Reversal of MRP7 (ABCC10)-mediated multidrug resistance by tariquidar.
Reversal of MRP7 (ABCC10)-mediated multidrug resistance by tariquidar.
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DOI：
10.1371/journal.pone.0055576
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chen ZS
中科院分区：
文献类型：
--
作者：
Sun YL;Chen JJ;Kumar P;Chen K;Sodani K;Patel A;Chen YL;Chen SD;Jiang WQ;Chen ZS
多药耐药蛋白7（Multidrug resistance protein 7，MRP 7，ABCC 10）是近年来发现的一种能在体内引起对紫杉烷类和核苷类等多种抗癌药物耐药的ATP结合盒（ATP binding cassette，ABC）家族成员。MRP 7在非小细胞肺癌细胞中高度表达，并且Mrp 7-KO小鼠对紫杉醇高度敏感，使得MRP 7成为非小细胞肺癌的有吸引力的化疗靶点。然而，目前只有少数MRP 7的抑制剂被鉴定，它们中没有一个已经进展到临床试验。我们使用MRP 7表达细胞来研究第三代P-糖蛋白抑制剂tariquidar是否可以抑制MRP 7介导的多药耐药（MDR）。我们发现，tariquidar在0.1和0.3 μM时，显著增强了MRP 7转染的HEK 293细胞对MRP 7底物的敏感性，并增加了紫杉醇的细胞内蓄积。我们进一步证明，tariquidar直接损害紫杉醇外排，并能下调MRP 7蛋白表达的浓度和时间依赖性的方式后，长期治疗。我们的研究结果表明，tariquidar在可达到的浓度下，通过抑制MRP 7蛋白表达和功能逆转MRP 7介导的MDR，因此代表了临床治疗化疗耐药癌症患者的有前途的治疗剂。
Multidrug resistance protein 7 (MRP7, ABCC10) is a recently discovered member of the ATP-binding cassette (ABC) family which are capable of conferring resistance to a variety of anticancer drugs, including taxanes and nucleoside analogs, in vivo. MRP7 is highly expressed in non-small cell lung cancer cells, and Mrp7-KO mice are highly sensitive to paclitaxel, making MRP7 an attractive chemotherapeutic target of non-small cell lung cancer. However, only a few inhibitors of MRP7 are currently identified, with none of them having progressed to clinical trials. We used MRP7-expressing cells to investigate whether tariquidar, a third generation inhibitor of P-glycoprotein, could inhibit MRP7-mediated multidrug resistance (MDR). We found that tariquidar, at 0.1 and 0.3 µM, significantly potentiated the sensitivity of MRP7-transfected HEK293 cells to MRP7 substrates and increased the intracellular accumulation of paclitaxel. We further demonstrated that tariquidar directly impaired paclitaxel efflux and could downregulate MRP7 protein expression in a concentration- and time-dependent manner after prolonged treatment. Our findings suggest that tariquidar, at pharmacologically achievable concentrations, reverses MRP7-mediated MDR through inhibition of MRP7 protein expression and function, and thus represents a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.
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DOI：
10.1158/1078-0432.ccr-10-1725
发表时间：
2011-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
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影响因子：
13.5
作者：
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影响因子：
3.6
作者：
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通讯作者：
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影响因子：
5.8
作者：
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Assaraf, Yehuda G.
DOI：
10.1007/s00432-007-0323-9
发表时间：
2008-05-01
影响因子：
3.6
作者：
Hubensack, Martina;Mueller, Christine;Buschauer, Armin
通讯作者：
Buschauer, Armin