title: The Aurora kinase inhibitor VE-465 has anticancer effects in pre-clinical studies of human hepatocellular carcinoma.
abstract: OBJECTIVE
  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.
authors.affiliation: National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
authors.forename: Zhong-Zhe
authors.initials: ZZ
authors.lastname: Lin
authors.forename: Hey-Chi
authors.initials: HC
authors.lastname: Hsu
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Hsu
authors.forename: Pei-Yen
authors.initials: PY
authors.lastname: Yeh
authors.forename: Chi-Ying F
authors.initials: CY
authors.lastname: Huang
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Huang
authors.forename: Te-Jung
authors.initials: TJ
authors.lastname: Chen
authors.forename: Sung-Hsin
authors.initials: SH
authors.lastname: Kuo
authors.forename: Chiun
authors.initials: C
authors.lastname: Hsu
authors.forename: Fu-Chang
authors.initials: FC
authors.lastname: Hu
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.forename: Ying
authors.initials: Y
authors.lastname: Chung
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008938:Mitosis / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064127:Aurora Kinases; D006657:Histones; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines