Review Cancer Prevention by Natural Compounds

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Drug Metab. Pharmacokin. 19 (4): 245–263 (2004).

Hiroyuki TSUDA1,2*,YutakaOHSHIMA1, Hiroshi NOMOTO2,Ken-ichiFUJITA2, Eiji MATSUDA2,3, Masaaki IIGO2,3, Nobuo TAKASUKA2,3 and Malcolm A. MOORE1,2 1Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 2Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, Tokyo, Japan

Full text of this paper is available at http://www.jssx.org

Summary: Increasing attention is being paid to the possibility of applying cancer chemopreventive agents for individuals at high risk of neoplastic development. For this purpose by natural compounds have practical advantages with regard to availability, suitability for oral application, regulatory approval and mechanisms of action. Candidate substances such as phytochemicals present in foods and their derivatives have been identiˆed by a combination of epidemiological and experimental studies. Plant constituents include vitamin derivatives, phenolic and ‰avonoid agents, organic sulfur compounds, isothiocyanates, curcumins, fatty acids and d-limonene. Examples of compounds from animals are unsaturated fatty acids and lactoferrin. Recent studies have indicated that mechanisms underlying chemopreventive potential may be combinations of anti-oxidant, anti-in‰ammatory, immune-enhancing, and anti-hormone eŠects, with modiˆcation of drug-metabolizing enzymes, in‰uence on the cell cycle and cell diŠerentiation, induction of apoptosis and suppression of proliferation and angiogenesis playing roles in the initiation and secondary modiˆcation stages of neoplastic development. Accordingly, natural agents are advantageous for application to humans because of their combined mild mechanism. Here we review naturally occurring compounds useful for cancer chemprevention based on in vivo studies with reference to their structures, sources and mechanisms of action.

Key words: cancer chemoprevention; natural agents; combined mechanisms

diet, physical inactivity and carcinogen containing Introduction foods, or alternatively by increasing exposure to beneˆ- The purpose of cancer prevention is to cause delay in cial in‰uences, including intake of chemopreventive onset of cancer, progression from precancerous lesion agents.3) The latter may be particularly practical because or recurrence after treatment, as an alternative to treat- they can be taken as supplements or by modulation of ment of cancer cases after clinical symptoms have the current diet status. One can envisage subjects for appeared. Therefore, ultimate goal of cancer prevention cancer chemoprevention falling into two groups, one at is preferably to live without cancer or with cancer high risk of cancer because of the presence of precan- without suŠering from symptoms until the natural cerous lesions or predisposing conditions, and the other termination of life (Fig. 1).1,2) being the apparently healthy general population (Fig. 2). Cancer can be prevented by either avoiding life style- Given di‹culties in ensuring that any compound will related risk factors such as the smoking habit, a Western not have any toxicity besides proven e‹cacy and convenience for use in the long term, the practical aim of chemoprevention, for the present, should best be nd This review is based on the Morning Seminar presentation in the 62 focused on high risk-groups. Furthermore, there are Annual Meeting of the Japanese Cancer Association held in Nagoya advantages with application of natural compounds so in 2003.

Received; May 17, 2004, Accepted; July 9, 2004 *To whom correspondence should be addressed: Dr. Hiroyuki TSUDA, Department of Molecular Toxicology, Nagoya City University, Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Tel. ＋81-52-853-8991, Fax. ＋81-52-853-8996, E-mail: htsuda＠med.nagoya-cu. ac.jp 3Present address: Cancer Prevention Basic Research Project, National Cancer Center Research Institute, Tsukiji 5–1-1, Chuo-ku, Tokyo 104–0045, Japan

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Fig. 3. Stages of chemical carcinogenesis and its chemoprevention. In the `initiation stage', a cell is `hit' by carcinogens with resultant DNA injury. The subsequent promotion and progression (post-initia- Fig. 1. ``Natural-End Cancer'' indicates either living without cancer tion) phase is characterized by clonal cell proliferation. Chemopreven- or living with cancer but without suŠering from cancer related tive compounds act to work in initiation stage by blocking carcinogens symptoms until the natural termination of life comes. to ``hit'' DNA; those which act on post-initiation stage suppress the growth of preneoplastic cells.

giving a êld eŠect, occurs through exposure to a carcinogen. This is enhanced by proliferation, because of ˆxation of DNA damage so that it becomes replicable as a mutation.7) The subsequent modulation phase is characterized by clonal expansion of initiated cell populations, these eventually becoming foci or nodules from which malignancies are thought most likely to arise. Exposure to chemical carcinogens-whether by topical, subcutaneous, intragastric, intraperitoneal or any other route-results in absorption, transport, entry into cells Fig. 2. The population are divided into two groups, one at high risk and metabolism by the phase I and phase II enzymes.8) with predisposing conditions, and the other being the apparently This results in activation and binding to macromolec- healthy general population. Use of chemopreventive measures by asymptomatic persons requires highly reliable toxicology data. ules, or inactivation and excretion of detoxiêd products, whether in man or experimental animals. Thus the products of phase I P450 metabolism may be that regulatory approval can be facilitated.4–6) Since more electrophilic than the parent compounds and carcinogenic processes are complex, agents possessing therefore will interact with all constituents of cells, both multiple mechanisms of action might be most promising within the cytoplasm and within the nuclei.9) Targets candidates. In this review, cancer chemopreventive include structural proteins and other components of agents are classiêd by their structure-based category membranes, as well as the RNA and DNA. However, with the focus on mechanistic aspects. with few exceptions, the vast majority of attention has been paid to interactions with the heritable material Stages in Neoplastic Development locked up in the DNA. Adduct formation has been Clearly, if we are to be successful in cancer described, not only for typical direct or indirect-acting chemoprevention we need to target speciˆc processes chemical carcinogens, but also hormones, irradiation, whichareknowntobeinvolvedinthemultistage UVlightandphysicalagentsorproceduressuchasin development of cancers. In the prevailing paradigm, situ freezing, known to be capable of initiating carcino- three stages can be recognized, ìnitiation', `modiˆca- genesis. Phase II enzymes, like sulfotransferase, quinine tion' (promotion or inhibition) and `progression', as reductase and the glutathione S-transferases, protect illustrated graphically in Fig. 3. In ìnitiation', either of cells from such insults by generating water-soluble single cell or multiple individual cells within a tissue, conjugated intermediates which are more readily p245 p.3 [100%]

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excreted. Phase II also can act as oxygen radical scavengers.10) It is generally accepted that, from oxidative processes alone, production of adducts by endogenous sources is exceedingly high and evolution has demanded an ability of cells to remove or repair damage to their DNA. Indeed, it has been shown that a number of repair systems have been generated and this protective in‰uence clearly needs to be taken into consideration. Experimentally it has been shown with transgenic animals that increased repair activity correlates with decreased sensitivity to carcinogens.11) However, if cell division occurs before repair can take place then any transmitted changes in one DNA strand will be replicated and no longer recognizable as an error. This is the basis for postulated proliferation Fig. 4. Utilization of physiological activities of compounds for requirement for initiation to occur. The observed chemoprevention. positive relationship between increased cell division and elevated sensitivity to initiation is perhaps best exempli- ˆed by performance of partial hepatectomy prior to application of a carcinogen. Thus the initiation phase is dependent on carcinogen activation, adduct formation and cell proliferation.12) For the second modulatory phase, growth is essential, and this is dependent on the balance between cell division and apoptosis. For the ˆnal progression to malignancy, further genetic changes are considered to be involved, due to a combination of exogenous and endogenous factors. For assessment of cancer chemopreventive agents we thus need to look at eŠects of diŠerent processes and therefore types of in‰uence. Thus for the assessment of chemopreventive eŠects, modulation of carcinogenesis is conceptionally divided into 3 stages, modiˆcation of initiation by chemical and Fig. 5. Mechanisms of chemoprevention. physical carcinogens, suppression of cell growth and delay in progression (Fig. 3). 5-hydroxycytosine and 8-nitroadenine, are pre- Processes and Potential for Preventive Action mutagenic and induce speciˆc types of gene mutations. Chemoprevention aims to utilize a part of physiologi- Furthermore, the presence of DNA damage can aŠect cal activities of compounds from plantsWanimals in their gene expression and cause aberrant gene regulation and natural environment (Fig. 4). Representative activities abnormal signaling. Thus RONOSS can contribute to relevant to prevention of carcinogenesis are illustrated carcinogenesis as ``preneoplastic'' lesions by virtue of in Fig. 5. The following are factors with relevance to both genetic and epigenetic mechanisms and anti- prevention of carcinogenesis in initiation-promotion- oxidants would therefore be expected to inhibit, both progression stages. because of alteration in relevant enzyme proˆles and a) Oxidative stress and anti-oxidant action: Reactive quenching.15,18) oxygen andWor nitrogen oxide species-induced stress b) In‰ammation and anti-in‰ammatory action: (RONOSS) and its downstream events are clearly im- Proliferation due to infectious agents such as hepatitis C portant for carcinogenesis. RONOSS can be induced by virus and Helicobacter pylori is a major factor in exposure of animals and humans to a variety of carcino- development of cancer in humans.19,20) Indeed, in‰am- genic xenobiotics and microorganisms13,14) and the matory states and associated chronically elevated levels various cellular alterations induced by RONOSS play of proliferation appear to predispose to cancer develop- crucial roles in carcinogenesis.15–17) DNA adduct ment in any site of the body and the metabolic pathways products, such as 8-hydroxydeoxyguanine (8-OHdG), that are switched on under such conditions are natural 2-hydroxyadenine, 8-hydroxyadenine, 5-hydroxyuracil, targets for chemoprevention.2,5,21,22) Therefore a great p245 p.4 [100%]

