Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers
Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers
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DOI：
10.1023/a:1018873702411
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发表时间：
1999-03-01
影响因子：
3.7
通讯作者：
Kabanov, AV
中科院分区：
文献类型：
--
作者：
Miller, DW;Batrakova, EV;Kabanov, AV
目的。利用表达多药耐药相关蛋白(MRP)的人胰腺癌细胞(PANC-1)，研究了Pluronic嵌段共聚物对MRP功能活性的影响。这些研究检测了在有无Pluronic P85(P85)、Pluronic L81(L81)和Pluronic F108(F108)的PANC-1细胞单层中MRP选择性探针荧光素(Flu)的聚集和外流。用P85处理PANC-1细胞后，流感的积聚呈浓度依赖性增加，并消除了这些细胞中泡隔间的流感隔离。P85对PANC-1细胞单层中的流感具有选择性作用。抑制MRP介导的转运依赖于Pluronic嵌段共聚物的组成：疏水性越强的共聚物对PANC-1单层(L81>；P85>；F108)摄取Flu的影响越大。本文首次证明了Pluronic嵌段共聚物抑制多药耐药相关蛋白(MRP)。Pluronic嵌段共聚物对MRP和P-糖蛋白药物外排系统的影响相似，表明单一的统一机制可能解释了观察到的抑制作用。
Purpose. Using monolayers of human pancreatic adenocarcinoma cells (Panc-1) that express multidrug resistance-associated protein (MRP), the present work investigates the effects of Pluronic block copolymers on the functional activity of MRP.Methods. The studies examined the accumulation and efflux of the MRP selective probe fluorescein (FLU) in Panc-1 cell monolayers with and without Pluronic P85 (P85), Pluronic L81 (L81) and Pluronic F108 (F108).Results. Treatment of Panc-1 cells with P85 resulted in concentration-dependent increases in FLU accumulation and elimination of FLU sequestration in vesicular compartments in these cells. The effects of P85 were selective for FLU in the Panc-1 cell monolayers. Inhibition of MRP-mediated transport was dependent on the composition of Pluronic block copolymer: the more hydrophobic copolymer had the greater effect on FLU uptake in Panc-1 monolayers (L81 > P85 > F108).Conclusions. This paper demonstrates for the first time that Pluronic block copolymers inhibit multidrug resistance-associated protein (MRP). The similarities in the effects of Pluronic block copolymers on MRP and P-glycoprotein drug efflux systems suggest that a single unifying mechanism may explain the inhibition observed.