|Title:||The Aurora kinase inhibitor VE-465 has anticancer effects in pre-clinical studies of human hepatocellular carcinoma||Authors:||ZHONG-ZHE LIN
|Issue Date:||2009||Journal Volume:||50||Journal Issue:||3||Start page/Pages:||518-527||Source:||Journal of Hepatology||Abstract:||
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. ? 2008 European Association for the Study of the Liver.
|ISSN:||0168-8278||DOI:||10.1016/j.jhep.2008.10.022||SDG/Keyword:||aurora kinase inhibitor; cyclopropanecarboxylic acid [4 [4 (4 methyl 1 piperazinyl) 6 (5 methyl 2h pyrazol 3 ylamino) 2 pyrimidinylthio]phenyl]amide; histone H3; protein serine threonine kinase; unclassified drug; ve 465; animal experiment; animal model; antineoplastic activity; apoptosis; article; cancer inhibition; cell cycle; cell proliferation; cell strain HepG2; confocal microscopy; controlled study; cytotoxicity; drug efficacy; drug screening; drug structure; endoreduplication; enzyme activity; enzyme inhibition; enzyme repression; flow cytometry; human; human cell; immunofluorescence test; in vivo study; liver cell carcinoma; mitosis; mouse; nonhuman; nude mouse; priority journal; protein dephosphorylation; Western blotting; xenograft; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Division; Cell Line, Tumor; Cell Survival; Histones; Humans; Liver Neoplasms; Mitosis; Piperazines; Protein-Serine-Threonine Kinases
|Appears in Collections:||病理學科所|
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