文章：

细胞内谷胱甘肽决定多发性骨髓瘤细胞中硼替佐米的细胞毒性

Intracellular glutathione determines bortezomib cytotoxicity in multiple myeloma cells

原文发布日期：2016-07-15

DOI: 10.1038/bcj.2016.56

类型: Original Article

开放获取: 是

英文摘要：

Multiple myeloma (myeloma in short) is an incurable cancer of antibody-producing plasma cells that comprise 13% of all hematological malignancies. The proteasome inhibitor bortezomib has improved treatment significantly, but inherent and acquired resistance to the drug remains a problem. We here show that bortezomib-induced cytotoxicity was completely dampened when cells were supplemented with cysteine or its derivative, glutathione (GSH) in ANBL-6 and INA-6 myeloma cell lines. GSH is a major component of the antioxidative defense in eukaryotic cells. Increasing intracellular GSH levels fully abolished bortezomib-induced cytotoxicity and transcriptional changes. Elevated intracellular GSH levels blocked bortezomib-induced nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2)-associated stress responses, including upregulation of the xCT subunit of the Xc- cystine-glutamate antiporter. INA-6 cells conditioned to increasing bortezomib doses displayed reduced bortezomib sensitivity and elevated xCT levels. Inhibiting Xc- activity potentiated bortezomib-induced cytotoxicity in myeloma cell lines and primary cells, and re-established sensitivity to bortezomib in bortezomib-conditioned cells. We propose that intracellular GSH level is the main determinant of bortezomib-induced cytotoxicity in a subset of myeloma cells, and that combined targeting of the proteasome and the Xc- cystine-glutamate antiporter can circumvent bortezomib resistance.

摘要翻译： 

多发性骨髓瘤（简称骨髓瘤）是一种无法治愈的抗体生成性浆细胞癌症，占所有血液系统恶性肿瘤的13%。蛋白酶体抑制剂硼替佐米显著改善了治疗效果，但对该药物的先天与获得性耐药仍是难题。本研究显示，在ANBL-6和INA-6骨髓瘤细胞系中，当细胞补充半胱氨酸或其衍生物谷胱甘肽（GSH）时，硼替佐米诱导的细胞毒性完全被抑制。GSH是真核细胞抗氧化防御体系的主要组成部分。提升细胞内GSH水平可完全消除硼替佐米引发的细胞毒性及转录变化。升高的细胞内GSH水平阻断了硼替佐米诱导的核因子E2相关因子2（NFE2L2，NRF2）相关应激反应，包括Xc-胱氨酸-谷氨酸逆向转运蛋白xCT亚基的上调。经过递增浓度硼替佐米处理的INA-6细胞表现出药物敏感性降低和xCT水平升高。抑制Xc-活性可增强硼替佐米在骨髓瘤细胞系及原代细胞中的细胞毒性，并使耐药细胞恢复对硼替佐米的敏感性。我们认为细胞内GSH水平是部分骨髓瘤细胞中硼替佐米诱导细胞毒性的主要决定因素，同时联合靶向蛋白酶体和Xc-胱氨酸-谷氨酸逆向转运蛋白可克服硼替佐米耐药。

原文链接：

Intracellular glutathione determines bortezomib cytotoxicity in multiple myeloma cells