2′-epi-2′-O-Acetylthevetin B extracted from seeds of Cerbera manghas L. induces cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells

被引:21
|
作者
Feng, Bo [1 ]
Guo, Yue-Wei [2 ]
Huang, Cai-Guo [1 ]
Li, Liang [2 ]
Chen, Ruo-Hua [3 ]
Jiao, Bing-Hua [1 ]
机构
[1] Second Mil Med Univ, Dept Biochem & Mol Biol, Shanghai 200433, Peoples R China
[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
[3] Changhai Hosp, Shanghai 200433, Peoples R China
关键词
2 '-epi-2 '-O-Acetylthevetin B (GHSC-74); Cell cycle arrest; Mitochondrial membrane potential (Delta psi(m)); Apoptosis-inducing factor (AIF); Reactive oxygen species (ROS); Caspase; Apoptosis; NF-KAPPA-B; ALPHA-INDUCED APOPTOSIS; NECROSIS-FACTOR-ALPHA; HUMAN LEUKEMIA-CELLS; NITROGEN-MUSTARD; DEATH; MITOCHONDRIA; ACTIVATION; ROS; KINASE;
D O I
10.1016/j.cbi.2009.10.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
2'-epi-2'-O-Acetylthevetin B (GHSC-74) is a cardiac glycoside isolated from the seeds of Cerbera manghas L We have demonstrated that GHSC-74 reduced the viability of HepG2 cells in a time-and dose-dependent manner. The present study was designed to explore cellular mechanisms whereby GHSC-74 led to cell cycle arrest and apoptosis in HepG2 cells. Cell cycle flow cytometry demonstrated that HepG2 cells treated with GHSC-74 (4 mu M) resulted in S and G2 phase arrest in a time-dependent manner, as confirmed by mitotic index analysis. G2 phase arrest was accompanied with down-regulation of CDC2 and Cyclin B1 protein. Furthermore, GHSC-74-induced apoptotic killing, as demonstrated by DNA fragmentation, DAPI staining, and flow cytometric detection of sub-G1 DNA content in HepG2 cells. GHSC-74 treatment resulted in a significant increase in reactive oxygen species, activation of caspase-9, dissipation of mitochondrial membrane potential, and translocation of apoptosis-inducing factor (AIF) from the mitochondrion to the nucleus in HepG2 cells. Nevertheless, after GHSC-74 exposure, no significant Fas and FasL up-regulation was observed in HepG2 cells by flow cytometry. In addition, treatment with antioxidant N-acetyl-L-cysteine (NAC) and broad-spectrum caspase inhibitor z-VAD-fmk partially prevented apoptosis but did not abrogate GHSC-74-induced nuclear translocation of AIR In conclusion, we have demonstrated that GHSC-74 inhibited growth of HepG2 cells by inducing S and G2 phase arrest of the cell cycle and by triggering apoptosis via mitochondrial disruption including both caspase-dependent and -independent pathways, and ROS generation. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:142 / 153
页数:12
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