Microsomal glutathione transferase 1 in anticancer drug resistance
Microsomal glutathione transferase 1 in anticancer drug resistance
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DOI：
10.1093/carcin/bgl148
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发表时间：
2007-02-01
期刊：
影响因子：
4.7
通讯作者：
Morgenstern, Ralf
中科院分区：
文献类型：
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作者：
Johansson, Katarina;Ahlen, Karin;Morgenstern, Ralf
谷胱甘肽转移酶 (GST) 在肿瘤中经常上调，并被认为在癌症化疗的多重耐药性中发挥重要作用。因此，GST 依赖性前药和抑制剂正在开发中。然而，尽管细胞抑制剂的解毒作用和肿瘤中的上调作用已被证明，但膜结合 GST 在耐药性中的潜在作用却知之甚少。因此，我们研究了膜结合微粒体 GST1 (MGST1) 在细胞抗癌药物耐药性中的作用。作为一种工具，我们开发了一种利用稳定过表达 MGST1 的 MCF7 细胞的细胞系统。在这里，我们首次在急性毒性试验（MTT 测定）以及长期集落形成效率细胞毒性试验中证明 MGST1 可以保护细胞免受几种细胞抑制药物（苯丁酸氮芥、美法仑和顺铂）的侵害。值得注意的是，这些细胞不会过度表达多药物转运蛋白，这是该系统中研究的某些其他 GST 提供保护的先决条件。所使用的细胞抑制药物包括已知/预测为底物以及非底物的药物。因此，该机制很可能需要直接解毒和下游保护细胞免受氧化应激。
Glutathione transferases (GSTs) are often upregulated in tumors and have been suggested to play an important role in multiple drug resistance in cancer chemotherapy. As a consequence GST-dependent pro-drugs and inhibitors are being developed. Little is known, however, on the potential role of membrane-bound GSTs in drug resistance despite the fact that detoxication of cytostatic drugs and upregulation in tumors has been demonstrated. Therefore, we have studied the involvement of membrane-bound microsomal GST1 (MGST1) in cellular resistance to anticancer drugs. As a tool we have developed a cell system utilizing MCF7 cells stably overexpressing MGST1. Here, we show for the first time that MGST1 can protect cells from several cytostatic drugs, chlorambucil, melphalan and cisplatin in an acute toxicity test (MTT assay) as well as a long-term colony forming efficiency cytotoxicity test. It is of note that these cells do not overexpress multidrug transporters, a prerequisite for protection with certain other GSTs investigated in this system. The cytostatic drugs used comprise both those that are known/predicted to be substrates as well as non-substrates. Thus, the mechanism most probably entails both direct detoxication and downstream protection of the cells from oxidative stress.