Chemopreventive role of etoricoxib (MK-0663) in experimental colon cancer: induction of mitochondrial proapoptotic factors.

This study explored the role of intrinsic mitochondrial membrane potential (DeltaPsiM) in etoricoxib-mediated apoptosis in 1,2-dimethylhydrazine dihydrochloride (DMH) induced colon cancer. Male Sprague--Dawley rats were divided into four groups: control, DMH, DMH+etoricoxib and etoricoxib. After 6 weeks of treatment period, animals were killed and colons were analyzed for morphological and histopathological features. Well-characterized preneoplastic aberrations such as multiple plaque lesions, hyperplasia and dysplasia were found in the DMH-treated group whereas these features were reduced with coadministration of etoricoxib and DMH. DeltaPsiM was assessed by 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazol carbocyanine iodide (JC-1) fluorescent staining of the isolated colonocytes. DMH treatment led to a significant increase in DeltaPsiM which was found to be low in the DMH+etoricoxib group. The expression of important proapoptotic proteins, cytochrome C and Bax, were analyzed by western blot and immunohistochemistry. DMH treatment reduced the expression of Bax and cytochrome C whereas etoricoxib promoted the expression of the same. Protein expression of antiapoptotic protein Bcl-2 was also studied in colonic mucosa and was found high in the DMH-treated group and low in DMH+etoricoxib treated animals. Etoricoxib treatment may exert its chemopreventive action in colon carcinogenesis by modulating the DeltaPsiM.