Chung Wook Joon, Lyons Susan A, Nelson Gina M, Hamza Hashir, Gladson Candece L, Gillespie G Yancey, Sontheimer Harald
Department of Neurobiology, Civitan International Research Center, The University of Alabama, Birmingham, Alabama 35294-0021, USA.
J Neurosci. 2005 Aug 3;25(31):7101-10. doi: 10.1523/JNEUROSCI.5258-04.2005.
Glial cells play an important role in sequestering neuronally released glutamate via Na+-dependent transporters. Surprisingly, these transporters are not operational in glial-derived tumors (gliomas). Instead, gliomas release glutamate, causing excitotoxic death of neurons in the vicinity of the tumor. We now show that glutamate release from glioma cells is an obligatory by-product of cellular cystine uptake via system xc-, an electroneutral cystine-glutamate exchanger. Cystine is an essential precursor for the biosynthesis of glutathione, a major redox regulatory molecule that protects cells from endogenously produced reactive oxygen species (ROS). Glioma cells, but not neurons or astrocytes, rely primarily on cystine uptake via system xc- for their glutathione synthesis. Inhibition of system xc- causes a rapid depletion of glutathione, and the resulting loss of ROS defense causes caspase-mediated apoptosis. Glioma cells can be rescued if glutathione status is experimentally restored or if glutathione is substituted by alternate cellular antioxidants, confirming that ROS are indeed mediators of cell death. We describe two potent drugs that permit pharmacological inhibition of system xc-. One of these drugs, sulfasalazine, is clinically used to treat inflammatory bowel disease and rheumatoid arthritis. Sulfasalazine was able to reduce glutathione levels in tumor tissue and slow tumor growth in vivo in a commonly used intracranial xenograft animal model for human gliomas when administered by intraperitoneal injection. These data suggest that inhibition of cystine uptake into glioma cells through the pharmacological inhibition of system xc- may be a viable therapeutic strategy with a Food and Drug Administration-approved drug already in hand.
神经胶质细胞在通过钠依赖性转运体隔离神经元释放的谷氨酸方面发挥着重要作用。令人惊讶的是，这些转运体在神经胶质细胞衍生的肿瘤（胶质瘤）中不起作用。相反，胶质瘤会释放谷氨酸，导致肿瘤附近的神经元发生兴奋性毒性死亡。我们现在表明，胶质瘤细胞释放谷氨酸是通过系统xc-进行细胞胱氨酸摄取的必然副产物，系统xc-是一种电中性的胱氨酸-谷氨酸交换体。胱氨酸是谷胱甘肽生物合成的必需前体，谷胱甘肽是一种主要的氧化还原调节分子，可保护细胞免受内源性产生的活性氧（ROS）的侵害。胶质瘤细胞主要依靠通过系统xc-摄取胱氨酸来合成谷胱甘肽，而神经元或星形胶质细胞则不然。抑制系统xc-会导致谷胱甘肽迅速耗尽，由此导致的活性氧防御丧失会引发半胱天冬酶介导的细胞凋亡。如果通过实验恢复谷胱甘肽状态或用替代的细胞抗氧化剂替代谷胱甘肽，胶质瘤细胞可以得到挽救，这证实活性氧确实是细胞死亡的介质。我们描述了两种能够对系统xc-进行药理学抑制的强效药物。其中一种药物柳氮磺胺吡啶在临床上用于治疗炎症性肠病和类风湿性关节炎。在常用的人类胶质瘤颅内异种移植动物模型中，通过腹腔注射给药时，柳氮磺胺吡啶能够降低肿瘤组织中的谷胱甘肽水平并减缓体内肿瘤生长。这些数据表明，通过对系统xc-进行药理学抑制来抑制胶质瘤细胞摄取胱氨酸可能是一种可行的治疗策略，而且已经有了一种获得美国食品药品监督管理局批准的药物。
