Role of Glutathione in the Regulation of Cisplatin Resistance in Cancer Chemotherapy
Role of Glutathione in the Regulation of Cisplatin Resistance in Cancer Chemotherapy
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DOI：
10.1155/2010/430939
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发表时间：
2010-01-01
期刊：
影响因子：
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通讯作者：
Kuo, Macus Tien
中科院分区：
文献类型：
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作者：
Chen, Helen H. W.;Kuo, Macus Tien
谷胱甘肽(GSH)在调节顺铂(CDDP)敏感性方面的作用已被提出三种机制，从而影响其最终的杀伤能力：(I)GSH可能是促进多药耐药蛋白2(MRP2)介导的CDDP在哺乳动物细胞中外流的辅因子，因为MRP2基因转导的细胞被证明具有CDDP耐药性；(Ii)GSH可能作为氧化还原调节的细胞保护剂，基于许多CDDP耐药细胞过度表达GSH和γ-谷氨酰半胱氨酸合成(Gamma-GCS)的观察；(Iii)GSH可能作为铜(Cu)螯合剂发挥作用。升高的GSH表达耗尽了细胞的生物有效铜库，导致高亲和力铜转运蛋白(HCtr1)的上调，而hCtr1也是一种CDDP转运蛋白。已有研究表明，GSH基因的过表达对CDDP的毒性具有增敏作用。这篇综述描述了这三个模型是如何发展起来的，并对它们在癌细胞治疗中对顺铂整体细胞毒性的重要性进行了批判性的综述。
Three mechanisms have been proposed for the role of glutathione (GSH) in regulating cisplatin (CDDP) sensitivities that affects its ultimate cell-killing ability: (i) GSH may serve as a cofactor in facilitating multidrug resistance protein 2- (MRP2-) mediated CDDP efflux in mammalian cells, since MRP2-transfected cells were shown to confer CDDP resistance; (ii) GSH may serve as a redox-regulating cytoprotector based on the observations that many CDDP-resistant cells overexpress GSH and gamma-glutamylcysteine synthesis (gamma-GCS), the rate-limiting enzyme for GSH biosynthesis; (iii) GSH may function as a copper (Cu) chelator. Elevated GSH expression depletes the cellular bioavailable Cu pool, resulting in upregulation of the high-affinity Cu transporter (hCtr1) which is also a CDDP transporter. This has been demonstrated that overexpression of GSH by transfection with gamma-GCS conferred sensitization to CDDP toxicity. This review describes how these three models were developed and critically reviews their importance to overall CDDP cytotoxicity in cancer cell treatments.