Repurposing the anti-epileptic drug sodium valproate as an adjuvant treatment for diffuse intrinsic pontine glioma.
Repurposing the anti-epileptic drug sodium valproate as an adjuvant treatment for diffuse intrinsic pontine glioma.
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DOI：
10.1371/journal.pone.0176855
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Gill SS
中科院分区：
文献类型：
--
作者：
Killick-Cole CL;Singleton WGB;Bienemann AS;Asby DJ;Wyatt MJ;Boulter LJ;Barua NU;Gill SS
针对弥漫性内在脑桥胶质瘤（DIPG）的表观遗传学变化可能为患者提供一种新的治疗选择。本报告表明，丙戊酸钠（一种组蛋白去乙酰化酶抑制剂（HDACi））可在体外DIPG细胞中以相加和协同方式增加卡铂的细胞毒性。丙戊酸钠导致三种独立离体细胞系中DIPG细胞活力呈剂量依赖性降低。此外，丙戊酸钠导致组蛋白H3乙酰化增加。细胞活力的变化与体外DIPG细胞中的凋亡诱导一致，通过膜联蛋白V染色的流式细胞术分析和通过蛋白质印迹法评估凋亡标志物来确定。随后，使用神经元和胶质细胞标记物的免疫荧光染色来确定正常大鼠海马细胞中的毒性。在检测的三种DIPG细胞系中，用丙戊酸钠预处理细胞增强了卡铂的细胞毒性作用。这些结果表明，丙戊酸钠导致组蛋白H3乙酰化增加，表明HDAC抑制，这与细胞活力降低呈负相关。通过诱导DIPG细胞中的细胞凋亡降低细胞活力。丙戊酸钠增强卡铂的细胞毒性，并促使进一步的工作，以确定这两种药物之间的协同作用的机制，并确定体内疗效。这些结果支持使用丙戊酸钠作为DIPG的辅助治疗。
Targeting epigenetic changes in diffuse intrinsic pontine glioma (DIPG) may provide a novel treatment option for patients. This report demonstrates that sodium valproate, a histone deacetylase inhibitor (HDACi), can increase the cytotoxicity of carboplatin in an additive and synergistic manner in DIPG cells in vitro. Sodium valproate causes a dose-dependent decrease in DIPG cell viability in three independent ex vivo cell lines. Furthermore, sodium valproate caused an increase in acetylation of histone H3. Changes in cell viability were consistent with an induction of apoptosis in DIPG cells in vitro, determined by flow cytometric analysis of Annexin V staining and assessment of apoptotic markers by western blotting. Subsequently, immunofluorescent staining of neuronal and glial markers was used to determine toxicity in normal rat hippocampal cells. Pre-treatment of cells with sodium valproate enhanced the cytotoxic effects of carboplatin, in three DIPG cell lines tested. These results demonstrate that sodium valproate causes increased histone H3 acetylation indicative of HDAC inhibition, which is inversely correlated with a reduction in cell viability. Cell viability is reduced through an induction of apoptosis in DIPG cells. Sodium valproate potentiates carboplatin cytotoxicity and prompts further work to define the mechanism responsible for the synergy between these two drugs and determine in vivo efficacy. These findings support the use of sodium valproate as an adjuvant treatment for DIPG.