The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized
The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized
复制标题
DOI：
10.1016/j.ccr.2006.08.027
复制
发表时间：
2006-11-01
期刊：
影响因子：
50.3
通讯作者：
Huang, David C. S.
中科院分区：
文献类型：
--
作者：
van Delft, Mark F.;Wei, Andrew H.;Huang, David C. S.
由于细胞凋亡在过度表达促生存Bcl-2蛋白的恶性细胞中受损，因此模仿其天然拮抗剂BH 3-only蛋白的药物可能克服化学抗性。在测试的七种推定的BH 3模拟物中，只有ABT-737触发Bax/Bak介导的凋亡。尽管ABT-737对Bcl-2、Bcl-X-L和Bcl-w具有高亲和力，但许多细胞类型被证明对ABT-737无效。我们表明，这种耐药性反映了ABT-737无法靶向另一种促生存亲戚Mcl-1。通过几种策略下调Mcl-1赋予了对ABT-737的敏感性。此外，在小鼠淋巴瘤模型中强制Mcl-1表达赋予抗性。相反，过表达Bcl-2的细胞对ABT-737仍然高度敏感。因此，ABT-737应该证明在具有低Mcl-1水平的肿瘤中有效，或者当与抑制Mcl-1的药剂组合时，甚至治疗过表达Bcl-2的那些肿瘤。
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.