期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 771, 期 -, 页码 130-138出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2015.12.026
关键词
Vacuolar H+-ATPase; Diphyllin glycoside derivatives; Reactive oxygen species; Apoptosis; Autophagy
资金
- National Natural Science Foundation of China [31171143, 31471141, 81373400]
- Priority Academic Program Development of Jiangsu Higher Education Institution (PAPD)
- Natural Science Fund of Nantong University [13Z005]
- Natural Science Foundation of Jiangsu Province [BK2012229]
The vacuolar H+-ATPase (V-ATPase) has recently been proposed as a key target for new strategies in cancer treatment. Our previous work has proved that diphyllin glycoside is a novel inhibitor of V-ATPase. Here the cytotoxic effects of ZT-25, the most potent diphyllin glycoside derivatives, were studied and some of the underlying mechanisms were elucidated. ZT-25 displayed strong cytotoxicity on several cancer cell lines and relatively low cytotoxicity on human fetal hepatic cells (WRL-68) at submicromolar concentrations. In human hepatoma cells HepG2, ZT-25 induced G(1)/G(0) phase arrest and apoptosis, as well as mitochondrial membrane potential (MMP) dissipation and ATP depletion. Furthermore, Bcl-2 protein decreased, while Bax protein and cleaved caspase-3 protein increased upon ZT-25 treatment. Benzyloxycarbony (Cbz)-L-Val-Ala-Asp (OMe)-fluoromethylketone (Z-VAD-FMK), a well-known pan-caspase inhibitor, attenuated ZT-25-induced cell death, suggesting the involvement of caspase-dependent pathway. Intriguingly, ZT-25 induced autophagy in HepG2 cells as characterized by increased the conversion of LC3 I to LC3 II, Beclin-1 expression and autophagosome formation. Meanwhile, p-mTOR expression was decreased which indicated that ZT-25-induced autophagy might be mediated through the suppression of mTOR pathway. Inhibition of autophagy by 3-methyladenine (3-MA) and chloroquine (CQ) obviously promoted ZT-25-induced cell death, suggesting the protective role of autophagy. Increased intracellular ROS level was found to be the early event in ZT-25-treated HepG2 cells. Inhibition of ROS generation by N-acetyl-L-cysteine (NAC) attenuated ZT-25-induced cell death and autophagy. Together, these results provide key insights into the ZT-25-induced cytotoxicity in HepG2 cells, which will have a great impact on the further development of diphyllin derivatives. (C) 2015 Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据