Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737
Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737
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DOI：
10.1158/0008-5472.can-06-2203
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Tse, Christin
中科院分区：
文献类型：
--
作者：
Tahir, Stephen K.;Yang, Xiufen;Tse, Christin
ABT-737是一种新型的Bcl-2拮抗剂，对小细胞肺癌（SCLC）细胞系具有单药活性。在这里，我们评估了Bcl-2家族成员对几种SCLC细胞系对ABT-737的体外细胞反应的贡献。相对较高水平的Bcl-2、Bcl-X-L、Bim和Noxa以及较低水平的Mcl-1表征了对ABT-737敏感的初始SCLC细胞系。相反，Bcl-2和Noxa的相对水平的进行性降低和Mcl-1水平的进行性增加表征了H146细胞在长期暴露于ABT-737后的抗性增加。用小干扰RNA敲低Mcl-1可通过增强ABT-737诱导的凋亡而使两种耐药SCLC细胞系H196和DMS 114敏感。同样，上调Noxa使H196细胞对ABT-737敏感。与DNA损伤剂的联合处理与ABT-737具有极强的协同作用，并且与H196细胞中Mcl-1的下调和Noxa、Puma和Bim的上调相关。因此，对ABT-737敏感的SCLC细胞表达靶蛋白Bcl-2和Bcl-XL，而Mcl-1和调节Mcl-1功能的因子似乎有助于SCLC细胞对ABT-737的总体抗性。总体而言，这些观察结果提供了关于ABT-737在SCLC中疗效的机制基础的进一步见解，并将有助于分析患者并帮助合理设计联合治疗。
ABT-737 is a novel and potent Bcl-2 antagonist with single-agent activity against small-cell lung cancer (SCLC) cell lines. Here, we evaluated the contribution of Bcl-2 family members to the in vitro cellular response of several SCLC cell lines to ABT-737. Relatively higher levels of Bcl-2, Bcl-X-L, Bim and Noxa, and lower levels of Mcl-1 characterized naive SCLC cell lines that were sensitive to ABT-737. Conversely, a progressive decrease in the relative levels of Bcl-2 and Noxa and a progressive increase in Mcl-1 levels characterized the increased resistance of H146 cells following chronic exposure to ABT-737. Knockdown of Mcl-1 with small interfering RNA sensitized two resistant SCLC cell lines H196 and DMS114 to ABT-737 by enhancing the induction of apoptosis. Likewise, up-regulation of Noxa sensitized H196 cells to ABT-737. Combination treatment with DNA-damaging agents was extremely synergistic with ABT-737 and was associated with the down-regulation of Mcl-1 and the up-regulation of Noxa, Puma, and Bim in H196 cells. Thus, SCLC cells sensitive to ABT-737 expressed the target proteins Bcl-2 and Bcl-XL, whereas Mcl-1 and factors regulating Mcl-1 function seem to contribute to the overall resistance of SCLC cells to ABT-737. Overall, these observations provide further insight as to the mechanistic bases for ABT-737 efficacy in SCLC and will be helpful for profiling patients and aiding in the rational design of combination therapies.