Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells
Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells
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DOI：
10.3390/ijms20184575
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发表时间：
2019-09-02
影响因子：
5.6
通讯作者：
Pesic, Milica
中科院分区：
文献类型：
--
作者：
Dinic, Jelena;Podolski-Renic, Ana;Pesic, Milica
热休克蛋白90 （Hsp90）伴侣蛋白与多种参与癌症发生和癌症进展的客户蛋白相互作用。然而，Hsp90抑制剂由于其高毒性、对癌细胞缺乏选择性以及被p -糖蛋白（P-gp）等多药耐药（MDR）的膜转运蛋白挤压而无法作为抗癌药物。认识到新化合物抑制P-gp功能和/或表达的潜力在寻找有效的抗癌药物中是必不可少的。合成了11种含有异唑啉萘醌核心的Hsp90抑制剂，并在P-gp过表达的敏感和相应耐药癌细胞（人非小细胞肺癌和结直肠腺癌）组成的两种MDR模型中进行了评估。我们研究了Hsp90抑制剂对细胞生长抑制、P-gp活性和P-gp表达的影响。对细胞生长和P-gp抑制作用进行构效关系分析。化合物5、7、9直接与P-gp相互作用，抑制其atp酶活性。通过分子对接研究确定了它们潜在的P-gp结合位点。此外，这些化合物在MDR结直肠癌细胞中下调P-gp的表达，对癌细胞表现出良好的相对选择性，而化合物5以浓度依赖的方式逆转了对阿霉素和紫杉醇的耐药。因此，化合物5、7和9可能是治疗P-gp过表达癌症的有希望的候选者。
Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure-activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.