Isakovic A, Harhaji L, Stevanovic D, Markovic Z, Sumarac-Dumanovic M, Starcevic V, Micic D, Trajkovic V
Institute of Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.
Cell Mol Life Sci. 2007 May;64(10):1290-302. doi: 10.1007/s00018-007-7080-4.
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.
本研究首次报道了著名的抗糖尿病药物二甲双胍具有双重抗胶质瘤作用。在C6大鼠胶质瘤细胞系的低密度培养中，二甲双胍阻断细胞周期在G(0)/G(1)期的进展，而不诱导明显的细胞死亡。另一方面，在汇合的C6培养物中，二甲双胍导致大量依赖半胱天冬酶的凋亡，这与c-Jun氨基末端激酶（JNK）激活、线粒体去极化和氧化应激相关。阻断线粒体通透性转换的药物（环孢素A）和氧自由基产生的药物（N-乙酰半胱氨酸）可完全阻止二甲双胍引发的凋亡，而JNK激活抑制剂（SP600125）或糖酵解抑制剂（氟化钠、碘乙酸）则提供部分保护。二甲双胍的抗胶质瘤作用被AMP激活的蛋白激酶（AMPK）抑制剂化合物C减弱，而被AMPK激动剂AICAR模拟。在人胶质瘤细胞系U251中观察到类似的效应，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耐药。
