pitavastatin and Precancerous-Conditions

Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-db/db (db/db) obese mice.. Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks.. At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of TNF-α and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition.. Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Apoptosis; bcl-Associated Death Protein; Cocarcinogenesis; Crosses, Genetic; Diethylnitrosamine; Drug Screening Assays, Antitumor; Dyslipidemias; Fatty Liver; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-6; Leptin; Lipids; Liver; Liver Diseases; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Organ Size; Precancerous Conditions; Proto-Oncogene Proteins c-bcl-2; Quinolines; Tumor Necrosis Factor-alpha

Obesity and related metabolic abnormalities are risk factors for colorectal cancer. A state of chronic inflammation and adipocytokine imbalance may play a role in colorectal carcinogenesis. Statins, which are commonly used for the treatment of hyperlipidemia, are known to possess anti-inflammatory effects. Statins also exert chemopreventive properties against various cancers. The present study examined the effects of pitavastatin, a recently developed lipophilic statin, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were administrated weekly subcutaneous injections of AOM (15 mg/kg body weight) for 4 weeks and then were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 8 weeks. Feeding with either dose of pitavastatin significantly reduced the number of colonic premalignant lesions, beta-catenin accumulated crypts, by inhibiting proliferation and the surrounding inflammation. Pitavastatin increased the serum levels of adiponectin while conversely decreasing the serum levels of total cholesterol, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-18, and leptin. Pitavastatin also caused a significant increase in the expression of phosphorylated form of the AMP-activated kinase (AMPK) protein on the colonic mucosa of AOM-treated mice. In addition, the expression levels of TNF-alpha, IL-6, IL-18, and COX-2 mRNAs on the colonic mucosa of AOM-treated mice were decreased by treatment with this agent. These findings suggest that pitavastatin attenuates chronic inflammation and improves the imbalance of adipocytokines, both of which are caused by the presence of excess adipose tissues, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model. Therefore, some types of statins, including pitavastatin, may be a useful chemoprevention modality for colon cancer in obese individuals.

Topics: Animals; Azoxymethane; Carcinogens; Cell Division; Colonic Neoplasms; Cytokines; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Precancerous Conditions; Quinolines