| 19404643 |
Howard AN, Bridges KA, Meyn RE, Chandra J: ABT-737, a BH3 mimetic, induces glutathione depletion and oxidative stress. Cancer Chemother Pharmacol. 2009 Dec;65(1):41-54. Epub 2009 Apr 29.
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. |
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