Effects of white tea, EGCG and caffeine on PhIP-induced tumorigenesis and    β   -catenin expression

LB-144

There is growing interest in the health benefits of tea. We observed previously that, when administered post-initiation, white tea and its equivalent concentrations of EGCG and caffeine inhibited colonic aberrant crypts induced in the rat by 2-amino-1-methy-6-phenylimidazo[4,5-b]pyridine (PhIP). In the present study, rats were initiated with PhIP (50 mg/kg, every day by oral gavage) for 2 wks, followed by 4 wks of high fat (HF) diet. After 3 such cycles of PhIP/HF diet, 2% (w/v) white tea, 0.05% EGCG, 0.08% caffeine, or citrate-buffered water alone was administered as sole source of drinking fluid, until the study was terminated at 52 wks. Overall survival was enhanced by EGCG and attenuated by caffeine, but no significant change was effected by white tea (P>0.05). Unexpectedly, a higher incidence of colon tumors was seen in rats treated with white tea (68.8%, P<0.05) and caffeine (73.3%, P<0.05), compared with PhIP/HF controls (41.6%). White tea and caffeine, but not EGCG, also increased the average volume of colon tumors, whereas tumors in several other tissues were suppressed significantly by caffeine (P<0.05). The β-catenin gene mutation frequency was enhanced significantly by caffeine (79% vs 35.7% in PhIP/HF controls, P<0.05), with more mutations detected in Ctnnb1 codon 34. Quantitative real-time PCR showed that mRNA levels of β-catenin itself, and its target genes c-myc, c-jun and cyclin D1, were highly expressed in PhIP-induced colon tumors, but only c-myc changes were correlated with tumor promotion by white tea and caffeine. In colonic crypts, BrdU incorporation was enhanced significantly by caffeine (P<0.05), but not by white tea or EGCG, whereas cleaved caspase 3 was inhibited by both white tea and caffeine. The data imply that white tea and caffeine promoted colon tumors via enhanced survival of cells with β-catenin mutations, due to changes in the ratio of apoptosis to cell proliferation and enhanced activation of β-catenin/T-cell factor target genes. Work supported by NIH grants CA90890 and CA65525.