Is inhibition of cyclooxygenase required for the chemopreventive effect of NSAIDs in colon cancer? A model reconciling the current contradiction

NSAIDs are powerful chemopreventive agents for colon cancer, but their mechanism of action remains unknown. Their best recognized pharmacological property is inhibition of the enzyme cyclooxygenase (COX), which catalyzes the synthesis of prostaglandins; however, additional effects are well documented. Current studies on the mechanism of the chemopreventive effect of NSAIDs lead to two contradictory conclusions: NSAIDs prevent colon cancer either by inhibiting the activity of COX, or through mechanisms that do not require COX inhibition. To resolve this apparent conflict, after examining several alternatives, we propose a model, which assumes that both mechanisms are correct but that they exert their effect either on different steps of the multistep process of colon carcinogenesis or on different control mechanisms. This postulated dual action of NSAIDs may explain their remarkable effectiveness in colon cancer prevention. Unraveling these mechanistic details can be very rewarding for the design of more refined approaches to cancer chemoprevention and for a deeper understanding of colorectal carcinogenesis. (C) 2000 Harcourt Publishers Ltd.