Author/Authors :
van Delft، نويسنده , , Mark F. and Wei، نويسنده , , Andrew H. and Mason، نويسنده , , Kylie D. and Vandenberg، نويسنده , , Cassandra J. and Chen، نويسنده , , Lin and Czabotar، نويسنده , , Peter E. and Willis، نويسنده , , Simon N. and Scott، نويسنده , , Clare L. and Day، نويسنده , , Catherine L. and Cory، نويسنده , , Suzanne and Adams، نويسنده , , Jerry M. and Roberts، نويسنده , , Andrew W. and Huang، نويسنده , , David C.S.، نويسنده ,
Abstract :
Summary
apoptosis is impaired in malignant cells overexpressing prosurvival Bcl-2 proteins, drugs mimicking their natural antagonists, BH3-only proteins, might overcome chemoresistance. Of seven putative BH3 mimetics tested, only ABT-737 triggered Bax/Bak-mediated apoptosis. Despite its high affinity for Bcl-2, Bcl-xL, and Bcl-w, many cell types proved refractory to ABT-737. We show that this resistance reflects ABT-737ʹs inability to target another prosurvival relative, Mcl-1. Downregulation of Mcl-1 by several strategies conferred sensitivity to ABT-737. Furthermore, enforced Mcl-1 expression in a mouse lymphoma model conferred resistance. In contrast, cells overexpressing Bcl-2 remained highly sensitive to ABT-737. Hence, ABT-737 should prove efficacious in tumors with low Mcl-1 levels, or when combined with agents that inactivate Mcl-1, even to treat those tumors that overexpress Bcl-2.
