title: Exploiting mitochondrial dysfunction for effective elimination of imatinib-resistant leukemic cells.
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.
authors.affiliation: Equipe 4 UMR 837 Inserm, Faculté de Médecine, Université de Lille II, Lille, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Kluza
authors.forename: Manel
authors.initials: M
authors.lastname: Jendoubi
authors.forename: Caroline
authors.initials: C
authors.lastname: Ballot
authors.forename: Abir
authors.initials: A
authors.lastname: Dammak
authors.forename: Aurélie
authors.initials: A
authors.lastname: Jonneaux
authors.forename: Thierry
authors.initials: T
authors.lastname: Idziorek
authors.forename: Sami
authors.initials: S
authors.lastname: Joha
authors.forename: Véronique
authors.initials: V
authors.lastname: Dauphin
authors.forename: Myriam
authors.initials: M
authors.lastname: Malet-Martino
authors.forename: Stéphane
authors.initials: S
authors.lastname: Balayssac
authors.forename: Patrice
authors.initials: P
authors.lastname: Maboudou
authors.forename: Gilbert
authors.initials: G
authors.lastname: Briand
authors.forename: Pierre
authors.initials: P
authors.lastname: Formstecher
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D001549:Benzamides; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D000068877:Imatinib Mesylate; D017879:Isothiocyanates / Q000494:pharmacology; D007938:Leukemia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001152:Arsenicals; D001549:Benzamides; D017879:Isothiocyanates; D010087:Oxides; D010879:Piperazines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C058305:phenethyl isothiocyanate; D000068877:Imatinib Mesylate; D005947:Glucose; D000077237:Arsenic Trioxide