Kuroda Junya, Puthalakath Hamsa, Cragg Mark S, Kelly Priscilla N, Bouillet Philippe, Huang David C S, Kimura Shinya, Ottmann Oliver G, Druker Brian J, Villunger Andreas, Roberts Andrew W, Strasser Andreas
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14907-12. doi: 10.1073/pnas.0606176103. Epub 2006 Sep 22.
Cell killing is a critical pharmacological activity of imatinib to eradicate Bcr/Abl+ leukemias. We found that imatinib kills Bcr/Abl+ leukemic cells by triggering the Bcl-2-regulated apoptotic pathway. Imatinib activated several proapoptotic BH3-only proteins: bim and bmf transcription was increased, and both Bim and Bad were activated posttranslationally. Studies using RNAi and cells from gene-targeted mice revealed that Bim plays a major role in imatinib-induced apoptosis of Bcr/Abl+ leukemic cells and that the combined loss of Bim and Bad abrogates this killing. Loss of Bmf or Puma had no effect. Resistance to imatinib caused by Bcl-2 overexpression or loss of Bim (plus Bad) could be overcome by cotreatment with the BH3 mimetic ABT-737. These results demonstrate that Bim and Bad account for most, perhaps all, imatinib-induced killing of Bcr/Abl+ leukemic cells and suggest previously undescribed drug combination strategies for cancer therapy.
细胞杀伤是伊马替尼根除Bcr/Abl+白血病的关键药理活性。我们发现伊马替尼通过触发Bcl-2调节的凋亡途径来杀伤Bcr/Abl+白血病细胞。伊马替尼激活了几种仅含BH3结构域的促凋亡蛋白：bim和bmf的转录增加，并且Bim和Bad在翻译后均被激活。使用RNA干扰和来自基因靶向小鼠的细胞进行的研究表明，Bim在伊马替尼诱导的Bcr/Abl+白血病细胞凋亡中起主要作用，并且Bim和Bad的共同缺失会消除这种杀伤作用。Bmf或Puma的缺失没有影响。由Bcl-2过表达或Bim（加Bad）缺失引起的对伊马替尼的耐药性可通过与BH3模拟物ABT-737联合治疗来克服。这些结果表明，Bim和Bad介导了大部分（可能是全部）伊马替尼诱导的对Bcr/Abl+白血病细胞的杀伤作用，并提示了先前未描述的癌症治疗药物联合策略。
