Kluza 2011 PLoS One
| 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 |
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-1Ξ±, 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. β’ Keywords: Leukemia cell line, syngeneic mouse tumor model, chronic myeloid leukemia (CML) patients, imatinib, HIF-1Ξ±, NADH, pro-oxidants PEITC and Trisenox
β’ O2k-Network Lab: FR Lille Neviere R, FR Lille Vienne JC
Labels:
Pathology: Cancer
Stress:RONS; Oxidative Stress"RONS; Oxidative Stress" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property.
Organism: Human, Mouse
Tissue;cell: Blood cells
Preparation: Intact cells, Permeabilized cells
Enzyme: TCA Cycle and Matrix Dehydrogenases"TCA Cycle and Matrix Dehydrogenases" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property.
Regulation: Substrate; Glucose; TCA Cycle"Substrate; Glucose; TCA Cycle" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property.
Coupling state: OXPHOS
HRR: Oxygraph-2k
