Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, INF400, 69120 Heidelberg, Germany.
Cells. 2023 Apr 20;12(8):1200. doi: 10.3390/cells12081200.
Patients diagnosed with isocitrate dehydrogenase mutant (IDH) 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 IDH 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 IC value below 100 µM in 5/6 GSCs (mean 44.7 µM; range 17.4-98.0 µM), approximating the possible c for oxcarbazepine in patient serums. Furthermore, the treated GSC spheroids were 82% smaller (mean volume 1.6 nL vs. 8.7 nL; = 0.01 (live/dead fluorescence staining)), and the apoptotic events increased by more than 50% (caspase-3/7 activity; = 0.006). Taken together, this drug screen of a large series of antiepileptic drugs identified oxcarbazepine as a potent proapoptotic drug in IDH GSCs, which combines antiepileptic and antineoplastic properties to treat this seizure-prone patient population.
患有异柠檬酸脱氢酶突变（IDH）神经胶质瘤的患者经常会出现癫痫发作。虽然其临床过程比 IDH 野生型神经胶质瘤的侵袭性弱，但最近的发现表明，癫痫活动可以促进肿瘤增殖。然而，目前尚不清楚抗癫痫药物是否通过抑制肿瘤生长而具有额外的价值。在这项研究中，对六种患者来源的 IDH 神经胶质瘤干细胞（GSCs）中 20 种 FDA 批准的抗癫痫药物（AED）的抗肿瘤特性进行了测试。使用 CellTiterGlo-3D 测定法评估细胞增殖。筛选出的两种药物（奥卡西平和吡仑帕奈）表现出抗增殖作用。随后进行的八点剂量反应曲线证明了这两种药物的剂量依赖性生长抑制，但只有奥卡西平在 5/6 的 GSCs 中达到了低于 100 μM 的 IC 值（平均 44.7 μM；范围 17.4-98.0 μM），接近奥卡西平在患者血清中的可能 c 值。此外，经处理的 GSC 球体缩小了 82%（平均体积 1.6 nL 与 8.7 nL； = 0.01（死活荧光染色）），且凋亡事件增加了 50%以上（半胱天冬酶-3/7 活性； = 0.006）。总之，对一大系列抗癫痫药物进行的药物筛选发现，奥卡西平是 IDH GSCs 中一种有效的促凋亡药物，它结合了抗癫痫和抗肿瘤特性，可用于治疗这种易发生癫痫的患者群体。
