| Literature DB >> 17097561 |
Mark F van Delft1, 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.
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.Entities:
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Year: 2006 PMID： 17097561 PMCID： PMC2953559 DOI： 10.1016/j.ccr.2006.08.027
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743