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Suppression of Intestinal Polyposis in Mdr1-deficient Apc^Min/+ Mice¹

Cancer Proteomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan

Aberrant transactivation of a certain set of target genes by the ß-catenin and T-cell factor/lymphoid enhancer factor complex has been considered crucial for the initiation of intestinal tumorigenesis. The human multidrug resistance (MDR)1 (ABCB1) gene contains multiple ß-catenin-T-cell factor4-binding elements in its promoter and is one of the immediate targets of the complex. In the current study, we have further substantiated the biological involvement of MDR1 in intestinal tumorigenesis based on the following evidence: (a) aberrant induction of the Mdr1a (Abcb1a) gene product, P-glycoprotein, associated with nuclear accumulation of the ß-catenin protein, was observed even in nascent microscopic adenomas of Min mice; (b) Mdr1-deficient Min (Apc^Min/+Mdr1a/b^-/-) mice developed significantly fewer intestinal polyps than did Apc^Min/+Mdr1a/b^+/+ mice; and (c) Inhibitors of P-glycoprotein, verapamil, and cyclosporin A had a suppressive effect on the in vitro polypoid growth of IEC6 expressing stabilized (N89) ß-catenin protein. Inhibitors of P-glycoprotein may be included in a novel class of chemopreventive agents against colorectal carcinogenesis.

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