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Menadione Reduction by Pharmacological Doses of Ascorbate Induces an Oxidative Stress That Kills Breast Cancer CellsFrom the Université Catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group, PMNT Unit, Belgium Correspondence: Please address correspondence to Pedro Buc Calderon, avenue E. Mounier 73, 1200 Bruxelles, Belgium.
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
Key Words: ascorbate-menadione redox cycling • calcium homeostasis • glycolysis • mitogen-activated protein kinase • MCF7 cells • oxidative stress
International Journal of Toxicology, Vol. 28, No. 1,
33-42 (2009) |
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-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.