title: Suppression of intestinal polyp development in Apc(Min/+) mice through inhibition of P-glycoprotein using verapamil.
abstract: P-glycoprotein (P-gp; encoded by the Mdr1a gene) is known to be associated with colon tumorigenesis through transcriptional activation and/or epigenetic modification. We investigated whether inhibition of P-gp function might decrease intestinal tumorigenesis. We used verapamil as an inhibitor of P-gp function in Apc(Min/+) mice, which lack a functional Apc gene product. We determined the number of intestinal polyps and 1-year survival rates after the ingestion of 10, 25, and 50 mg/kg/day verapamil contained in dry pellets. The number of polyps in Mdr1a(+/+)Apc(Min/+) mice fed with pellets containing verapamil was significantly lower than that in mice fed with verapamil-free pellets. The 1-year survival rate of verapamil-fed mice was also improved in a dose-dependent manner. These results were similar to data from P-gp knockout mice. These results indicated that it might be possible to use verapamil to inhibit polyp development during the early stage of colon carcinogenesis. Thus, we propose a novel chemopreventive agent for colorectal cancer that acts by inhibiting P-gp function.
authors.affiliation: Division of Molecular Biology, Nagasaki International University, Nagasaki, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Gen
authors.initials: G
authors.lastname: Fujii
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mutoh
authors.forename: Masa
authors.initials: M
authors.lastname: Yasunaga
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Morimasa
authors.initials: M
authors.lastname: Wada
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D004195:Disease Models, Animal; D017491:Genes, APC / Q000502:physiology; D007417:Intestinal Polyps / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014700:Verapamil / Q000008:administration & dosage*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014700:Verapamil