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deal of interest has been concentrated on non-steroidal reduction of heterocyclic amines-DNA adducts anti-in‰ammatory drugs (NSAID'S) which act by inhi- formation. These compounds are called an ``interceptor bition of prostaglandin endoperoxidaseWcycloxygenase molecule''.40–42) (COX) and other factors which may have an impact.23–26) g) Angiogenesis and anti-angiogenic action: The It should be remembered that under certain conditions, question of whether preneoplasias or early stage tumors the proliferation stimulus associated with in‰ammation can continue to grow to a large extent is dependent on may preferentially act on tumor precursors, as stressed the availability of nutrients to sustain anabolism. This earlier.21,27) in turn will require a su‹cient blood supply and because c) Hormone-dependent growth and anti-hormone of the generally solid nature of focal lesions, angiogene- action: Enhanced cell proliferation by the hormonal sis and therefore anti-angiogenic agents may clearly be milieu, with elevated cell turnover result from receptor- of importance.43) based signaling, is risk factor of cancer development.5,28) h) Signal transduction pathways and their regulation: For example, estrogen is a growth factor in the absence As a corollary to this, interference with signaling of progesterone29) and is a major factor for breast and pathways downstream of receptors for hormones and ovarian cancer.30) High levels of testosterone and low other factors responsible for cell regulation may result levels of sex-hormone binding globulin (SHBG) are in modiˆcation of the potential for growth, either by similarly considered to positively linked to prostate acting to increase mitosis or alter the level of apoptosis cancer development.31) Promotion of prostate carcino- occurring in a population and thus be targeted for genesis by testosterone has been shown in genetically cancer prevention.44–46) For example, farnesyltrans- susceptible rats.32) Since natural compounds with ferase, a critical enzyme that post-translationally obvious anti-hormone eŠects are not well known except modiˆes Ras and other farnesylated proteins, is an iso‰avone and related compounds, cancer prevention by important factor in Ras mediated carcinogenesis.47–49) these compounds require further experimentation. Included in such pathways are the molecular elements d) Immune activity and modulation: Since the responsible for control of passage through cell cycle immune system can in‰uence on growth either via checkpoints. eŠects on the in‰ammation status or by causing apopto- Mechanism and representative chemopreventive sis through the function of various cytokine species, it compounds are summarized in Table 1. may naturally be of importance for early stages in Chemopreventive Agents by their Structure Group neoplasia, in addition to its eŠects on frank malignancies.33–36) a) Carotenoids: Carotenoid group include beta- e) Xenobiotic metabolism and enzyme induction: carotene, alpha-carotene, lycopene, lutein, astaxanthin, Most carcinogens are metabolized into DNA-attacking cryptoxanthin and zeaxanthin. The majority of carote- moieties by phase I cytochrome P450 (CYP) enzymes. noids are derived from a 40-carbon polyene chain, Phase II enzymes, NAD(P)H (quinone acceptor)ox- which could be considered the backbone of the molecule idoreductase1 (NQO1), glutathione S-transferases (Fig. 6). Carotenoids are responsible for colors of (GST) and UDP-glucuronosyltransferases (UGT), in plants, fruits, ‰owers and ˆsh such as the orange of contrast, are responsible for detoxiˆcation and excre- carrots and citrus fruits, the reds of peppers and tion of activated products. Thus the balance between tomatoes, and the pink of salmon. Carotenoids also these plays important roles in preventing initiation of have eŠects on immune functions.51) Carotenoids were neoplasia because of its role in formation of adducts shown to be eŠective in reducing tumor development in and mutations and agents inducing drug-metabolizing organs such as lung, liver, colon and skin in experimen- enzymes are therefore obvious candidates for cancer tal animals.52) The hydrocarbon carotenoids are known chemoprevention. Metabolism may lead to an increased as carotenes, while oxygenated derivatives of these rate of chemical detoxiˆcation, but in other cases it hydrocarbons are known as xanthophylls. They possess causes chemical activation to toxic products.37) As anti-oxidant action as one of the mechanism for their indicated in a recent study, methoxsalen from the Ammi cancer preventive eŠects.53,54) majus plant, a potent inhibitor of CYP 2A6, which is an b) Vitamins (Fig. 7): 1) Vitamin C (Ascorbic acid); activating enzyme of tobacco speciˆc nitrosamines, Fruit sources are citrus fruits, fresh strawberries, can- clearly reduced mouse lung tumor development.38) A taloupe, pineapples and guava. Vegetable sources are great deal is known about individual CYP in‰uence9) broccoli, Brussels sprouts, tomatoes, spinach, kale, and speciˆc phase II species.39) green peppers, cabbage and turnips. Vitamin C acts as a f) Molecular association with carcinogen: Chlo- scavenger of oxygen radicals and also as competitive rophyllin was known to cause molecular association inhibitor of nitrosamine formation from nitrate and with heterocyclic amines to form larger molecule to amines in vivo.55,56) Many epidemiological studies block passage the cell membrane, thus causing indicate vitamin C intake is clearly related with cancer p245 p.5 [100%]

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Table 1. Summary of natural chemopreventive agents in diŠerent category of function

a. Anti-oxidant eŠects Carotenoids, Vitamin C, E, Sulfur compounds, Anthocyanin, Catechins, Ellagic acid, Flavonoids, Phenolic compounds and Polyphenols, Conjugated fatty acids, Curcumin b. Anti-in‰ammatory eŠects Cox1W2 inhibition Carotenoids, Vitamin C, E, Sulfur compounds, Anthocyanin, Catechins Ellagic acid, Flavonoids, Phenolic compounds, Polyphenols, Conjugated fatty acids, Curcumin Arachidonic acid cascade modiˆcation n-3 PUFA, Curcumin c. Immune enhancing eŠects NK, T cell activity Carotenoid, Flavonoids, Lactoferrin d. Hormone activity modulation Estrogenic: Genistein e. Xenobiotic metabolism and enzyme induction Phase I—CYP suppression Diallyl sulˆde, Catechins, CLA, Curcumin, Lactoferrin, Methoxsalen Phase II—GST, Quinone reductase induction Auraptene, Phenolic compounds, Curcumin, d-Limonene Carotenoids, Sulfur compounds, Catechins, Flavonoids, Indole-3-carbinol f. Apoptosis induction d-Limonene, Sulfur compounds, EGCG, CLA, lactoferrin g. Anti-angiogenesis CLA, Lactoferrin h. Cell diŠerentiation induction Vitamin A, Retinoids i. Interaction to cell cycle

Genistein (G0-G1 arrest) j. Modulation of oncogene signal transduction d-Limonene, Dehydroepiandrosterone (Ras cascade inhibition) k. Inhibition of intestinal absorption (Molecular association with HCA) Chlorophyll, Chlorophyllin l. Alteration in bacterial micro‰ora in the intestine Curcumin

Fig. 6. The structure of beta-catotene, alpha-carotene and lycopene.. p245 p.6 [100%]

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Fig. 7. The structure of vitamines A, C and E.

incidence.57,58) 2) Vitamin E (alpha-tocopherol); Vitamin E is a fat- soluble vitamin that exists in diŠerent forms. Vegetable oils, nuts, and green vegetables are the main dietary sources of vitamin E. Alpha-tocopherol is the most active form of vitamin E in humans, and is a powerful anti-oxidant with multiple roles.59) As with vitamin C, vitamin E also blocks the formation of nitrosamines in the stomach from nitrites ingested with the diet.4,60) In addition to anti-oxidant properties, it shows other functions such as anti-in‰ammatory action.61) 3) Vitamin A; The source of vitamin A is from carotenoids (precursors of vitamin A) in vegetables, marine foods and from retinyl esters, mostly retinyl palmitate, and from foods of animal origin. Carotenoids are metabolized to retinol or retinoic acid to act as vitamin A. Although not clearly shown in human studies, some Fig. 8. The structure of polyunsaturated fatty acids, docosahex- data indicate that vitamin A inhibited mammary aenoic acid (DHA), a-linolenic acid, and trans-9, cis-11 conjugated carcinogenesis in experimental animals. Possible linoleic acid. Conjugated linoleic acid has many isoforms depending on the positions of the double bond and whether they are cis- or trans- mechanism includes modulation of cell proliferation, forms. diŠerentiation, communication and adhesion.62,63) c) Polyunsaturated fatty acids (PUFAs) (Fig. 8): Unsaturated fatty acids are usually found in the form of hormone-related cancers showed a good correlation.64,65) vegetable-derived liquid oils, while saturated fatty acids DHA is well known to inhibit colon and other organ are usually found in solid animal fat (such as butter). carcinogenesis in rats.34,36,66,67) Perilla oil inhibited 7,12- Polyunsaturated fatty acids (PUFAs) are long-chain dimethylbenz[a]anthracene (DMBA)-induced mamma- fatty acids containing two or more double bonds. ry tumor induction in rats.68) Possible mechanism Docosahexaenoic acid (DHA), an omega-3 (n-3) fatty includes anti-in‰ammatory action by inhibiting acid with six cis double bonds and 22 carbons (22:6n-3) prostaglandin biosynthesis from linoleic acid.69) found in ˆsh oil. Alpha-linolenic acid (ALA) is an d) Conjugated linoleic acid (CLA) (Fig. 8): CLA is essential fatty acid highly concentrated in certain plant found naturally in beef, cheese and whole milk. Two oils such as ‰axseed oil and to a lesser extent, canola, CLA isomers (cis-9, trans-11 CLA and trans-10, cis-12 soy, perilla, and walnut oils. ALA is converted to CLA) have been shown to inhibit mammary and colon eicosapentaenoic (EPA) and DHA after ingestion. carcinogenesis in animals. The mechanisms are anti- Intakes of ˆsh and marine fatty acids and the risks of angiogenesis, apoptosis induction to cancer cells and cancers of the breast and prostate and of other alteration of fat metabolism.60–72) CLA might inhibit p245 p.7 [100%]

