Sidlauskas Kastytis, Sidlauskiene Ruta, Li Ningning, Liobikas Julius
Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania; Division of Neuropathology, Institute of Neurology, University College London, UK.
Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Neurosci Lett. 2017 Feb 3;639:207-214. doi: 10.1016/j.neulet.2017.01.007. Epub 2017 Jan 6.
Survival of patients with glioblastoma remains within the range of several months despite advances in therapeutic options. We have already shown that 5-hydroxy-1,4-naphthalenedione (juglone) exerts antiproliferative, anti-invasive, and cytotoxic effects on glioma C6 cells. Here, we further revealed that juglone is relatively selective to glioma cells as compared to the normal glial culture, and investigated its mechanisms of action. The incubation of glioma C6 cells with juglone generated high levels of reactive oxygen species (ROS). The produced ROS accounted for the anticancer effect of juglone as antioxidant N-acetylcysteine reduced both cytotoxic and antiproliferative activities of juglone. Furthermore, high resolution respirometry revealed that juglone decreased oxygen consumption mainly by affecting pyruvate/malate- and glutamate/malate-induced mitochondrial respiration. The inhibition of respiratory complex I by amytal decreased juglone-triggered generation of ROS and diminished its anticancer activity. Thus, our results indicate that juglone generates ROS through interaction with respiratory complex I in glioma C6 cells, and, in turn, induces the anticancer effects.
尽管治疗方案有所进展，但胶质母细胞瘤患者的生存期仍在几个月左右。我们已经表明，5-羟基-1,4-萘二酮（胡桃醌）对胶质瘤C6细胞具有抗增殖、抗侵袭和细胞毒性作用。在此，我们进一步揭示，与正常神经胶质细胞培养相比，胡桃醌对胶质瘤细胞具有相对选择性，并研究了其作用机制。用胡桃醌孵育胶质瘤C6细胞会产生高水平的活性氧（ROS）。所产生的ROS是胡桃醌抗癌作用的原因，因为抗氧化剂N-乙酰半胱氨酸降低了胡桃醌的细胞毒性和抗增殖活性。此外，高分辨率呼吸测定法显示，胡桃醌主要通过影响丙酮酸/苹果酸和谷氨酸/苹果酸诱导的线粒体呼吸来降低氧气消耗。阿米妥对呼吸复合体I的抑制降低了胡桃醌引发的ROS生成，并减弱了其抗癌活性。因此，我们的结果表明，胡桃醌通过与胶质瘤C6细胞中的呼吸复合体I相互作用产生ROS，进而诱导抗癌作用。
