The copper chelator ATN-224 induces peroxynitrite-dependent cell death in hematological malignancies

Kristy Lee, Margaret M. Briehl, Andrew P. Mazar, Ines Batinic-Haberle, Julio S. Reboucas, Betty Glinsmann-Gibson, Lisa M. Rimsza, Margaret E. Tome

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22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)157-167
Number of pages11
JournalFree Radical Biology and Medicine
Volume60
DOIs
StatePublished - Jul 1 2013

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Keywords

  • Bcl-2
  • CcOX
  • Free radicals
  • Leukemia
  • Lymphoma
  • Peroxynitrite
  • Porphyrins
  • SOD1

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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