A cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammmatory drugenhances the growth inhibitory effect of butyrate in colorectal carcinoma cells expressing COX-2 protein: regulation of COX-2 by butyrate

Epidemiological, clinical, animal and laboratory studies have all provided evidence for the protective effects of non-steroidal anti-inflammatory drug s (NSAIDs), such as aspirin, against colorectal cancer. The main establishe d target for NSAID action is cyclooxygenase (COX) and the inducible isoform , COX-2, is up-regulated in colorectal cancer. Rat intestinal epithelial ce lls transfected with a COX-2 expression vector have previously been found t o be resistant to butyrate-induced apoptosis, Butyrate, a byproduct of diet ary fibre fermentation, is known to induce differentiation and apoptosis in colorectal tumour cells in vitro, In recent years there has been considera ble interest in the possible role of dietary fibre/resistant starch in the prevention of colorectal cancer. In this study we investigated whether inhi bition of COX-2 with a highly selective COX-2 inhibitor (NS-398) would sens itize human colorectal carcinoma cells to the growth inhibitory effect of b utyrate, HT29 and S/KS colorectal carcinoma cell lines were treated for 72 h with 2 mM butyrate and/or 10 mu M NS-398, Addition of 10 mu M NS-398 alon e (to inhibit COX-2 activity) did not result in detectable growth inhibitio n in either of the cell lines. NS-398 enhanced sensitivity to the growth in hibitory effect of butyrate in HT29 cells expressing COX-2 protein, In cont rast, NS-398 did not sensitize SMS cells lacking detectable COX-2 protein a nd function las determined by prostaglandin E-2 production) to the growth i nhibitory effect of butyrate, In addition, we report that butyrate treatmen t of carcinoma (HT29) and adenoma (PC/AA/C1) cells leads to up-regulation o f COX-2 protein. Thus NS-398 only appears to sensitize human colorectal car cinoma cells expressing COX-2 protein to the growth inhibitory effect of bu tyrate, As COX-2 is up-regulated in colorectal carcinogenesis, this could h ave important implications for the selective inhibition of cells expressing COX-2 protein over those lacking COX-2 protein expression and for dietary modification to be considered alongside NSAIDs in the prevention, and possi bly treatment, of colorectal cancer.