双氯乙酸盐和二甲双胍的代谢靶向联合治疗抑制神经胶质瘤细胞系生长
Metabolic-targeted Combination Therapy With Dichloroacetate and Metformin Suppresses Glioblastoma Cell Line Growth and .
机构信息
Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania;
National Cancer Institute, Vilnius, Lithuania.
出版信息
In Vivo. 2021 Jan-Feb;35(1):341-348. doi: 10.21873/invivo.12265.
BACKGROUND/AIM: We investigated the hypothesis that dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and metformin (MET), an antidiabetic agent and complex I inhibitor, have synergistic cytotoxic effects in glioblastoma cells in vitro and in vivo.
MATERIALS AND METHODS
We performed dose response experiments and combination index calculation. Apoptotic and necrotic cells were estimated by flow cytometry. Cell metabolism was evaluated by Seahorse analysis and lactate export. Overall survival and tumor volume growth experiments were performed in C57BL/6 mice GL-261 allograft model.
RESULTS
DCA and MET showed dose-dependent cytotoxicity and synergistic effects. DCA alleviated the increase in lactate production induced by MET. Seahorse analysis showed that DCA treatment results in increased oxygen consumption rate, which is decreased by MET. DCA and MET significantly inhibited tumor growth and increased overall survival in mice.
CONCLUSION
Compounds targeting tumor cell metabolism could become potential treatment options for glioblastoma multiforme.
背景/目的：我们研究了一个假设，即丙酮酸脱氢酶激酶抑制剂二氯乙酸（DCA）和抗糖尿病药物及复合物 I 抑制剂二甲双胍（MET）在体外和体内对神经胶质瘤细胞具有协同细胞毒性作用。
材料和方法
我们进行了剂量反应实验和组合指数计算。通过流式细胞术估计凋亡和坏死细胞。通过 Seahorse 分析和乳酸盐外排评估细胞代谢。在 C57BL/6 小鼠 GL-261 同种异体移植模型中进行总生存和肿瘤体积生长实验。
结果
DCA 和 MET 表现出剂量依赖性细胞毒性和协同作用。DCA 减轻了 MET 诱导的乳酸产量增加。Seahorse 分析表明，DCA 处理导致耗氧量增加，而 MET 则降低了耗氧量。DCA 和 MET 显著抑制了小鼠肿瘤的生长并提高了总生存率。
结论
针对肿瘤细胞代谢的化合物可能成为多形性胶质母细胞瘤的潜在治疗选择。
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