Is COX-2 a 'collateral' target in cancer prevention?
NSAIDs (non-steroidal anti-inflammatory drugs) prevent colon and other cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug-developmental work focusing on COX (cyclo-oxygenase) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, one COX-2 inhibitor has been withdrawn from the market because of cardiovascular side effects, and there are concerns about a class effect. Evidence suggests that COX-2 may not be the only, or the ideal, target for cancer prevention; for example, COX-2 is not expressed in human aberrant crypt foci, the earliest recognizable pre-malignant lesion in the colon; COX-2 is expressed in less than half of the adenomas; in vitro data show that NSAIDs do not require the presence of COX-2 to prevent cancer; in familial adenomatous polyposis, the COX-2 inhibitor, celecoxib, had a modest effect, which was weaker than that of a traditional NSAID; and COX-2-specific inhibitors have several COX-2-independent activities, which may account for part of their cancer-preventive properties. The multiple COX-2-independent targets, and the limitations of COX-2 inhibitors, suggest the need to explore targets other than COX-2.
Kashfi
K
K
Department of Physiology and Pharmacology, City University of New York Medical School, NY 10031, USA.
Rigas
B
B
D011125:Adenomatous Polyposis Coli / Q000517:prevention & control; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000627:therapeutic use; D013450:Sulfones / Q000627:therapeutic use
D016588:Anticarcinogenic Agents; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D011464:Epoprostenol