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

Mark F. van Delft, Andrew H. Wei, Kylie D. Mason, Cassandra J. Vandenberg, Lin Chen, Peter E. Czabotar, Simon N. Willis, Clare L. Scott, Catherine L. Day, Suzanne Cory, Jerry M. Adams, Andrew W. Roberts, David C.S. Huang

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969 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)389-399
Number of pages11
JournalCancer Cell
Volume10
Issue number5
DOIs
Publication statusPublished - 1 Nov 2006
Externally publishedYes

Keywords

  • CELLCYCLE

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