The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized
- Author(s)
- van Delft, MF; Wei, AH; Mason, KD; Vandenberg, CJ; Chen, L; Czabotar, PE; Willis, SN; Scott, CL; Day, CL; Cory, S; Adams, JM; Roberts, AW; Huang, DCS;
- Details
- Publication Year 2006-11,Volume 10,Issue #5,Page 389-399
- Journal Title
- CANCER CELL
- Publication Type
- Journal Article
- Abstract
- Since 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-X-L, and Bcl-w, many cell types proved refractory to ABT-737. We show that this resistance reflects ABT-737's 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.
- Publisher
- CELL PRESS
- Keywords
- SMALL-MOLECULE INHIBITORS; MULTIPLE-MYELOMA CELLS; BH3-ONLY PROTEINS; DOWN-REGULATION; SELICICLIB CYC202; KINASE INHIBITOR; FAMILY PROTEINS; R-ROSCOVITINE; SURVIVAL; DEATH
- Publisher's Version
- https://doi.org/10.1016/j.ccr.2006.08.027
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- Refer to copyright notice on published article.
Creation Date: 2006-11-01 12:00:00