Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B.
Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B.
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DOI：
10.1158/0008-5472.can-08-1420
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发表时间：
2009-01-01
期刊：
影响因子：
11.2
通讯作者：
Kruh GD
中科院分区：
文献类型：
--
作者：
Hopper-Borge E;Xu X;Shen T;Shi Z;Chen ZS;Kruh GD
多药耐药蛋白7（MRP 7，ABCC 10）是一种ATP结合盒转运蛋白，其能够转运两亲性阴离子并赋予对多西他赛的耐药性，并且在较小程度上赋予对长春新碱和紫杉醇的耐药性（Hopper-Borge et al. Cancer Res 14：4927，2004）。虽然MRP 7的阻力曲线的一些细节是已知的，但泵的活性尚未完全确定。在此，通过对MRP 7转染的HEK 293细胞的分析显示，除了天然产物试剂之外，MRP 7还能够赋予对基于核苷的试剂如抗癌剂Ara-C和吉西他滨以及抗病毒剂ddC和PMEA的抗性。与外排泵的操作一致，MRP 7的表达减少了Ara-C和PMEA的积累。此外，MRP 7还能够赋予对微管稳定剂埃坡霉素B的抗性。MRP 7在缺乏P-糖蛋白和Mrp 1的小鼠胚胎成纤维细胞中的异位表达揭示了MRP 7对天然产物试剂具有广泛的耐药性。在这种药物敏感性细胞背景下，MRP 7赋予对多西他赛（46倍）、紫杉醇（116倍）、SN-38（65倍）、柔红霉素（7.5倍）、依托泊苷（11倍）和长春新碱（56倍）的高水平耐药性。丁硫克百威亚砜亚胺没有减弱MRP 7赋予的对多西他赛或AraC的耐药性。这些实验表明，MRP 7的耐药能力包括核苷类药物和一系列天然产物抗癌剂，包括对P-糖蛋白介导的转运不敏感的非紫杉烷类抗微管剂，并且与MRP 1和MRP 2不同，MRP 7介导的药物转运不涉及谷胱甘肽。
Multidrug Resistance Protein 7 (MRP7, ABCC10) is an ATP-binding cassette transporter that is able to transport amphipathic anions and confer resistance to docetaxel and to a lesser extent vincristine and paclitaxel (Hopper-Borge et al., Cancer Res 14: 4927, 2004). While some detail on the resistance profile of MRP7 is known, the activities of the pump have not been completely determined. Here it is shown by the analysis of MRP7-transfected HEK293 cells that in addition to natural product agents, MRP7 is also able to confer resistance to nucleoside-based agents such as the anticancer agents Ara-C and gemcitabine, and the antiviral agents ddC and PMEA. Consistent with the operation of an efflux pump, expression of MRP7 reduced the accumulation of Ara-C and PMEA. In addition, MRP7 is also able to confer resistance to the microtubule stabilizing agent epothilone B. Ectopic expression of MRP7 in mouse embryo fibroblasts deficient in P-glycoprotein and Mrp1 revealed that MRP7 has a broad resistance profile for natural product agents. In this drug sensitive cellular background, MRP7 conferred high levels of resistance to docetaxel (46-fold), paclitaxel (116-fold), SN-38 (65-fold), daunorubicin (7.5-fold), etoposide (11-fold) and vincristine (56-fold). Buthionine sulfoximine did not attenuate MRP7-conferred resistance to docetaxel or AraC. These experiments indicate that the resistance capabilities of MRP7 include nucleoside-based agents and a range of natural product anti-cancer agents that includes non-taxane anti-microtubule agents that are not susceptible to P-glycoprotein mediated transport, and that unlike MRP1 and MRP2, MRP7-mediated drug transport does not involve glutathione.