Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells.
Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells.
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P-糖蛋白的靶向抑制剂会增加化学治疗诱导的多药耐药性肿瘤细胞死亡率。
DOI：
10.1038/s41598-018-19325-x
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发表时间：
2018-01-17
影响因子：
4.6
通讯作者：
Wise JG
中科院分区：
文献类型：
--
作者：
Nanayakkara AK;Follit CA;Chen G;Williams NS;Vogel PD;Wise JG
ATP结合盒（ABC）转运蛋白的过表达通常与癌症化疗中的多药耐药（MDR）有关。P-糖蛋白（P-gp）是目前研究最多的与MDR相关的药物转运蛋白之一。目前没有批准的药物可用于癌症化疗的临床用途，以通过抑制P-糖蛋白逆转MDR。使用计算研究，我们以前确定了几种化合物，抑制P-gp靶向其核苷酸结合域，避免其药物结合域。当在耐药前列腺癌细胞系上测试时，这些化合物中的几种显示出成功的MDR逆转。使用MDR卵巢癌和前列腺癌细胞的常规二维细胞培养物和三维前列腺癌微肿瘤球体，我们在此证明了与化疗剂共同施用显著降低细胞活力和存活以及细胞运动性。未观察到P-gp抑制剂本身具有毒性。这些抑制剂增加了已知为P-gp转运底物的化疗剂和报告化合物的细胞滞留。我们还发现，这些化合物不是P-gp的转运底物，三种化合物中有两种抑制P-gp，但不抑制密切相关的ABC转运蛋白ABCG 2/BCRP。结果表明，这些P-gp抑制剂可能是未来药物开发的有前途的线索。
Overexpression of ATP-binding cassette (ABC) transporters is often linked to multidrug resistance (MDR) in cancer chemotherapies. P-glycoprotein (P-gp) is one of the best studied drug transporters associated with MDR. There are currently no approved drugs available for clinical use in cancer chemotherapies to reverse MDR by inhibiting P-glycoprotein. Using computational studies, we previously identified several compounds that inhibit P-gp by targeting its nucleotide binding domain and avoiding its drug binding domains. Several of these compounds showed successful MDR reversal when tested on a drug resistant prostate cancer cell line. Using conventional two-dimensional cell culture of MDR ovarian and prostate cancer cells and three dimensional prostate cancer microtumor spheroids, we demonstrated here that co-administration with chemotherapeutics significantly decreased cell viability and survival as well as cell motility. The P-gp inhibitors were not observed to be toxic on their own. The inhibitors increased cellular retention of chemotherapeutics and reporter compounds known to be transport substrates of P-gp. We also showed that these compounds are not transport substrates of P-gp and that two of the three inhibit P-gp, but not the closely related ABC transporter, ABCG2/BCRP. The results presented suggest that these P-gp inhibitors may be promising leads for future drug development.
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