Chemoprevention of azoxymethane-induced rat colon carcinogenesis by a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate.
ABSTRACT In our studies to find natural compounds with chemopreventive efficacy in foods, using azoxymethane (AOM)-induced colonic aberrant crypt foci and colonic mucosal cell proliferation as biomarkers, a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate (ACA), present in the edible plant Languas galanga from Thailand was found to be effective. This study was conducted to test the ability of ACA to inhibit AOM-induced colon tumorigenesis when it was fed to rats during the initiation or post-initiation phase. Male F344 rats were given three weekly s.c. injections of AOM (15 mg/kg body weight) to induce colonic neoplasms. They were fed diet containing 100 or 500 ppm ACA for 4 weeks, starting one week before the first dosing of AOM (the initiation feeding). The other groups were fed the ACA diet for 34 weeks, starting one week after the last AOM injection (the post-initiation feeding). At the termination of the study (week 38), AOM had induced 71% incidence of colonic adenocarcinoma (12/17 rats). The initiation feeding with ACA caused significant reduction in the incidence of colon carcinoma (54% inhibition by 100 ppm ACA feeding and 77% inhibition by 500 ppm ACA feeding, P = 0.03 and P = 0.001, respectively). The post-initiation feeding with ACA also suppressed the incidence of colonic carcinoma (45% inhibition by 100 ppm ACA feeding and 93% inhibition by 500 ppm ACA feeding, P = 0.06 and P = 0.00003, respectively). Such inhibition was dose-dependent and was associated with suppression of proliferation biomarkers, such as ornithine decarboxylase activity in the colonic mucosa, and blood and colonic mucosal polyamine contents. ACA also elevated the activities of phase II enzymes, glutathione S-transferase (GST) and quinone reductase (QR), in the liver and colon. These results indicate that ACA could inhibit the development of AOM-induced colon tumorigenesis through its suppression of cell proliferation in the colonic mucosa and its induction of GST and QR. The results confirm our previous finding that ACA feeding effectively suppressed the development of colonic aberrant crypt foci. These findings suggest possible chemopreventive ability of ACA against colon tumorigenesis.
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ABSTRACT: A continuing study of chemopreventive agents has focused on several categories of naturally occurring compounds that inhibit carcinogen activation and are effective in preventing carcinogen-induced neoplasia when administered at short time-intervals before carcinogen challenge. The inhibitory compounds are: aromatic isothiocyanates found in cruciferous vegetables, monoterpenes present in citrus fruits and caraway-seed oil, and organosulphur compounds occurring in Allium species. Preliminary work indicates that glucobrassicin and indoles existing in cruciferous vegetables also have these attributes. Almost all carcinogens that are consumed in food require metabolic activation. Thus, inhibition of carcinogen activation reactions could be effective against this type of exposure. In addition, three naturally occurring compounds, i.e. phenethyl isothiocyanate, D-limonene and dipropyl sulphide inhibit activation of the tobacco-specific carcinogen NNK, and accordingly may have the capacity to diminish carcinogenic response to exposures to tobacco. The property of cruciferous vegetables, orange oil, benzyl isothiocyanate, and D-limonene, to act as both blocking and suppressing agents has been discussed. Two possible mechanisms for this multi-phase activity were presented. The first is that these inhibitory substances activate a complex integrated defence mechanism against toxic compounds which entails both blocking and suppressing components. The blocking component is the initial line of defence, and the suppressing component constitutes a 'fail-safe' backup to assure that if any of the toxic material attacks cellular constituents, its effects will be nullified. The second possible mechanism considered is that the inhibitors, because of high reactivity, have multiple biological effects that are separate and not part of a single, coordinated response. Inhibitors that have both blocking and suppressing effects could be particularly useful as chemopreventive agents. A simple interim classification of foods in terms of their potential impact on the occurrences of cancer has been proposed.Proceedings of The Nutrition Society 08/1990; 49(2):173-83. · 3.67 Impact Factor
Article: Oncogenes and signal transduction.Cell 02/1991; 64(2):281-302. · 31.96 Impact Factor
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ABSTRACT: Aberrant crypts are putative preneoplastic lesions that have been proposed as intermediate biomarkers for colon cancer. The goals of these studies were to determine (i) if the colon cancer chemopreventive agent, sodium phytate, when started 1 week after a single dose of carcinogen, has any effect on the development of aberrant crypt foci (ACF) in treated rats; and (ii) if ACF at an early time period under these conditions correlate with the later formation of tumors in similarly treated animals. The number of ACF with four or more crypts was greater (P = 0.02, Mann-Whitney test) in rats with tumors compared with rats without tumors killed at 36 weeks after the injection of azoxymethane (AOM); the total number of ACF was not significantly different in these two groups. The incidence of tumors in F344 rats treated with AOM without phytate was 83% (10/12) compared to 25% (3/12) in rats treated with AOM plus phytate (P = 0.0045, two-tail Fisher's exact test). The finding of more (P = 0.005, Mann-Whitney test) ACF with four or more crypts in rats without phytate than in rats with phytate at 12 weeks after the injection of AOM is consistent with the hypothesis that the development of larger ACF (with four or more crypts) is predictive of the tumor incidence. These results validate the use of this parameter, i.e. ACF with four or more crypts, as an intermediate biomarker for tumor incidence in this system.Carcinogenesis 10/1992; 13(9):1509-12. · 5.64 Impact Factor