**5. Food-Borne Chemopreventive Agents**

A growing body of evidence suggests that a variety of food-derived constituents may exhibit properties that are preventive and/or protective of cancer formation [1,955–959]. Since 1940, almost half of antitumor drugs have been developed from natural products or

their derivatives [960]. In contrast, use of naturally occurring chemicals present in diet for cancer prevention and suppression (also referred to as chemoprevention) remains a highly debatable topic due to the lack of success in clinical trials [961–964].

The MoA underlying chemopreventive properties of naturally occurring agents varies [955]. Some compounds block tumor induction during the initiation stage, others exhibit inhibitory effects during promotion stage, and certain anticarcinogenic substances affect process of carcinogenesis at multiple points [963,965].

Inhibition of preneoplastic and neoplastic effects produced by established chemical carcinogens (including chemicals discussed in this review), has been described in experimental settings for several food constituents. For example, naturally occurring coumarins found in citrus fruits, tonka beans, parsnip, parsley, cinnamon bark oil and peppermint oil, including simple coumarins (coumarin, limettin) and linear furanocoumarins (imperatorin and isopimpinellin) inhibited formation of pro-mutagenic DNA adducts by DMBA in mouse mammary gland and skin [966,967] and formation of BaP DNA adducts and skin tumors in mice [966]. Significant inhibition of DNA adduct levels produced by the heterocyclic amine, PhIP, in rat colonic tissue has been reported after administration of black tea, constituent of mustard plant and papaya seeds, benzylisothiocyanate, and diterpenes, kahweol and cafestol, found in coffee beans [968]. In addition, kahweol and cafestol prevented covalent DNA binding of AFB1 in rat livers [969] and restricted tumor formation and growth caused by DMBA in hamster buccal pouch [970]. The flavonoid, nevadensin, which is present in basil and peppermint, significantly inhibited formation of ME specific DNA adducts and incidences of preneoplastic hepatocellular altered foci in the rat liver [971]. Naturally occurring in turmeric, curcumin has been shown to inhibit initiation and promotion of BaP-induced forestomach tumors and DMBA-induced skin tumors in mice [972] and stomach tumors induced by *N*-methyl-*N*- -nitro-*N*-nitrosoguanidine in rats [973]. Synthetic phenolic antioxidant BHT, which is often added to processed food, and its oxidative metabolites, 2,6-di-tert-butyl-4-hydroxymethylphenol and 2,6-di-tert-butyl-1,4 benzoquinone, inhibited DMBA-DNA adducts formation and tumorigenesis in mammary gland of rats [974]. BHT and BHA were also shown to inhibit the hepatocarcinogenicity of AFB1 in rats [952,975,976]. Monocyclic phenolics, HQ, inhibited cancer-initiating effects of 2-acetylaminofluorene, including formation of DNA adducts, cell proliferation and formation of preneoplastic foci, in rat liver [345]. Chlorophyll [977], which is available in green vegetables, as well as constituents of cruciferous vegetables, 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones [978], inhibited experimental hepatocarcinogenicity of AFB1 in rats. Other indoles, including indole-3-carbinol and 3,3- -diindolylmethane, also inhibited DMBA-induced mammary gland tumors in rats and BaP-induced forestomach neoplasms in mice [979]. A number of carotenoids, which are pigments present in yellow-orange vegetables, with some representatives of this class also serving as vitamin A precursors, mitigated bacterial mutagenicity of AFB1, BaP, IQ, and cyclophosphamide in *Salmonella typhimurium*, and clastogenicity of BaP and cyclophosphamide in mouse bone marrow micronucleus assay [980], and were shown to decrease risk of cancers in different sites, including skin, lung, liver and colon [981].

One of the major mechanisms believed to be involved in cancer prevention by chemicals present in diet is modification in the activity of enzymes which are involved in xenobiotic metabolism. Thus, inhibition of phase I enzymes blocks bioactivation of procarcinogens to reactive metabolites, while induction of phase II enzymes leads to increased detoxication and excretion of carcinogens. For example, the inhibitory effect of naturally occurring coumarins on formation DMBA and BaP DNA adducts, is suggested to be a result of CYP1A1/1B1 inhibition and induction of GST activities [966,967]. Inhibition of tumorigenic effects of a wide array of carcinogens has been also linked to modification of phase I and phase II enzyme activities. Such activity was suggested for constituents of cruciferous vegetables, isothiocyanates (sodium cyanate, tert-butyl isocyanate, phenethyl isothiocyanate, benzyl isothiocyanate and sulforaphane), which inhibited carcinogenicity of ethionine, 2-acetylaminofluorene, 3,3- -diaminobenzidine, m-toluylenediamine and *N*- butyl-*N*-(4-hydroxybutyl)nitrosamine in rat liver, DMBA in rat mammary gland, BaP and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mouse lung and 1,2-dimethylhydrazine in large intestine of mice [951,982–984]. Moreover, consumption of cruciferous vegetables, including broccoli, brussels sprouts and cauliflower, was demonstrated to significantly enhance detoxication and excretion of PhIP present in cooked meat in humans, due to induction of phase I (CYP1A2) and phase II (glucuronidation) metabolism [985]. In addition, isothiocyanate compound, sulforaphane, exhibits anti-inflammatory and pro-apoptotic properties, thus, contributing to chemoprevention [986]. It should be noted, however, that persistent enzyme induction may be undesirable for humans.

In addition to the effects mentioned above, many plant components (often referred to as phytochemicals), such as flavone derivatives, isoflavones, catechins, coumarins, phenylpropanoids, polyfunctional organic acids, phosphatides, tocopherols, ascorbic acid, and carotenes act as antioxidants counteracting formation of ROS and thereby, preventing oxidative stress and oxidative DNA damage [987–989]. For example, antioxidant effects of resveratrol were associated with inhibition of formation and promotion of skin and breast tumors induced by DMBA in mice or rats [990]. Evidence suggests that foodderived phytochemicals can potentiate antioxidant effects of each other, emphasizing the importance of whole food diets rich in fruits and vegetables [988].

Elucidation of mechanisms of tumor prevention on the molecular level, led to discovery of various signaling pathways and molecular targets that are affected by chemopreventive agents [955,963,965]. For example, butyrate-containing structured lipids and tributyrin, which can be found in wholegrains, vegetables, fruits, nuts and beans, have been shown to prevent and/or inhibit activation of major oncogenes and induce apoptosis at early stages of hepatocarcinogenesis [991]. Tumor-suppressive activity of tributyrin was enhanced by concurrent administration of folic acid [992]. Resveratrol (3,4- ,5-trihydroxy-trans-stilbene), which is present in the grape skins, peanuts and red wine, in addition to antioxidant effects, has been shown to modulate cell-cycle regulating pathways, such as MAPKs and NF-κB/AP-1, inducing apoptosis in carcinoma cell lines [993].

It should be noted, however, that some of the compounds described in this section can demonstrate dual effects in experimental settings. Thus, indole-3-carbinol, BHT and coumarin in addition to chemopreventive properties, under certain conditions, usually involving high exposures, can act as tumor promoters [935,994,995]. Nevertheless, presence of chemopreventive agents in diet and their beneficial effects on cancer prophylaxis in humans warrants further investigation.
