Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou, China.
Both the authors contributed equally to this article.
Cell Transplant. 2020 Jan-Dec;29:963689720981878. doi: 10.1177/0963689720981878.
Glioma is the most common malignant tumor in the central nervous system with a poor median survival. Valproic acid (VPA), a widely used antiepileptic drug, has been found to have antitumor effects on gliomas, but its role still has not been determined. In this study, we investigated VPA-induced apoptotic and autophagic effects on human U251 and SNB19 cells by cell counting kit-8 assay, flow cytometry, terminal deoxynucleotidyl transferase-mediated nick end labeling staining, western blots, and immunofluorescence assay in vitro, and then we further explored the role of autophagy in apoptosis by using the selective antagonist MHY1485. The data showed that VPA inhibited U251 and SNB19 glioma cells viability in a dose-dependent and time-dependent manner and induced apoptosis through the mitochondria-dependent pathway in vitro. In addition, VPA activated the Akt/mTOR pathway by decreasing their protein phosphorylation to promote cellular apoptosis. Surprisingly, the mTOR agonist MHY1485, causing a strong elevation of mTOR activity, partially reduced apoptosis ratio, which supposing that the autophagy of VPA is involved in the regulation of apoptosis. These findings suggest that VPA enhanced apoptosis by promoting autophagy via Akt/mTOR signaling in glioma, which could be further evaluated as a reliable therapy for glioma.
神经胶质瘤是中枢神经系统最常见的恶性肿瘤，中位生存期较差。丙戊酸（VPA）是一种广泛使用的抗癫痫药物，已被发现对神经胶质瘤具有抗肿瘤作用，但作用仍未确定。在这项研究中，我们通过细胞计数试剂盒-8 测定法、流式细胞术、末端脱氧核苷酸转移酶介导的缺口末端标记染色、Western blot 和免疫荧光测定法在体外研究了 VPA 对人 U251 和 SNB19 细胞的诱导凋亡和自噬作用，然后进一步通过使用选择性拮抗剂 MHY1485 来探讨自噬在凋亡中的作用。数据显示，VPA 以剂量和时间依赖的方式抑制 U251 和 SNB19 神经胶质瘤细胞的活力，并通过线粒体依赖性途径在体外诱导细胞凋亡。此外，VPA 通过降低其蛋白磷酸化来激活 Akt/mTOR 通路，从而促进细胞凋亡。令人惊讶的是，mTOR 激动剂 MHY1485 引起 mTOR 活性的强烈升高，部分降低了凋亡比例，这表明 VPA 的自噬参与了凋亡的调节。这些发现表明，VPA 通过 Akt/mTOR 信号通路促进自噬增强神经胶质瘤的凋亡，这可能进一步评估为神经胶质瘤的可靠治疗方法。
