Chemoprevention of Colon Cancer by Select ... - ACS Publications


B. S. Reddy. Division of Nutritional Carcinogenesis, American Health Foundation, ... Chemoprevention refers to the administration of chemical agents, ...
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Chapter 3

Chemoprevention of Colon Cancer by Select Phytochemicals

Downloaded by UNIV OF MICHIGAN ANN ARBOR on October 23, 2014 | http://pubs.acs.org Publication Date: September 24, 1998 | doi: 10.1021/bk-1998-0701.ch003

B. S. Reddy Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, NY 10595

Cancer of the colon is the leading cause of cancer deaths in the United States and western countries. Epidemiological data, including both cohort and case-control studies suggest that plant foods including fruits and vegetables have preventive potential. Plant foods are a good source of potentially antimutagenic and anticarcinogenic agents including carotenoids, allium compounds, and curcuminoids, to cite a few. Laboratory studies have provided relevant mechanistic and efficacy data on the role of specific phytochemicals in the carcinogenic process. Dietary administration of diallyl disulfide, anetholetrithione, curcumin, caffeic acid esters, and phytic acid inhibits colon carcinogenesis in the rodent model. Mechanistically, organosulfur compounds have been found to modulate the formation and bioactivation of carcinogens whereas curcumin and caffeic acid esters have been shov/n to induce phase II enzymes and inhibit cyclooxygenase and/or lypoxygenase activities suggesting that the modulation of arachidonic acid by these agents may play a role in their chemopreventive activity.

Several human epidemiological studies and supporting data from laboratory animal studies suggest that dietary factors play an important role in the etiology of several cancers. Epidemiological studies, both cohort and case-control, strongly suggest that consumption of certain vegetables and fruits reduce the risk of development of cancers at many sites including colon (7). Among specific categories of vegetables, higher intake of cruceferous vegetables was associated with lower risk for colon cancer development (7). There are many biologically plausible reasons as to why dietary intake of plant foods might slow or prevent the occurrence of cancer. Fruits and vegetables are a good source of potentially anticarcinogenic and antimutagenic substances including carotenoids, vitamin E, selenium, dietary fiber,

©1998 American Chemical Society

In Functional Foods for Disease Prevention I; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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24 dithiolethiones, protease inhibitors, oligofructoses, allium compounds, and curcuminoids, to cite a few. Inhibition of development of cancer by administration of dietary factors that directly and/or indirectly inhibit the cancer-producing effects of genotoxic and promoting substances offers an excellent approach to cancer prevention. As our understanding of the mechanisms of carcinogenesis has increased, possibilities have emerged for interfering at multiple points along carcinogenic process namely during initiation, promotion and progression. Chemoprevention refers to the administration of chemical agents, both naturally occurring micronutrients and non-nutrients in foods and synthetic, to prevent the initiational and promotional events occurring during the process of neoplastic development (2,3). Wattenberg (3) has classified chemopreventive agents into three broad categories, with distinctly different functions; these include the agents that can block the metabolic activation of carcinogens; agents that can prevent the formation of carcinogens from precursors; and agents that can suppress the expression of neoplasia in cells previously exposed to an effective dose of carcinogen. In addition, several chemopreventive agents have been shown to inhibit tumorigenesis both by blocking the metabolic activation of carcinogens and by suppressing the promotion and progression of tumors. Several micronutrients and non-nutrients present in food fit very well into these categories. The great diversity of the compounds is a positive feature indicating the possibility that a variety of approaches to cancer prevention by these agents can be made and that the options for selecting the right chemopreventive agents will be large (3). Naturally-occurring non-nutrient substances that have been intensely investigated for their potential chemopreventive properties include organosulfur compounds, aromatic isothiocyanates, dithiolethiones, polyphenols, curcumin, phytic acid, and ellagic acid, to cite a few. This chapter does not attempt to review all compounds present in food but focuses on few a agents that have been shown to inhibit colon carcinogenesis.

