prevention of the US National Cancer Institute is reported (Table 1 in [19]). Among the 65 agents tested, about 20% concerns phytochemicals mostly involved in phase I trials, few in phase II, none in phase III [19]. This observation, suggest that despite the enormous amount of data available in the Literature on the chemopreventive potential of phytochemicals, a lot of work must be done before planning an application in humans. In the following paragraphs, we will review several the aspect of the chemopreventive activity of known phytochemicals that may soon enter the final phase of clinical trials. Genistein Genistein is a soy isoflavone identified as dietary components having an important role in reducing the incidence of breast and prostate cancers, giving a rationale for the lower incidence of these forms of cancer in Asian countries such as Japan and China that consume a traditional diet high in soy products, compared to United States and European countries (reviewed in [108]). Moreover, it has been shown that genistein inhibits the activation of NF-κB and AKT signaling pathways, both of which are known to maintain a homeostatic balance between cell survival and apoptosis. More in details, genistein treatment abrogated NFκB DNA binding in cell lines and in UV-light-stimulated skin of SENCAR (sensitivity to carcinogenesis) mice [109111]. Inactivation of NF-κB by genistein was also associated with downregulation of AKT in several cell lines [112, 113], suggesting that inhibition of the interaction between AKT and NF-κB might be interpreted as a novel mechanism responsible for pro-apoptotic activity of genistein. In pancreatic tumor cell lines, STAT3 constitutive activation was inhibited by both genistein, indicating that STAT3 activation provided an important and appropriate target for chemoprevention in pancreatic cancer treatment [114, 115]. Genistein has also been shown to inhibit the carcinogenesis in animal models. Recently, the expression of androgen and estrogen receptors (growth factor receptors that signal via tyrosine protein kinases) in prostates of TRAMP mice was investigated. Genistein in the diet significantly downregulated cell proliferation, the tyrosine kinase regulated proteins, EGFR (epidermal growth factor receptor) and IGF-


1R (insuline growth factor receptor 1), and the downstream ERK-1 and 2 [116]. Several clinical trials are reported in the recent Literature on the potential use of genistein as chemopreventive agent. In a recent study, the pharmacokinetic parameters of two different preparations of unconjugated soy isoflavones (which contain 43% and 90% genistein, respectively) were investigated in human subjects. Oral administration of soy isoflavones gave plasma concentrations of genistein that were associated with antimetastatic activity in vitro [117]. Similarly, safety studies of purified unconjugated genistein were performed at doses of 1-16 mg/kg body/weight in healthy subjects. Dietary supplements of purified unconjugated isoflavones administered to humans in single doses exceeding normal dietary intake manifold resulted in minimal clinical toxicity [118]. To support the protective effect of genistein, a recent study assessed the potential genotoxicity of a purified soy unconjugated isoflavone mixture in men with prostate cancer, demonstrating that, although isoflavones are capable of inducing genetic damage in vitro, a similar effect was not observed in subjects treated with a purified soy unconjugated isoflavone mixture [119]. In a non-randomized, non-blinded trial designed to determine the effects of acute exposure to a dietary supplement of isoflavones in men with clinically significant prostate cancer before radical prostatectomy, it has been reported that dietary isoflavones may halt the progression of prostate cancer by inducing apoptosis in low-moderate grade tumors [120]. On the contrary, more recently, a genisteinrich extract failed to lower prostate-specific antigen (PSA) in patients with prostate cancer. However, 8 of 13 evaluated patients in the active surveillance group had either no rise or a decline in PSA levels of less than 50% [121]. Curcumin Curcumin (diferuloylmethane), a yellow pigment that is present in the rhizome of turmeric (Curcuma longa L.) is a natural product widely used as a spice in food. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, to downregulate transcription factors NF-κB, AP1 and Egr-1 (Early Growth Response-1); downregulate the expression of COX-1 and -2 genes, lipopolysaccharide (LOX)-induced COX-2, iNOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; downregulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of JNK, protein tyrosine kinases and protein serine/threonine kinases with the aromatic moiety is especially crucial for activity [122]. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent (reviewed in [123]. In details, pretreatment of human colonic epithelial cells with curcumin inhibited TNF-α-induced COX-2 gene transcription [124]. Curcumin also suppressed the TNF-α-induced nuclear translocation and NF-κB activation [124, 125]. In addition, curcumin inhibited IκBα phosphorylation in human and murine cells [126, 127] via suppression of IKK activity. In this respect, curcumin and TRAIL (tumor necrosis factorrelated apoptosis-inducing ligand) cooperatively interacted to promote death of LNCaP cell (an androgen-sensitive human prostate cancer cell line) [128]. Recently, JNK, but not p38

