Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal carcinoge nesis and prevent or revert the growth of premalignant colonic polyps. They inhibit cyclooxygenase (COX) but recent data indicate that this is not the only or even the most important mechanism of inhibition in colorectal tumo r cells. We have used colonic carcinoma and adenoma cell lines to study the effects of the NSAID sulindac sulfide, its COX-inactive metabolite, sulind ac sulfone, and the isoenzyme-specific inhibitors SC58125, SC236 and SC5856 0 on tumor cell growth in relation to COX-2 expression and prostaglandin pr oduction. To establish the role of COX-2 in NSAID action, we constructed cl ones expressing different levels of COX-2 from SW480 cells. All five compou nds inhibited DNA synthesis and/or induced apoptosis, each with a character istic pattern. ID(50)s were very similar in all the cell lines and were ind ependent of COX expression, except for the COX-1 inhibitor SC58560, which w as least effective in HT29/HI1, the cell line expressing the highest level of COX-1 (ID50 70 muM; in other cells lines the ID50 was 15 muM). For all o ther compounds ID50 concentrations varied less than two-fold: 25-40, 40-90 and 150 muM for SC236, sulindac sulfide and sulindac sulfone, respectively. SC58125 was the weakest inhibitor, never causing >50% cell loss. All compo unds modulated expression of Bcl-2 and Bak and activated caspase 3, Overexp ression of COX-2 in SW480 cells protected them against induction of apoptos is by sulindac sulfide. The effect was restricted to clones producing high levels of prostaglandin E-2, In summary, our data indicate that both COX-de pendent and COX-independent mechanisms are involved in NSAID-induced growth in colorectal tumor cells. The concentrations necessary to inhibit growth were higher than serum concentrations that can be obtained in vivo, indicat ing that the therapeutic effect of NSAIDs cannot be explained by a direct e ffect of NSAIDs on the epithelial cells alone. For therapeutic purposes, co mpounds using different targets could be used to minimize side effects whil e optimizing therapeutic effect.