Chemoprevention by Pravastatin, a 3‐Hydroxy‐3‐methylglutaryl‐coenzyme A Reductase Inhibitor, of N‐Methyl‐N‐nitrosourea‐induced Colon Carcinogenesis in F344 Rats

Abstract

A potential chemopreventive action of pravastatin (Pr), a 3‐hydroxy‐3‐methylglutaryl‐coenzyme A redutase inhibitor, on colon carcinogenesis was evaluated in F344 rats. All rats at 7 weeks of age received an intrarectal dose of 2 mg of N‐methyl‐N‐nitrosourea 3 times weekly for 2 weeks in experiment I (2 groups of 16 rats each), and for 3 weeks in experiment II (4 groups of 30 rats each). They were given drinking water containing 0 ppm (control) or 200 ppm Pr during weeks 1 to 40 in experiment I, and containing 0 ppm (control), 25 ppm, 5 ppm and 1 ppm Pr during weeks 4 to 40 in experiment II. The body weight gains, and food and water intakes were similar in all the groups. The incidence of colon carcinomas at termination of the experiment at week 40 was not different in the 200 ppm Pr and control groups in experiment I (63% vs. 69%), while it was significantly lower in the 25 ppm and 5 ppm groups, but not in the 1 ppm Pr group, compared with the control group in experiment II (50%, 48%, and 77% vs. 80%). This inhibitory effect of Pr against colon carcinogenesis was not related to the cholesterol‐lowering effect of this agent. We postulate that Pr inhibits the promotion stage of colon carcinogenesis, perhaps through modulation of cholesterol synthesis in situ in the colonic mucosa, thereby suppressing farnesyl isoprenylation of growth‐regulating proteins such as p21 ras.

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

“…atorvastatin in both concentrations did not change serum triacylglycerols, total cholesterol, and LDL-cholesterol. Similarly, inhibitory effect of pravastatin against colon carcinogenesis in rats was not related to the cholesterol-lowering effect of this agent (Narisawa et al 1996). And similarly in another experiment of rat mammary carcinogenesis mentioned above, atorvastatin and lovastatin did not decrease serum triacylglycerols in animals, but in contrary to previous studies, drugs did not demonstrate significant antineoplastic effects in mammary gland carcinogenesis (Lubet et al 2009).…”

Mevalonate Promotes the Growth of Tumors Derived from Human Cancer Cells in Vivo and Stimulates Proliferation in Vitro with Enhanced Cyclin-dependent Kinase-2 Activity

“…Although the effect of pravastatin on the growth of experimental mammary tumors or gastrointestinal tumors in rodents has not been reported, at physiological concentrations, pravastatin does not inhibit the proliferation of human breast cancer cells (50) or gastric carcinoma cells (51) in culture. Interestingly, pravastatin does inhibit the growth of colon tumors in rats (52) and mice (53), in keeping with its ability to inhibit HMG-CoA reductase in intestinal cells (49,54). A reduced risk of colorectal cancer has also been reported in one human trial of pravastatin (16).…”

Statins are potential anticancerous agents (Review)

“…Statin-induced effects and the underlined mechanism in different cancer cell lines are presented in Table I. besides their in vitro efficacy, statins have also been shown to have in vivo antitumor effects in various animal models of cancer. Their efficacy as chemopreventive agents has been demonstrated in radiation-induced mammary tumorigenesis (22), chemical-induced colon tumorigenesis in rodent models (23,24), human myeloid leukemia and glioma cancer cells inoculated in severe combined immunodeficient mice (25,26), and chemical-induced lung tumor in mice (27). Statins have also been shown to reduce metastasis in rat lymphoma (28), rat fibrosarcoma (29), mouse mammary tumor (30), murine colon tumor (31) and mouse melanoma (32).…”