Organosulfur Compounds Diallyl Disulfide. Organosulfur compounds present in garlic and onions, such as allyl sulfide, allyl disulfide, and allyl methyl di- and trisulfides, and garlic and onion oils have been found to inhibit carcinogenesis at several organ sites (4,5). Allyl methyl trisulfide, diallyl sulfide, and diallyl trisulfide administered orally prior to carcinogen treatment (initiation stage) inhibited benzo[a]pyrene[B(a)P]-induced and nitrosodiethylamine-induced forestomach tumors in mice (4). In these studies, the compound to most inhibit tumorigenesis was dially disulfide. Also, diallyl disulfide administered during the initiation phase inhibited Nnitrosomethylbenzylamine-induced esophageal tumorigenesis in rats (5). The effect of diallyl disulfide on colon carcinogenesis was also investigated in the laboratory animal models (6,7). Diallyl disulfide administered in the diet prior to

In Functional Foods for Disease Prevention I; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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Downloaded by UNIV OF MICHIGAN ANN ARBOR on October 23, 2014 | http://pubs.acs.org Publication Date: September 24, 1998 | doi: 10.1021/bk-1998-0701.ch003

carcinogen treatment inhibited 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats. The inhibitory effects of these compounds during the initiation phase may be due to inhibition of carcinogen activation through the suppression of oxidative metabolism of carcinogen. Administration of diallyl disulfide during the postinitiation phase inhibited DMH-induced colon carcinogenesis in rats, but this inhibition of colon carcinogenesis was associated with the retardation of body weight gain. We have investigated the effect of dietary diallyl disulfide on azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats (7). Also, the effects of this agent on the activities of phase II enzymes, namely glutathione s-transferase (GST), NAD(P)H-dependent quinone reductase (QR), and UDP-glucuronsosyl transferase (UDP-GT) in the colon were determined. Prior to initiation of chemoprevention study, the maximum tolerated dose (MTD) level of diallyl disulfide was determined in a subchronic toxicity study. The M T D of diallyl disulfide was found to be 250 ppm. Dietary administration of 100 and 200 ppm diallyl disulfide equivalent to 40 and 80% M T D levels significantly inhibited the invasive adenocarcinomas of the colon (Table I). The inhibition of colon carcinogenesis by diallyl disulfide is associated with an increase in the activities of detoxifying enzymes such as GST, QR and UDP-GT in the colonic mucosa and tumors (Table II). It is possible that the protective effect of diallyl disulfide may be accounted for, at least in part, by its ability to induce the detoxifying enzymes in the colon. However, the mechanism of chemopreventive activity of this agent administered during the postinitiation period is not clearly known. Anethole Trithione. Several studies indicate that organosulfur compounds present in cruceferous vegetables (Brussels sprouts, cauliflower and cabbage) such as dithiolethiones have a role in cancer inhibition (3). Anethole trithione, a substituted dithiolthione has been evaluated in our laboratory for its chemopreventive activity against AOM-induced colon carcinogenesis (7). The M T D level of anethole trithione was found to be 250 ppm in male F344 rats. Administration of 200 ppm of anethole trithione in the diet significantly suppressed the incidence (percentage of animals with tumors) and multiplicity (tumors/animal) of both invasive and non-invasive adenocarcinomas of the colon whereas feeding of 100 ppm anethole trithione inhibited the invasive adenocarcinomas of the colon (Table I). Administration of anethole trithione strikingly increased the activities of GST, QR, and UDP-GT in the colonic mucosa and tumors (Table II). Although the exact mechanisms involved in its protective effects against colon carcinogenesis are not clearly elucidated, it appears that anethole trithione may, in part, inhibit colon carcinogenesis by blocking the formation of or trapping ultimate carcinogen electroophiles and/or by decreasing activation of carcinogen and by suppressing the effect of promoters in the target organ (5). The results of this study should provide a stimulus to design additional studies on the mechanisms of colon tumor inhibition by organosulfur compounds during the postinitiation stage of carcinogenesis.

In Functional Foods for Disease Prevention I; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

In Functional Foods for Disease Prevention I; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

13

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67 37 40

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53 53 58 47

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81 47 43

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78 64 64 58

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1.50±1.04 0.66±0.54 0.70±0.98

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1.66±0.21 1.33+0.22 1.10±0.21 1.00±0.18 0.64±0.15

Chemopreventive Properties of Organosulfur and Antiinflammatory Compounds Against Colon Carcinogenesis in Male F344 Rats* Adenocarcinoma incidence (percent animals with tumors) Adenocarcinomas/animal Invasive Noninvasive Total

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Reddy et al. (7); Rao et al. (15). Five-week old male F344 rats were fed the control diet and experimental diets containing various chemoprevetnive agents. Two weeks later, all animals were given s.c. injections of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight, once weekly for 2 weeks. All animals were continued on their respective dietary regimen until the termination of the experiment 52 weeks after the A O M treatment. M e a n ± S D (n=36) Significantly different from the control diet group, p