title: Pharmacological inhibition of beta-catenin in hepatoblastoma cells.
abstract: OBJECTIVE
  The proto-oncogene beta-catenin is linked to an abnormal activation of the Wnt/beta-catenin-pathway and shows mutations in 50-90 % of hepatoblastoma (HB). Corresponding, the recently published murine orthotopic HB model differs from the former subcutaneous model by nuclear beta-catenin distribution. As the nuclear localization of beta-catenin is considered to reflect a more aggressive tumor growth, the influence of beta-catenin inhibition on cell viability and drug-efficiency in HB cells was analyzed.
  
  
  METHODS
  Beta-catenin distribution in HB cells was analyzed by immunofluorescence. The influence of beta-catenin inhibitors Celecoxib, Etodolac, ICG001, and MET kinase inhibitor (SU11274) alone and in combination with cisplatin (CDDP) on HB cell lines (HuH6, HepT1) was evaluated by cell viability assays and BrdU incorporation.
  
  
  RESULTS
  Celecoxib and ICG001 reduced dose-dependently HB cell viability and decreased nuclear beta-catenin in cultivated HB cells. Etodolac was without influence at concentrations up to 100 μM. Combinations of Celecoxib or ICG001 with MET kinase inhibitor or CDDP resulted in additive reduction of cell viability.
  
  
  CONCLUSIONS
  Pharmaceutical beta-catenin inhibitors can modulate the nuclear localization of beta-catenin and reduce cell viability of HB cells in vitro. These promising effects might optimize the outcome of high-risk HB. The orthotopic HB model is a suitable basis for further in vivo studies.
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany. verenaellerkamp@gmail.com
authors.forename: V
authors.initials: V
authors.lastname: Ellerkamp
authors.forename: J
authors.initials: J
authors.lastname: Lieber
authors.forename: C
authors.initials: C
authors.lastname: Nagel
authors.forename: J
authors.initials: J
authors.lastname: Wenz
authors.forename: S W
authors.initials: SW
authors.lastname: Warmann
authors.forename: J
authors.initials: J
authors.lastname: Fuchs
authors.forename: S
authors.initials: S
authors.lastname: Armeanu-Ebinger
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D017308:Etodolac / Q000494:pharmacology; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011720:Pyrazoles / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011720:Pyrazoles; D011744:Pyrimidinones; D013449:Sulfonamides; D051176:beta Catenin; D017308:Etodolac; D000068579:Celecoxib; D002945:Cisplatin