期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 60, 期 -, 页码 157-167出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2013.02.003
关键词
SOD1; CcOX; Bcl-2; Peroxynitrite; Lymphoma; Leukemia; Porphyrins; Free radicals
资金
- National Cancer Institute [CA09213, CA71768]
- H Foundation Funds
- Arizona Cancer Center [CA023074]
- Lymphoma SPORE CA [130805]
- [1P50CA130805-04]
- [U01 CA151461-02]
- [P50 HL107186-01]
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. (C) 2013 Elsevier Inc. All rights reserved.
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