Modulation of inflammatory changes in early stages of colon cancer through activation of PPARgamma by diclofenac.
The role of peroxisome proliferator-activated receptor gamma (PPARgamma) was investigated in 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colon carcinogenesis for 6 weeks (early stage) and its chemoprevention by diclofenac in a rat model. Morphological analysis revealed a marked occurrence of preneoplastic features, that is, multiple plaque lesions in the colonic mucosa. Administration of diclofenac at the anti-inflammatory dose along with DMH resulted a significant weakening of these lesions, thus proving the chemopreventive efficacy of diclofenac, which is a preferentially selective inhibitor for the proinflammatory enzyme, cyclooxygenase-2 (COX-2). The colonic mucosa showed increased protein expression and the enhanced activity of COX-2 in the DMH group, whereas the constitutively expressed COX-1 remained unaltered. Diclofenac treatment resulted in a significant reduction in COX-2 expression and its activity. The inflammatory changes were also demonstrated by nuclear factor-kappaB DNA binding activity, which was found to be increased after DMH treatment, thereby leading to the procarcinogenic effects, which were also adequately corrected by diclofenac. PPARgamma expression was found to be decreased after DMH treatment as seen both by western blot and immunohistochemistry. In addition, the protein expression of the apoptotic protease activating factor-1 was studied in the colonic mucosa to observe the role of apoptosis in this study, which showed a distinct decline in the DMH-treated animals. The expression of the protein was, however, recovered by diclofenac treatment to the level of the controls. It is possible that diclofenac may be exerting its chemopreventive action through PPARgamma, a ligand dependent transcription factor, which in turn activates apoptosis through inhibition of COX-2 and simultaneous activation of apoptotic protease activating factor-1.
Kaur
Jasmeet
J
Department of Biophysics, Punjab University, Chandigarh, India.
Sanyal
Sankar Nath
SN
D019813:1,2-Dimethylhydrazine; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D002273:Carcinogens; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004008:Diclofenac / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D047495:PPAR gamma / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D016588:Anticarcinogenic Agents; D053477:Apoptotic Protease-Activating Factor 1; D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D047495:PPAR gamma; D004008:Diclofenac; D051546:Cyclooxygenase 2; D019813:1,2-Dimethylhydrazine