期刊
CANCER CHEMOTHERAPY AND PHARMACOLOGY
卷 65, 期 1, 页码 41-54出版社
SPRINGER
DOI: 10.1007/s00280-009-1001-1
关键词
ABT-737; Bcl-2; Apoptosis; ROS; Glutathione
资金
- [RO1 CA69003]
- [RO1 CA115811]
This study assessed the role of oxidative stress and loss of glutathione in ABT-737-induced apoptosis. 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. 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. 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.
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