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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.

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Verrax, Julien [UCL] Vanbever, Stéphanie Stockis, Julie [UCL] Taper, Henryk [UCL] Buc Calderon, Pedro [UCL]

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.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't
Access type Accès restreint
Publication date 2007
Journal information "International Journal of Cancer" - Vol. 120, no. 6, p. 1192-7 (2007)
Peer reviewed yes
Publisher JohnWiley & Sons, Inc. ((United States) Hoboken)
issn 0020-7136
e-issn 1097-0215
Publication status Publié
Affiliations UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique
UCL - MD/FARM - Ecole de pharmacie
MESH Subject Antioxidants - pharmacology ; Apoptosis ; Ascorbic Acid - pharmacology ; Enzyme Activation ; Glycolysis - drug effects ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology - metabolism ; NAD - deficiency ; Necrosis ; Oxidative Stress ; Poly(ADP-ribose) Polymerases - metabolism ; Tumor Cells, Cultured ; Vitamin K 3 - pharmacology
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Bibliographic reference Verrax, Julien ; Vanbever, Stéphanie ; Stockis, Julie ; Taper, Henryk ; Buc Calderon, Pedro. 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.. In: International Journal of Cancer, Vol. 120, no. 6, p. 1192-7 (2007)
Permanent URL http://hdl.handle.net/2078.1/10796