PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR.
PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR.
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DOI：
10.1016/j.apsb.2014.02.003
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发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Chen ZS
中科院分区：
文献类型：
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作者：
Anreddy N;Patel A;Sodani K;Kathawala RJ;Chen EP;Wurpel JN;Chen ZS
多药耐药蛋白7(MRP7，ABCC10)是新近发现的三磷酸腺苷结合盒(ABC)转运蛋白家族成员，对紫杉烷、长春花碱和核苷类似物等多种抗肿瘤药物具有足够的耐药性。临床研究表明，与正常健康肺组织相比，非小细胞肺癌(NSCLC)中MRP7的表达增加。最近的研究表明，与野生型小鼠相比，mRP7−/−小鼠模型对紫杉醇的敏感性增加。这表明MRP7在耐药的形成中起关键作用。本课题组最近报道了一种特异性的成纤维细胞生长因子受体(FGFR)抑制剂PD173074可以显著逆转P-糖蛋白介导的MDR。然而，PD173074是否能与其他MRP成员相互作用并抑制其活性尚不清楚。在本研究中，我们研究了PD173074逆转MRP7介导的多药耐药的能力。我们发现，在无毒浓度下，PD173074可以显著增加细胞对MRP7底物的敏感性。机制研究表明，PD173074(1μ摩尔/L)通过抑制紫杉醇的转运活性，在不改变MRP7蛋白表达水平的情况下，显著增加紫杉醇在细胞内的蓄积，进而减少紫杉醇的外排，从而为临床治疗化疗耐药的癌症患者提供了一种有前途的治疗药物。PD173074通过抑制细胞转运功能，在不改变MRP7蛋白表达水平的情况下，显著增加抗癌药物在细胞内的蓄积，有望成为临床治疗化疗耐药癌症患者的药物。
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. PD173074 significantly increased the intracellular accumulation of anti-cancer drugs by inhibiting the transport function without altering expression levels of the MRP7 protein, there by representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.