title: Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells.
abstract: Oxidative stress generated by ascorbate-driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition, loss of calcium homeostasis, DNA damage and changes in mitogen activated protein kinases (MAPK) activities. Cell death is mediated by necrosis rather than apoptosis or macroautophagy. Neither 3-methyladenine nor Z-VAD affects cytotoxicity by ascorbate/menadione (Asc/Men). BAPTA-AM, by restoring cellular capacity to reduce MTT, underlines the role of calcium in the necrotic process. Oxidative stress-mediated cell death is shown by the opposite effects of N-acetylcysteine and 3-aminotriazole. Moreover, oxidative stress induces DNA damage (protein poly-ADP-ribosylation and gamma-H2AX phosphorylation) and inhibits glycolysis. Asc/Men deactivates extracellular signal-regulated kinase (ERK) while activating p38, suggesting an additional mechanism to kill MCF7 cells. Since ascorbate is taken up by cancer cells and, due to their antioxidant enzyme deficiency, oxidative stress should affect cancer cells to a greater extent than normal cells. This differential sensitivity may have clinical applications.
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group, PMNT Unit, Belgium.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Beck
authors.forename: Julien
authors.initials: J
authors.lastname: Verrax
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dejeans
authors.forename: Henryk
authors.initials: H
authors.lastname: Taper
authors.forename: Pedro Buc
authors.initials: PB
authors.lastname: Calderon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D024483:Vitamin K 3 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004338:Drug Combinations; D013778:Tetrazolium Salts; D013844:Thiazoles; D009243:NAD; D019344:Lactic Acid; D024483:Vitamin K 3; D000255:Adenosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C022616:thiazolyl blue; D001205:Ascorbic Acid