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or ERK signaling has been proved to plays an important role in curcumin mediated apoptosis in human colon cancer cells. Curcumin treatment also induced JNK dependent sustained phosphorylation of Jun, stimulation of AP1 transcriptional activity, as well as inhibition of constitutive NF-κB transcriptional activity [129]. Curcumin stimulated expression of Nrf2 by inactivating the Nrf2–Keap 1 complex, leading to an increase in activity and expression of HO-1 [130]. The molecule might also increase nuclear translocation of Nrf2 and AREpRE DNA binding activity [131]. Finally, curcumin inhibited growth of colon cancer cells by targeting β-catenin-mediated transactivation and cell-cell adhesion pathways [132] and decreased β-catenin expression in Min mouse [133], probably activating βcatenin cleavage by caspase [134]. Curcumin has been shown to suppress tumor promotion in a mouse model of skin carcinogenesis by preventing the PMA-induced activation of both NF-κB and AP1 [135] via the phosphorylation-dependent inhibition of IκBα degradation and nuclear translocation of the p65 subunit of NF-κB [136]. In a different model of colon carcinogenesis, addition of curcumin to the diet of F344 male rats reduced the number of aberrant crypt foci by 49% in young rats and by 55% in old rats indicating that age may play a significant role in the efficacy of chemoprevention of colon cancer by curcumin [137]. However, in Long-Evans Cinnamon rats, an inbred mutant strain which develops acute hepatitis, chronic liver injury and liver tumors curcumin did not show any chemopreventive activity [138]. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day [123, 139]. A recent dose-escalation study was designed to explore the pharmacology of curcumin in humans. A daily dose of 3.6 g curcumin engendered significant decreases in inducible PGE(2) (Prostaglandin E2) production in blood compared with levels observed immediately predose, suggesting that a daily oral dose of 3.6 g of curcumin is advocated for phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract [140]. (-)-Epigallocatechin-3-Gallate It has been hypothesized that green tea and/or its constituents could be effective for chemoprevention of prostate cancer, based on geographical observations suggesting that the incidence of prostate cancer is lower in Japanese and Chinese populations that consume green tea. Among the numerous polyphenols isolated from green tea, the catechin (-)-epigallocatechin-3-gallate (EGCG) predominates and is the main target of anticancer research. Several studies suggest that EGCG and other catechins are poorly absorbed and undergo substantial biotransformation to species that include glucuronides, sulfates, and methylated compounds. However, preclinical research is promising, and EGCG appears to be ready for further study in phase II and III trials (reviewed in [141]. In human prostate cancer cells DU145 (androgen insensitive) and LNCaP (androgen sensitive), it has been found that EGCG induced apoptosis, cell-growth arrest, and deregulation of the cyclin kinase inhibitor p21WAF [142]. The ability of EGCG to inhibit cell cycle progression

