Control of COX-2 and iNOS gene expressions by aspirin and salicylate

Abstract

Aspirin is an ‘‘old’’ drug with a number of new pharmacological actions. When it was synthesized over a century ago based on the action of salicylate, it was used in treating symptoms (fever and pain) associated with inflammation. Its mechanism of action was unknown until several decades later when Professor Sir John Vane discovered that its action is mediated by inhibiting prostaglandin synthesis [1]. This monumental discovery has provided a fundamental understanding of how aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) work. Aspirin use was known to be associated with a mild bleeding problem but the cause was unclear. Sir John’s work coupled with the discovery of thromboxane (TX) A2 as an active mediator of platelet aggregation by Professor Bengt Samuelsson led to the discovery that aspirin caused platelet dysfunction by inhibiting TXA2 synthesis. These clinical observations lay the foundation for the use of aspirin in preventing myocardial infarction and ischemic stroke. Aspirin and its parental compound, salicylic acid (aspirin and salicylate compounds will be collectively called salicylates), are recently shown to have other potential therapeutic actions such as control of colon cancer growth [2,3]. The anti-inflammatory action as well as anti-cancer and anti-neurodegenerative actions of aspirin are generally attributed to its inhibition of cyclooxygenase (COX) activity. However, results from recent studies cast doubts about this explanation. There is strong evidence that the inducible COX, i.e., COX-2 but not the housekeeping COX-1, is responsible for inflammation and tumorigenesis [4,5]. Aspirin exhibits weaker inhibition of COX-2 than COX-1 catalytic activity. It is two to three orders of magnitude