title: Inhibition of intestinal polyp formation by pitavastatin, a HMG-CoA reductase inhibitor.
abstract: It has been suggested that hyperlipidemia is positively associated with colon carcinogenesis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, reduce serum lipid levels. In this study, we clarified the effects of a novel chemically synthesized statin, pitavastatin, on intestinal polyp formation in Min mice, and further examined serum lipid and adipocytokine levels, and proinflammatory and adipocytokine gene levels in intestinal mucosa of Min mice. Treatment with pitavastatin at doses of 20 and 40 ppm decreased the total number of polyps dose-dependently to 85.2% and 65.8% (P < 0.05) of the untreated value, respectively. Serum levels of total cholesterol and triglyceride were slightly reduced and those of IL-6, leptin, and MCP-1 were decreased by 40-ppm pitavastatin treatment. mRNA expression levels of cyclooxygenase-2, IL-6, inducible nitric oxide (iNOS), MCP-1, and Pai-1 were significantly reduced in intestinal nonpolyp parts by pitavastatin treatment. Among them, iNOS mRNA levels were also reduced in the intestinal polyps. Moreover, oxidative stress represented by 8-nitroguanosine in the small intestinal epithelial cells was reduced by pitavastatin treatment. Related to these proinflammatory genes, PPARγ activity was activated in the intestinal nonpolyp parts and in the liver of Min mice with pitavastatin treatment. These results indicated that pitavastatin has potential benefit for the suppression of intestinal polyp development.
authors.affiliation: Cancer Prevention Basic Research Project, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Teraoka
authors.forename: Michihiro
authors.initials: M
authors.lastname: Mutoh
authors.forename: Shinji
authors.initials: S
authors.lastname: Takasu
authors.forename: Toshiya
authors.initials: T
authors.lastname: Ueno
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugimura
authors.forename: Keiji
authors.initials: K
authors.lastname: Wakabayashi
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000097:blood; D002784:Cholesterol / Q000097:blood; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006151:Guanosine / Q000031:analogs & derivatives / Q000097:blood; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000097:blood; D007417:Intestinal Polyps / Q000517:prevention & control*; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000097:blood; D009574:Nitro Compounds / Q000097:blood; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011804:Quinolines / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: C481144:8-nitroguanosine; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D020738:Leptin; D009574:Nitro Compounds; D017395:Plasminogen Activator Inhibitor 1; D011804:Quinolines; D014280:Triglycerides; D006151:Guanosine; D002784:Cholesterol; D052247:Nitric Oxide Synthase Type II; C108475:pitavastatin