Sensitization of cells overexpressing multidrug-resistant proteins by Pluronic P85
Sensitization of cells overexpressing multidrug-resistant proteins by Pluronic P85
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DOI：
10.1023/a:1026179132599
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发表时间：
2003-10-01
影响因子：
3.7
通讯作者：
Kabanov, AV
中科院分区：
文献类型：
--
作者：
Batrakova, EV;Li, S;Kabanov, AV
目的。本研究评价了Pluronic P85(P85)对表达多药耐药相关蛋白MRP1和MRP2的细胞的化疗增敏作用。细胞模型包括MRP1和MRP2转基因的MDCKII细胞以及过表达MRP1的阿霉素选择的COR-L23/R细胞。检测P85对长春花碱和阿霉素细胞蓄积和细胞毒作用的影响。机制研究表征了P85对细胞内三磷酸腺苷和还原型谷胱甘肽水平以及细胞内三磷酸腺苷酶和谷胱甘肽S转移酶活性的影响。在高表达MRP1和MRP2的细胞中，观察到在P85存在的情况下，长春花碱和阿霉素的积累显著增加，尽管在亲本细胞中药物积累没有显著的变化。P85处理对MRP-ATPase活性有抑制作用。此外，P85在这些细胞中引起的ATP耗竭与先前报道的Pgp过表达细胞的情况类似。此外，经P85处理后，细胞内GSH水平降低，GST活性降低。在MRP过表达的细胞中，P85能显著增强长春花碱和阿霉素的细胞毒作用。这项研究表明，P85可以使过度表达MRP1和MRP2的细胞增敏，这可能有助于对表现出这些耐药机制的癌症进行化疗。
Purpose. This study evaluated the chemosensitizing effects of Pluronic P85 (P85) on cells expressing multidrug resistance-associated proteins, MRP1 and MRP2.Methods. Cell models included MRP1- and MRP2-transfected MDCKII cells as well as doxorubicin-selected COR-L23/R cells overexpressing MRP1. Effects of P85 on cellular accumulation and cytotoxicity of vinblastine and doxorubicin were determined. Mechanistic studies characterized the effects of P85 on ATP and reduced glutathione (GSH) intracellular levels as well as MRP ATPase and glutathione-S-transferase (GST) activities in these cells.Results. Considerable increases of vinblastine and doxorubicin accumulation in the cells overexpressing MRP1 and MRP2 in the presence of P85 were observed, although no statistically significant changes in drug accumulation in the parental cells were found. P85 treatment caused an inhibition of MRP ATPase activity. Furthermore, P85 induced ATP depletion in these cells similar to that previously reported for Pgp-overexpressing cells. In addition, reduction of GSH intracellular levels and decrease of GST activity were observed following P85 treatment. Finally, significant enhancement of cytotoxicity of vinblastine and doxorubicin by P85 in MRP-overexpressing cells was demonstrated.Conclusions. This study suggests that P85 can sensitize cells overexpressing MRP1 and MRP2, which could be useful for chemotherapy of cancers that display these resistant mechanisms.