Targeting COX-2 expression by natural compounds: a promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy.

Cyclooxygenase (COX)-2 is a pro-inflammatory immediate early response protein, chronically up-regulated in many pathological conditions. In autoimmune diseases, it is responsible for degenerative effects whereas in cancer, it correlates with poor prognosis. A constitutive expression of COX-2 is triggered since the earliest steps of carcinogenesis. Consequently, strategies aimed at inhibiting COX-2 enzymatic activity have been clinically applied for the treatment of autoimmune disorders; in addition, the same approaches are currently investigated for anti-cancer purposes. However, COX-2 protein inhibitors (i.e., NSAIDs and COXIBs) are not amenable to prolonged administration since they may cause severe side effects, and efforts are underway to identify alternative approaches for chemoprevention/therapy. COX-2 expression is a multi-step process, highly regulated at transcriptional and post-transcriptional levels. Defects in the modulation of one or both of these steps may be found in pathological conditions. Targeting COX-2 expression may therefore represent a promising strategy, by which the same preventive and therapeutic benefits may be gained while avoiding the severe side effects of COX-2 enzymatic inhibition. Naturally occurring compounds derived from plants/organisms represent a huge source of biologically active molecules, that remains largely unexplored. Derived from plants/organisms used in traditional forms of medicine or as dietary supplements, these compounds have been experimentally investigated for their anti-inflammatory and anti-cancer potential. In this review, we will analyze how natural compounds may modulate the multistep regulation of COX-2 gene expression and discuss their potential as a new generation of COX-2 targeting agents alternative to the synthetic COX-2 inhibitors.