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)

Gayle A. Orner, Wan Mohaiza Dashwood, Carmen A. Blum, G. Darío Díaz, Qingjie Li, Mohamad Al-Fageeh, Niall Tebbutt, Joan K. Heath, Matthias Ernst, Roderick H. Dashwood

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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 Apcmin mouse, white and green teas given at human-relevant concentrations (1.5% w/v, 2-min brew), and sulindac (80ppm in the drinking water), each suppressed polyp formation by ∼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 β-catenin (A33ΔNβ-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 Apcmin and A33ΔNβ-cat mice, white tea plus sulindac treatment markedly attenuated the expression of β-catenin protein, and this was recapitulated in vitro in cells transiently transfected with β-catenin plus Tcf-4 and treated with tea or the major tea polyphenol epigallocatechin-3-gallate (EGCG). Expression of a β-catenin/Tcf reporter was inhibited by EGCG in the transfected cells, and the β-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 β-catenin/Tcf signaling pathway.

Original languageEnglish (US)
Pages (from-to)121-127
Number of pages7
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume506-507
DOIs
StatePublished - Sep 30 2002
Externally publishedYes

Keywords

  • APC
  • Aberrant crypt foci
  • Heterocyclic amines
  • Polyps
  • Tcf/Lef
  • β-Catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis

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