NSAIDs and cancer prevention: Targets downstream of COX-2

Preclinical and clinical studies have clearly shown a benefit of non-steroidal anti-inflammatory drug (NSAID) use in reducing cancer risk. However, the adverse gastrointestinal and cardiovascular side effects associated with NSAIDs and COX-2 selective inhibitors (coxibs) have provoked more scrutiny of the precise role of specific downstream mediators in the prostaglandin (PG) signaling cascade. NSAIDs and coxibs inhibit PG biosynthesis. One of the PGs produced at high levels in the tumor microenvironment is PGE₂, which is thought to play a major role in cancer progression. Thus, a better understanding of PGE₂ signaling could enable identification of novel and safer therapeutic targets downstream of the cyclooxygenase enzymes. We review the emerging molecular mechanisms by which COX-2-derived PGE₂ is involved in cancer progression and delineate potential opportunities for development of novel pharmacologic approaches utilizing this pathway.