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causing a G0/G1-phase arrest and a subsequent induction of apoptosis has been also reported in human epidermoid carcinoma (A431) [143], probably through a mechanism mediated by NF-κB inhibition [144, 145]. More recently, using a cDNA microarray, it has been found that EGCG treatment of LNCaP cells resulted in induction of genes that functionally exhibit growth-inhibitory effects, and repression of genes that belong to the G-protein signaling network [146]. DNA microarray analysis has also been applied in a different study to demonstrate that EGCG induced temporal changes in gene expression mediated by hydrogen peroxide production [147]. In this context, it has been reported that EGCG causes differential oxidative environments in tumor versus normal epithelial cells, but the role that EGCG, hydrogen peroxide and intracellular catalase play in the epithelial system is largely unknown [148]. The activity of EGCG to modulate NFκB/AP1 activity has been demonstrated by several studies. EGCG suppressed malignant transformation in a PMA-stimulated mouse epidermal JB6 cell line by blocking activation of AP1 [149-152] or NF-κB [153]. The reduction of PI3K–AKT–NF-κB signaling pathway by EGCG is mediated through inhibition of ERBB2 receptor tyrosine phosphorylation [154, 155]. EGCG also induced caspase-3-mediated cell death and transcriptionally activation of phase II detoxifying enzymes through ARE/ EpRE via activation of all three MAPK pathways (ERK, JNK and p38) [156, 157]. Finally, EGCG inhibited the βcatenin–Tcf4 activity in HEK293 cells [158]. In animal models, EGCG is known to exert chemopreventive effects in many cancer models, including transgenic TRAMP mice that spontaneously develop prostate cancer. While 100% of TRAMP mice developed prostate cancer, only 20% of those receiving 0.3% green tea catechins in drinking water developed the neoplasm [159]. In a different study, it was observed increased expression of genes related to angiogenesis such as vascular endothelial growth factor (VEGF) and those related to metastasis, such as matrix metalloproteinases (MMP)-2 and MMP-9 in prostate cancer of TRAMP mice [142]. Such a study has been confirmed by a recent work where green tea or purified EGCG administered to mice in the drinking water inhibited angiogenesis in vivo in the Matrigel sponge model and restrained KS (Kaposi's sarcoma) tumor growth [160]. EGCG and other catechins are poorly absorbed and undergo substantial biotransformation. However, preclinical researches are promising and EGCG appears to be ready for phase II and III trials [reviewed in [141]. In this context, clinical studies have been recently conducted demonstrating that it is safe for healthy individuals to take EGCG or Polyphenon E (a defined, decaffeinated green tea polyphenol mixture) in amounts equivalent to the EGCG content in 8-16 cups of green tea once a day, or in divided doses twice a day for 4 weeks. The Authors reported a 60% increase in the systemic availability of free EGCG after chronic green tea polyphenol administration at a high daily bolus dose (8001600 mg EGCG or Polyphenon E once daily) [161, 162]. In an earlier study, the apparent bioavailability of the prominent catechins from black tea was assessed in humans. Approximately only 1.68% of ingested catechins were present in the plasma, urine and feces. Plasma concentrations of individual tea catechins after a single oral dose in humans


differed significantly in their pharmacokinetic behaviour [163]. In summary, the catechins appeared to be absorbed in amounts that were small relative to intake [164]. The systemic availability of EGCG increased at higher doses, possibly due to saturable presystemic elimination of orally administered green tea polyphenols [165]. EGCG is also under study because of its antioxidant and sunscreen protective activity, as well as for UVB signal transduction blocking activity [166]. In fact, EGCG treatment of human epidermal keratinocytes resulted in significant inhibition of ultraviolet (UV)-B-light-induced activation of IKKα, degradation of IκBα and nuclear translocation of p65 [167]. Finally, green tea extracts in a form of ointment and capsule were effective for treating cervical lesions, suggesting that green tea extracts can be a potential therapy regimen for patients with HPV infected cervical lesions [168]. Resveratrol A number of excellent reviews have been recently published on resveratrol (3,4',5-trihydroxy-transstilbene), a red wine polyphenol present in grapes (Vitis vinifera), extensively studied for its chemopreventive activity [169174]. Numerous intracellular pathways triggered by resveratrol converge with the activation of NF-κB and AP1 (reviewed in [169-174]). More in details, resveratrol inhibited PMA-induced COX2 expression and catalytic activity, via the cyclic-AMP response element (CRE), in human mammary epithelial cells [175]. Resveratrol also induced apoptosis and reduced the constitutive activation of NF-κB in both rat and human cell lines [176, 177]. The molecule was also apoptogenic in mouse JB6 epidermal cells where it caused p53 phosphorylation mediated by ERK and p38 [178]. Resveratrol also inhibited the TNF-induced activation of MEK and JNK and abrogated TNF-induced caspase activation [179]. Finally, resveratrol downregulated β-catenin expression in several cancer cell lines [180]. In animal models, resveratrol has been involved in cell cycle regulation in the SKH-1 hairless mouse skin after multiple exposures to UVB (180 mJ/cm2) radiations. The molecule was topically applied on the skin of SKH-1 hairless mice prior to UVB exposure. Topical application of resveratrol revealed that the molecule was able to downregulate UV-mediated increases in critical cell cycle regulatory proteins, such as proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase (cdk)-2, -4 and -6, cyclinD1, and cyclin-D2. Further, resveratrol was also found to cause significant decreases in UVB-mediated upregulation of MAPK [181]. In a different study, it has been reported that resveratrol blocked UVB-mediated activation of NF-κB in dose- and time-dependent manner in the normal human epidermal keratinocytes. Resveratrol treatment of keratinocytes also inhibited UVB-mediated phosphorylation and degradation of IκBα, and activation of IKKα [182].


