ABT-737, a BH3 mimetic, induces glutathione depletion and oxidative stress.
OBJECTIVE
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.
Howard
Adrienne N
AN
Department of Pediatrics Research, The University of Texas M D Anderson Cancer Center, Box 853, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Bridges
Kathleen A
KA
Meyn
Raymond E
RE
Chandra
Joya
J
D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D005978:Glutathione / Q000187:drug effects* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019169:Jurkat Cells; D009596:Nitrophenols / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014162:Transfection
C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D013481:Superoxides; D006861:Hydrogen Peroxide; D020169:Caspases; D005978:Glutathione