[PDF][PDF] The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized

MF Van Delft, AH Wei, KD Mason, CJ Vandenberg… - Cancer cell, 2006 - cell.com
MF Van Delft, AH Wei, KD Mason, CJ Vandenberg, L Chen, PE Czabotar, SN Willis, CL Scott…
Cancer cell, 2006cell.com
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 …
Summary
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-xL, 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.
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