Mitochondria-targeting drugs arsenic trioxide and lonidamine bypass the resistance of TPA-differentiated leukemic cells to apoptosis

DOI PDF 被引用文献2件
  • Olivier Sordet
    From the Faculty of Medicine and Pharmacy, INSERM U517 and INSERM U498, IFR 100, Dijon, France.
  • Cédric Rébé
    From the Faculty of Medicine and Pharmacy, INSERM U517 and INSERM U498, IFR 100, Dijon, France.
  • Ingrid Leroy
    From the Faculty of Medicine and Pharmacy, INSERM U517 and INSERM U498, IFR 100, Dijon, France.
  • Jean-Marie Bruey
    From the Faculty of Medicine and Pharmacy, INSERM U517 and INSERM U498, IFR 100, Dijon, France.
  • Carmen Garrido
    From the Faculty of Medicine and Pharmacy, INSERM U517 and INSERM U498, IFR 100, Dijon, France.
  • Carole Miguet
    From the Faculty of Medicine and Pharmacy, INSERM U517 and INSERM U498, IFR 100, Dijon, France.
  • Gérard Lizard
    From the Faculty of Medicine and Pharmacy, INSERM U517 and INSERM U498, IFR 100, Dijon, France.
  • Stéphanie Plenchette
    From the Faculty of Medicine and Pharmacy, INSERM U517 and INSERM U498, IFR 100, Dijon, France.
  • Laurent Corcos
    From the Faculty of Medicine and Pharmacy, INSERM U517 and INSERM U498, IFR 100, Dijon, France.
  • Eric Solary
    From the Faculty of Medicine and Pharmacy, INSERM U517 and INSERM U498, IFR 100, Dijon, France.

書誌事項

公開日
2001-06-15
DOI
  • 10.1182/blood.v97.12.3931
公開者
American Society of Hematology

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説明

<jats:p>Exposure of U937 human leukemic cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) induces their differentiation into monocyte/macrophage-like cells. This terminal differentiation is associated with a resistant phenotype to apoptosis induced by the topoisomerase II inhibitor etoposide. The inhibition occurs upstream of the mitochondrial release of cytochrome c and the activation of procaspase-2, -3, -6, -7, -8, and -9. By using cell-free systems, it was demonstrated that the mitochondrial pathway to cell death that involves mitochondrial membrane depolarization, cytochrome c release and cytosolic activation of procaspases by cytochrome c/dATP remains functional in TPA-differentiated U937 cells. Accordingly, 2 drugs recently shown to target the mitochondria, namely lonidamine and arsenic trioxide, bypass the resistance of TPA-differentiated U937 cells to classical anticancer drugs. Cell death induced by the 2 compounds is associated with mitochondrial membrane depolarization, release of cytochrome c and Smac/Diablo from the mitochondria, activation of caspases, poly(ADP-ribose) polymerase cleavage and internucleosomal DNA fragmentation. Moreover, the decreased glutathione content associated with the differentiation process amplifies the ability of arsenic trioxide to activate the mitochondrial pathway to cell death. Similar results were obtained by comparing undifferentiated and TPA-differentiated human HL60 leukemic cells. These data demonstrate that mitochondria-targeting agents bypass the resistance to classical anticancer drugs induced by TPA-mediated leukemic cell differentiation.</jats:p>

収録刊行物

  • Blood

    Blood 97 (12), 3931-3940, 2001-06-15

    American Society of Hematology

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