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

PLoS ONE, ISSN: 1932-6203, Vol: 6, Issue: 7, Page: e21924
2011
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Article Description

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. © 2011 Kluza et al.

Bibliographic Details

http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=79960630736&origin=inward; http://dx.doi.org/10.1371/journal.pone.0021924; http://www.ncbi.nlm.nih.gov/pubmed/21789194; https://dx.plos.org/10.1371/journal.pone.0021924.g007; http://dx.doi.org/10.1371/journal.pone.0021924.g007; https://dx.plos.org/10.1371/journal.pone.0021924.g006; http://dx.doi.org/10.1371/journal.pone.0021924.g006; https://dx.plos.org/10.1371/journal.pone.0021924.g003; http://dx.doi.org/10.1371/journal.pone.0021924.g003; https://dx.plos.org/10.1371/journal.pone.0021924.g002; http://dx.doi.org/10.1371/journal.pone.0021924.g002; https://dx.plos.org/10.1371/journal.pone.0021924.g005; http://dx.doi.org/10.1371/journal.pone.0021924.g005; https://dx.plos.org/10.1371/journal.pone.0021924; https://dx.plos.org/10.1371/journal.pone.0021924.g001; http://dx.doi.org/10.1371/journal.pone.0021924.g001; https://dx.plos.org/10.1371/journal.pone.0021924.g004; http://dx.doi.org/10.1371/journal.pone.0021924.g004; https://dx.doi.org/10.1371/journal.pone.0021924; https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021924; https://dx.doi.org/10.1371/journal.pone.0021924.g002; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0021924.g002; https://dx.doi.org/10.1371/journal.pone.0021924.g001; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0021924.g001; https://dx.doi.org/10.1371/journal.pone.0021924.g004; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0021924.g004; https://dx.doi.org/10.1371/journal.pone.0021924.g007; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0021924.g007; https://dx.doi.org/10.1371/journal.pone.0021924.g006; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0021924.g006; https://dx.doi.org/10.1371/journal.pone.0021924.g003; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0021924.g003; https://dx.doi.org/10.1371/journal.pone.0021924.g005; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0021924.g005; http://dx.plos.org/10.1371/journal.pone.0021924.g003; http://dx.plos.org/10.1371/journal.pone.0021924.g001; http://dx.plos.org/10.1371/journal.pone.0021924.g007; http://dx.plos.org/10.1371/journal.pone.0021924.g002; https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0021924&type=printable; http://dx.plos.org/10.1371/journal.pone.0021924.g005; http://www.plosone.org/article/metrics/info:doi/10.1371/journal.pone.0021924; http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0021924&type=printable; http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021924; http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0021924; http://dx.plos.org/10.1371/journal.pone.0021924; http://dx.plos.org/10.1371/journal.pone.0021924.g004; http://dx.plos.org/10.1371/journal.pone.0021924.g006

Jérome Kluza; Manel Jendoubi; Caroline Ballot; Abir Dammak; Aurélie Jonneaux; Thierry Idziorek; Sami Joha; Véronique Dauphin; Myriam Malet-Martino; Stéphane Balayssac; Patrice Maboudou; Gilbert Briand; Pierre Formstecher; Bruno Quesnel; Philippe Marchetti; Janine Santos

Public Library of Science (PLoS)

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