Exploiting mitochondrial dysfunction for effective elimination of imatinib-resistant leukemic cells

PLoS One. 2011;6(7):e21924. doi: 10.1371/journal.pone.0021924. Epub 2011 Jul 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arsenic Trioxide
  • Arsenicals / pharmacology
  • Benzamides
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Respiration / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Electron Transport / drug effects
  • Energy Metabolism / drug effects
  • Glucose / metabolism
  • Imatinib Mesylate
  • Isothiocyanates / pharmacology
  • Leukemia / metabolism
  • Leukemia / pathology*
  • Leukemia / physiopathology*
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / pathology*
  • Mitochondria / ultrastructure
  • Models, Biological
  • Oxidative Stress / drug effects
  • Oxides / pharmacology
  • Piperazines / pharmacology*
  • Pyrimidines / pharmacology*
  • Reactive Oxygen Species / metabolism

Substances

  • Arsenicals
  • Benzamides
  • Isothiocyanates
  • Oxides
  • Piperazines
  • Pyrimidines
  • Reactive Oxygen Species
  • phenethyl isothiocyanate
  • Imatinib Mesylate
  • Glucose
  • Arsenic Trioxide