Cyclooxygenase-2 inhibitors and inflammatory bowel disease

Cyclooxygenase (COX) enzyme-dependent arachidonic acid metabolites occupy key positions in important physiologic processes such as immunity, reproduction, and vascular integrity. There are two known isoforms of COX, 1 and 2. COX-1 is a constitutive enzyme, important for mucosal integrity that produces cytoprotective and antiinflammatory prostaglandins. COX-2 is the inducible form of the enzyme and is markedly increased at sites of inflammation. The two COX genes have been cloned, and expression of COX-2 mRNA and protein has been shown to be elevated in several human inflammatory processes including inflammatory bowel disease (IBD) and malignancies, as well as in animal models of IBD and carcinogenesis. In this regard, recent evidence has implicated COX-2 in gastric, esophageal and colorectal carcinogenesis. Indeed, increased COX-2 expression was noticed in Barretts esophagus and esophageal adenocarcinomas, gastric carcinomas, and colorectal adenomas and carcinomas. COX-2 appears to be mutagenic and tumorigenic in vitro. Moreover, COX-2 overexpression may inhibit apoptosis and increases invasiveness of malignant cells. In addition, COX-2 overexpression enhances prostaglandin (PG) synthesis and the importance of prostaglandins (PGE2) in the progression of a chronic inflammation or neoplasia has long been recognized. Although the release of these compounds in response to tissue injury seems to be a key event in the reparative process and inflammatory response, it is becoming clear that they are implicated in cell proliferation and inhibition of immune surveillance; therefore, overproduction of PGs could favor malignant growth. Specifically, high levels of proinflammatory leukotrienes (LTs) and up-regulated expression of COX-2 are characteristic of inflammation, including IBD, and have been implicated in cell survival and early colon carcinogenesis. LTs cause a timeand dose-dependent increase in expression and/or membrane accumulation of COX-2, beta-catenin, and Bcl-2, as well as PGE2 production, and the effects of LTs on these transformation-associated proteins correlate well with the ability of LTs to reduce programmed cell death. Therefore, these observations suggest that IBD is associated with the expression and distribution of proteins that are characteristic of transformed cells and such pathological conditions may involve a signaling mechanism comprising an altered rate of apoptosis. On the other hand, inhibition of COX-2 prevents growth of cancer xenografts in nude mice, and aspirin use (which inhibits both COX-1 and COX-2) decreases the risk of developing malignancy. Also, COX2 inhibition results in suppression of neoplastic polyps in the APC knockout mouse, a model of familial adenomatous polyposis. Specifically, there are already strong indications that inhibitors of the NF-êBregulated gene COX-2; e.g., celecoxib and aspirin prevent colon cancer. Indeed, celecoxib inhibits NF-êB activation through inhibition of IêBK and Akt activation leading to downregulation of synthesis of COX-2 and other genes needed for inflammation, proliferation and carcinogenesis. Therefore, applying COX-2 selective (or nonselective) inhibitors reduces inflammation, suppresses carcinogenesis in the gastrointestinal (GI) tract and could be an effective and promising way to prevent cancer.