Wu Zhuo-Xun, Yang Yuqi, Wang Jing-Quan, Zhou Wen-Min, Chen Junyu, Fu Yi-Ge, Patel Ketankumar, Chen Zhe-Sheng, Zhang Jian-Ye
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.
Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Front Pharmacol. 2021 Jan 14;11:615824. doi: 10.3389/fphar.2020.615824. eCollection 2020.
The emergence of multidrug resistance (MDR) has been a major issue for effective cancer chemotherapy as well as targeted therapy. One prominent factor that causes MDR is the overexpression of ABCB1 transporter. In the present study, we revealed that the Aurora kinase inhibitor GSK-1070916 is a substrate of ABCB1. GSK-1070916 is a newly developed inhibitor that is currently under clinical investigation. The cytotoxicity assay showed that overexpression of ABCB1 significantly hindered the anticancer effect of GSK-1070916 and the drug resistance can be abolished by the addition of an ABCB1 inhibitor. GSK-1070916 concentration-dependently stimulated ABCB1 ATPase activity. The HPLC drug accumulation assay suggested that the ABCB1-overexpressing cells had lower levels of intracellular GSK-1070916 compared with the parental cells. GSK-1070916 also showed high binding affinity to ABCB1 substrate-binding site in the computational docking analysis. In conclusion, our study provides strong evidence that ABCB1 can confer resistance to GSK-1070916, which should be taken into consideration in clinical setting.
多药耐药性（MDR）的出现一直是有效进行癌症化疗以及靶向治疗的主要问题。导致MDR的一个突出因素是ABCB1转运蛋白的过表达。在本研究中，我们发现极光激酶抑制剂GSK-1070916是ABCB1的底物。GSK-1070916是一种新开发的抑制剂，目前正处于临床研究阶段。细胞毒性试验表明，ABCB1的过表达显著阻碍了GSK-1070916的抗癌效果，并且通过添加ABCB1抑制剂可以消除耐药性。GSK-1070916以浓度依赖性方式刺激ABCB1的ATP酶活性。高效液相色谱药物蓄积试验表明，与亲代细胞相比，ABCB1过表达的细胞内GSK-1070916水平较低。在计算机对接分析中，GSK-1070916对ABCB1底物结合位点也表现出高结合亲和力。总之，我们的研究提供了有力证据，表明ABCB1可赋予对GSK-1070916的耐药性，在临床环境中应予以考虑。
