NONSTEROIDAL ANTIINFLAMMATORY DRUGS, SHORT-CHAIN FATTY-ACIDS, AND REACTIVE OXYGEN-METABOLISM IN HUMAN COLORECTAL-CANCER CELLS

Nonsteroidal anti-inflammatory drugs (NSAIDs) and short-chain fatty ac ids are effective suppressors of colorectal cancer that may work in pa rt by accentuating apoptosis of transformed cells. Since reactive oxyg en species (ROS) can play an important role in regulating cell growth and cell death, we determined the effect of the NSAIDs indomethacin an d salicylic acid, and the short-chain fatty acids butyrate and propion ate on ROS metabolism in the HT-29 human colorectal carcinoma cell lin e. We find that all of these agents increase cellular peroxide generat ion, as determined by two independent assays. Arachidonic acid was als o found to increase ROS generation, and could synergize with indometha cin in this reaction. The NSAIDs and short-chain fatty acids under stu dy all possess a carboxyl group, and this carboxyl group is essential for salicylic acid's ability to increase ROS production. Although the two NSAIDs examined increase peroxide production, they were both found to suppress superoxide generation by vitamin K3 (menadione), a redox cycling compound similar to those found in the colon. The short-chain fatty acids did not have this activity. The ability of these NSAIDs an d short-chain fatty acids to alter cellular ROS metabolism may contrib ute to their chemopreventive activity. (C) 1998 Elsevier Science B.V.