Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma.
Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma.
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DOI：
10.18632/oncotarget.10919
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发表时间：
2016-08-30
期刊：
影响因子：
--
通讯作者：
Brodie C
中科院分区：
文献类型：
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作者：
Jiang W;Finniss S;Cazacu S;Xiang C;Brodie Z;Mikkelsen T;Poisson L;Shackelford DB;Brodie C
胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤，预后差。在这里，我们研究了苯丙氨酸，一种线粒体复合物I抑制剂和更有效的化学类似物的糖尿病药物二甲双胍对细胞生长的抑制和诱导胶质瘤干细胞（GSC）的凋亡的影响，使用在体外和体内模型。苯丙氨酸抑制GSC的自我更新，降低干细胞和间充质标志物的表达，增加miR-124、137和let-7的表达。let-7的沉默通过与抑制H19和HMGA 2表达相关的途径消除了苯丙氨酸对GSC自我更新的影响。此外，我们证明，苯丙氨酸抑制肿瘤生长，并延长了原位移植GSC的小鼠的总生存期。联合治疗的phenolamine和替莫唑胺产生了增加的抗肿瘤作用，在体外和体内的GSC。此外，二氯乙酸，一种糖酵解酶丙酮酸脱氢酶激酶的抑制剂，减少由双胍诱导的乳酸中毒，增强苯丙氨酸对诱导GSC中细胞死亡的作用，并延长异种移植荷瘤小鼠的生存期。我们的研究结果首次表明，菲林匹定靶向GSC，并可以有效地与目前的GBM治疗和GSC根除疗法相结合。
Glioblastoma (GBM) is the most aggressive primary brain tumor with poor prognosis. Here, we studied the effects of phenformin, a mitochondrial complex I inhibitor and more potent chemical analog of the diabetes drug metformin on the inhibition of cell growth and induction of apoptosis of glioma stem cells (GSCs) using both in vitro and in vivo models. Phenformin inhibited the self-renewal of GSCs, decreased the expression of stemness and mesenchymal markers and increased the expression of miR-124, 137 and let-7. Silencing of let-7 abrogated phenformin effects on the self-renewal of GSCs via a pathway associated with inhibition of H19 and HMGA2 expression. Moreover, we demonstrate that phenformin inhibited tumor growth and prolonged the overall survival of mice orthotopically transplanted with GSCs. Combined treatments of phenformin and temozolomide exerted an increased antitumor effect on GSCs in vitro and in vivo. In addition, dichloroacetate, an inhibitor of the glycolysis enzyme pyruvate dehydrogenase kinase, that decreases lactic acidosis induced by biguanides, enhanced phenformin effects on the induction of cell death in GSCs and prolonged the survival of xenograft-bearing mice. Our results demonstrate for the first time that phenformin targets GSCs and can be efficiently combined with current therapies for GBM treatment and GSC eradication.