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.
Tanwar
Lalita
L
Department of Biophysics, Panjab University, Chandigarh, India.
Vaish
Vivek
V
Sanyal
Sankar Nath
SN
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000517:prevention & control*; D045304:Cytochromes c / Q000096:biosynthesis; D000077613:Etoricoxib; D019254:Genes, bcl-2 / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011725:Pyridines; D013450:Sulfones; D045304:Cytochromes c; D000077613:Etoricoxib