Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines
Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines
复制标题
丙戊酸诱导的自噬与神经胶质瘤细胞系的氧化应激有关
DOI：
10.1093/neuonc/nop005
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发表时间：
2010-04-01
期刊：
影响因子：
15.9
通讯作者：
Chen, Zhong-Ping
中科院分区：
文献类型：
--
作者：
Fu, Jun;Shao, Cui-Jie;Chen, Zhong-Ping
自噬是一种替代性的肿瘤抑制机制，它克服了恶性胶质瘤对放疗和化疗的巨大抵抗力。本研究报道了广泛使用的抗癫痫药物丙戊酸（VPA）诱导胶质瘤细胞自噬。自噬，VPA诱导的细胞死亡的关键，是独立的细胞凋亡，即使凋亡机制是熟练的。VPA诱导的氧化应激发生在自噬的上游。氧化应激还激活细胞外信号调节激酶1/2（ERK 1/2）通路，而阻断该通路抑制自噬并诱导凋亡。肌醇不能减轻VPA诱导的自噬，这表明与锂不同的机制。此外，VPA与其他自噬诱导剂如雷帕霉素、Ly 294002和替莫唑胺在体外和体内神经胶质瘤细胞中联合使用时，可增强自噬细胞死亡，但不促进细胞凋亡，这可能需要进一步研究其在恶性神经胶质瘤患者中可能的临床应用。
Autophagy represents an alternative tumor-suppressing mechanism that overcomes the dramatic resistance of malignant gliomas to radiotherapy and proapoptotic-related chemotherapy. This study reports that valproic acid (VPA), a widely used anti-epilepsy drug, induces autophagy in glioma cells. Autophagy, crucial for VPA-induced cell death, is independent of apoptosis, even though apoptotic machinery is proficient. Oxidative stress induced by VPA occurs upstream of autophagy. Oxidative stress also activates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, whereas blocking this pathway inhibits autophagy and induces apoptosis. VPA-induced autophagy cannot be alleviated by inositol, suggesting a mechanism different from that for lithium. Moreover, VPA potentiates autophagic cell death, but not apoptosis, when combined with other autophagy inducers such as rapamycin, Ly294002, and temozolomide in glioma cells both in vitro and in vivo, which may warrant further investigation toward possible clinical application in patients with malignant gliomas.