PT  - JOURNAL ARTICLE
AU  - Simone Cardaci
AU  - Giuseppe Filomeni
AU  - Giuseppe Rotilio
AU  - Maria R. Ciriolo
TI  - Reactive Oxygen Species Mediate p53 Activation and Apoptosis Induced by Sodium Nitroprusside in SH-SY5Y Cells
AID  - 10.1124/mol.108.048975
DP  - 2008 Nov 01
TA  - Molecular Pharmacology
PG  - 1234--1245
VI  - 74
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/74/5/1234.short
4100  - http://molpharm.aspetjournals.org/content/74/5/1234.full
SO  - Mol Pharmacol2008 Nov 01; 74
AB  - Sodium nitroprusside (SNP) is a water-soluble iron nitrosyl complex clinically used as a powerful vasodilator for treatment of hypertension; and, in basic research, it has been used to mainly investigate the cytotoxic effects of nitrosative stress. Although NO is considered a pharmacologically active molecule, not all of the biological effects of SNP are dependent on its NO moiety. To elucidate the molecular executioner(s) responsible for SNP cytotoxicity, this study determines the involvement of oxidative stress in p53 activation and apoptotic induction elicited by SNP in SH-SY5Y neuroblastoma cells. We demonstrate that proapoptotic activity of SNP is independent of NO production, because SNP and its 2-day light-exhausted compound SNPex trigger apoptosis to the same extent. We provide evidence for the occurrence of oxidative stress and oxidative damage during both SNP and SNPex exposure and demonstrate that iron-derived reactive oxygen species (ROS) are the genuine mediators of their cytotoxicity. We show that p53 is equally activated upon both SNP and SNPex treatments. Moreover, as demonstrated by small interfering RNA experiments, we indicate its primary role in the induction of apoptosis, suggesting the ineffectiveness of NO in its engagement. The attenuation of p53 levels, obtained by oxy-radical scavengers, is consistent with the recovery of cell viability and ROS decrease, demonstrate that SNP-mediated p53 activation is an event triggered by ROS and/or ROS-mediated damages. Together, our results suggest that investigations of the physiopathological effects of SNP should consider the role of ROS, other than NO, particularly in some conditions such as apoptotic induction and p53 activation. The American Society for Pharmacology and Experimental Therapeutics