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The Essential Role of the Mitochondria and Reactive Oxygen Species in Cisplatin-Mediated Enhancement of Fas Ligand-Induced Apoptosis in Malignant Pleural Mesothelioma

  • John H. Stewart IV
    Affiliations
    Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina

    Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Author Footnotes
    1 Fellow of the Clinical Research Training Program, NIH.
    Thai-Lan Tran
    Footnotes
    1 Fellow of the Clinical Research Training Program, NIH.
    Affiliations
    Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Nicole Levi
    Affiliations
    Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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  • Wilson S. Tsai
    Affiliations
    Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • David S. Schrump
    Affiliations
    Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Dao M. Nguyen
    Correspondence
    To whom correspondence and reprint requests should be addressed at the Cancer Research Center, National Cancer Institute, National Institutes of Health, Room 4W-4-3940, 10 Center Drive, Bethesda, MD 20892.
    Affiliations
    Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Author Footnotes
    1 Fellow of the Clinical Research Training Program, NIH.
      Cytotoxic chemotherapeutic drugs such as cisplatin (CDDP) synergistically interact with soluble Fas ligand (sFasL) to mediate profound induction of apoptosis in cancer cells, particularly those refractory to this death-inducing ligand. The goal of this study was to evaluate the roles of the mitochondria-dependent apoptotic cascade and the CDDP-generated reactive oxygen species (ROS) in mediating the supra-additive enhancement of cytotoxicity and apoptosis in combination-treated malignant pleural mesothelioma (MPM) cells.
      MPM cells were treated with sequential CDDP/sFasL in vitro. Cell viability and apoptosis were determined by MTT and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays. Stable transfectants expressing high levels of Bcl2 were created by retroviral gene transfer. Specific proteolytic activity of caspases 3, 8, and 9 were measured using fluorescent substrates.
      Pretreating MPM cells with CDDP increased their susceptibility to sFasL by 2- to more than 20-fold. Overexpression of either Bcl-2, the selective caspase 9 inhibitor z-LEHD-fmk, or the antioxidant N-acetylcysteine significantly abrogated combination-induced cytotoxicity and apoptosis. Moreover, the robust activation of caspase 8 in combination-treated cells was completely suppressed by Bcl-2 overexpression, thus implicating a mitochondria-mediated amplification feedback loop. As an in vivo correlate, sequential intraperitoneal administration of CDDP and sFasL significantly inhibited the growth of intraperitoneal MPM human xenografts in nude mice.
      Our data indicate that the mitochondria-dependent feedback loop of the caspase activation cascade and the generation of ROS are both essential in mediating profound cytotoxicity and apoptosis of MPM cells treated with CDDP and sFasL. This mechanistic study establishes a the translational framework for the clinical application of sequential CDDP/sFasL in the treatment of MPM.

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