- 作者：Zhong-Zhe Lin ; Hey-Chi Hsu ; Chih-Hung Hsu ; Pei-Yen Yeh ; Chi-Ying F. Huang ; Yung-Feng Huang ; Te-Jung Chen ; Sung-Hsin Kuo ; Chiun Hsu ; Fu-Chang Hu ; Yung-Ming Jeng ; Ying Chung ; Ann-Lii Cheng
- 关键词：Aurora kinases ; Hepatocellular carcinoma ; Small-molecule inhibitor ; Apoptosis ; Xenograft
- 刊名：Journal of Hepatology
- 出版年：2009
- 出版时间：March 2009
- 年：2009
- 卷：50
- 期：3
- 页码：518-527
- 全文大小：2599 K
Background/Aims
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and novel therapies are urgently needed. Recently, aberrant expression of Aurora kinases has been reported in various human cancers including HCC. We sought to investigate the potential of a potent and selective Aurora kinase inhibitor, VE-465, for targeted therapy of HCC.Methods
Cytotoxicity effects of VE-465 were tested in Huh-7 and HepG2 cell lines. Inhibition of Aurora kinase activity was demonstrated by Western blotting and immunofluorescence staining. Mitotic perturbation was visualized by confocal microscopy. Cell cycle profiles and apoptosis were assessed by flow cytometry. In vivo efficacy was determined in nude mice with human HCC xenografts.
Results
We demonstrated that VE-465 induced proliferation blockade, histone H3 (Ser10) dephosphorylation, mitotic disturbance, endoreduplication, and apoptosis in Huh-7 and HepG2 cells. We also found that VE-465 suppressed Aurora kinase activity, prevented tumor growth, and induced apoptosis in a Huh-7 xenograft model.
Conclusions
These findings show that VE-465 has potent anticancer effects in human HCC. Inhibitors of Aurora kinases may deserve further exploration as molecular targeted agents against HCC.