The Antiepileptic Drug Oxcarbazepine Inhibits the Growth of Patient-Derived Isocitrate Dehydrogenase Mutant Glioma Stem-like Cells.
The Antiepileptic Drug Oxcarbazepine Inhibits the Growth of Patient-Derived Isocitrate Dehydrogenase Mutant Glioma Stem-like Cells.
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诊断为异柠檬酸脱氢酶（IDH）突变脑肿瘤的患者经常遭受癫痫发作，癫痫发作被证明促进肿瘤生长。抗癫痫药物可能会打破这种恶性循环。然而，目前尚不清楚哪些抗癫痫药物可能具有额外的抗肿瘤作用。本研究采用20种常用抗癫痫药物对患者源性肿瘤模型进行了实验。只有奥卡西平促进了额外的肿瘤细胞杀伤，使其成为一种有趣的药物，用于这一特殊人群的脑肿瘤患者。诊断为异柠檬酸脱氢酶突变（IDHmut）胶质瘤的患者经常遭受癫痫发作。尽管其临床病程不如IDH野生型具有侵袭性，但最近的发现表明癫痫活动可促进肿瘤增殖。然而，目前尚不清楚抗癫痫药物是否通过抑制肿瘤生长而赋予额外的价值。在这项研究中，20种fda批准的抗癫痫药物（AEDs）在6个患者来源的IDHmut胶质瘤干细胞样细胞（GSCs）中进行了抗肿瘤特性测试。使用celltiterglod - 3d测定法评估细胞增殖。筛选的两种药物（奥卡西平和perampanel）显示出抗增殖作用。随后的8点剂量-反应曲线证明了两种药物的剂量依赖性生长抑制作用，但只有奥卡西平在5/6个GSCs中达到低于100µM的IC50值（平均44.7µM，范围17.4-98.0µM），接近奥卡西平在患者血清中的可能cmax。此外，处理后的GSC球体体积缩小82%（平均体积1.6 nL比8.7 nL, p = 0.01（活/死tm荧光染色）），凋亡事件增加50%以上（caspase-3/7活性，p = 0.006）。综上所述，这一系列抗癫痫药物的药物筛选确定了奥卡西平是IDHmut GSCs中有效的促凋亡药物，它结合了抗癫痫和抗肿瘤的特性来治疗这一易发作的患者群体。
Patients diagnosed with isocitrate dehydrogenase (IDH)-mutated brain tumors frequently suffer from seizures, and the seizures were shown to promote tumor growth. Anti-seizure medications (antiepileptic drugs) might be able to break this vicious circle. However, it is not yet known which antiepileptic drugs might have additional anti-tumor effects. In this study, 20 commonly used antiepileptic drugs were tested on patient-derived tumor models. Only oxcarbazepine promoted additional tumor cell killing, making it an interesting drug to use in this special population of brain tumor patients. Patients diagnosed with isocitrate dehydrogenase mutant (IDHmut) gliomas suffer frequently from seizures. Although the clinical course is less aggressive than that of its IDH wildtype counterpart, recent discoveries have shown that epileptic activity can promote tumor proliferation. However, it is not known if antiepileptic drugs confer additional value by inhibiting tumor growth. In this study, the antineoplastic properties of 20 FDA-approved antiepileptic drugs (AEDs) were tested in six patient-derived IDHmut glioma stem-like cells (GSCs). Cell proliferation was assessed using the CellTiterGlo-3D assay. Two of the screened drugs (oxcarbazepine and perampanel) demonstrated an antiproliferative effect. A subsequent eight-point dose–response curve proved the dose-dependent growth inhibition for both drugs, but only oxcarbazepine reached an IC50 value below 100 µM in 5/6 GSCs (mean 44.7 µM; range 17.4–98.0 µM), approximating the possible cmax for oxcarbazepine in patient serums. Furthermore, the treated GSC spheroids were 82% smaller (mean volume 1.6 nL vs. 8.7 nL; p = 0.01 (live/deadTM fluorescence staining)), and the apoptotic events increased by more than 50% (caspase-3/7 activity; p = 0.006). Taken together, this drug screen of a large series of antiepileptic drugs identified oxcarbazepine as a potent proapoptotic drug in IDHmut GSCs, which combines antiepileptic and antineoplastic properties to treat this seizure-prone patient population.
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