Wang De-Shen, Patel Atish, Sim Hong-May, Zhang Yun-Kai, Wang Yi-Jun, Kathawala Rishil J, Zhang Hui, Talele Tanaji T, Ambudkar Suresh V, Xu Rui-Hua, Chen Zhe-Sheng
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA.
J Cell Biochem. 2014 Aug;115(8):1381-91. doi: 10.1002/jcb.24787.
ARRY-334543 is a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters. Lung cancer cell line NCI-H460 and its ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for the reversal study. Our results demonstrated that ARRY-334543 (1.0 μM) significantly reversed ABCG2-mediated multidrug resistance (MDR) by directly inhibiting the drug efflux function of ABCG2, resulting in the elevated intracellular accumulation of chemotherapeutic drugs in the ABCG2-overexpressing cell lines. In addition, in isolated membranes, ARRY-334543 stimulated ATPase activity and inhibited photolabeling of ABCG2 with [(125)I]-iodoarylazidoprazosin in a concentration-dependent manner indicating that this drug directly interacts at the drug-binding pocket of this transporter. ARRY-334543 (1.0 μM) only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR suggesting that it exhibits high affinity toward ABCG2. Moreover, homology modeling predicted the binding conformation of ARRY-334543 at Arg482 centroid-based grid of ABCG2. However, ARRY-334543 at reversal concentrations did not affect the expression level of ABCG2, AKT and ERK1/2 and regulate the re-localization of ABCG2. We conclude that ARRY-334543 significantly reverses drug resistance mediated by ABCG2.
ARRY-334543是一种ErbB1和ErbB2酪氨酸激酶的小分子抑制剂。我们开展本研究以确定ARRY-334543是否可通过与ABC转运蛋白相互作用来增强传统抗癌药物的疗效。肺癌细胞系NCI-H460及其ABCG2过表达的NCI-H460/MX20，以及ABCG2、ABCB1和ABCC10过表达的转染细胞系用于逆转研究。我们的结果表明，ARRY-334543（1.0 μM）通过直接抑制ABCG2的药物外排功能，显著逆转了ABCG2介导的多药耐药（MDR），导致化疗药物在ABCG2过表达细胞系中的细胞内蓄积增加。此外，在分离的膜中，ARRY-334543以浓度依赖性方式刺激ATP酶活性并抑制[(125)I]-碘芳基叠氮基哌唑对ABCG2的光标记，表明该药物直接在该转运蛋白的药物结合口袋处相互作用。ARRY-334543（1.0 μM）仅轻微逆转ABCB1介导的MDR，并部分逆转ABCC10介导的MDR，提示它对ABCG2具有高亲和力。此外，同源建模预测了ARRY-334543在基于ABCG2的Arg482质心网格处的结合构象。然而，逆转浓度的ARRY-334543不影响ABCG2、AKT和ERK1/2的表达水平，也不调节ABCG2的重新定位。我们得出结论，ARRY-334543可显著逆转由ABCG2介导的耐药。