been involved in different studies concerning anti-oxidant, anti-inflammatory, anti-proliferative or apoptotic effects in cell culture models (reviewed in [183]. At molecular level, quercetin effects are multiple, but not fully understood. It modulates cellular neoplastic phenotype by down-regulating the expression of oncogenes (H-ras, c-myc and K-ras) and anti-oncogenes (p53) [184, 185], or up-regulating p21WAF1 and p27KIP1 [186]. Quercetin effects on cell proliferation also depend on its ability to inhibit different tyrosine and serine-threonine kinases, such as PKC, PI3K, [187] and CK2 [188, 189], all kinases whose activities are linked to survival pathways (MAPK, AKT/PKB) [190, 191]. Recently, our group demonstrated that quercetin was neither cytotoxic, nor apoptotic per se; however, in association with a CD95 activator (anti-CD95), increased synergistically apoptosis in different cell lines [192, 193]. This effect was independent from the antioxidant activity of the molecule. Novel data suggest that quercetin might interact with other death receptor-mediated cell death pathways, such as TRAIL, with similar effects extending the possibility that the molecule might sensitize cancer cells to apoptotic stimuli1. This combination strategy for chemoprevention might contribute to kill cancer cells through different targets: the extrinsic pathway of death receptors, and the pleitropic activity of quercetin. Growing evidence suggests an antitumoral activity of quercetin in animal models [176]. In addition, a positive clinical trials (phase I) indicated that quercetin can be safely administered. Its plasma levels inhibited lymphocyte tyrosine kinase activity with evidence of antitumor activity [194]. Consumption of quercetin in onions and apples was found to be inversely associated with lung cancer risk in Hawaii population [195, 196]. The effect of onions was particularly strong against squamous cell carcinoma. Increased plasma level of quercetin following a meal of onions was accompanied by increased resistance to strand breakage by lymphocyte DNA and decreased levels of some oxidative metabolites in the urine [197]. CONCLUSION It has been calculated that there were 10.8 million new cases, 6.7 million deaths and 22 million persons alive with cancer in the year 2002. Because of growth and aging of the world population, cancer will increase markedly in future years, with an estimation that in 2025, in the absence of any change risk, there would be 10.5 million new cases2. On the same time, the efforts and the hopes of the most important international agencies involved in cancer research are to reduce or eliminate the suffering for cancers within the next decade or so2. This ambitious goal can be achieved only improving early cancer detection and introducing chemopreventive programs on large scale population. In this context, the implementation of chemoprevention by dietary phytochemicals represents an inexpensive, readily applicable approach to control and reduce cancer incidence.

Quercetin Quercetin (3, 3', 4', 5, 7-pentahydroxyflavone) is one of the major dietary flavonoid, found in a broad range of fruits, vegetables and beverage such as tea and wine, with a daily intake in European countries of 25-30 mg. This molecule has

1

Russo et al., unpublished. D.M. Parkin, personal communication, Third Annual AACR International Conference: Frontiers in Cancer Prevention Research. Seattle, WA, USA, October 16-20, 2004. 2

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Despite the extremely high number of encouraging results obtained on cell cultures and animal models, employment of phytochemicals in clinic is far to be imminent. One of the major obstacle concerns the high concentrations of phytochemicals achieved in vitro, which might not be attained in vivo, with the same molecules administrated in the diet. Therefore, it is desirable new intervention trials to assess the real chemopreventive capacity of the most promising agents. In parallel, combination chemoprevention might represent a new strategy that can play a major role in the future of cancer prevention, similarly to combination chemotherapy in the treatment of invasive cancers [198]. In the classical way of studying cancer, research starts from the disease followed by gene identification and ending with specific cancer gene targeting and drug development. As recently reviewed [199], the advent of the new science of chemoprevention changed this view. In chemoprevention, natural products, such as phytochemicals, take the top of the pyramid: based on epidemiological and experimental studies, these agents are isolated from their natural sources, purified and assayed to investigate their ability to kill precancerous and cancerous cells. Since the end point for both views is cancer eradication, a scientific and political effort must be done to complement each other in order to discovery novel ways to fight cancer. ACKNOWLEDGEMENT This work has been partially supported by grant “Benefits and risks of dietary antioxidants in preventing chronic and degenerative pathologies” from Ministero della Salute (Ricerca Finalizzata 2002, Roma, Italy)

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Received: November 1, 2004

Accepted: November 5, 2004

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