Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells
Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells
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Chk1 抑制剂 MK-8776 恢复 P-糖蛋白过表达癌细胞中化疗药物的敏感性
DOI：
10.3390/ijms20174095
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发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Chen, Zhe-Sheng
中科院分区：
文献类型：
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作者：
Cui, Qingbin;Cai, Chao-Yun;Chen, Zhe-Sheng
P-糖蛋白（P-gp）是由ATP结合盒（ABC）转运蛋白亚家族B成员1（ABCB 1）基因编码的，是ABC转运蛋白中最重要的底物跨膜转运蛋白之一。它的过度表达是导致肿瘤多药耐药（MDR）的主要原因之一，而MDR是导致肿瘤治疗失败的主要原因。在这里，我们报告了检查点激酶（Chk）1抑制剂MK-8776，一种临床试验中的候选药物，可以恢复KB-C2，SW 620/Ad 300细胞和过表达P-gp的人胚肾（HEK）293/ABCB 1细胞中作为P-gp底物的化疗药物的敏感性。MK-8776显着增强细胞[H-3]-紫杉醇积聚并抑制P-gp的外排功能，而不减少其表达并影响其在癌细胞中的细胞定位。此外，MK-8776（0-40 μ M）可刺激P-gp中ATP酶的活性，是对照组的4.1倍。此外，计算机辅助分子对接研究表明，MK-8776与P-gp底物结合位点的关键残基形成阳离子-π键和π-π相互作用。我们的研究表明，MK-8776可以显着提高化疗药物的敏感性，P-gp的底物，提供了重要的信息，其应用于逆转MDR。
P-glycoprotein (P-gp), which is encoded by the ATP-binding cassette (ABC) transporter subfamily B member 1 (ABCB1) gene, is one of the most pivotal ABC transporters that transport its substrates across the cell membrane. Its overexpression is one of the confirmed causes of multidrug resistance (MDR), which results in the failure of cancer treatment. Here, we report that checkpoint kinase (Chk) 1 inhibitor MK-8776, a drug candidate in clinical trial, can restore the sensitivity of chemotherapeutics that are substrates of P-gp in KB-C2, SW620/Ad300 cells and human embryonic kidney (HEK)293/ABCB1 cells that overexpress P-gp. MK-8776 remarkably enhanced the cellular [H-3]-paclitaxel accumulation and suppressed the efflux function of P-gp without reducing its expression and affecting its cellular localization in cancer cells. Furthermore, MK-8776 (0-40 mu M) stimulated the activity of ATPase in P-gp, which was 4.1-fold greater than the control. In addition, MK-8776 formed a cation-pi bond and pi-pi interaction with key residues of the substrate-binding site in P-gp, as indicated by computer-aided molecular docking study. Our study indicated that MK-8776 may significantly enhance the sensitivity of chemotherapeutics that are substrates of P-gp, providing important information for its application in the reversal of MDR.