NTERNATIONAL J OURNAL OF P HARMACY & L IFE S CIENCES Cyclooxygenase - 2 : Pathway form anti - inflammatory to Anti - cancer drugs

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 similarit ies, 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, ep idemio logic, and clin ical studies suggest that non-steroidal anti-in flammatory drugs (NSAIDs), part icularly 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 co lorectal 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 Key-Words: Cyclooxygenase-2, NSAID’S, Prostaglandins, Anti-cancer, Anti-inflammatory agents . Introduction The revolution in biology over the past two decades has resulted in radically new approaches and opportunities for drug discovery. There has been an incredibly rap id increase in the rate of determination of three-dimensional structures of biomolecules. Many of these macromolecules are important drug targets and it is now possible to use the knowledge of the threedimensional structures as a good basis for drug design. We propose to illustrate this in the case of cyclooxygenase-2, an enzyme responsible for inflammat ion 1 . This area has attracted immense attention in the last few years and a large number of original research articles and a good number of scientific and popular review articles have been published 1-6 . * Corres ponding Author: E-mail: [email protected] Mob. 9039839796 Aspirin or acetylsalicyclic acid, the prototype of non steroidal anti-inflammatory agents (NSAIDs) was first produced and marketed by Bayer in March 1899. NSAIDs are even today among the most widely used therapeutic agents with a total annual sale in excess of US $ 10 billion. They are used for the treatment of a broad spectrum of pathophysiological conditions such as headaches, discomfort associated with minor in juries and alleviation of severe pain caused by inflammatory, cancer and degenerative joint diseases such as osteo and rheumatoid arthritis 1 . COX: Biological function and regulation In the 1980s, Bailey and Needleman proposed the concept of the cyclooxygenase (COX) enzyme as a major regulatory step in prostaglandin (PG) synthesis 7 . COX enzymes catalyze the formation of the prostaglandin endoperoxide from arachidonic acid (AA) to prostaglandin H2 (PGH2). It has both cyclooxygenase activity, which catalyzes the Review Article [Gupta & Yadav, 2(2):Feb., 2011]