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 Rimsza, Margaret E. Tome

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 2013
Externally publishedYes

Fingerprint

Peroxynitrous Acid
Cell death
Hematologic Neoplasms
Chelating Agents
Copper
Cell Death
Superoxide Dismutase
Oxidative stress
Electron Transport Complex IV
Oxidative Stress
Mitochondria
tetrathiomolybdate
Mitochondrial Membrane Potential
Choline
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Oxidants
Doxorubicin
Oxidation-Reduction
B-Lymphocytes
Up-Regulation

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Lee, K., Briehl, M. M., Mazar, A. P., Batinic-Haberle, I., Reboucas, J. S., Glinsmann-Gibson, B., ... Tome, M. E. (2013). The copper chelator ATN-224 induces peroxynitrite-dependent cell death in hematological malignancies. Free Radical Biology and Medicine, 60, 157-167. https://doi.org/10.1016/j.freeradbiomed.2013.02.003

The copper chelator ATN-224 induces peroxynitrite-dependent cell death in hematological malignancies. / Lee, Kristy; Briehl, Margaret M.; Mazar, Andrew P.; Batinic-Haberle, Ines; Reboucas, Julio S.; Glinsmann-Gibson, Betty; Rimsza, Lisa; Tome, Margaret E.

In: Free Radical Biology and Medicine, Vol. 60, 07.2013, p. 157-167.

Research output: Contribution to journalArticle

Lee, K, Briehl, MM, Mazar, AP, Batinic-Haberle, I, Reboucas, JS, Glinsmann-Gibson, B, Rimsza, L & Tome, ME 2013, 'The copper chelator ATN-224 induces peroxynitrite-dependent cell death in hematological malignancies', Free Radical Biology and Medicine, vol. 60, pp. 157-167. https://doi.org/10.1016/j.freeradbiomed.2013.02.003
Lee, Kristy ; Briehl, Margaret M. ; Mazar, Andrew P. ; Batinic-Haberle, Ines ; Reboucas, Julio S. ; Glinsmann-Gibson, Betty ; Rimsza, Lisa ; Tome, Margaret E. / The copper chelator ATN-224 induces peroxynitrite-dependent cell death in hematological malignancies. In: Free Radical Biology and Medicine. 2013 ; Vol. 60. pp. 157-167.
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