Cyclooxygenase-2 and Cancer Treatment: Understanding the Risk Should Be Worth the Reward

Abstract

Targeting the prostaglandin (PG) pathway is potentially a critical intervention for the prevention and treatment of cancer. Central to PG biosynthesis are two isoforms of cyclooxygenase (COX 1 and 2), which produce prostaglandin H₂ (PGH₂) from plasma membrane stores of fatty acids. COX-1 is constitutively expressed, whereas COX-2 is an inducible isoform upregulated in many cancers. Differences between COX-1 and COX-2 catalytic sites enabled development of selective inhibitors. Downstream of the COX enzymes, prostaglandin E₂ synthase converts available PGH₂ to prostaglandin E₂ (PGE₂), which can stimulate cancer progression. Significant research efforts are helping identify more selective targets and fully elucidate the downstream targets of prostaglandin E₂-mediated oncogenesis. Nonetheless, as a key rate-limiting control point of PG biosynthesis, COX-2 continues to be an important anticancer target. As we embark upon a new era of individualized medicine, a better understanding of the individual risk and/or benefit involved in COX-2 selective targeting is rapidly evolving. This review endeavors to summarize developments in our understanding of COX-2 and its downstream targets as vital areas of anticancer research and to provide the current status of an exciting aspect of molecular medicine. Clin Cancer Res; 16(5); 1384–90