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Iminophosphorane-organogold(III) complexes induce cell death through mitochondrial ROS production
Authors:Vela Laura  Contel María  Palomera Luis  Azaceta Gemma  Marzo Isabel
Institution:
  • a Department of Biochemistry and Molecular and Cellular Biology, University of Zaragoza, Spain
  • b Department of Chemistry, Brooklyn College and The Graduate Center, The City University of New York, Brooklyn, NY, 11210, USA
  • c Department of Hematology, Hospital Clínico Universitario ‘Lozano Blesa’, Zaragoza, Spain
  • Abstract:Gold compounds are being investigated as potential antitumor drugs. Some gold(III) derivatives have been shown to induce cell death in solid tumors but their mechanism of action differs from that of cisplatin, since most of these compounds do not bind to DNA. We have explored cellular events triggered by three different iminophosphorane-organogold(III) compounds in leukemia cells (a neutral compound with two chloride ligands Au{κ2-C,N-C6H4(PPh2 = N(C6H5)-2}Cl2] 1, and two cationic compounds with either a dithiocarbamate ligand Au{κ2-C,N-C6H4(PPh2 = N(C6H5)-2}(S2CN-Me2)]PF62, or a water-soluble phosphine and a chloride ligand Au{κ2-C,N-C6H4(PPh2 = N(C6H5)-2}(P{Cp(m-C6H4-SO3Na)2}3) Cl]PF63). All three compounds showed higher toxicity against leukemia cells when compared to normal T-lymphocytes. Compounds 1 and 2 induced both necrosis and apoptosis, while 3 was mainly apoptotic. Necrotic cell death induced by 1 and 2 was Bax/Bak- and caspase-independent, while apoptosis induced by 3 was Bax/Bak-dependent. Reactive oxygen species (ROS) production at the mitochondrial level was a critical step in the antitumor effect of these compounds.
    Keywords:Antitumor agents  Organogold(III) compounds  ROS  Mitochondria  Bcl-2 family  Caspases
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