Evaluation of antiproliferative efficacy of selected COX-2 inhibitors in rat colon cancer

Colorectal cancer (CRC) is the third most common cancer worldwide and has a complex aetiology consisting of environmental and genetic factors. The dimethyhydrazine (DMH) is an agent well-established, and widely used for experimental colon carcinogenesis. Early diagnosis and treatment of CRCs are of importance for improving the survival. Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents against a variety of cancers owing to their capability in blocking the tumor development and cellular proliferation. In the present study, it was aimed to evaluate the chemopreventive effects two NSAIDs (diclofenac and celecoxib) on tumor development and proliferation in experimental CRC model. Wistar rats divided into four groups. Rats in group 1 received 1 mL DMSO and 1 mM EDTA for initial 12 weeks and treated with only DMSO for remaining 13 weeks served as control. Group 2 rats received DMH (25 mg/kg body weight) once a week subcutaneously for the first 12 weeks and treated with 1 mL DMSO throughout experimental period which represent the colon cancer bearing rats. Group 3 and 4 received DMH as in group 2. In addition, Group 3 rats received diclofenac (8 mg/kg body weight) and group 4 received celecoxib (6 mg/kg body weight) via oral gavage 25 weeks every day. The serum levels of CEA, HIF-1α, PCNA, and Ki-67 were determined by ELISA. Western blot analysis was utilized to detect the expression of the PTEN, PI3K and Akt. The levels of CEA, HIF-1α, PCNA and Ki-67 increased following DMH treatment. Administration of the selected chemoprevetive agents significantly returned these levels to near normal, which points out the anti-carcinogenic efficacy of diclofenac and celecoxib. Western blot analysis revealed that treatment with DMH lead to loss of PTEN and also elevate PI3K and Akt protein expression levels. The findings also revealed that rats received diclofenac and celecoxib treatment show markedly increased PTEN protein expression and decreased PI3K and Akt protein expressions. These results indicate that the nonselective or selective COX-2 inhibiting agents protects against the development of major forms of cancer and suppress DMH induced cell proliferation.