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 journalArticlepeer-review

28 Scopus citations

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 - 2009

Keywords

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

ASJC Scopus subject areas

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

Fingerprint

Dive into the research topics of 'ABT-737, a BH3 mimetic, induces glutathione depletion and oxidative stress'. Together they form a unique fingerprint.

Cite this