1. Int J Toxicol. 2009 Jan-Feb;28(1):33-42.

Menadione reduction by pharmacological doses of ascorbate induces an oxidative
stress that kills breast cancer cells.

Beck R, Verrax J, Dejeans N, Taper H, Calderon PB.

Université Catholique de Louvain, Louvain Drug Research Institute, Toxicology and
Cancer Biology Research Group, PMNT Unit, 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 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.

PMID: 19482829 [PubMed - indexed for MEDLINE]