1: Int J Cancer. 2007 Mar 15;120(6):1192-7.

Role of glycolysis inhibition and poly(ADP-ribose) polymerase activation in
necrotic-like cell death caused by ascorbate/menadione-induced oxidative stress
in K562 human chronic myelogenous leukemic cells.

Verrax J, Vanbever S, Stockis J, Taper H, Calderon PB.

Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie, Département
des sciences pharmaceutiques, Université Catholique de Louvain, Belgium.

Among different features of cancer cells, two of them have retained our interest:
their nearly universal glycolytic phenotype and their sensitivity towards an
oxidative stress. Therefore, we took advantage of these features to develop an
experimental approach by selectively exposing cancer cells to an oxidant insult
induced by the combination of menadione (vitamin K(3)) and ascorbate (vitamin C).
Ascorbate enhances the menadione redox cycling, increases the formation of
reactive oxygen species and kills K562 cells as shown by more than 65% of LDH
leakage after 24 hr of incubation. Since both lactate formation and ATP content
are depressed by about 80% following ascorbate/menadione exposure, we suggest
that the major intracellular event involved in such a cytotoxicity is related to 
the impairment of glycolysis. Indeed, NAD(+) is rapidly and severely depleted, a 
fact most probably related to a strong Poly(ADP-ribose) polymerase (PARP)
activation, as shown by the high amount of poly-ADP-ribosylated proteins. The
addition of N-acetylcysteine (NAC) restores most of the ATP content and the
production of lactate as well. The PARP inhibitor dihydroxyisoquinoline (DiQ) was
able to partially restore both parameters as well as cell death induced by
ascorbate/menadione. These results suggest that the PARP activation induced by
the oxidative stress is a major but not the only intracellular event involved in 
cell death by ascorbate/menadione. Due to the high energetic dependence of cancer
cells on glycolysis, the impairment of such an essential pathway may explain the 
effectiveness of this combination to kill cancer cells. (c) 2006 Wiley-Liss, Inc.

PMID: 17163414 [PubMed - indexed for MEDLINE]

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