Biochem Pharmacol 2011 Nov;82 (9): 1066-72. [IF:4.889]
Mcl-1 downregulation by YM155 contributes to its synergistic anti-tumor activities with ABT-263.
Tang H , Shao H , Yu C , Hou J .
Department of Oral and Maxicallifacial Surgery, The Affiliated Stomatology Hospital of Sun Yet-sen University, Guangzhou, Guangdong 510055, China.
广州中山大学附属口腔医院口腔颌面外科
Abstract
YM155, a small-molecule survivin suppressant, exhibits anti-tumor activities in vitro, in vivo and in clinical trials. However, the mechanism of YM155 action remains unclear. In this study, YM155 was administered to a panel of cell lines and the effects of YM155 on Bcl-2 family members were analyzed. Our results show that YM155 strikingly downregulates Mcl-1 in a broad spectrum of cancer cell lines and that the Mcl-1 modulation occurs at the transcriptional level, independently of survivin modulation or caspase activity. Furthermore, analysis of the contribution of Mcl-1 or survivin downregulation to YM155-induced cell death in vitro showed that knockdown of Mcl-1 sensitizes cells to YM155-induced cytotoxicity. Finally, our data demonstrate that downregulation of Mcl-1 by YM155 synergistically lowers the threshold of Bcl-2 family member inhibitor ABT-263-induced cell death. Our findings reveal a novel mechanism by which survivin-independent Mcl-1 suppression plays a critical role in YM155-mediated anti-tumor activities. YM155 treatment in combination with ABT-263 thus affords a new strategy for cancer treatment.
摘要：
YM155是一种小分子生存素抑制剂，在试管、活的有机体及临床试验中显现出抗肿瘤活性。然而，YM155的作用机制仍不明了。在这项研究当中，YM155被输送到一组细胞株当中，然后分析其对Bcl-2族系的影响。我们的研究结果表明，YM155在广泛的癌细胞系谱中能明显下调Mcl-1，Mcl-1的调节是通过转录进行的，是一种独立的生存素或半胱氨酸天冬氨酸蛋白酶活性的调节。另外，通过对试管中因Mcl-1或生存素下调而使YM155诱导细胞死亡的这种作用进行分析，表明Mcl-1的降低使细胞对YM155诱导的细胞毒变得敏感。最后，我们的数据证明，YM155引起的Mcl-1下调对降低Bcl-2族系抑制剂ABT-263诱导细胞死亡的阈值有协同作用。我们的发现揭示了一种新作用机制，即单独的生存素抑制剂Mcl-1在YM155-介导的抗肿瘤活性中扮有至关重要的角色。这样，通过YM155与ABT-263的联合治疗，可以为癌症的治疗提供一种新的方案。
