Tahir Stephen K, Yang Xiufen, Anderson Mark G, Morgan-Lappe Susan E, Sarthy Aparna V, Chen Jun, Warner Robert B, Ng Shi-Chung, Fesik Stephen W, Elmore Steve W, Rosenberg Saul H, Tse Christin
Global Pharmaceutical Product Research Division, Abbott Laboratories, Abbott Park Road, Abbott Park, IL 60064, USA.
Cancer Res. 2007 Feb 1;67(3):1176-83. doi: 10.1158/0008-5472.CAN-06-2203.
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 naïve 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-X(L), 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.
ABT-737是一种新型强效Bcl-2拮抗剂，对小细胞肺癌（SCLC）细胞系具有单药活性。在此，我们评估了Bcl-2家族成员对几种SCLC细胞系对ABT-737体外细胞反应的贡献。对ABT-737敏感的原始SCLC细胞系的特征是Bcl-2、Bcl-X(L)、Bim和Noxa水平相对较高，而Mcl-1水平较低。相反，慢性暴露于ABT-737后，H146细胞耐药性增加的特征是Bcl-2和Noxa的相对水平逐渐降低，Mcl-1水平逐渐升高。用小干扰RNA敲低Mcl-1可通过增强凋亡诱导使两种耐药SCLC细胞系H196和DMS114对ABT-737敏感。同样，Noxa的上调使H196细胞对ABT-737敏感。与DNA损伤剂联合治疗与ABT-737具有极强的协同作用，并与H196细胞中Mcl-1的下调以及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-X(L)，而Mcl-1及其调节因子似乎对SCLC细胞对ABT-737的总体耐药性有贡献。总体而言，这些观察结果为ABT-737在SCLC中的疗效机制提供了进一步的见解，将有助于对患者进行分析，并有助于合理设计联合治疗方案。
