Kluza 2011 PLoS One

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Kluza J, Jendoubi M, Ballot C, Dammak A, Jonneaux A, Idziorek T, Joha S, Dauphin V, Malet-Martino M, Balayssac S, Maboudou P, Briand G, Formstecher P, Quesnel B, Marchetti P (2011) Exploiting mitochondrial dysfunction for effective elimination of imatinib-resistant leukemic cells. PLoS One 6:e21924

» PMID: 21789194 Open Access

Kluza J, Jendoubi M, Ballot C, Dammak A, Jonneaux A, Idziorek T, Joha S, Dauphin V, Malet-Martino M, Balayssac S, Maboudou P, Briand G, Formstecher P, Quesnel B, Marchetti P (2011) PLoS One

Abstract: Challenges today concern chronic myeloid leukemia (CML) patients resistant to imatinib. There is growing evidence that imatinib-resistant leukemic cells present abnormal glucose metabolism but the impact on mitochondria has been neglected. Our work aimed to better understand and exploit the metabolic alterations of imatinib-resistant leukemic cells. Imatinib-resistant cells presented high glycolysis as compared to sensitive cells. Consistently, expression of key glycolytic enzymes, at least partly mediated by HIF-1α, was modified in imatinib-resistant cells suggesting that imatinib-resistant cells uncouple glycolytic flux from pyruvate oxidation. Interestingly, mitochondria of imatinib-resistant cells exhibited accumulation of TCA cycle intermediates, increased NADH and low oxygen consumption. These mitochondrial alterations due to the partial failure of ETC were further confirmed in leukemic cells isolated from some imatinib-resistant CML patients. As a consequence, mitochondria generated more ROS than those of imatinib-sensitive cells. This, in turn, resulted in increased death of imatinib-resistant leukemic cells following in vitro or in vivo treatment with the pro-oxidants, PEITC and Trisenox, in a syngeneic mouse tumor model. Conversely, inhibition of glycolysis caused derepression of respiration leading to lower cellular ROS. In conclusion, these findings indicate that imatinib-resistant leukemic cells have an unexpected mitochondrial dysfunction that could be exploited for selective therapeutic intervention.

Keywords: Leukemia cell line, syngeneic mouse tumor model, chronic myeloid leukemia (CML) patients, imatinib, HIF-1α, NADH, pro-oxidants PEITC and Trisenox

O2k-Network Lab: FR Lille Neviere R, FR Lille Vienne JC


Labels: Pathology: Cancer  Stress:Oxidative stress;RONS  Organism: Human, Mouse  Tissue;cell: Blood cells  Preparation: Intact cells, Permeabilized cells  Enzyme: TCA cycle and matrix dehydrogenases  Regulation: Substrate  Coupling state: OXPHOS 

HRR: Oxygraph-2k