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首页> 外文期刊>Cellular Physiology and Biochemistry >Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma
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Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

机译：抗癫痫药丙戊酸在胶质母细胞瘤中的细胞作用

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>Background/Aims: Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug is used to treat epileptic seizure of glioblastoma patients. Besides its antiepileptic activity, VPA has been attributed further functions that improve the clinical outcome of glioblastoma patients. Those comprise the inhibition of some histone deacetylase (HDAC) isoforms which reportedly may result in radiosensitization. Retrospective analysis of patient data, however, could not unequivocally confirm a prolonged survival of glioblastoma patients receiving VPA. The present study aimed to identify potential VPA targets at the cellular level. Methods: To this end, the effect of VPA on metabolism, Ca2+-, biochemical and electro-signaling, cell-cycling, clonogenic survival and transfilter migration was analyzed in three human glioblastoma lines (T98G, U-87MG, U251) by MTT assay, Ca2+ imaging, immunoblotting, patch-clamp recording, flow cytometry, delayed plating colony formation and modified Boyden chamber assays, respectively. In addition, the effect of VPA on clonogenic survival of primary glioblastoma spheroid cultures treated with temozolomide and fractionated radiation was assessed by limited dilution assay. Results: In 2 of 3 glioblastoma lines, clinical relevant concentrations of VPA slightly slowed down cell cycle progression and decreased clonogenic survival. Furthermore, VPA induced Ca2+ signaling which was accompanied by pronounced K+ channel activity and transfilter cell migration. VPA did not affect metabolic NAD(P)H formation or radioresistance of the glioblastoma lines. Finally, VPA did not impair clonogenic survival or radioresistance of temozolomide-treated primary spheroid cultures. Conclusions: Combined, our in vitro data do not propose a general use of VPA as a radiosensitizer in anti-glioblastoma therapy.
机译：> 背景/目的： 丙戊酸（VPA）是一种抗惊厥和稳定情绪的药物，用于治疗胶质母细胞瘤患者的癫痫发作。除了抗癫痫活性，VPA还被赋予了改善胶质母细胞瘤患者临床疗效的其他功能。那些抑制某些组蛋白脱乙酰基酶（HDAC）同工型，据报道可能导致放射增敏。然而，对患者数据的回顾性分析不能明确证实接受VPA的胶质母细胞瘤患者的生存期较长。本研究旨在确定细胞水平的潜在VPA目标。 方法： 为此，VPA对代谢，Ca 2 + -，生化和电信号传导，细胞循环，克隆形成的影响通过MTT分析，Ca 2 + 成像，免疫印迹，膜片钳记录，流式细胞术，延迟的平板菌落形成，分析了三种人类胶质母细胞瘤系（T98G，U-87MG，U251）的存活率和跨膜迁移和改进的Boyden室测定法。另外，通过有限稀释试验评估了VPA对用替莫唑胺和分级放射治疗的原发性胶质母细胞瘤球状培养物克隆形成存活的影响。 结果： 在3个胶质母细胞瘤品系中的2个中，临床相关浓度的VPA稍微减慢了细胞周期进程并降低了克隆形成存活率。此外，VPA诱导Ca 2 + 信号传导，并伴随着明显的K + 通道活性和跨膜细胞迁移。 VPA不会影响胶质母细胞瘤细胞系的代谢NAD（P）H的形成或放射抗性。最后，VPA不会损害替莫唑胺治疗的原球体培养物的克隆形成存活率或抗辐射性。 结论： 综上所述，我们的体外数据未提出将VPA作为抗胶质母细胞瘤治疗中的放射增敏剂的一般用途。

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