title: In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma.
abstract: OBJECTIVE
  Hepatoblastoma (HB) has a poor prognosis in advanced stages. The aim of this study was to enhance effectiveness of chemotherapy with antineoplastic kinase inhibitors.
  
  
  METHODS
  Viability was monitored in HB cells (HUH6, HepT1) in monolayer and spheroid cultures treated with kinase inhibitors VX-680, Wee1-InhibitorII, and SU11274 alone or in combination with cisplatin (CDDP) using MTT assays. Apoptosis was revealed by Caspase-3 assay. Western blot and immunohistochemical analyses were performed to determine histone H3 phosphorylation.
  
  
  RESULTS
  Among the kinase inhibitors strongest anti-proliferative effect on HB cells was documented for VX-680. HUH6 cells responded more sensitively to the Aurora kinase inhibitor as HepT1 cells (IC(50) 8 and 16.6 μM, respectively). While VX-680 and CDDP showed no additive effects, the combination of VX-680 and histone deacetylase inhibitor SAHA had a synergistic effect on the proliferation of HUH6 cells. The inhibition with VX-680 led to reduced histone H3 phosphorylation, to an increase of apoptotic cells, and to morphological changes such as vacuolization and swelling of the cells and nuclei.
  
  
  CONCLUSIONS
  The data provide evidence that VX-680 might improve treatment results in HB with increased Aurora kinase activity by inhibiting cell proliferation and induction of apoptosis.
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany. alexander.dewerth@med.uni-tuebingen.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Dewerth
authors.forename: Timo
authors.initials: T
authors.lastname: Wonner
authors.forename: Justus
authors.initials: J
authors.lastname: Lieber
authors.forename: Verena
authors.initials: V
authors.lastname: Ellerkamp
authors.forename: Steven W
authors.initials: SW
authors.lastname: Warmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Fuchs
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
mesh_terms: D064127:Aurora Kinases; D004354:Drug Screening Assays, Antitumor; D018197:Hepatoblastoma / Q000188:drug therapy*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064127:Aurora Kinases; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines