Sildenafil protects epithelial cell through the inhibition of xanthine oxidase and the impairment of ROS production.
Xanthine oxidase (XO) plays an important role in various forms of ischemic and vascular injuries, inflammatory diseases and chronic heart failure. The XO inhibitors allopurinol and oxypurinol held considerable promise in the treatment of these conditions both in experimental animals and in human clinical trials. More recently, an endothelium-based protective effect of sildenafil has been reported in preconditioning prior to ischemia/reperfusion in healthy human subjects. Based on the structural similarities between allopurinol and oxypurinol with sildenafil and with zaprinast the authors have investigated the potential effects of these latter compounds on the buttermilk XO and on non-tumourigenic (HMEC) and malignant (MCF7) human mammary epithelial cells. Both sildenafil and 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 and of the resulting decrease of free oxygen radical production that may influence the expression of NADPH oxidase and PDE-5.
Taibi
Gennaro
G
Dipartimento di Oncologia Sperimentale e Applicazioni Cliniche, Sezione di Biochimica e Oncologia Clinica, AOUP Paolo Giaccone', Università di Palermo, Via Del Vespro 129, 90127 Palermo, Italy. gtaibi@unipa.it
Carruba
Giuseppe
G
Miceli
Vitale
V
Cocciadiferro
Letizia
L
Cucchiara
Angela
A
Nicotra
Concetta M A
CM
D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D011688:Purinones / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000068677:Sildenafil Citrate; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D010879:Piperazines; D011687:Purines; D011688:Purinones; D017382:Reactive Oxygen Species; D013450:Sulfones; D000068677:Sildenafil Citrate; D014969:Xanthine Oxidase; C011145:zaprinast