Dacomitinib antagonizes multidrug resistance (MDR) in cancer cells by inhibiting the efflux activity of ABCBI and ABCG2 transporters
Dacomitinib antagonizes multidrug resistance (MDR) in cancer cells by inhibiting the efflux activity of ABCBI and ABCG2 transporters
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DOI：
10.1016/j.canlet.2018.01.021
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Trombetta, Louis D.
中科院分区：
文献类型：
--
作者：
Fan, Ying-Fang;Zhang, Wei;Trombetta, Louis D.
化疗的多药耐药（MDR）的发展仍然是癌症治疗中的一个主要挑战。已经认识到导致MDR的许多机制，但最重要的机制之一是三磷酸腺苷（ATP）结合盒（ABC）转运蛋白的过表达，通过该转运蛋白，各种抗癌药物对抗其浓度梯度的外排由ATP提供动力。近年来，小分子酪氨酸激酶抑制剂（TKI）已被开发用于治疗各种过表达表皮生长因子受体（EGFR）的人类癌症。同时，一些TKI已被证明能够抑制ABC转运蛋白介导的MDR。达克替尼（PF-00299804）是第二代不可逆TKI，在一些临床前和临床试验中显示出积极的抗癌活性。由于许多TKI是ABC转运蛋白的底物或抑制剂，因此本研究探讨了dacomitinib是否可以与介导MDR的ABC亚家族成员相互作用，包括ABCB 1（P-gp）、ABCG 2（BCRP）和ABCC 1（MRP 1）。结果显示，1.0 μ M dacomitinib通过拮抗ABCB 1和ABCG 2过表达细胞系中的药物外排功能，显著逆转了ABCB 1和ABCG 2介导的耐药性，但不逆转ABCC 1介导的耐药性。对ABCB 1过表达细胞的逆转作用比对ABCG 2过表达细胞的逆转作用更强。此外，逆转浓度的dacomitinib既不影响蛋白表达水平，也不影响ABCB 1和ABCG 2的定位。因此，这种调节作用的机制可能如下：首先，作为ABCB 1或ABCG 2转运体的抑制剂，dacomitinib以非竞争性方式稳定地结合于跨膜结构域（TMD）中的药物底物位点;或者第二，dacomitinib以浓度依赖性方式抑制ATP酶活性并维持TMD构象的稳定性，从而抑制ABCBI或ABCG 2的药物外排功能传送器。这项研究提供了一种有用的联合治疗策略，dacomitinib和ABCB 1和/或ABCG 2转运蛋白的底物在ABCB 1或ABCG 2过表达的癌症。(C)2018爱思唯尔B. V.保留所有权利。
The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Numerous mechanisms have been recognized that cause MDR, but one of the most important mechanisms is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters, through which the efflux of various anticancer drugs against their concentration gradients is powered by ATP. In recent years, small molecular tyrosine kinase inhibitors (TKIs) have been developed for treatment in various human cancers overexpressing epidermal growth factor receptor (EGFR). At the same time, some TKIs have been shown to be capable of inhibiting ABC transporter-mediated MDR. Dacomitinib (PF-00299804) is a second generation, irreversible TKI, which has shown positive anticancer activities in some preclinical and clinical trials. As many TKIs are substrates or inhibitors of ABC transporters, this study investigates whether dacomitinib could interact with ABC subfamily members that mediate MDR, including ABCB1 (P-gp), ABCG2 (BCRP) and ABCC1 (MRP1). The results showed that dacomitinib at 1.0 mu M significantly reversed drug resistance mediated by ABCB1 and ABCG2, but not ABCC1, doing so by antagonizing the drug efflux function in ABCB1- and ABCG2-overexpressing cell lines. The reversal effect on ABCB1-overexpressing cells is more potent than that on ABCG2-overexpressing cells. In addition, dacomitinib at reversal concentration affected neither the protein expression level nor the localization of ABCB1 and ABCG2. Therefore, the mechanisms of this modulating effect are likely to be the following: first, as an inhibitor of ABCB1 or ABCG2 transporters, dacomitinib binds to drug substrate site in transmembrane domains (TMD) stably in a noncompetitive manner; or second, dacomitinib inhibits ATPase activity and maintains the stability of TMD conformation in a concentration dependent manner thereby inhibiting the drug efflux function of ABCBI or ABCG2 transporter. This study provides a useful combinational therapeutic strategy with dacomitinib and substrates of ABCB1 and/or ABCG2 transporters in ABCB1- or ABCG2-overexpressing cancers. (C) 2018 Elsevier B.V. All rights reserved.