Celecoxib, a cyclooxygenase-2 inhibitor, prevents induction of liver preneoplastic lesions in rats

Background/Aims: Several studies suggest that cyclooxygenase-2 (COX-2) inhibitors are chemopreventive agents against colon, breast and skin cancer. In this study, we evaluated the chemopreventive effect of celecoxib, a specific COX-2 inhibitor, on the development of liver preneoplastic lesions in rats. Methods: Male Sprague-Dawley rats were fed during 5 weeks either a control or an experimental diet containing 1500 ppm celecoxib on a medium-term hepatocarcinogenesis protocol. Livers were collected and evaluated by histological and biochemical assays. Results: A reduction by 80 and 90% both in the number and size of altered hepatic foci was observed in the group treated with celecoxib during hepatocarcinogenesis treatment, respectively. No evidence of apoptosis was observed in our present study, however, the expression of the proliferation markers such as PCNA and Ki-67 was drastically reduced. Interestingly, neither COX-2 expression nor prostaglandin-E-2 (PGE(2)) production were altered by the hepatocarcinogenic treatment or celecoxib treatment. Finally, celecoxib inhibited the translocation of Rel A/p65 to the nucleus with significant effect on stability of the repressor I kappa B-alpha. Conclusions: This is the first demonstration that a specific COX-2 inhibitor, celecoxib, possesses striking chemopreventive activity, inhibiting preneoplastic lesions during hepatocarcinogenesis in vivo, suggesting that celecoxib effects are mediated by PGE(2)-independent mechanisms. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.