Dong Xing-Duo, Zhang Meng, Ma Xiubin, Wang Jing-Quan, Lei Zi-Ning, Teng Qiu-Xu, Li Yi-Dong, Lin Lusheng, Feng Weiguo, Chen Zhe-Sheng
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.
First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, China.
Front Cell Dev Biol. 2020 Aug 27;8:865. doi: 10.3389/fcell.2020.00865. eCollection 2020.
Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) remains one of the most vital factors leading to multidrug resistance (MDR). It is important to enhance the effect and bioavailability of chemotherapeutic drugs that are substrates of ABCB1 transporter in ABCB1-overexpression cancer cells and reverse ABCB1-mediated MDR. Previous, we uncovered that the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is a potent reversal agent to overcomes paclitaxel resistance in ABCB1-overexpressing cells and tumors. In this study, we explored whether RN486, another BTK inhibitor, was competent to surmount ABCB1-mediated MDR and promote relevant cancer chemotherapy. We found that RN486 significantly increased the efficacy of paclitaxel and doxorubicin in both drug-selected carcinoma cells and transfected cells overexpressing ABCB1. Mechanistic studies indicated that RN486 dramatically attenuated the drug efflux activity of ABCB1 transporter without altering its expression level or subcellular localization. The ATPase activity of ABCB1 transporter was not affected by low concentrations but stimulated by high concentrations of RN486. Moreover, an interaction between RN486 with ABCB1 substrate-binding and inhibitor binding sites was verified by docking simulation. The results from our study suggest that RN486 could be a reversal agent and could be used in the novel combination therapy with other antineoplastic drugs to conquer MDR-mediated by ABCB1 transporter in clinics.
ATP结合盒亚家族B成员1（ABCB1）的过表达仍然是导致多药耐药（MDR）的最重要因素之一。增强ABCB1过表达癌细胞中作为ABCB1转运蛋白底物的化疗药物的效果和生物利用度，并逆转ABCB1介导的MDR，这一点很重要。此前，我们发现布鲁顿酪氨酸激酶（BTK）抑制剂依鲁替尼是一种有效的逆转剂，可克服ABCB1过表达细胞和肿瘤中的紫杉醇耐药性。在本研究中，我们探讨了另一种BTK抑制剂RN486是否能够克服ABCB1介导的MDR并促进相关癌症化疗。我们发现，RN486显著提高了紫杉醇和阿霉素在药物筛选的癌细胞和过表达ABCB1的转染细胞中的疗效。机制研究表明，RN486显著减弱了ABCB1转运蛋白的药物外排活性，而不改变其表达水平或亚细胞定位。ABCB1转运蛋白的ATP酶活性不受低浓度RN486的影响，但受高浓度RN486的刺激。此外，通过对接模拟验证了RN486与ABCB底物结合位点和抑制剂结合位点之间的相互作用。我们的研究结果表明，RN486可能是一种逆转剂，可用于与其他抗肿瘤药物联合进行新的联合治疗，以克服临床上由ABCB1转运蛋白介导的MDR。
