ABT-737, a BH3 mimetic, induces glutathione depletion and oxidative stress

Adrienne N. Howard, Kathleen A. Bridges, Raymond E. Meyn, Joya Chandra

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Purpose: This study assessed the role of oxidative stress and loss of glutathione in ABT-737-induced apoptosis. Methods: Jurkat human acute lymphocytic leukemia cells and HeLa cells transfected with a tet-regulated Bcl-2 expression system were treated with ABT-737 or its less active stereoisomer. GSH concentrations, intracellular reactive oxygen species (ROS), caspase activation and apoptotic DNA fragmentation were measured. Results: ABT-737 induced oxidative stress through decreased GSH and increased intracellular hydrogen peroxide and superoxide levels. Apoptotic DNA fragmentation and caspase activation were the consequences of this oxidative stress. Combining ABT-737 with ROS-inducing agents such as adaphostin or etoposide enhanced cell death. Conclusions: These results demonstrate that inhibition of Bcl-2 causes a loss of GSH, an increase in ROS, caspase activation and subsequent apoptosis. Clinically, redox alterations as a consequence of Bcl-2 inhibition by ABT-737 should be considered in devising combination therapies with this novel agent or its derivatives.

Original languageEnglish (US)
Pages (from-to)41-54
Number of pages14
JournalCancer chemotherapy and pharmacology
Volume65
Issue number1
DOIs
StatePublished - Apr 30 2009

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Oxidative stress
Glutathione
Oxidative Stress
Caspases
Reactive Oxygen Species
Chemical activation
NSC 680410
DNA Fragmentation
Apoptosis
Stereoisomerism
DNA
Etoposide
Cell death
Precursor Cell Lymphoblastic Leukemia-Lymphoma
HeLa Cells
Superoxides
Hydrogen Peroxide
Oxidation-Reduction
Cell Death
ABT-737

Keywords

  • ABT-737
  • Apoptosis
  • Bcl-2
  • Glutathione
  • ROS

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

ABT-737, a BH3 mimetic, induces glutathione depletion and oxidative stress. / Howard, Adrienne N.; Bridges, Kathleen A.; Meyn, Raymond E.; Chandra, Joya.

In: Cancer chemotherapy and pharmacology, Vol. 65, No. 1, 30.04.2009, p. 41-54.

Research output: Contribution to journalArticle

Howard, Adrienne N. ; Bridges, Kathleen A. ; Meyn, Raymond E. ; Chandra, Joya. / ABT-737, a BH3 mimetic, induces glutathione depletion and oxidative stress. In: Cancer chemotherapy and pharmacology. 2009 ; Vol. 65, No. 1. pp. 41-54.
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