H2O2 preferentially synergizes with nitroprusside to induce apoptosis associated with superoxide dismutase dysregulation in human melanoma irrespective of p53 status: Antagonism by o-phenanthroline |
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| Authors: | Luis A Gomez-Sarosi Mary Strasberg-Rieber Manuel Rieber |
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| Institution: | 1. Service de rhumatologie, CHU de Nantes, place Alexis-Ricordeau, 44093 Nantes cedex 01, France;2. Service de bactériologie-hygiène hospitalière, CHU de Nantes, place Alexis-Ricordeau, 44093 Nantes cedex 01, France;3. CRCINA, inserm, université d’Angers, université de Nantes, Nantes, France;4. Service de rhumatologie, CHU d’Ambroise-Paré, AP–HP, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, France;1. Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Kentucky College of Medicine, Lexington, KY;2. Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY;1. Area of Electron Microscopy, Department of Animal Pathology, School of Agronomy and Veterinary, National University of Río Cuarto, Argentina;2. Department of Animal Reproduction, School of Agronomy and Veterinary, National University of Río Cuarto, Argentina;3. National Scientific and Technical Research Council (CONICET), Argentina;1. East Hospital, Tongji University School of Medicine, Shanghai, China;2. Department of Anatomy and Neurobiology, The Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, China;3. Tianjin Hospital, Tianjin Academy of Integrative Medicine, Tianjin, China |
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| Abstract: | The pro-oxidant hydrogen peroxide (H2O2) 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 H2O2 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 H2O2 were partly cytotoxic, preferentially potentiation of H2O2 toxicity was evidenced with intact or lex-SNP. No comparable increase of H2O2 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 + H2O2] 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 + H2O2], 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 H2O2 toxicity, irrespective of p53 status. |
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