title: The copper chelator ATN-224 induces peroxynitrite-dependent cell death in hematological malignancies.
abstract: Chemoresistance due to oxidative stress resistance or upregulation of Bcl-2 contributes to poor outcome in the treatment of hematological malignancies. In this study, we utilize the copper-chelator drug ATN-224 (choline tetrathiomolybdate) to induce cell death in oxidative stress-resistant cells and cells overexpressing Bcl-2 by modulating the cellular redox environment and causing mitochondrial dysfunction. ATN-224 treatment decreases superoxide dismutase 1 (SOD1) activity, increases intracellular oxidants, and induces peroxynitrite-dependent cell death. ATN-224 also targets the mitochondria, decreasing both cytochrome c oxidase (CcOX) activity and mitochondrial membrane potential. The concentration of ATN-224 required to induce cell death is proportional to SOD1 levels, but independent of Bcl-2 status. In combination with doxorubicin, ATN-224 enhances cell death. In primary B-cell acute lymphoblastic leukemia patient samples, ATN-224 decreases the viable cell number. Our findings suggest that ATN-224's dual targeting of SOD1 and CcOX is a promising approach for treatment of hematological malignancies either as an adjuvant or as a single agent.
authors: Department of Pathology, University of Arizona, Tucson, AZ 85724, USA.
authors: Kristy
authors: K
authors: Lee
authors: Margaret M
authors: MM
authors: Briehl
authors: Andrew P
authors: AP
authors: Mazar
authors: Ines
authors: I
authors: Batinic-Haberle
authors: Julio S
authors: JS
authors: Reboucas
authors: Betty
authors: B
authors: Glinsmann-Gibson
authors: Lisa M
authors: LM
authors: Rimsza
authors: Margaret E
authors: ME
authors: Tome
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000008:administration & dosage*; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008982:Molybdenum / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000503:physiopathology; D061251:Primary Cell Culture; D019253:Proto-Oncogene Proteins c-bcl-2; D013312:Stress, Physiological / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D020298:U937 Cells
chemical_list: D002614:Chelating Agents; D019253:Proto-Oncogene Proteins c-bcl-2; C000606290:SOD1 protein, human; D030421:Peroxynitrous Acid; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1