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 language | English (US) |
---|---|
Pages (from-to) | 41-54 |
Number of pages | 14 |
Journal | Cancer chemotherapy and pharmacology |
Volume | 65 |
Issue number | 1 |
DOIs | |
State | Published - 2009 |
Keywords
- ABT-737
- Apoptosis
- Bcl-2
- Glutathione
- ROS
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)