Cyclooxygenase-2: Pathway form anti-inflammatory to Anti-cancer drugs

Abstract

Cyclooxygenase, an enzyme involved in the conversion of C-20 acids to prostaglandins, exists in two isoforms. COX-1 is constitutively expressed and has a gastroprotective function. COX-2, induced at the site of injury, is responsible for the expression of pro-inflammatory prostaglandins. Despite overall similarities, COX-1 and COX-2 show subtle difference in amino acid composition at the active sites. COX-2 has valine at positions 89 and 523, while COX-1 has isoleucine, resulting in larger space availability in the former. Further, the presence of valine at position 434 in COX-2 as against isoleucine in COX-1 allows a gate mechanism to operate in favour of the former Numerous experimental, epidemiologic, and clinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), particularly the highly selective cyclooxygenase (COX)-2 inhibitors, have promising  anticancer as well as anti-inflammatory activity. NSAIDs restore normal apoptosis in human adenomatous colorectal polyps and in various cancer cell lines that have lost adenomatous polyposis coli gene function. NSAIDs also inhibit angiogenesis in cell culture and rodent models of angiogenesis. Many epidemiologic studies have found that long-term use of NSAIDs is associated with a lower risk of colorectal cancer, adenomatous polyps, and, to some extent, other carcinogens. Non steroidal anti-inflammatory drugs (NSAIDs) produce their therapeutic effects through inhibition of COX, the enzyme that makes prostaglandins. Nonselective inhibition of COX isoenzyme leads to not only beneficial therapeutic effects but also a number of damaging effects. Beneficial effects are due to inhibition of COX-2 and damaging effects are due to inhibition of physiological COX-1. The present review discusses the biology as well as the role of these COX isoenzymes in various prevalent pathophysiological conditions