Evaluation of Simvastatin as CDK4 Inhibitor for the Treatment of Colon Cancer Associated with Diabetes Mellitus

Abstract

BACKGROUND AND OBJECTIVES Colon cancer a matter of concern for most countries across the globe and is one of the rapidly increasing types of cancer. Cancer of colon is considered to be a common malignancy of the gastrointestinal tract and the main reason behind this in the twenty first century is modern life styles, westernization and industrialization. Colorectal carcinoma is ranked among the top three cancers of the world behind lung and prostate cancer .An impressive data collected over past shows strong potential association between diabetes mellitus and colon cancer. The excess risk of colon cancer has reached to 30% in Type 2 diabetes mellitus patients. It has been reported that insulin plays an important role in the colorectal carcinogenesis and the mechanism unifying between two diseases is hyperinsulinemia. Cyclins and cyclin dependent kinases (CDKs) are regulatory molecules governing multiplication of the cells by promoting cell cycle phase transitions. Insulin has also been demonstrated to promote cellular mitogenic stimulation and facilitate the transition of the cells through G-1 phase in the cell cycle. CDK4-E2F-PRB pathways directly regulate the insulin secretion process in the β-cells. Thus, by blocking the CDK protein activity the cell growth can be halted and hence cell progression in cancer cells can be prevented. Moreover, by regulating β- cells and their proliferation, CDK4 also contributes to diabetes mellitus. Taking into consideration these facts we hypothesize that CDK4 can serve as a common target for colon cancer as well as for diabetes mellitus. Moreover, previous studies revealed that Simvastatinexert anticancer effects in different cancers like prostate, colon etc.Hence, the objective of the present investigation was to study the effect of Simvastatin on colon cancer associated with type 2 diabetes mellitus and to determine its mechanism of action. MATERIALS AND METHODS Type 2 Diabetes Mellitus were induced by giving high fed diet containing 58% fat, 25%protein and 17% carbohydrate, as a percentage of total kcal ad libitum, the diseasedgroups were fed with high fat diet for 2 weeks after which single low dose of thestreptozotocin (35mg/kg, ip) was given. After 6 weeks, diabetes was confirmed and 1, 2-dimethylhydrazine (25mg/kg, sc) weekly administration was administered upto 20 weeks.Rats were treated with Simvastatin (3.6 mg/kg, po) from 24th week upto 28th week. At the end of 28th week various biochemical parameters like glucose, Hb1Ac, Insulin, CEA were analyzed. Animals were sacrificed; tumor volume, tumor burden and tumor incidence were calculated. Colon tissue was subjected to analyses of oxidative stress parameters, histopathological studies and mRNA expression of p53 and CDK4. In vitro studies like MTT assay, clonogenic assay and scratch assay were also carried out.