He Mingliang, Luo Ming, Chen Shu, Li Kaishu, Zheng Meiguang, Weng Yinlun, Pi Rongbiao, Liu Anmin
Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University Guangzhou 510120, PR China.
Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University Guangzhou 510120, PR China.
Int J Clin Exp Med. 2015 Oct 15;8(10):18434-40. eCollection 2015.
Glioblastoma (GBM) is the most common brain tumor with high abilities of proliferation, migration and invasion. As is well-known, the peritumoral excitotoxic neuronal cell loss caused by glutamate, secreted by GBM cells, through activated N-methyl-D aspartate receptor (NMDAR) of neuronal cell. What's more, glutamate benefits the migration of GBM cells. However, the glutamate will not kill the GBM cells itself, which may be due to the deficiency of NMDAR. Fasudil, a ROCK inhibitor, was applied for subarachnoid hemorrhage (SAH) in clinic for many years. And it was found to be of potential to inhibit the proliferation, migration and invasion of GBM cells. In present study, we applied fasudil on the primary human GBM cells to further investigate the reduction of cell viability combined with glutamate. Combination treatment of glutamate and fasudil could significantly decrease the cell viability and elevate the level of LDH compared with fasudil treatment alone. What's more, MK-801, a NMDAR antagonist, could partially abolish this death caused by combination treatment. Further study found that the expression level of NMDAR-2B was elevated after treatment with fasudil in GBM cells. These results demonstrated fasudil could increase the expression level of NMDAR, which is necessary for glutamate to work. In a word, our research has provided a new sight of medicine combination in the treatment of GBM.
胶质母细胞瘤（GBM）是最常见的脑肿瘤，具有高度的增殖、迁移和侵袭能力。众所周知，GBM细胞分泌的谷氨酸通过激活神经元细胞的N-甲基-D-天冬氨酸受体（NMDAR）导致瘤周兴奋性毒性神经元细胞死亡。此外，谷氨酸有利于GBM细胞的迁移。然而，谷氨酸本身不会杀死GBM细胞，这可能是由于NMDAR的缺乏。法舒地尔是一种ROCK抑制剂，已在临床上用于蛛网膜下腔出血（SAH）多年。并且发现它具有抑制GBM细胞增殖、迁移和侵袭的潜力。在本研究中，我们将法舒地尔应用于原代人GBM细胞，以进一步研究其与谷氨酸联合使用时对细胞活力的降低作用。与单独使用法舒地尔治疗相比，谷氨酸和法舒地尔联合治疗可显著降低细胞活力并提高乳酸脱氢酶（LDH）水平。此外，NMDAR拮抗剂MK-801可部分消除联合治疗引起的这种细胞死亡。进一步研究发现，GBM细胞经法舒地尔治疗后，NMDAR-2B的表达水平升高。这些结果表明，法舒地尔可增加NMDAR的表达水平，而这是谷氨酸发挥作用所必需的。总之，我们的研究为GBM治疗中的药物联合应用提供了新的视角。
