Inhibition of glutamate cysteine ligase activity sensitizes human breast cancer cells to the toxicity of 2-deoxy-D-glucose
Inhibition of glutamate cysteine ligase activity sensitizes human breast cancer cells to the toxicity of 2-deoxy-D-glucose
复制标题
DOI：
10.1158/0008-5472.can-05-3462
复制
发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Spitz, DR
中科院分区：
文献类型：
--
作者：
Andringa, KK;Coleman, NC;Spitz, DR
有人假设，癌细胞通过谷胱甘肽依赖的过氧化物酶增加葡萄糖代谢，以保护免受过氧化氢代谢的影响。2-脱氧-D-葡萄糖，抑制葡萄糖代谢，已被证明对癌细胞产生细胞毒性，这部分是由硫醇代谢中断所介导的。在本研究中，用2-脱氧-D-葡萄糖连续处理人乳腺癌细胞24小时，总谷胱甘肽含量以及谷胱甘肽合成途径第一酶[谷氨酸半胱氨酸连接酶(GCL)L]的表达被诱导了2.0倍。在2-脱氧-D-葡萄糖暴露过程中，用L-丁硫氨酸-[S，R]-亚磺胺(BSO)抑制GCL活性可显著增强2-脱氧-D-葡萄糖的细胞毒性作用，并引起氧化应激终点的增加，包括氧化谷胱甘肽和氧化敏感荧光探针法测定的稳态促氧化剂水平。这些结果表明，用2-脱氧-D-葡萄糖处理人乳腺癌细胞会引起代谢氧化应激，伴随着GCL mRNA的稳态水平、GCL活性和谷胱甘肽含量的增加。此外，用BSO抑制2-脱氧-D-葡萄糖介导的GCL活性增加了氧化应激的终点，并使癌细胞对2-脱氧-D-葡萄糖诱导的细胞毒性变得敏感。这些结果支持这样一种假设，即能够抑制葡萄糖和过氧化氢代谢的药物组合可能提供一种有效的生化策略，使人类癌细胞对代谢氧化应激敏感。
It has been hypothesized that cancer cells increase glucose metabolism to protect against metabolic fluxes of hydroperoxides via glutathione-dependent peroxidases. 2-Deoxy-D-glucose, inhibits glucose metabolism and has been shown to cause cytotoxicity in cancer cells that is partially mediated by disruptions in thiol metabolism. In the current study, human breast cancer cells were continuously treated (24 hours) with 2-deoxy-D-glucose, and total glutathione content as well as the expression of the first enzyme in the glutathione synthetic pathway [glutamate cysteine ligase (GCL)l were found to be induced 2.0-fold. Inhibiting GCL activity during 2-deoxy-D-glucose exposure using L-buthionine-[S,R]-sulfoximine (BSO) significantly enhanced the cytotoxic effects of 2-deoxy-D-glucose and caused increases in endpoints indicative of oxidative stress, including % oxidized glutathione and steady-state levels of pro-oxidants as assayed using an oxidation-sensitive fluorescent probe. These results show that treatment of human breast cancer cells with 2-deoxy-D-glucose causes metabolic oxidative stress that is accompanied by increases in steady-state levels of GCL mRNA, GCL activity, and glutathione content. Furthermore, inhibition of 2-deoxy-D-glucose-mediated induction of GCL activity with BSO increases endpoints indicative of oxidative stress and sensitizes cancer cells to 2-deoxy-D-glucose-induced cytotoxicity. These results support the hypothesis that drug combinations capable of inhibiting both glucose and hydroperoxide metabolism may provide an effective biochemical strategy for sensitizing human cancer cells to metabolic oxidative stress.