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angiogenesis in vivo, a hypothesis that was subsequently (ferulic acid, auraptene), ‰avonoid structure and poly- conˆrmed. The anti-angiogenic eŠect is mediated, in phenols. Flavonoids are a ubiquitous group of poly- part, through a CLA-induced decrease in serum and phenolic substances present in most plants, concentrat- mammary gland VEGF (vascular endothelial growth ed in seeds, fruit skin or peel, bark, and ‰owers. The factor) and ‰k-1. The data suggest that CLA may be an structural components common to these molecules excellent candidate for prevention of breast cancer.70). include two benzene rings on either side of a 3-carbon Recent studies showed CLA also have similar inhibitory ring (Fig. 10). A great number of plant medicines eŠect on development of colon preneoplastic aberrant contain ‰avonoids, which have been reported as having crypt foci.73) anti-bacterial, anti-in‰ammatory, anti-mutagenic and e) Organosulfur compounds (Fig. 9): Organosulfur anti-carcinogenic eŠects. Multiple combinations of compounds such as diallyl sulˆde, N-acetylcysteine and hydroxyl groups, sugars, oxygens, and methyl groups S-allyl cysteine present in garlic and onion oil have been attached to these structures form the various classes of shown to inhibit colon, forestomach, esophagus, mam- ‰avonoids such as ‰avanols, ‰avanones, ‰avones, mary gland, and lung carcinogenesis of experimental ‰avan-3-ols (catechins), anthocyanins, anthocyanidin animals.74–78) These compounds were known to induce and iso‰avones. Flavonoids have been shown to be phase II enzymes such as glutathione S-transferase potent anti-oxidants, capable of scavenging hydroxyl (GST), NAD(P)H-dependent quinone reductase, and radicals, superoxide anions, and lipid peroxy radicals. UDP-glucuronosyl transferase, in the liver and colonic 1) Auraptene (Fig. 11); Auraptene, a citrus polyphenol, mucosa. However, they also were found to enhance showed inhibition of colon, oral cavity and esophagus liver carcinogenesis by causing increase in polyamine carcinogenesis. Increased activities of Phase II enzymes biosynthesis.79) Induction of apoptosis may be the major and suppression of cell proliferation and lipid peroxida- contributing factor for anti-tumorigenic properties of tion in the colonic mucosa may explain the inhibitory diallyl sulˆde.80) Anti-proliferative activity has been eŠects.82–85) described in several tumor cell lines, which is possibly 2) Ferulic acid (Fig. 11); Ferulic acid, known to be mediated by induction of apoptosis and alterations of contained in rice germ and coŠee bean, was shown to the cell cycle.81) inhibit colon and tongue carcinogenesis.86,87) In addition f) Phenolic compounds: Phenolic compounds in- to their anti-oxidant activity, induction of GST and clude compounds with single or two benzene rings quinone reductase (QR) activities in liver and colonic mucosa was suggested as the mechanism of inhibition of carcinogenesis.88) 3) SilymarinWsilychristinWsilydianin (Fig. 12); Silyma- rin, ‰avonoid complex containing silybin, silydianin, and silychrisin derived from the milk thistle plant was shown to inhibit colon, tongue and bladder carcinogen- Fig. 9. The structure of organosulfur compounds, diallyl sulˆde and esis, mainly by its strong anti-oxidant eŠects.89–91) isothiocyanate. 4) AnthocyaninWanthocyanidin (Fig. 12); Anthocyanin

Fig. 10. The structure of ‰avonoid compounds. These compounds exhibit anti-oxidant and anti-in‰ammatory eŠects. p245 p.8 [100%]

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Fig. 11. Structure of phenolic compounds, ferulic acid and auraptene.

Fig. 13. Structure of green tea polyphenols, cathechin, epicathecin and epigallocathecin gallate (EGCG).

5) Soy iso‰avones (Fig. 12); Genistein and daidzein, iso‰avone derivatives related to coumarin, are found in soy products. They have estrogenic and anti-oxidant activities.98) Incidences of breast and prostate cancer are relatively low in China and Japan where relatively high amounts of soy products are consumed and this has lead to a suggestion of protective eŠects.98–101) In fact there is now a very large body of evidence, from both epidemiological and experimental animal studies in vivo pointing to inhibitory potential on cancer development in many organ sites.102) The overwhelming conclusion from both in vivo and in vitro data is that soy products or constituents such as genistein or daidzein can act as cancer preventive agents in the mammary gland,103–105) and possibly in endometrium, ovary, prostate and stomach, by both hormone-related and non-hormone- related mechanisms.106,107) There are also data support- ing protective eŠects on the colon, liver, thyroid, skin and lung tumor development, with very few reports of adverse toxic and carcinogenesis promotion eŠects.102,108) Phytoestrogens may act via eŠects on vitamin D metabolism.109) Reduced level of male sex Fig. 12. Structure of polyphenolic compounds, they all share a hormone, dehydroepiandrosterone, by soy iso‰avones 110) ‰avonoid moiety. as a result of inhibition of 5 alpha-reductase activity may act against tumor development.102,111) Genistein also causes cell cycle G2-M arrest.112) pigments are responsible for the red, purple, and blue 6) Green tea polyphenols (Fig. 13); Green tea colors of many fruits, vegetables, cereal grains, and polyphenols, classiˆed as members of the ‰avonoid ‰owers. Proanthocyanin from grape seed showed group, including epigallocatechin, epicatechin gallate inhibition of rat mammary and colon and mouse skin (ECG) and epigallocatechin-3-gallate (EGCG) have carcinogenesis.92,93) It also reduced colon tumor develop- been shown to inhibit carcinogenesis in many ment by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyr- organs.41,108,113–116) Anti-oxidant activity, apoptotic idine (PhIP), a postulated human carcinogen, and potentials to carcinogen-initiated and interaction to cell nitrosamine-induced lung carcinogenesis.94,95) Its action cycle are the mechanism for the inhibitory eŠects. may be related to anti-oxidant, anti-in‰ammatory, anti- EGCG inhibits AP-1 activity in the epidermis of a trans- peroxidative and immune-enhancing eŠects.96,97) genic mouse model.113,117) p245 p.9 [100%]

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Fig. 14. The structure of curcumin and d-limonene.

Fig. 15. The structure of chlorophyll and chrolophyllin. Chlorophyll has 2 isoforms, a and b.

g) Turmelic and curcumin (Fig. 14): Turmeric is one makes plants green and is a good blocking agent against of the key ingredients in many curries, giving them color free radicals generated through metabolic process of and ‰avor. Curcumin derived from Turmelic (Curcuma heterocyclic amines and a‰atoxin, resulting in modula- longer) gives curry its yellow color and having both tion of apoptosis, cell proliferation, and beta-cateninW strong anti-oxidant and anti-in‰ammatory proper- Tcf signaling.123–125) They also form molecular associa- ties.4,118,119) Curcumin inhibited chemically induced skin, tion with heterocyclic amines to block absorption from forestomach, and colon carcinogenesis in post-initiation the intestinal epithelium causing reduction of heterocy- stage in animals.119) clic amines-DNA adducts formation.126) For this reason, h) d-Limonene (Fig. 14): d-Limonene is a major they have been called an ``interceptor molecule''. For constituent of several citrus oils (orange, lemon, manda- example, chlorophyllin administration caused reduced rin, lime, and grapefruit) and many other plant species. level of a‰atoxin-DNA adducts in individuals at high It is used as a component of ‰avorings and fragrances, risk of liver cancer.40) Chlorophyllin also exhibited as a chemical intermediate. d-Limonene inhibited rat anti-promotion eŠect on DMBA-TPA-induced mouse mammary and other tumor development.50,120–122) One of skin carcinogenesis.127) the explanation is inhibition of farnesyl protein trans- j) Chitin and chitosan (Fig. 16): Chitin and chitosan ferase and p21ras association to the cell membrane.122) are polysaccharide polymers containing more than i) ChlorophyllWChlorophyllin (Fig. 15): Chloro- 5,000 acetylglucosamine and glucosamine units, respec- phyll is the green pigment found in higher plants, as tively, and their molecular weights are over one million well as algae. Chlorophyllin is a semi-synthetic sodiumW Daltons. Chitin is found in fungi, arthropods and copper derivative of chlorophyll. In contrast to chlo- marine invertebrates. Commercially, chitin is derived rophyll, chlorophyllin is water-soluble. Chlorophyllin is from the exoskeletons of crustaceans (shrimp, crab and a semi-synthetic form of the natural chlorophyll that other shellˆsh). Chitosan is obtained from chitin by a p245 p.10 [100%]

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Fig. 18. The structure of dehydroepiandrosterone.

Fig. 16. The structure of crustacea derived ˆbers, chitin and chirosan.

Fig. 17. The structure of isothiocyanates.

deacetylation process. Chitin, the polysaccharide polymer from which chitosan is derived, is a cellulose- like polymer consisting mainly of unbranched chains of Fig. 19. The structure of bovine lactoferrin. (Courtesy of Dr. K. N-acetyl-D-glucosamine. Deacetylated chitin, or chito- Shimazaki, Graduate School of Agriculture, Hokkaido University) san, is comprised of chains of D-glucosamine. When ingested, chitosan can be considered a dietary ˆber. Chitin and chitosan inhibit colon carcinogenesis.124,128) the phosphate shunt responsible for providing ribose k) Isothiocyanates (Fig. 17): Isothiocyanates units for DNA synthesis.135,136) present in cruciferous plants such as Brassica m) Lactoferrin and its digested fragments (Fig. 19): vesitableswere known to inhibit cytochrome P450 Lactoferrin is a single chain glycoprotein folded into (CYP) isoforms. They induced increased expression of two globular units, each of which can bind one ferric GST, NADPH: quinone oxidoreductase, aldo-keto ion (Fe3＋) together with a bicarbonate ion. In the reductase and gamma-glutamylcysteine synthetase.129) ``natural state'', bovine lactoferrin (bLF) is only partly These responses were coordinated at the transcription saturated with iron (15¿20z) and has a salmon pink level by nuclear factor-erythroid 2 p45-related factor-2 color. In breast milk, the lactoferrin found is essentially acting through the anti-oxidantWelectrophile enhancer apo-lactoferrin.137) The bLF has a molecular weight of response element and stimulated by the mitogen-activat- about 80 kDa. The complete amino acid sequence of ed protein kinaseWextracellular signal-regulated kinase bovine lactoferrin has been determined to contain 689 kinase kinase-1 and c-Jun N-terminal kinase-1 (JNK1) amino acids. pathway. Isothiocyanates also induced apoptosis of bLF and its digested fragments have been found to pre-cancerous cells and tumor cells activated by caspase- remarkably inhibit colon, esophagus, lung, and bladder 8 and potentiated by JNK1.118,130–132) carcinogenesis in rats when administered orally in the l) Dehydroepidandrosterone (Fig. 18): The adrenal post-initiation stage.138–140) It also inhibit colon and liver hormone dehydroepiandrosterone (DHEA) was shown carcinogenesis when administered concurrently with to inhibit colon, prostate, thyroid and several other carcinogenic heterocyclic amines (Table 1), possibly by organ carcinogenesis in animals.133,134) It acts as an suppression of phase I enzyme, cytochrome P450 1A2 inhibitor of the mevalonate pathway as well as aŠecting (CYP1A2) activity.141) Anti-metastatic eŠects were p245 p.11 [100%]

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Table 2. Summary of bLF cancer prevention

Time of application (2z and 0.2z)a Animal species Carcinogen Post-initiation Concurrent Organ End-point

Rat AOM ○ Colon Adc DHPN ○ Lung Adc ○ Thyroid Ad＋Adc ○ Esophagus Pap＋SCC 4-NQO ○○Tongue SCC BHBN ○ Bladder Pap＋TCC PhlP ○ Prostate PIN PhlP ○ Colon ACF DEN-MelQx ○ Liver, Colon GST-P＋,ACF Mouse ApcMin Jejunum Ad

, Inhibition of carcinogenesis. a,2.0z and 0.2z dose＝90 and 9 gW60 kg B.W., respectively Ad, Adenoma; Adc, Adenocarcinoma. Pap, Papilloma; SCC, Squamous cell carcinoma; TCC, Transitional cell carcinoma GST-P＋, Glutathione S-transferase positive foci; ACF, Aberrant crypt foci.

