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PD173074 a selective FGFR inhibitor reverses MRP7 (ABCC10)-mediated MDR

机译:选择性FGFR抑制剂PD173074逆转MRP7(ABCC10)介导的MDR

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摘要

Multidrug resistance protein 7 (MRP7, ABCC10) is a recently identified member of the ATP-binding cassette (ABC) transporter family, which adequately confers resistance to a diverse group of antineoplastic agents, including taxanes, vinca alkaloids and nucleoside analogs among others. Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas (NSCLC) compared to a normal healthy lung tissue. Recent studies revealed increased paclitaxel sensitivity in the Mrp7−/− mouse model compared to their wild-type counterparts. This demonstrates that MRP7 is a key contributor in developing drug resistance. Recently our group reported that PD173074, a specific fibroblast growth factor receptor (FGFR) inhibitor, could significantly reverse P-glycoprotein-mediated MDR. However, whether PD173074 can interact with and inhibit other MRP members is unknown. In the present study, we investigated the ability of PD173074 to reverse MRP7-mediated MDR. We found that PD173074, at non-toxic concentration, could significantly increase the cellular sensitivity to MRP7 substrates. Mechanistic studies indicated that PD173074 (1 μmol/L) significantly increased the intracellular accumulation and in-turn decreased the efflux of paclitaxel by inhibiting the transport activity without altering expression levels of the MRP7 protein, thereby representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.
机译:耐多药蛋白7(MRP7,ABCC10)是ATP结合盒(ABC)转运蛋白家族中最近被鉴定的成员,它充分赋予了对多种抗肿瘤药的抗性,包括紫杉烷,长春花生物碱和核苷类似物等。临床研究表明,与正常健康的肺组织相比,非小细胞肺癌(NSCLC)中MRP7表达增加。最近的研究表明,与野生型小鼠相比,Mrp7 -/-小鼠模型中紫杉醇的敏感性增加。这表明MRP7是产生耐药性的关键因素。最近,我们的小组报告说,PD173074是一种特定的成纤维细胞生长因子受体(FGFR)抑制剂,可以显着逆转P-糖蛋白介导的MDR。但是,PD173074是否可以与其他MRP成员相互作用并抑制其他MRP成员尚不清楚。在本研究中,我们研究了PD173074逆转MRP7介导的MDR的能力。我们发现无毒浓度的PD173074可以显着提高细胞对MRP7底物的敏感性。机理研究表明,PD173074(1μmol/ L)通过抑制转运活性而不改变MRP7蛋白的表达水平,显着增加了紫杉醇的细胞内蓄积,进而降低了紫杉醇的流出,从而代表了一种有希望的临床治疗药物。化学抗性癌症患者。

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