Aspirin Reduces Cancer Risk by Restricting cAMP Production

Researchers have found that the anticancer properties of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are due to their inhibition of the enzyme cyclo-oxygenase-2 (COX-2), which results in lowered production of cyclic adenosine monophoshate (cAMP), an inhibitor of apoptosis.

One of the earliest molecular events in 80% of colon cancers is overexpression of COX-2, a rate-limiting enzyme of prostaglandin (PG) production. Prior studies have shown that long-term use of NSAIDs inhibits COX-2 and is associated with a 40-50% reduction in the incidence of colon cancer. In a new study published July 1, 2003, in the online edition of the Proceedings of the National Academy of Sciences, investigators at the University of California, San Diego (USA; www.ucsd.edu), identified the specific site where NSAIDs have a regulatory effect on apoptosis.

The study found that increased COX-2 activity caused the major PGE2 receptors on epithelial cells, EP2 and EP4, to increase cAMP production, which promotes growth and inhibits apoptosis in some cell types. Furthermore, substances that stimulated cAMP synthesis such as PGE2, cholera toxin, and a membrane-permeant cAMP analog, protected normal and transformed intestinal epithelial cells from apoptosis. This protection was associated with cAMP-mediated, rapid induction of cellular inhibitor of apoptosis protein (c-IAP)-2.

The authors concluded, "These results help to explain the cancer chemoprotective effects of nonsteroidal anti-inflammatory drugs by defining a mechanism through which cAMP signaling can promote the development of colorectal and possibly other epithelial cancers by means of disruption of normal apoptotic processes.”



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