A lipophilic statin, pitavastatin inhibits inflammation-associated mouse colon carcinogenesis Free

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We investigated that whether a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pitavastatin suppresses inflammation-related colon carcinogenesis in mice. To induce neoplasms in the inflamed colon, male CD-1 (ICR) mice were initiated with a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg bw) and followed by 2 % (w/v) dextran sodium sulfate (DSS) in drinking water for 7 days, starting one week after AOM exposure. They were then fed the experimental diets mixed with pitavastatin at two dose levels (1 and 10 ppm) for17 weeks, starting one week after the cessation of DSS treatment. The development of preneoplastic and neoplastic colonic lesions was histologically assessed at wks 5, 10, and 20 by counting their incidence and multiplicity. In addition, we immunohistochemically investigated the effects of pitavastatin on the indices of proliferating cell nuclear antigen (PCNA)-, apoptosis-, and nitrotyrosine-positive cells in colonic epithelial malignancy. The levels of serum cholesterol and triglyceride were also measured. At wk 20, feeding with pitavastatin significantly inhibited the occurrence of colonic adenocarcinoma (72% reduction by 1 ppm pitavastatin, p<0.001 and 62% reduction by 10 ppm pitavastatin, p<0.01) together with the reduction in the PCNA- and nitrotyrosine-positive rates and the increase in the apoptotic index of the malignancies. As for clinical chemistry, serum levels of total cholesterol and triglyceride were significantly decreased by the treatment. Our results thus clearly indicated that pitavastatin in diet is effective for inhibiting colitis-related colon carcinogenesis in mice through modulating the cell proliferating activity and/or hyperlipidemic state. Our findings also suggest possible application of pitavastatin in suppressing colon carcinogenesis in inflamed colon of humans.