Nonsteroidal anti-inflammatory drugs, short-chain fatty acids, and reactive oxygen metabolism in human colorectal cancer cells.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and short-chain fatty acids are effective suppressors of colorectal cancer that may work in part by accentuating apoptosis of transformed cells. Since reactive oxygen species (ROS) can play an important role in regulating cell growth and cell death, we determined the effect of the NSAIDs indomethacin and salicylic acid, and the short-chain fatty acids butyrate and propionate on ROS metabolism in the HT-29 human colorectal carcinoma cell line. We find that all of these agents increase cellular peroxide generation, as determined by two independent assays. Arachidonic acid was also found to increase ROS generation, and could synergize with indomethacin in this reaction. The NSAIDs and short-chain fatty acids under study 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 and short-chain fatty acids to alter cellular ROS metabolism may contribute to their chemopreventive activity.