Sildenafil protects epithelial cell through the inhibition of xanthine oxidase and the impairment of ROS production

Recent reports suggest that xanthine oxidase (XO), a modified form of the native xanthine dehydrogenase enzyme, plays an important role in various forms of ischemic and vascular injuries, inflammatory diseases, and chronic heart failure. The XO inhibitors allopurinol and its oxidation product oxypurinol held considerable promises in the treatment of these conditions both in experimental animals and in human clinical trials. More recently, an endothelium-based protective effect of sildenafil, a well-known type-5 phosphodiesterase inhibitor, has been reported in preconditioning prior to ischemia/reperfusion in healthy human subjects. Based on the structural similarities between allopurinol and oxypurinol with sildenafil (pyrimidine and pyrazole rings), and with zaprinast (featuring pyrimidine and triazolo rings), we have investigated the potential effects of these latter compounds on the buttermilk purified XO and on nontumorigenic (HMEC) and malignant (MCF7) human mammary epithelial cells. Both sildenafil and, to a lesser extent, zaprinast induced a significant and consistent decrease of XO expression and activity in either cell line. In MCF7 cells only, this effect was associated with the abrogation of xanthine-induced cytotoxicity. Overall, the data suggest that the protective effect of sildenafil on epithelial cells is a consequence of the inhibition of the XO enzyme and of the resulting decrease of free oxygen radical production that may influence the expression of NADPH oxidase and PDE-5.