Table 3. Summarized mechanism of lactoferrin eŠects observed in vivo

1. Induction of IL 18 and caspase1 in small intestine epithelium 2. Induction of NK cells, CD8＋,CD4＋,IFNg＋ T cells in mucosa propria of the small intestine 3. Inhibition of CYP1A2 induction, a carcinogenic heterocyclic amine activating enzyme 4. Induction of apoptosis in carcinogen-initiated colon epithelium by activation of Fas and caspase-8 and caspase-3 5. Inhibition of angiogenesis

in mice.148) As summarized in Fig. 20, inhibitory eŠect Fig. 20. Mechanisms of chemopreventionmediatedbylactoferrin. of bLF is mediated by mixed activities, which satisfy a Lactoferrin satisˆes 5 out of the 10 mechanistic categories of half, 5 (see shaded letters) out of 10, of important chemopreventive action as shown in Fig. 5. functions of chemoprevention.137,149,150) Current Situation for Chemopreventive Agents moreover detected when bLF was given intragastrically An overview of the ˆndings for a variety of diŠerent to mice bearing highly metastatic Colon carcinoma 26 types of agents, where they inhibit and the mechanisms cells (Co 26Lu), with apparent enhancing in‰uence on is given in Table 1. The great interest in developing local and systemic immunity.142) Marked increase in the chemical agents that might have appreciation as number of cytotoxic T and NK cells in the mucosal layer chemopreventive agents has driven a large body of of the small intestine and peripheral blood cells was thus research and a great deal has been published. However, found, this in turn enhancing the production of interleu- in contrast to the large number of compounds for which kin 18 (IL-18) and caspase-1 in the epithelial cells of the e‹cacy has been proven in experimental models, rela- intestine, with possible consequent induction of interfe- tively few clinical trials have been performed and none ron (IFN)-gamma positive cells.143,144) bLF also inhibited has, so far, proven a net beneˆt conferred by natural angiogenesis stimulated by tumor cells in vivo and in compounds (Tables 6 and 7). vitro.145) Inductionofapoptosisinthecolonepithelial Previous clinical trials have shown the eŠectiveness of and also leukemic cells possibly related with increase in the following: polyprenoic acid (acyclic retinoid) for expression of Fas and apoptosis linked caspase was also hepatocellular carcinoma; tamoxifen for breast cancer; demonstrated144,146,147) (Table 2). Furthermore, the retinoic acids for head and neck tumor; and aspirin, a recombinant bovine and human lactoferrin was shown COX-2 inhibitor, for colorectal cancer. Despite the to inhibit growth of human cell carcinomas transplanted advantageous eŠects of some of these agents, their toxic p245 p.12 [100%]

256 Hiroyuki TSUDA et al.

Table 4. Summary of action, target organ, stages of application, tested animals and results of clinical trial (1)

Compound Action Organ stagea Animalb Clinicalc study

b-Carotene Anti-oxidant Oral cavity I, P R, M × Immune enhancing Liver, Skin Lycopene Anti-oxidant Stomach I, P R × Immune enhancing Colon Mammary gl.d Urinary bladder Vitamin A Cell diŠerentiation Colon, Liver I, P R, M × Prostate Mammary gl. Vitamin E Anti-oxidant Esophagus I, P R, M × Liver Mammary gl. DHA Anti-in‰ammatory Colon I, P R, M － Lung Mammary gl. a-Linoleic acid Anti-in‰ammartory Stomach I, P R, M － Skin Mammary gl. Diallyl sulˆde Drug metabolizing Esophagus I, P R, M － enzyme modiˆcation Colon, Liver Isothiocyanate Drug metabolizing Esophagus I, P R, M － enzyme modiˆcation Colon, Liver Lung Anthocyanin Anti-oxidant Colon IR,M × Anti-in‰ammatory Pancreas Mammary gl. a. I, Initiation stage; P, Post Initiation stage; C, Concurrent administration b. R, Rat; M, Mouse c. ×,Limited¿Inadequate; －, Lack of evidence of preventive eŠect d. gl., gland

eŠects must also be of concern at the same time. For magnitude but also in direction. This variation and example, in a chemoprevention trial of lung cancer, response likely depend on individual genetic polymor- beta-carotene was unexpectedly found to increase the phisms andWor interactions among dietary components risk of lung cancer among high-risk groups. It is also that in‰uence absorption, metabolism, or site of action. noted that large-scale clinical trials demand large Research priorities include investigation of possible research grants, which may not be aŠordable in Japan moleculartargetsformicronutrientsandwhethergenet- and other countries of Asia. Chemoprevention is still an ic and epigenetic events dictate direction and magnitude emerging ˆeld of oncology where researchers in both of the response.4) basic and clinical sciences face great challenges.151) It should be borne in mind that health beneˆts of fruit According to publication from International Agency for and vegetables are from additive and synergistic Research on Cancer (IARC) and the authors survey, combinations of phytochemicals.57) With natural agents number of compounds shown to be eŠective in human the hope is that their availability, lack of obvious toxici- clinical trial are extremely limited as compared to those ty at eŠective dose and ability to act by various diŠerent showntobeeŠectiveinanimalstudies(Figs. 6 and 7). mechanisms, will eventually allow their introduction, Based on preclinical results, selected agents have been ˆrstforhighriskcasesandthenasprimarypreventive and are now being evaluated in phase I, II and III measures in the general population. clinical interventions for various cancers. Development of valid surrogate end point biomarkers is essential to Acknowledgements: Studies conducted by the author accelerate progress in cancer prevention clinical and were supported by a Grant-in Aid for the Second Term intervention studies.152) Comprehensive 10-Year Strategy for Cancer Control Micronutrients currently being examined in National from the Ministry of Health, Labour and Welfare, a Cancer Institute (NCI)-sponsored phase I, II, or III Grant-in Aid from the Ministry of Health, Labour and chemoprevention trials for prostate, breast, and colon Welfare and a Grant-in Aid from the Ministry of cancers include iso‰avones, lycopene, selenized yeast, Education, Science, Sports, Culture and Technology, selenomethionine, selenium, vitamin E, perillyl alcohol, Japan. During the drafting of this paper Malcolm A folic acid, vitamin D, calcium, and curcumin. The Moore was the recipient of a Foreign Research Fellow- response to micronutrients may vary not only in ship from the Foundation for Promotion of Cancer p245 p.13 [100%]

Cancer Prevention by Natural Compounds 257

Table 5. Summary of action, target organ, stages of application, tested animals and results of clinical trial (2)

Compound Action Organ Stagea Animalb Clinicalc study

EGCG Anti-oxidant Esophagus I, P R, M － Drug metabolizing Stomach enzyme modiˆcation Colon Urinary bladdr Mammary gl.d Lung, Liver Genistein Estrogenic Prostate I R × Cell proliferation CLA Anti-oxidant Mammary gl. P R － Drug metabolizing enzyme modiˆcation Apoptosis Auraptene Anti-in‰ammatory Oral cavity I, P R － Drug metabolizing Esophagus enzyme midiˆcation Colon d-Limonene Oncogene Mammary gl. I R － Apoptosis Curcumin Anti-oxidant Oral cavity Anti-in‰ammatory Stomach Drug metabolizing Colon, Skin I, P R, M － enzyme modiˆcation Anti-microbial Lactoferin Immune enhance Tongue I, P, C R ? Drug metabolizing Esophagus enzyme modiˆcation Stomach Apoptosis Liver, Colon Anti-angiogenesis Urinary bladder Mammary gl. Lung

a. I, lnitiation stage; P, Post initiation stage; C, Concurrent administration b. R, Rat; M, Mouse c. ×,Limited¿Inadequate; －, Lack of evidence of preventive eŠect d. gl., gland

Table 6. Evaluation of chemopreventive agents tested in animals Table 7. Evaluation of chemopreventive agents tested in humans (from IARC and authors) (from IARC and authors)

Su‹cient Limited Not No Su‹cient Limited Not No evidence evidence classiˆable eŠect evidence evidence classiˆable eŠect aspirin a-carotene* all-trans-N-ethyl tamoxifen aspirin piroxicam b-carotene* sulindac lycopene* retinoic acid retinamide celecoxib sulindac indomethacin vitamin A* piroxicam lutein* acitretin interferon-a sho-saiko-to* canthaxanthin* ˆber* indomethacin fucoxanthin* targretin a-carotene* b-carotene* vitamin A* LGD 1550 lycopene* canthaxanthin* etretinate lutein* 4-hydroxyphenyl 9-cis- fucoxanthin* retinamide retinoic acid 9-cis- celecoxib curcumin* retinoic acid tamoxifen nimesulide 4-hydroxyphenyl d-limonene* ellagic acid* retinamide catechins* indole-3-carbinol* etretinate S-methylcysteine* acitretin lactoferrin* N-ethyl auraptene* retinamide protocatechuic LGD 1550 acid* *, Natural compound targretin* diallyl sulˆde* N-CWS* DHA* genistein**, Natural compound p245 p.14 [100%]

