title: Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway.
abstract: Cell death is generally believed to occur either by accidental, lytic necrosis or by programmed cell death, that is, apoptosis. The initiation and execution of cell death, however, is far more complex and includes pathways like caspase-independent apoptosis or actively triggered necrosis. In this study, we investigated the mechanisms of cell death induced by arsenic trioxide (arsenite, As2O3), a clinically efficient agent in anticancer therapy. As2O3-induced cell death coincides with cytochrome c release, facilitates mitochondrial permeability transition and is sensitive to inhibition by Bcl-x(L), indicating that cell demise is regulated through the mitochondrial apoptosis pathway. Nevertheless, only little caspase-3 activation was observed and As2O3-induced cell death was only weakly obstructed by the broad spectrum caspase inhibitor z-VAD-fmk. Moreover, disruption of caspase-9 or -2 failed to decrease the amount of As2O3-mediated cell death. Interestingly, As2O3-induced cell death had a predominantly necrosis-like phenotype as assessed by Annexin-V/propidium iodide staining and LDH release. Finally, blocking glutathione synthetase by buthionine sulfoximine enhanced the As2O3-mediated necrosis-like cell death without increasing caspase-3 cleavage. As2O3 does, however, not directly inhibit caspases, but appears to interfere with caspase activation. Altogether, our data clearly delineate a mode of As2O3-triggered cell death that differs considerably from that induced by conventional anticancer drugs. These findings may explain the capability of As2O3 to efficiently kill even chemoresistant tumor cells with disturbed apoptosis signaling and caspase activation, a frequent finding in malignancy.
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité, Campus Berlin-Buch, Robert-Rössle-Klinik, Humboldt Universität, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Scholz
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieder
authors.forename: Lilian
authors.initials: L
authors.lastname: Stärck
authors.forename: Frank
authors.initials: F
authors.lastname: Essmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Peter T
authors.initials: PT
authors.lastname: Daniel
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053143:Caspase 2; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure*; D009336:Necrosis; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: D001152:Arsenicals; C494811:BCL2L1 protein, human; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C506433:CASP9 protein, human; D053143:Caspase 2; D053453:Caspase 9; D020169:Caspases; D000077237:Arsenic Trioxide