Response of Apc(min) and A33 (delta N beta-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-phenylimidazo[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 Apc(min) 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 approximately 50%, 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 (A 33(delta N beta-cat) mutant mice) developed colonic aberrant crypt foci (ACF) spontaneously, but PhIP treatment increased the incidence and number of ACF per colon. In the normal-looking intestinal mucosa of Apc(min) and A 33(delta N beta-cat) mice, white tea plus sulindac treatment markedly attenuated the expression of beta-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-3-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.
D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D007093:Imidazoles / Q000633:toxicity; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010936:Plant Extracts / Q000494:pharmacology*; D011127:Polyps / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D013467:Sulindac / Q000494:pharmacology*; D013662:Tea; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; D000894:Anti-Inflammatory Agents, Non-Steroidal; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004338:Drug Combinations; D007093:Imidazoles; D010936:Plant Extracts; D013662:Tea; D015534:Trans-Activators; D051176:beta Catenin; D013467:Sulindac; D002392:Catechin; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C045651:epigallocatechin gallate; D008156:Luciferases