258 Hiroyuki TSUDA et al.

Research Program for Invitation of Foreign Resear- atherosclerosis, and acquired immunodeˆciency syn- chers. The author would thank Dr. Mitsuaki Maeda of drome. Free Radic. Biol. Med., 33: 192–200 (2002). Kitazato University for his kind advice regarding the 17) Owuor, E. D. and Kong, A. N.: Antioxidants and chemical structure of compounds. oxidants regulated signal transduction pathways. Biochem. Pharmacol., 64: 765–770 (2002). References 18) Nakae, D., Umemura, T. and Kurokawa, Y.: Reactive Oxygen and Nitrogen Oxide Species-induced Stress, a 1) Kitagawa, T., Hara, M., Sano, T. and Sugimura, T.: Major Intrinsic Factor Involved in Carcinogenic The concept of Tenju-gann, or ``natural-end cancer''. Processes and a Possible Target for Cancer Prevention. Cancer, 83: 1061–1065 (1998). AsianPac.J.CancerPrev., 3: 313–318 (2002). 2) Sugimura, T.: An overview of cancer prevention. Eur. 19) Pisani, P., Parkin, D. M., Munoz, N. and Ferlay, J.: J. Cancer Prev., 5 Suppl 2: 1–8 (1996). Cancer and infection: estimates of the attributable 3) Wattenberg, L. W.: An overview of chemoprevention: fraction in 1990. Cancer Epidemiol Biomarkers Prev., current status and future prospects. Proc. Soc. Exp. 6: 387–400 (1997). Biol. Med., 216: 133–141 (1997). 20) Moore, M. A. and Tsuda, H.: Chronically elevated 4) Greenwald, P., Milner, J. A., Anderson, D. E. and proliferation as a risk factor for neoplasia. Eur. J. McDonald, S. S.: Micronutrients in cancer Cancer Prev., 7: 353–385 (1998). chemoprevention. Cancer Metastasis Rev., 21: 217–230 21) Moore, M. A., Tsuda, H., Tamano, S., Hagiwara, A., (2002). Imaida, K., Shirai, T. and Ito, N.: Marriage of a 5) Ames,B.N.,Gold,L.S.andWillett,W.C.:The medium-term liver model to surrogate markers–a causes and prevention of cancer. Proc. Natl. Acad. Sci. practical approach for risk and beneˆt assessment. USA, 92: 5258–5265 (1995). Toxicol. Pathol., 27: 237–242 (1999). 6) Tanaka, T., Kohno, H. and Mori, H.: Chemopreven- 22) Preston-Martin,S.,Pike,M.C.,Ross,R.K.and tion of Colon Carcinogenesis by Dietary Non-nutritive Henderson, B. E.: Epidemiologic evidence for the Compounds. Asian Pac. J. Cancer Prev., 2: 165–177 increased cell proliferation model of carcinogenesis. (2001). Environ Health Perspect., 101 Suppl 5: 137–138 (1993). 7) Wattenberg, L. W.: Chemoprevention of cancer. Prev. 23) Weitzman, S. A. and Gordon, L. I.: In‰ammation and Med., 25: 44–45 (1996). cancer: role of phagocyte-generated oxidants in 8) Ito, N., Hasegawa, R., Imaida, K., Hirose, M., carcinogenesis. Blood, 76: 655–663 (1990). Asamoto, M. and Shirai, T.: Concepts in multistage 24) Subbaramaiah, K., Zakim, D., Weksler, B. B. and carcinogenesis. Crit.Rev.Oncol.Hematol., 21: Dannenberg, A. J.: Inhibition of cyclooxygenase: a 105–133 (1995). novel approach to cancer prevention. Proc. Soc. Exp. 9) Kamataki, T., Fujita, K., Nakayama, K., Yamazaki, Biol. Med., 216: 201–210 (1997). Y., Miyamoto, M. and Ariyoshi, N.: Role of human 25) Wakabayashi, K.: NSAIDs as Cancer Preventive cytochrome P450 (CYP) in the metabolic activation of Agents. Asian Pac. J. Cancer Prev., 1: 97–113 (2000). nitrosamine derivatives: application of genetically 26) IARC: Non-Steroidal Anti-In‰ammatory Drugs, engineered Salmonella expressing human CYP. Drug IARC Handbooks of Cancer Prevention, Vol. 1, Metab. Rev., 34: 667–676 (2002). IARC, 1997, pp. 202. 10) Wattenberg, L. W.: Inhibition of carcinogenesis by 27) Farber, E.: Cell proliferation as a major risk factor for minor dietary constituents. Cancer Res., 52: 2085s– cancer: a concept of doubtful validity. Cancer Res., 55: 2091s (1992). 3759–3762 (1995). 11) Ishikawa,T.,Zhang,S.S.,Qin,X.,Takahashi,Y., 28) Moore, M. A., Park, C. B. and Tsuda, H.: Implica- Oda, H., Nakatsuru, Y. and Ide, F.: DNA repair and tions of the hyperinsulinaemia-diabetes-cancer link for cancer: lessons from mutant mouse models. Cancer preventive eŠorts. Eur. J. Cancer Prev., 7: 89–107 Sci., 95: 112–117 (2004). (1998). 12) Wattenberg, L. W.: Inhibition of tumorigenesis in 29) Holland, M. B. and Roy, D.: Estrone-induced cell animals. IARC Sci. Publ., 151–158 (1996). 13) Hussain, S. P., Hofseth, L. J. and Harris, C. C.: proliferation and diŠerentiation in the mammary gland Radicalcausesofcancer.Nat. Rev. Cancer, 3: 276–285 ofthefemaleNoblerat.Carcinogenesis, 16: 1955–1961 (2003). (1995). 14) Kohen, R. and Nyska, A.: Oxidation of biological 30) Henderson, B. E., Ross, R. K. and Pike, M. C.: systems: oxidative stress phenomena, antioxidants, Hormonal chemoprevention of cancer in women. redox reactions, and methods for their quantiˆcation. Science, 259: 633–638 (1993). Toxicol. Pathol., 30: 620–650 (2002). 31) Gann, P. H., Hennekens, C. H., Ma, J., Longcope, C. 15) Ohshima, H.: Genetic and epigenetic damage induced and Stampfer, M. J.: Prospective study of sex hormone by reactive nitrogen species: implications in carcino- levels and risk of prostate cancer. J. Natl. Cancer Inst., genesis. Toxicol. Lett., 140–141: 99–104 (2003). 88: 1118–1126 (1996). 16) Olinski, R., Gackowski, D., Foksinski, M., Rozalski, 32) Pollard, M. and Luckert, P. H.: Promotional eŠects of R., Roszkowski, K. and Jaruga, P.: Oxidative DNA testosterone and dietary fat on prostate carcinogenesis damage: assessment of the role in carcinogenesis, in genetically susceptible rats. Prostate, 6: 1–5 (1985). p245 p.15 [100%]

