Cox-2, iNOS and p53 as play-makers of tumor angiogenesis (Review)

Cyclooxygenases (COXs) are key enzymes in the conversion of arachidonic aci d to prostaglandins (PGs) and other eicosanoids. Nitric oxide synthase (NOS ) is the enzyme that catalyzes the formation of nitric oxide (NO), a regula tor of vascular permeability, from the guanidino nitrogen atom of L-arginin e. Two isoforms of both enzymes occur: a constitutive one, Cox-1 and the in ducible counterpart Cox-2; also NOS has a constitutive counterparts (cNOS) and an inducible form, called iNOS. The inducible isoforms of both enzymes are of maximum interest. It has been recently shown that cyclooxygenase-2 ( Cox-2) is inducible by a variety of stimuli and that eicosanoids, mainly of the PGE2 species, are inducers of basic regulator of angiogenesis, includi ng VEGF/VPF, bFGF, TGF-beta, PDGF, and endothelin-l. In addition, iNOS is i nducible by Cox-2. p53 downregulates the angiogenic process sit various lev els: it induces thrombospondin-l, a powerful antiangiogenic factor, downreg ulates VEGF and NOS and, in addition, down-regulates hypoxia-induced angiog enesis, either inducing apoptosis or enhancing antiangiogenetic factors. It is noteworthy how important the p53 oncosuppressor is in the angiogenesis of solid tumor growth. Cox-2, iNOS and p53 are thus fundamental play-makers of the angiogenic process: they are discussed in detail and a tentative hi erarchical cascade is proposed.