Keul Jonathan, Sperling Swetlana, Rohde Veit, Ninkovic Milena
The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.
The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
Anticancer Res. 2025 May;45(5):1813-1823. doi: 10.21873/anticanres.17561.
BACKGROUND/AIM: In glioblastoma multiforme (GBM), a deadly brain tumor, glucose is one of the main fuels for accelerated growth. Patients with GBM are also exposed to excess glucose through hyperglycemia in diabetes mellitus. In addition, dexamethasone (Dex), a corticosteroid commonly administered for controlling cerebral oedema, causes additional excess glucose. Therefore, targeting glucose metabolism is an attractive therapeutic intervention for GBM treatment. We have recently shown that riluzole (Ril), a drug used to treat amyotrophic lateral sclerosis (ALS), has an effect on some detrimental Dex-induced metabolic changes in GBM. Therefore, we examined the effect of the combination of metformin (Met), widely used to treat type 2 diabetes, and Ril on GBM cells.
The 3-(4, 5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to determine cell viability of U87MG after treatment with Ril, Met, Ril plus Met (Ril+Met) and the addition of Dex to this co-treatment. Cell migration was assessed by the xCELLigence system, matrix metalloproteinase 2 (MMP2) activation by zymography assay and gene expression by real-time polymerase chain reaction (RT-PCR).
Co-treatment with Ril and Met was effective in killing GBM cells and reducing the expression of genes involved in glucose and stem cell metabolism. Furthermore, combination of Ril and Met reduced MMP2 activation. But co-administration increased the migration of U87MG cells. The addition of Dex to this combination reversed the unfavorable effects of Ril+Met on cell migration.
Ril+Met co-treatment had a positive effect in terms of GBM cell death, decreased expression of genes involved in glucose metabolism and stemness, and reduced MMP2 activation. Disadvantage of Ril+Met treatment was increased cell migration. Taken together, these drug combinations may also allow the reduction of the concentration of Dex to minimize its side effects.
背景/目的：在多形性胶质母细胞瘤（GBM）这一致命性脑肿瘤中，葡萄糖是加速肿瘤生长的主要能量来源之一。GBM患者还因糖尿病导致的高血糖而暴露于过量葡萄糖中。此外，常用于控制脑水肿的皮质类固醇地塞米松（Dex）会导致额外的葡萄糖过量。因此，针对葡萄糖代谢进行靶向治疗是GBM治疗中一种有吸引力的干预措施。我们最近发现，用于治疗肌萎缩侧索硬化症（ALS）的药物利鲁唑（Ril）对Dex诱导的GBM中一些有害代谢变化有影响。因此，我们研究了广泛用于治疗2型糖尿病的二甲双胍（Met）与Ril联合使用对GBM细胞的影响。
采用3-(4,5-二甲基噻唑)-2,5-二苯基四氮唑溴盐（MTT）法测定利鲁唑、二甲双胍、利鲁唑加二甲双胍（Ril+Met）处理以及在此联合处理中加入地塞米松后U87MG细胞的活力。通过xCELLigence系统评估细胞迁移，通过酶谱分析评估基质金属蛋白酶2（MMP2）的激活情况，并通过实时聚合酶链反应（RT-PCR）分析基因表达。
Ril与Met联合处理可有效杀死GBM细胞，并降低参与葡萄糖和干细胞代谢的基因表达。此外，Ril与Met联合使用可降低MMP2的激活。但联合给药会增加U87MG细胞的迁移。在此联合处理中加入地塞米松可逆转Ril+Met对细胞迁移的不利影响。
Ril+Met联合处理在GBM细胞死亡、降低参与葡萄糖代谢和干性的基因表达以及减少MMP2激活方面具有积极作用。Ril+Met处理的缺点是细胞迁移增加。综上所述，这些药物联合使用还可能允许降低地塞米松的浓度，以尽量减少其副作用。