Cancer Prevention by Natural Compounds 259

33) KelloŠ, G. J., Boone, C. W., Steele, V. E., Fay, J. R., anticancer therapeutic development. J. Clin. Oncol., Lubet,R.A.,Crowell,J.A.andSigman,C.C.: 17: 3631–3652 (1999). Mechanistic considerations in chemopreventive drug 48) Cox, A. D.: Farnesyltransferase inhibitors: potential development. J. Cell Biochem. Suppl., 20: 1–24 (1994). role in the treatment of cancer. Drugs, 61: 723–732 34) Roynette,C.E.,Calder,P.C.,Dupertuis,Y.M.and (2001). Pichard, C.: n-3 polyunsaturated fatty acids and colon 49) Gould, M. N., Moore, C. J., Zhang, R., Wang, B., cancer prevention. Clin. Nutr., 23: 139–151 (2004). Kennan, W. S. and Haag, J. D.: Limonene 35) Bouic, P. J.: The role of phytosterols and phytostero- chemoprevention of mammary carcinoma induction lins in immune modulation: a review of the past 10 following direct in situ transfer of v-Ha-ras. Cancer years. Curr. Opin. Clin. Nutr. Metab. Care, 4: 471–475 Res., 54: 3540–3543 (1994). (2001). 50) Y-J, Surh,: Cancer chemoprevention with dietary 36) Ip, C.: Review of the eŠects of trans fatty acids, oleic phytochemicals. Nature Rev., 3: 768–780 (2003). acid, n-3 polyunsaturated fatty acids, and conjugated 51) Hughes, D. A.: EŠects of carotenoids on human linoleic acid on mammary carcinogenesis in animals. immune function. Proc. Nutr. Soc., 58: 713–718 Am.J.Clin.Nutr., 66: 1523S–1529S (1997). (1999). 37) Wolfe, M. F. and Seiber, J. N.: Environmental activa- 52) IARC: Carotenoids, IARC Handbooks of Cancer tion of pesticides. Occup. Med., 8: 561–573 (1993). Prevention, Vol. 2, IARC, 1998, pp. 326. 38) Takeuchi, H., Saoo, K., Yokohira, M., Ikeda, M., 53) Limpens, J., van Weerden, W. M., Kramer, K., Maeta, H., Miyazaki, M., Yamazaki, H., Kamataki, Pallapies, D., Obermuller-Jevic, U. C. and Schroder, T. and Imaida, K.: Pretreatment with 8-methoxypsora- F. H.: Re: Prostate carcinogenesis in N-methyl-N- len, a potent human CYP2A6 inhibitor, strongly nitrosourea (NMU)-testosterone-treated rats fed inhibits lung tumorigenesis induced by 4-(methyl- tomato powder, lycopene, or energy-restricted diets. J. nitrosamino)-1-(3-pyridyl)-1-butanone in female AWJ Natl. Cancer Inst., 96: 554; author reply 554–555 mice. Cancer Res., 63: 7581–7583 (2003). (2004). 39) Begleiter, A., Sivananthan, K., Curphey, T. J. and 54) Nishino, H., Murakoshi, M., Ii, T., Takemura, M., Bird, R. P.: Induction of NAD(P)H quinone: Kuchide, M., Kanazawa, M., Mou, X. Y., Wada, S., oxidoreductase1 inhibits carcinogen-induced aberrant Masuda, M., Ohsaka, Y., Yogosawa, S., Satomi, Y. crypt foci in colons of Sprague-Dawley rats. Cancer and Jinno, K.: Carotenoids in cancer chemopreven- Epidemiol. Biomarkers Prev., 12: 566–572 (2003). tion. Cancer Metastasis Rev., 21: 257–264 (2002). 40) Egner, P. A., Wang, J. B., Zhu, Y. R., Zhang, B. C., 55) Fong,Y.Y.andChan,W.C.:EŠectofascorbateon Wu,Y.,Zhang,Q.N.,Qian,G.S.,Kuang,S.Y., amine-nitrite carcinogenicity. IARC Sci. Publ., Gange, S. J., Jacobson, L. P., Helzlsouer, K. J., 461–464 (1976). Bailey, G. S., Groopman, J. D. and Kensler, T. W.: 56) Oliveira, C. P., Kassab, P., Lopasso, F. P., Souza, H. Chlorophyllin intervention reduces a‰atoxin-DNA P., Janiszewski, M., Laurindo, F. R., Iriya, K. and adducts in individuals at high risk for liver cancer. Laudanna, A. A.: Protective eŠect of ascorbic acid in Proc.Natl.Acad.Sci.USA, 98: 14601–14606 (2001). experimental gastric cancer: reduction of oxidative 41) Dashwood, R. H., Xu, M., Hernaez, J. F., Hasaniya, stress. World J. Gastroenterol, 9: 446–448 (2003). N., Youn, K. and Razzuk, A.: Cancer chemopreven- 57) Lee, K. W., Lee, H. J., Surh, Y. J. and Lee, C. Y.: tive mechanisms of tea against heterocyclic amine VitaminCandcancerchemoprevention: reappraisal. mutagens from cooked meat. Proc. Soc. Exp. Biol. Am. J. Clin. Nutr., 78: 1074–1078 (2003). Med., 220: 239–243 (1999). 58) Liu, R. H.: Health beneˆts of fruit and vegetables are 42) Dashwood, R. H.: Modulation of heterocyclic amine- from additive and synergistic combinations of induced mutagenicity and carcinogenicity: an `A-to-Z' phytochemicals. Am.J.Clin.Nutr., 78: 517S–520S guide to chemopreventive agents, promoters, and (2003). transgenic models. Mutat. Res., 511: 89–112 (2002). 59) Sung, L., Greenberg, M. L., Koren, G., Tomlinson, G. 43) Vainio, H.: Targeting angiogenesis–a novel mode in A., Tong, A., Malkin, D. and Feldman, B. M.: cancer chemoprevention. AsianPac.J.CancerPrev., Vitamin E: the evidence for multiple roles in cancer. 4: 83–86 (2003). Nutr. Cancer, 46: 1–14 (2003). 44) Kong, A. N., Yu, R., Hebbar, V., Chen, C., Owuor, 60) Hagiwara, A., Boonyaphiphat, P., Tanaka, H., E., Hu, R., Ee, R. and Mandlekar, S.: Signal transduc- Kawabe, M., Tamano, S., Kaneko, H., Matsui, M., tion events elicited by cancer prevention compounds. Hirose, M., Ito, N. and Shirai, T.: Organ-dependent Mutat. Res., 480–481: 231–241 (2001). modifying eŠects of caŠeine, and two naturally 45) Katzenellenbogen, B. S. and Frasor, J.: Therapeutic occurring antioxidants alpha-tocopherol and n-tritria- targeting in the estrogen receptor hormonal pathway. contane-16,18-dione, on 2-amino-1-methyl-6- Semin. Oncol., 31: 28–38 (2004). phenylimidazo[4,5-b]pyridine (PhIP)-induced mam- 46) Greten,F.R.andKarin,M.:TheIKKWNF-kappaB mary and colonic carcinogenesis in female F344 rats. activation pathway-a target for prevention and treat- Jpn. J. Cancer Res., 90: 399–405 (1999). ment of cancer. Cancer Lett., 206: 193–199 (2004). 61) Brigelius-Flohe, R., Kelly, F. J., Salonen, J. T., 47) Rowinsky, E. K., Windle, J. J. and Von HoŠ, D. D.: Neuzil, J., Zingg, J. M. and Azzi, A.: The European Ras protein farnesyltransferase: A strategic target for perspective on vitamin E: current knowledge and p245 p.16 [100%]

260 Hiroyuki TSUDA et al.

future research. Am.J.Clin.Nutr., 76: 703–716 (1993). (2002). 76) Takada, N., Yano, Y., Wanibuchi, H., Otani, S. and 62) IARC: Retinoids, IARC Handbooks of Cancer Fukushima, S.: S-methylcysteine and cysteine are Prevention, Vol. 4, IARC, 1999, pp. 331. inhibitors of induction of glutathione S-transferase 63) IARC: Vitamin A, IARC Handbooks of Cancer placental form-positive foci during initiation and Prevention, Vol. 3, IARC, 1998, pp. 261. promotion phases of rat hepatocarcinogenesis. Jpn. J. 64) Terry, P. D., Rohan, T. E. and Wolk, A.: Intakes of Cancer Res., 88: 435–442 (1997). ˆsh and marine fatty acids and the risks of cancers of 77) Fukushima, S., Takada, N., Hori, T. and Wanibuchi, the breast and prostate and of other hormone-related H.: Cancer prevention by organosulfur compounds cancers: a review of the epidemiologic evidence. Am. J. from garlic and onion. J. Cell Biochem. Suppl., 27: Clin. Nutr., 77: 532–543 (2003). 100–105 (1997). 65) Stoll, B. A.: N-3 fatty acids and lipid peroxidation in 78) Fukushima, S., Takada, N., Wanibuchi, H., Hori, T., breast cancer inhibition. Br. J. Nutr., 87: 193–198 Min, W. and Ogawa, M.: Suppression of chemical (2002). carcinogenesis by water-soluble organosulfur com- 66) Takahashi, M., Fukutake, M., Isoi, T., Fukuda, K., pounds. J. Nutr., 131: 1049S–1053S (2001). Sato, H., Yazawa, K., Sugimura, T. and 79) Takada, N., Kitano, M., Chen, T., Yano, Y., Otani, S. Wakabayashi, K.: Suppression of azoxymethane- and Fukushima, S.: Enhancing eŠects of organosulfur induced rat colon carcinoma development by a ˆsh oil compounds from garlic and onions on hepatocarcino- component, docosahexaenoic acid (DHA). Carcino- genesis in rats: association with increased cell prolifera- genesis, 18: 1337–1342 (1997). tion and elevated ornithine decarboxylase activity. Jpn. 67) Toriyama-Baba, H., Iigo, M., Asamoto, M., Iwahori, J. Cancer Res., 85: 1067–1072 (1994). Y., Park, C. B., Han, B. S., Takasuka, N., Kakizoe, 80) Arora, A. and Shukla, Y.: Induction of apoptosis by T.,Ishikawa,C.,Yazawa,K.,Araki,E.andTsuda, diallyl sulˆde in DMBA-induced mouse skin tumors. H.: Organotropic chemopreventive eŠects of n-3 Nutr. Cancer, 44: 89–94 (2002). unsaturated fatty acids in a rat multi-organ carcinogen- 81) Bianchini, F. and Vainio, H.: Allium vegetables and esis model. Jpn. J. Cancer Res., 92: 1175–1183 (2001). organosulfur compounds: do they help prevent cancer? 68) Hirose, M., Masuda, A., Ito, N., Kamano, K. and Environ. Health Perspect., 109: 893–902 (2001). Okuyama, H.: EŠects of dietary perilla oil, soybean oil 82) Kawabata, K., Tanaka, T., Yamamoto, T., Hara, A., and saŒower oil on 7,12-dimethylbenz[a]anthracene Murakami, A., Koshimizu, K., Ohigashi, H., Stoner, (DMBA) and 1,2-dimethyl-hydrazine (DMH)-induced G. D. and Mori, H.: Suppression of N- mammary gland and colon carcinogenesis in female nitrosomethylbenzylamine-induced rat esophageal SD rats. Carcinogenesis, 11: 731–735 (1990). tumorigenesis by dietary feeding of auraptene. J. Exp. 69) Iigo, M., Nakagawa, T., Ishikawa, C., Iwahori, Y., Clin. Cancer Res., 19: 45–52 (2000). Asamoto, M., Yazawa, K., Araki, E. and Tsuda, H.: 83) Tanaka, T., Kawabata, K., Kakumoto, M., Makita, Inhibitory eŠects of docosahexaenoic acid on colon H., Hara, A., Mori, H., Satoh, K., Murakami, A., carcinoma 26 metastasis to the lung. Br. J. Cancer, 75: Kuki, W., Takahashi, Y., Yonei, H., Koshimizu, K. 650–655 (1997). and Ohigashi, H.: Citrus auraptene inhibits chemically 70) Ip,M.M.,Masso-Welch,P.A.andIp,C.:Prevention induced colonic aberrant crypt foci in male F344 rats. of mammary cancer with conjugated linoleic acid: role Carcinogenesis, 18: 2155–2161 (1997). of the stroma and the epithelium. J. Mammary Gland 84) Tanaka, T., Kawabata, K., Kakumoto, M., Hara, A., Biol. Neoplasia, 8: 103–118 (2003). Murakami, A., Kuki, W., Takahashi, Y., Yonei, H., 71) Belury, M. A.: Dietary conjugated linoleic acid in Maeda,M.,Ota,T.,Odashima,S.,Yamane,T., health: physiological eŠects and mechanisms of action. Koshimizu, K. and Ohigashi, H.: Citrus auraptene Annu. Rev. Nutr., 22: 505–531 (2002). exerts dose-dependent chemopreventive activity in rat 72) Kim, K. H. and Park, H. S.: Dietary supplementation large bowel tumorigenesis: the inhibition correlates of conjugated linoleic acid reduces colon tumor with suppression of cell proliferation and lipid peroxi- incidence in DMH-treated rats by increasing apoptosis dation and with induction of phase II drug-metaboliz- with modulation of biomarkers. Nutrition, 19: 772–777 ing enzymes. Cancer Res., 58: 2550–2556 (1998). (2003). 85) Tanaka, T., Kawabata, K., Kakumoto, M., 73) Kohno, H., Suzuki, R., Noguchi, R., Hosokawa, M., Matsunaga, K., Mori, H., Murakami, A., Kuki, W., Miyashita, K. and Tanaka, T.: Dietary conjugated Takahashi, Y., Yonei, H., Satoh, K., Hara, A., linolenic acid inhibits azoxymethane-induced colonic Maeda, M., Ota, T., Odashima, S., Koshimizu, K. and aberrant crypt foci in rats. Jpn. J. Cancer Res., 93: Ohigashi, H.: Chemoprevention of 4-nitroquinoline 1- 133–142 (2002). oxide-induced oral carcinogenesis by citrus auraptene 74) Das, S.: Garlic-A Natural Source of Cancer Preventive in rats. Carcinogenesis., 19: 425–431 (1998). Compounds. Asian Pac. J. Cancer Prev., 3: 305–311 86) Kawabata, K., Yamamoto, T., Hara, A., Shimizu, M., (2002). Yamada, Y., Matsunaga, K., Tanaka, T. and Mori, 75) Reddy, B. S., Rao, C. V., Rivenson, A. and KelloŠ, H.: Modifying eŠects of ferulic acid on azoxymethane- G.: Chemoprevention of colon carcinogenesis by induced colon carcinogenesis in F344 rats. Cancer Lett., organosulfur compounds. Cancer Res., 53: 3493–3498 157: 15–21 (2000). p245 p.17 [100%]

