Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis
Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis
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DOI：
10.1007/s00018-007-7080-4
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发表时间：
2007-05-01
影响因子：
8
通讯作者：
Trajkovic, V.
中科院分区：
文献类型：
--
作者：
Isakovic, A.;Harhaji, L.;Trajkovic, V.
本研究首次报告了著名的抗糖尿病药物二甲双胍的双重抗神经胶质瘤作用。在 C6 大鼠神经胶质瘤细胞系的低密度培养物中，二甲双胍阻断 G(0)/G(1) 期的细胞周期进展，而不诱导显着的细胞死亡。另一方面，在汇合的 C6 培养物中，二甲双胍引起大量诱导与 c-Jun N 末端激酶 (JNK) 激活、线粒体去极化和氧化应激相关的 caspase 依赖性细胞凋亡。二甲双胍引发的细胞凋亡可被阻断线粒体通透性转变（环孢菌素 A）和氧自由基产生（N-乙酰半胱氨酸）的药物完全阻止，而 JNK 激活抑制剂（SP600125）或糖酵解抑制剂（氟化钠、碘乙酸钠）则提供部分保护。二甲双胍的抗神经胶质瘤作用被化合物 C（一种 AMP 激活蛋白激酶 (AMPK) 抑制剂）减弱，并被 AMPK 激动剂 AICAR 模拟。在人神经胶质瘤细胞系 U251 中观察到类似的效果，而大鼠原代星形胶质细胞对二甲双胍的抗增殖和促凋亡作用完全抵抗。
The present study reports for the first time a dual antiglioma effect of the well-known antidiabetic drug metformin. In low-density cultures of the C6 rat glioma cell line, metformin blocked the cell cycle progression in G(0)/G(1) phase without inducing significant cell death. In confluent C6 cultures, on the other hand, metformin caused massive induction of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation, mitochondrial depolarization and oxidative stress. Metformin-triggered apoptosis was completely prevented by agents that block mitochondrial permeability transition (cyclosporin A) and oxygen radical production (N-acetylcisteine), while the inhibitors of JNK activation (SP600125) or glycolysis (sodium fluoride, iodoacetate) provided partial protection. The antiglioma effect of metformin was reduced by compound C, an inhibitor of AMP-activated protein kinase (AMPK), and was mimicked by the AMPK agonist AICAR. Similar effects were observed in the human glioma cell line U251, while rat primary astrocytes were completely resistant to the antiproliferative and proapoptotic action of metformin.