NSAID inhibition of GI cancer growth: clinical implications and molecular mechanisms of action.
Epidemiological studies suggest that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) reduce the incidence of and mortality from colorectal, gastric, and esophageal cancers. The precise mechanisms by which NSAIDs exert their chemopreventive effects are not fully explained, but likely involve inhibition of cyclo-oxygenase, the enzyme that converts arachidonic acid to prostaglandins. Two isoforms of this enzyme, cyclo-oxygenase 1 (COX-1) and COX-2, have been identified. COX-2 is absent in normal mucosa but is overexpressed in colonic, gastric, and esophageal cancers, as well as their precursor lesions. The inhibition of COX-2 through either pharmacological agents or gene deletion results in suppression of colonic polyp formation. NSAIDs reduce colonic, gastric, and esophageal cancer cell growth, in part, by inducing apoptosis. However, the antineoplastic effects of NSAIDs may be partly independent of their ability to inhibit COX-2. The mechanisms involved in the antineoplastic actions of NSAIDs include inhibition of angiogenesis (essential for delivery of oxygen and nutrients to a growing tumor), induction of apoptosis (which is usually reduced in cancer cells) by stimulation of proapoptotic genes, and direct inhibition of cancer cell growth by blocking signal transduction pathways responsible for cell proliferation.
Husain
Syeda S
SS
Medical Service, Department of Veterans Affairs Medical Center, Long Beach, California, USA.
Szabo
Imre L
IL
Tamawski
Andrzej S
AS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D018890:Chemoprevention; D004064:Digestive System / Q000187:drug effects / Q000503:physiopathology; D005770:Gastrointestinal Neoplasms / Q000503:physiopathology* / Q000517:prevention & control*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents