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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lee, K; Briehl, MM; Mazar, AP; Batinic-Haberle, I; Reboucas, JS; Glinsmann-Gibson, B; Rimsza, LM; Tome, ME

Published Date

  • July 2013

Published In

Volume / Issue

  • 60 /

Start / End Page

  • 157 - 167

PubMed ID

  • 23416365

Pubmed Central ID

  • PMC3654089

Electronic International Standard Serial Number (EISSN)

  • 1873-4596

Digital Object Identifier (DOI)

  • 10.1016/j.freeradbiomed.2013.02.003


  • eng

Conference Location

  • United States