Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, 80045, United States.
Biochem Pharmacol. 2012 Apr 15;83(8):1005-12. doi: 10.1016/j.bcp.2011.11.016. Epub 2011 Nov 28.
Chemotherapy is central to the current treatment modality for primary human brain tumors, but despite high-dose and intensive treatment regimens there has been little improvement in patient outcome. The development of tumor chemoresistance has been proposed as a major contributor to this lack of response. While there have been some improvements in our understanding of the molecular mechanisms underlying brain tumor drug resistance over the past decade, the contribution of glutathione (GSH) and the GSH-related enzymes to drug resistance in brain tumors have been largely overlooked. GSH constitutes a major antioxidant defense system in the brain and together with the GSH-related enzymes plays an important role in protecting cells against free radical damage and dictating tumor cell response to adjuvant cancer therapies, including irradiation and chemotherapy. Glutamate cysteine ligase (GCL), glutathione synthetase (GS), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferases (GST), and GSH complex export transporters (GS-X pumps) are major components of the GSH-dependent enzyme system that function in a dynamic cascade to maintain redox homeostasis. In many tumors, the GSH system is often dysregulated, resulting in a more drug resistant phenotype. This is commonly associated with GST-mediated GSH conjugation of various anticancer agents leading to the formation of less toxic GSH-drug complexes, which can be readily exported from the cell. Advances in our understanding of the mechanisms of drug resistance and patient selection based on biomarker profiles will be crucial to adapt therapeutic strategies and improve outcomes for patients with primary malignant brain tumors.
化疗是目前原发性人脑肿瘤治疗模式的核心，但尽管采用了高剂量和强化治疗方案，患者的预后仍未见明显改善。肿瘤化疗耐药的发展被认为是导致这种反应不足的主要原因。尽管在过去十年中，我们对脑肿瘤药物耐药的分子机制有了一些了解，但谷胱甘肽（GSH）及其相关酶在脑肿瘤耐药中的作用在很大程度上被忽视了。GSH 是大脑中主要的抗氧化防御系统，与 GSH 相关的酶一起，在保护细胞免受自由基损伤和决定肿瘤细胞对辅助癌症治疗（包括放疗和化疗）的反应方面发挥着重要作用。谷氨酰半胱氨酸连接酶（GCL）、谷胱甘肽合成酶（GS）、谷胱甘肽过氧化物酶（GPx）、谷胱甘肽还原酶（GR）、谷胱甘肽-S-转移酶（GST）和 GSH 复合输出转运蛋白（GS-X 泵）是 GSH 依赖性酶系统的主要组成部分，它们在一个动态级联反应中发挥作用，以维持氧化还原平衡。在许多肿瘤中，GSH 系统经常失调，导致更具耐药性的表型。这通常与 GST 介导的各种抗癌药物的 GSH 结合有关，导致形成毒性较小的 GSH-药物复合物，这些复合物可以很容易地从细胞中输出。深入了解耐药机制和基于生物标志物谱的患者选择，对于调整治疗策略和改善原发性恶性脑肿瘤患者的预后至关重要。
