Response of Apcmin and A33ΔNβ-cat mutant mice to treatment with tea, sulindac, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)

There is growing interest in the potential health benefits of tea, and a recent report described the potent antimutagenic activity of white tea in comparison with green tea against several heterocyclic amines, including 2-amino-1-methyl-6-phenytimidazo[4,5-b]pyridine (PhIP) [Mutat. Res. 495 (2001) 61]. We compared the inhibitory effects of white and green teas with sulindac, a nonsteroidal anti-inflammatory agent, in two different mouse models of intestinal tumorigenesis. In the Apemin mouse, white and green teas given at human-relevant concentrations (1.5 % w/v, 2-min brew), and sulindac (80 ppm in the drinking water), each suppressed polyp formation by similar to50%, and the combination of white tea plus sulindac was more effective than either treatment alone (P = 0.05). Mice expressing an N-terminally truncated, oncogenic version of beta-catenin (A33(DeltaNbeta-cat) mutant mice) developed colonic aberrant crypt foci (ACF) spontaneously, but PUP treatment increased the incidence and number of ACF per colon. In the normal-looking intestinal mucosa of Apc(min) and A33(DeltaNbeta-cat) mice, white tea plus sulindac treatment markedly attenuated the expression of R-catenin protein, and this was recapitulated in vitro in cells transiently transfected with beta-catenin plus Tcf-4 and treated with tea or the-major tea polyphenol epigallocatechin-beta-gallate (EGCG). Expression of a beta-catenin/Tcf reporter was inhibited by EGCG in the transfected cells, and the beta-catenin/Tcf target genes cyclin D1 and c-jun were downregulated in vivo by tea plus sulindac treatment. Collectively, the data support a chemopreventive role for tea and sulindac against intermediate and late stages of colon cancer, via effects on the beta-catenin/Tcf signaling pathway. (C) 2002 Elsevier Science B.V. All rights reserved.