H(2)O(2) preferentially synergizes with nitroprusside to induce apoptosis associated with superoxide dismutase dysregulation in human melanoma irrespective of p53 status: Antagonism by o-phenanthroline.

Abstract

The pro-oxidant hydrogen peroxide (H(2)O(2)) is converted to a reactive oxygen species by transition metals like iron. Since mutations in the p53 tumor suppressor gene contribute to drug resistance, we used genetically-matched human C8161 melanoma harbouring wt or DN-R175H mutant p53, to investigate the influence of p53 status on the potentiation of H(2)O(2) toxicity by: (a) intact sodium nitroprusside or nitroferricyanide (SNP), (b) its light-exhausted NO-depleted form (lex-SNP), (c) potassium ferricyanide, or (d) ferric ammonium sulphate. Whereas single treatments with SNP or H(2)O(2) were partly cytotoxic, preferentially potentiation of H(2)O(2) toxicity was evidenced with intact or lex-SNP. No comparable increase of H(2)O(2) toxicity was induced by ferricyanide, ferric ammonium sulphate or S-nitroso-N-acetyl penicillamine (SNAP), a known NO donor lacking iron. Immune blotting revealed apoptosis-associated PARP cleavage induced by [SNP+H(2)O(2)] irrespective of p53 status. This correlated with an eightfold induction of [Mn-SOD; SOD2] in wt p53 melanoma cells, and with a super-induction of the same enzyme reciprocal with loss of [Cu,Zn-SOD; SOD1], in mutant p53 cells. All these changes were antagonized by the anti-oxidant N-acetylcysteine or the iron chelator o-phenanthroline. We hypothesize that superoxide dismutase imbalance and iron-dependent redox changes involving OH species generated from a Fenton reaction between [SNP+H(2)O(2)], may be important in this anti-tumor activity. Although tumor drug resistance is frequently associated with DN-p53 mutations, our data shows for the first time the preferential ability of SNP to enhance H(2)O(2) toxicity, irrespective of p53 status.

• Authors: Luis A Gomez-Sarosi, Mary Strasberg-Rieber, Manuel Rieber
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 188 Issue 1 Pg. 134-43 (Oct 06 2010) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 20674559 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Phenanthrolines
• Tumor Suppressor Protein p53
• Nitroprusside
• Hydrogen Peroxide
• Superoxide Dismutase
• 1,10-phenanthroline

Topics

• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Drug Synergism
• Genotype
• Humans
• Hydrogen Peroxide (pharmacology)
• Melanoma (enzymology, metabolism, pathology)
• Nitroprusside (pharmacology)
• Phenanthrolines (pharmacology)
• Superoxide Dismutase (metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)