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Molecular Pharmacology

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Research ArticleArticle

Reactive Oxygen Species Mediate p53 Activation and Apoptosis Induced by Sodium Nitroprusside in SH-SY5Y Cells

Simone Cardaci, Giuseppe Filomeni, Giuseppe Rotilio and Maria R. Ciriolo
Molecular Pharmacology November 2008, 74 (5) 1234-1245; DOI: https://doi.org/10.1124/mol.108.048975
Simone Cardaci
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Giuseppe Filomeni
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Giuseppe Rotilio
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Maria R. Ciriolo
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Abstract

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.

Footnotes

  • The work was partially supported by grants from Ministero della Salute (to M.R.C.)

  • S.C. and G.F. contributed equally to this work.

  • ABBREVIATIONS: RNS, reactive nitrogen species; SNP, sodium nitroprusside; ROS, reactive oxygen species; AMS, ammonium sulfamate; DMSO, dimethyl sulfoxide; DMTU, dimethyl thiourea; DEF; deferoxamine mesylate; TEMPOL, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl; DMEM, Dulbecco's modified Eagle's medium; SNPex, photoexhausted sodium nitroprusside; PBS, phosphate-buffered saline; siScr, scramble small interfering RNA duplex; NOx, nitrites and nitrates; PAGE, polyacrylamide gel electrophoresis; Hsp, heat shock protein; PARP, poly(ADP-ribose) polymerase; GSH, reduced glutathione; GSSG, glutathione disulfide; DCFH-DA, 2′,7′-dichlorodihydrofluorescein diacetate; DNP, 2,4-dinitrophenylhydrazine; siRNA, small interfering RNA; zVAD-fmk, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone; P-H2A.X, phosphoactive histone H2A.X.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received May 19, 2008.
    • Accepted August 1, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (5)
Molecular Pharmacology
Vol. 74, Issue 5
1 Nov 2008
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Research ArticleArticle

Reactive Oxygen Species Mediate p53 Activation and Apoptosis Induced by Sodium Nitroprusside in SH-SY5Y Cells

Simone Cardaci, Giuseppe Filomeni, Giuseppe Rotilio and Maria R. Ciriolo
Molecular Pharmacology November 1, 2008, 74 (5) 1234-1245; DOI: https://doi.org/10.1124/mol.108.048975

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Research ArticleArticle

Reactive Oxygen Species Mediate p53 Activation and Apoptosis Induced by Sodium Nitroprusside in SH-SY5Y Cells

Simone Cardaci, Giuseppe Filomeni, Giuseppe Rotilio and Maria R. Ciriolo
Molecular Pharmacology November 1, 2008, 74 (5) 1234-1245; DOI: https://doi.org/10.1124/mol.108.048975
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