Cancer Prevention by Natural Compounds 261

87) Tanaka,T.,Kojima,T.,Kawamori,T.,Wang,A., vents photocarcinogenesis in SKH-1 hairless mice: Suzui, M., Okamoto, K. and Mori, H.: Inhibition of 4- relationship to decreased fat and lipid peroxidation. nitroquinoline-1-oxide-induced rat tongue carcinogene- Carcinogenesis, 24: 1379–1388 (2003). sis by the naturally occurring plant phenolics caŠeic, 98) Sarkar, F. H. and Li, Y.: Soy iso‰avones and cancer ellagic, chlorogenic and ferulic acids. Carcinogenesis, prevention. Cancer Invest., 21: 744–757 (2003). 14: 1321–1325 (1993). 99) Messina,M.J.andLoprinzi,C.L.:Soyforbreast 88) Han, B. S., Park, C. B., Takasuka, N., Naito, A., cancer survivors: a critical review of the literature. J. Sekine, K., Nomura, E., Taniguchi, H., Tsuno, T. and Nutr., 131: 3095S-3108S (2001). Tsuda, H.: A ferulic acid derivative, ethyl 3-(4?-ge- 100) Messina, M. J.: Emerging evidence on the role of soy in ranyloxy-3-methoxyphenyl)-2-propenoate, as a new reducing prostate cancer risk. Nutr. Rev., 61: 117–131 candidate chemopreventive agent for colon carcinogen- (2003). esis in the rat. Jpn. J. Cancer Res., 92: 404–409 (2001). 101) Adlercreutz, H.: Phytoestrogens and breast cancer. J. 89) Kohno, H., Tanaka, T., Kawabata, K., Hirose, Y., Steroid Biochem. Mol. Biol., 83: 113–118 (2002). Sugie, S., Tsuda, H. and Mori, H.: Silymarin, a natur- 102) Tsuda, H., Naito, A., Kim, C. K., Fukamachi, K., ally occurring polyphenolic antioxidant ‰avonoid, Nomoto, H. and Moore, M. A.: Carcinogenesis and its inhibits azoxymethane-induced colon carcinogenesis in modiˆcation by environmental endocrine disruptors: in male F344 rats. Int. J. Cancer, 101: 461–468 (2002). vivo experimental and epidemiological ˆndings. Jpn. J. 90) Yanaida, Y., Kohno, H., Yoshida, K., Hirose, Y., Clin. Oncol., 33: 259–270 (2003). Yamada, Y., Mori, H. and Tanaka, T.: Dietary 103) Casanova, M., You, L., Gaido, K. W., Archibeque- silymarin suppresses 4-nitroquinoline 1-oxide-induced Engle,S.,Janszen,D.B.andHeck,H.A.: tongue carcinogenesis in male F344 rats. Carcinogene- Developmental eŠects of dietary phytoestrogens in sis, 23: 787–794 (2002). Sprague-Dawley rats and interactions of genistein and 91) Vinh, P. Q., Sugie, S., Tanaka, T., Hara, A., Yamada, daidzein with rat estrogen receptors alpha and beta in Y.,Katayama,M.,Deguchi,T.andMori,H.: vitro. Toxicol. Sci., 51: 236–244 (1999). Chemopreventive eŠects of a ‰avonoid antioxidant 104) Chan, H. Y. and Leung, L. K.: A potential protective silymarin on N-butyl-N-(4-hydroxybutyl)nitrosamine- mechanism of soya iso‰avones against 7,12-dimethyl- induced urinary bladder carcinogenesis in male ICR benz[a]anthracene tumour initiation. Br. J. Nutr., 90: mice. Jpn. J. Cancer Res., 93: 42–49 (2002). 457–465 (2003). 92) Singletary,K.W.andMeline,B.:EŠectofgrapeseed 105) Constantinou, A. I., Lantvit, D., Hawthorne, M., Xu, proanthocyanidins on colon aberrant crypts and breast X., van Breemen, R. B. and Pezzuto, J. M.: tumors in a rat dual-organ tumor model. Nutr. Cancer, Chemopreventive eŠects of soy protein and puriˆed soy 39: 252–258 (2001). iso‰avones on DMBA-induced mammary tumors in 93) Zhao,J.,Wang,J.,Chen,Y.andAgarwal,R.:Anti- female Sprague-Dawley rats. Nutr. Cancer, 41: 75–81 tumor-promoting activity of a polyphenolic fraction (2001). isolated from grape seeds in the mouse skin two-stage 106) Lian, Z., Niwa, K., Tagami, K., Hashimoto, M., Gao, initiation-promotion protocol and identiˆcation of J., Yokoyama, Y., Mori, H. and Tamaya, T.: procyanidin B5–3?-gallate as the most eŠective antiox- Preventive eŠects of iso‰avones, genistein and idant constituent. Carcinogenesis, 20: 1737–1745 daidzein, on estradiol-17beta-related endometrial (1999). carcinogenesis in mice. Jpn. J. Cancer Res., 92: 94) Hagiwara, A., Miyashita, K., Nakanishi, T., Sano, 726–734 (2001). M., Tamano, S., Kadota, T., Koda, T., Nakamura, 107) Fournier, D. B., Erdman, J. W., Jr. and Gordon, G. M., Imaida, K., Ito, N. and Shirai, T.: Pronounced B.: Soy, its components, and cancer prevention: a inhibition by a natural anthocyanin, purple corn color, review of the in vitro, animal, and human data. Cancer of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Epidemiol. Biomarkers Prev., 7: 1055–1065 (1998). (PhIP)-associated colorectal carcinogenesis in male 108) Park, O. J. and Surh, Y. J.: Chemopreventive F344 rats pretreated with 1,2-dimethylhydrazine. potential of epigallocatechin gallate and genistein: Cancer Lett., 171: 17–25 (2001). evidence from epidemiological and laboratory studies. 95) Yamagishi, M., Natsume, M., Osakabe, N., Okazaki, Toxicol. Lett., 150: 43–56 (2004). K., Furukawa, F., Imazawa, T., Nishikawa, A. and 109) Cross, H. S., Kallay, E., Lechner, D., Gerdenitsch, Hirose, M.: Chemoprevention of lung carcinogenesis W., Adlercreutz, H. and Armbrecht, H. J.: Phytoes- by cacao liquor proanthocyanidins in a male rat multi- trogens and Vitamin D Metabolism: A New Concept organ carcinogenesis model. Cancer Lett., 191: 49–57 for the Prevention and Therapy of Colorectal, (2003). Prostate, and Mammary Carcinomas. J. Nutr., 134: 96) Wang, H., Nair, M. G., Strasburg, G. M., Chang, Y. 1207S-1212S (2004). C., Booren, A. M., Gray, J. I. and DeWitt, D. L.: 110) Yi, M. A., Son, H. M., Lee, J. S., Kwon, C. S., Lim, Antioxidant and antiin‰ammatory activities of anthoc- J.K.,Yeo,Y.K.,Park,Y.S.andKim,J.S.: yanins and their aglycon, cyanidin, from tart cherries. Regulation of male sex hormone levels by soy iso‰a- J. Nat. Prod., 62: 294–296 (1999). vones in rats. Nutr. Cancer, 42: 206–210 (2002). 97) Mittal, A., Elmets, C. A. and Katiyar, S. K.: Dietary 111) Ho, S. C., Woo, J. L., Leung, S. S., Sham, A. L., feeding of proanthocyanidins from grape seeds pre- Lam, T. H. and Janus, E. D.: Intake of soy products is p245 p.18 [100%]

