iNOS/COX-2 Pathway Interaction: A Good Molecular Target for Cancer Treatment

An increase in the expression and activity of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) has been shown in several types of human tumors. A large body of evidence has demonstrated that these two enzymes are involved in tumor progression through several molecular mechanisms, such as promotion of tumor cell proliferation, inhibition of apoptosis and stimulation of angiogenesis. iNOS and COX-2 share a number of similarities in terms of pathophysiological phenomena and are often co-expressed in cancer tissues. The product of iNOS, nitric oxide (NO), has been demonstrated to modulate COX-2 expression and prostaglandin production in both inflammatory and tumor experimental models. Cyclic GMP and peroxynitrite, the coupling product of NO and superoxide, appear as the most important pathways by which NO may regulate COX-2 expression. We have recently shown that both NO- and COX-2-related angiogenesis is mediated by an increase in VEGF production in colorectal cancer. We also provided evidence that NO can stimulate COX activity and that its pro-angiogenic effect is mainly mediated by COX-2-related PGE2 production. The purpose of this review is to summarize experimental data on the molecular mechanisms underlying iNOS-COX-2 cross-talk and investigate the pathophysiological significance of this interaction in cancer. Given the availability of highly selective inhibitors of both iNOS and COX-2, dual inhibition of these enzymes appears as a promising therapeutic tool in the treatment of various types of human cancers by producing a possible synergistic anti-tumor effect.