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大豆异黄酮对人肝癌细胞凋亡诱导及G2-M期阻滞的影响:涉及半胱天冬酶-3激活、Bcl-2和Bcl-XL下调以及Cdc2激酶活性。

Effects of soy isoflavones on apoptosis induction and G2-M arrest in human hepatoma cells involvement of caspase-3 activation, Bcl-2 and Bcl-XL downregulation, and Cdc2 kinase activity.

作者信息

Su Shu-Jem, Chow Nan-Haw, Kung Mei-Lang, Hung Thu-Ching, Chang Kee-Lung

机构信息

Department of Medical Technology, FooYin University, Kaohsiung 831 Taiwan.

出版信息

Nutr Cancer. 2003;45(1):113-23. doi: 10.1207/S15327914NC4501_13.

Abstract

Genistein, biochanin-A, and daidzein, the predominant soy isoflavones, have been reported to lower the risk of cancer, but it is not known whether they protect against human hepatoma cancer. This study was designed to investigate their effects on cell growth, the cell cycle, and apoptosis induction in the human hepatoma cell lines, HepG2, Hep3B, Huh7, PLC, and HA22T. Genistein, biochanin-A, and daidzein inhibited growth of all five lines in a dose-dependent manner. DNA fragmentation studies and the TUNEL assay demonstrated that isoflavones caused tumor cell death by induction of apoptosis. Activation of caspase-3 and cleavage of the caspase-3 substrate, poly(ADP-ribose)polymerase, was seen in hepatoma cells after 24 hours' exposure to isoflavones. In addition, isoflavone cytotoxicity correlated with downregulation of Bcl-2 and Bcl-XL expression. Synergistic effects of the three isoflavones were observed on cell growth inhibition, apoptosis induction, and anti-apoptotic protein expression. Flow cytometry showed that genistein, but not biochanin-A or daidzein, induced progressive and sustained accumulation of hepatoma cancer cells in the G2/M phase as a result of inhibition of Cdc2 kinase activity. Coapplication of caffeine prevented this cell cycle arrest, but not apoptosis, showing that cell cycle arrest was not necessary for apoptosis. Furthermore, the isoflavones combination also had a significant tumor-suppressive effect in nude mice. These results suggest that isoflavones might be promising agents for the treatment of human hepatoma.

摘要

染料木黄酮、鹰嘴豆芽素A和大豆苷元是大豆中的主要异黄酮,据报道它们可降低患癌风险,但它们是否能预防人类肝癌尚不清楚。本研究旨在调查它们对人肝癌细胞系HepG2、Hep3B、Huh7、PLC和HA22T的细胞生长、细胞周期及凋亡诱导的影响。染料木黄酮、鹰嘴豆芽素A和大豆苷元均以剂量依赖的方式抑制所有这五种细胞系的生长。DNA片段化研究和TUNEL检测表明,异黄酮通过诱导凋亡导致肿瘤细胞死亡。在暴露于异黄酮24小时后的肝癌细胞中,可见半胱天冬酶-3的激活及半胱天冬酶-3底物聚(ADP-核糖)聚合酶的裂解。此外,异黄酮的细胞毒性与Bcl-2和Bcl-XL表达的下调相关。观察到三种异黄酮在细胞生长抑制、凋亡诱导及抗凋亡蛋白表达方面具有协同作用。流式细胞术显示,由于Cdc2激酶活性受到抑制,染料木黄酮而非鹰嘴豆芽素A或大豆苷元可诱导肝癌细胞在G2/M期进行性和持续性积累。咖啡因的共同应用可阻止这种细胞周期阻滞,但不能阻止凋亡,这表明细胞周期阻滞对于凋亡并非必需。此外,异黄酮组合在裸鼠中也具有显著的肿瘤抑制作用。这些结果表明,异黄酮可能是治疗人类肝癌的有前景的药物。

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