A cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug enhances 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 drugs (NSAIDs), such as aspirin, against colorectal cancer. The main established target for NSAID action is cyclooxygenase (COX) and the inducible isoform, COX-2, is up-regulated in colorectal cancer. Rat intestinal epithelial cells transfected with a COX-2 expression vector have previously been found to be resistant to butyrate-induced apoptosis. Butyrate, a by-product of dietary fibre fermentation, is known to induce differentiation and apoptosis in colorectal tumour cells in vitro. In recent years there has been considerable interest in the possible role of dietary fibre/resistant starch in the prevention of colorectal cancer. In this study we investigated whether inhibition of COX-2 with a highly selective COX-2 inhibitor (NS-398) would sensitize human colorectal carcinoma cells to the growth inhibitory effect of butyrate. HT29 and S/KS colorectal carcinoma cell lines were treated for 72 h with 2 mM butyrate and/or 10 μM NS-398. Addition of 10 μM NS-398 alone (to inhibit COX-2 activity) did not result in detectable growth inhibition in either of the cell lines. NS-398 enhanced sensitivity to the growth inhibitory effect of butyrate in HT29 cells expressing COX-2 protein. In contrast, NS-398 did not sensitize S/KS cells lacking detectable COX-2 protein and function (as determined by prostaglandin E2 production) to the growth inhibitory effect of butyrate. In addition, we report that butyrate treatment of carcinoma (HT29) and adenoma (PC/AA/C1) cells leads to up-regulation of COX-2 protein. Thus NS-398 only appears to sensitize human colorectal carcinoma cells expressing COX-2 protein to the growth inhibitory effect of butyrate. As COX-2 is up-regulated in colorectal carcinogenesis, this could have 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 possibly treatment, of colorectal cancer.