NSAIDs May Prevent Colon Cancer Through Apoptosis, Not Anti-inflammatory Effects

April 1, 1996

There already is a strong body of evidence suggesting that long-term, consistent use of nonsteroidal anti-inflammatory agents (NSAIDs) reduces the relative risk of colon cancer. Questions recently have been raised, however, concerning the way in which these drugs exert their protective effect.

There already is a strong body of evidence suggesting that long-term,consistent use of nonsteroidal anti-inflammatory agents (NSAIDs)reduces the relative risk of colon cancer. Questions recentlyhave been raised, however, concerning the way in which these drugsexert their protective effect.

"The concepts regarding the way these drugs work have beenchallenged and perhaps are wrong," said Dennis Ahnen, MD,at the National Conference on Colorectal Cancer, sponsored bythe American Cancer Society.

The anti-inflammatory action of NSAIDs actually may not be criticalto the chemoprevention of colon cancer. Rather, NSAIDs may influencecolon cancer through the induction of apoptosis, or programmedcell death, said Dr. Ahnen, associate director, Cancer Preventionand Control, University of Colorado Cancer Center, Denver.

He predicted that breakthroughs in the investigation of coloncancer chemo-prevention in the next few years will focus on themechanism of action of NSAIDs. "We need to know the mechanismof action at both the biological and the biochemical levels sowe can design better chemopreventive agents," he said.

Sulindac Research

Studies of the biologic actions of sulindac suggest that the mechanismof action of NSAIDs may be more complex than previously thought,David S. Alberts, MD, said at the conference. Sulindac has propertiessimilar to those of aspirin and has been shown to reduce the numberand size of polyps in individuals with familial adenomatous polyposis.

The agent is metabolized into two principal compounds, said Dr.Alberts, director, Cancer Prevention and Control, Arizona CancerCenter, Tucson. One compound is the active drug sulindac sulfide,which inhibits PGE2, a stable prostaglandin produced in the gastrointestinalmucosa. The other is sulindac sulfone, an inactive metabolite.

While sulindac sulfone decreased the number of intestinal tumorsin a dose-responsive manner in an animal model, it did not inhibitPGE2, as would be expected if the drug affected the arachidonicacid pathway, Dr. Alberts said.

More recent data indicate that sulindac may operate through apoptosis."Our research group at the Universities of Colorado and Arizonahas used chromatin condensation, morphological or DNA fragmentationstudies, to show that sulindac and its sulfone metabolite induceapoptosis, not necrosis, in colon tumor cells," Dr. Albertssaid.

He believes that this is "very likely a common mechanismthrough which chemopreventive agents are working. We know thisis the case with anticancer drugs at this point."