262 Hiroyuki TSUDA et al.

associated with better plasma lipid proˆles in the Hong (2003). Kong Chinese population. J. Nutr., 130: 2590–2593 124) Anzai, N., Taniyama, T., Nakandakari, N., Sugiyama, (2000). C.,Negishi,T.,Hayatsu,H. and Negishi, K.: Inhibi- 112) Su, S. J., Chow, N. H., Kung, M. L., Hung, T. C. and tion of DNA adduct formation and mutagenic action Chang, K. L.: EŠects of soy iso‰avones on apoptosis of 3-amino-1-methyl-5h-pyrido[4,3-b]indole by chlo- induction and G2-M arrest in human hepatoma cells rophyllin-chitosan in rpsL transgenic mice. Jpn. J. involvement of caspase-3 activation, Bcl-2 and Bcl-XL Cancer Res., 92: 848–853 (2001). downregulation, and Cdc2 kinase activity. Nutr. 125) Guo, D., Schut, H. A., Davis, C. D., Snyderwine, E. Cancer, 45: 113–123 (2003). G., Bailey, G. S. and Dashwood, R. H.: Protection by 113) Barthelman, M., Bair, W. B., 3rd, Stickland, K. K., chlorophyllin and indole-3-carbinol against 2-amino- Chen, W., Timmermann, B. N., Valcic, S., Dong, Z. 1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-in- and Bowden, G. T.: (－)-Epigallocatechin-3-gallate duced DNA adducts and colonic aberrant crypts in the inhibition of ultraviolet B-induced AP-1 activity. F344 rat. Carcinogenesis, 16: 2931–2937 (1995). Carcinogenesis, 19: 2201–2204 (1998). 126) Dashwood, R., Yamane, S. and Larsen, R.: Study of 114) Fujiki, H., Suganuma, M., Okabe, S., Sueoka, N., the forces of stabilizing complexes between chlo- Komori, A., Sueoka, E., Kozu, T., Tada, Y., Suga, K., rophylls and heterocyclic amine mutagens. Environ. Imai, K. and Nakachi, K.: Cancer inhibition by green Mol. Mutagen., 27: 211–218 (1996). tea. Mutat. Res., 402: 307–310 (1998). 127) Kim, J., Yook, J. I., Park, K. K., Jung, S. Y., Hong, 115) Hernaez, J., Xu, M. and Dashwood, R.: EŠects of tea J. C., Kim, K. J., Kim, J. A. and Chung, W. Y.: Anti- and chlorophyllin on the mutagenicity of N-hydroxy- promotion eŠect of chlorophyllin in DMBA-TPA-in- IQ: studies of enzyme inhibition, molecular complex duced mouse skin carcinogenesis. Anticancer Res., 20: formation, and degradationWscavenging of the active 1493–1498 (2000). metabolites. Environ. Mol. Mutagen., 30: 468–474 128) Torzsas, T. L., Kendall, C. W., Sugano, M., Iwamoto, (1997). Y. and Rao, A. V.: The in‰uence of high and low 116) Suganuma, M., Okabe, S., Sueoka, N., Sueoka, E., molecular weight chitosan on colonic cell proliferation Matsuyama, S., Imai, K., Nakachi, K. and Fujiki, H.: and aberrant crypt foci development in CF1 mice. Green tea and cancer chemoprevention. Mutat. Res., Food Chem. Toxicol., 34: 73–77 (1996). 428: 339–344 (1999). 129) Munday, R. and Munday, C. M.: Selective induction 117) Lambert, J. D. and Yang, C. S.: Mechanisms of cancer of phase II enzymes in the urinary bladder of rats by prevention by tea constituents. J. Nutr., 133: 3262S- allyl isothiocyanate, a compound derived from 3267S (2003). Brassica vegetables. Nutr. Cancer, 44: 52–59 (2002). 118) Thapliyal, R. and Maru, G. B.: Inhibition of 130) Tang, L. and Zhang, Y.: Isothiocyanates in the cytochrome P450 isozymes by curcumins in vitro and in chemoprevention of bladder cancer. Curr. Drug vivo. Food Chem. Toxicol., 39: 541–547 (2001). Metab., 5: 193–201 (2004). 119) Kawamori, T., Lubet, R., Steele, V. E., KelloŠ, G. J., 131) Spitz, M. R., Duphorne, C. M., Detry, M. A., Pillow, Kaskey, R. B., Rao, C. V. and Reddy, B. S.: P.C.,Amos,C.I.,Lei,L.,deAndrade,M.,Gu,X., Chemopreventive eŠect of curcumin, a naturally Hong, W. K. and Wu, X.: Dietary intake of isothioc- occurring anti-in‰ammatory agent, during the promo- yanates: evidence of a joint eŠect with glutathione tionWprogression stages of colon cancer. Cancer Res., S-transferase polymorphisms in lung cancer risk. 59: 597–601 (1999). Cancer Epidemiol. Biomarkers Prev., 9: 1017–1020 120) Maltzman,T.H.,Hurt,L.M.,Elson,C.E.,Tanner, (2000). M. A. and Gould, M. N.: The prevention of 132) Thornalley, P. J.: Isothiocyanates: mechanism of nitrosomethylurea-induced mammary tumors by d- cancer chemopreventive action. Anticancer Drugs, 13: limonene and orange oil. Carcinogenesis, 10: 781–783 331–338 (2002). (1989). 133) Rao, K. V., Johnson, W. D., Bosland, M. C., Lubet, 121) Crowell, P. L. and Gould, M. N.: Chemoprevention R. A., Steele, V. E., KelloŠ, G. J. and McCormick, D. and therapy of cancer by d-limonene. Crit. Rev. L.: Chemoprevention of rat prostate carcinogenesis by Oncog., 5: 1–22 (1994). early and delayed administration of dehydroepian- 122) Chen, X., Yano, Y., Hasuma, T., Yoshimata, T., drosterone. Cancer Res., 59: 3084–3089 (1999). Yinna, W. and Otani, S.: Inhibition of farnesyl protein 134) Shibata, M., Hasegawa, R., Imaida, K., Hagiwara, A., transferase and P21ras memebrane association by d- Ogawa,K.,Hirose,M.,Ito,N.andShirai,T.: limonene in human pancreas tumor cells in vitro. Chin. Chemoprevention by dehydroepiandrosterone and Med. Sci. J., 14: 138–144 (1999). indomethacin in a rat multiorgan carcinogenesis 123) Blum,C.A.,Xu,M.,Orner,G.A.,DarioDiaz,G., model. Cancer Res., 55: 4870–4874 (1995). Li, Q., Dashwood, W. M., Bailey, G. S. and 135) Schulz, S. and Nyce, J. W.: Inhibition of protein Dashwood, R. H.: Promotion versus suppression of rat isoprenylation and p21ras membrane association by colon carcinogenesis by chlorophyllin and chlorophyll: dehydroepiandrosterone in human colonic adenocarci- modulation of apoptosis, cell proliferation, and beta- noma cells in vitro. Cancer Res., 51: 6563–6567 (1991). cateninWTcf signaling. Mutat. Res., 523–524: 217–223 136) Gordon, G. B., Shantz, L. M. and Talalay, P.: Modulation of growth, diŠerentiation and carcinogen- p245 p.19 [100%]

Cancer Prevention by Natural Compounds 263

esis by dehydroepiandrosterone. Adv. Enzyme. Regul., 144) Wang, W. P., Iigo, M., Sato, J., Sekine, K., Adachi, I. 26: 355–382 (1987). and Tsuda, H.: Activation of intestinal mucosal 137) Tsuda, H., Sekine, K., Ushida, Y., Kuhara, T., immunity in tumor-bearing mice by lactoferrin. Jpn. J. Takasuka, N., Iigo, M., Han, B. S. and Moore, M. A.: Cancer Res., 91: 1022–1027 (2000). Milk and dairy products in cancer prevention: focus on 145) Shimamura, M., Yamamoto, Y., Ashino, H., Oikawa, bovine lactoferrin. Mutat. Res., 462: 227–233 (2000). T.,Hazato,T.,Tsuda,H.,Iigo,M.Bovinelactoferrin 138) Sekine, K., Watanabe, E., Nakamura, J., Takasuka, inhibits tumor-induced angiogenesis. Int. J. Cancer, N.,Kim,D.J.,Asamoto,M.,Krutovskikh,V.,Baba- 111: 111–116 (2004). Toriyama,H.,Ota,T.,Moore,M.A.,Masuda,M., 146) Roy, M. K., Kuwabara, Y., Hara, K., Watanabe, Y. Sugimoto, H., Nishino, H., Kakizoe, T. and Tsuda, and Tamai, Y.: Peptides from the N-terminal end of H.: Inhibition of azoxymethane-initiated colon tumor bovine lactoferrin induce apoptosis in human leukemic by bovine lactoferrin administration in F344 rats. Jpn. (HL-60) cells. J. Dairy Sci., 85: 2065–2074 (2002). J. Cancer Res., 88: 523–526 (1997). 147) Fujita. K-I, Matsuda, E., Sekine, K., Iigo, M., Tsuda, 139) Sekine, K., Ushida, Y., Kuhara, T., Iigo, M., Baba- H. Lactoferrin enhances Fas expression and apoptosis Toriyama, H., Moore, M. A., Murakoshi, M., Satomi, in the colon mucosa of azoxymethane-treated rats, Y., Nishino, H., Kakizoe, T. and Tsuda, H.: Inhibition Carcinogenesis, 25: 1–6 (2004). of initiation and early stage development of aberrant 148) Varadhachary, A., Wolf, J. S., Petrak, K., O7Malley, crypt foci and enhanced natural killer activity in male Jr.,Spadaro,M.,Curcio,C.,Forni,G.,Pericle,F.: rats administered bovine lactoferrin concomitantly Oral lactoferrin Inhibits growth of established tumors with azoxymethane. Cancer Lett., 121: 211–216 (1997). and potentiates conventional chemotherapy. Int. J. 140) Ushida, Y., Sekine, K., Kuhara, T., Takasuka, N., Cancer, 111: 398–403 (2004). Iigo, M. and Tsuda, H.: Inhibitory eŠects of bovine 149) Tsuda, H., Sekine, K., Takasuka, N., Toriyama-Baba, lactoferrin on intestinal polyposis in the Apc(Min) H. and Iigo, M.: Prevention of colon carcinogenesis mouse. Cancer Lett., 134: 141–145 (1998). andcarcinomametastasisbyorallyadministered 141) Fujita,K.,Ohnishi,T.,Sekine,K.,Iigo,M.and bovine lactoferrin in animals. Biofactors, 12: 83–88 Tsuda, H.: Down-regulation of 2-amino-3,8- (2000). dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced 150) Tsuda, H., Sekine, K., Fujita, K. and Ligo, M.: Cancer CYP1A2 expression is associated with bovine lactofer- prevention by bovine lactoferrin and underlying rin inhibition of MeIQx-induced liver and colon mechanisms–a review of experimental and clinical carcinogenesis in rats. Jpn. J. Cancer Res., 93: 616–625 studies. Biochem. Cell Biol., 80: 131–136 (2002). (2002). 151) Kakizoe, T.: Chemoprevention of cancer–focusing on 142) Iigo, M., Kuhara, T., Ushida, Y., Sekine, K., Moore, clinical trials. Jpn. J. Clin. Oncol., 33: 421–442 (2003). M. A. and Tsuda, H.: Inhibitory eŠects of bovine 152) Greenwald, P., McDonald, S. S. and Anderson, D. E.: lactoferrin on colon carcinoma 26 lung metastasis in An evidence-based approach to cancer prevention mice. Clin.Exp.Metastasis, 17: 35–40 (1999). clinical trials. Eur. J. Cancer Prev., 11 Suppl 2: S43–47 143) Iigo, M., Shimamura, M., Matsuda, E., Fujita, K., (2002). Nomoto, H., Satoh, J., Kojima, S., Alexander, D. B., Moore, M. A. and Tsuda, H.: Orally administered bovine lactoferrin induces caspase-1 and interleukin-18 in the mouse intestinal mucosa: a possible explanation for inhibition of carcinogenesis and metastasis. Cytokine, 25: 36–44 (2004).