Pharmacological inhibition of beta-catenin in hepatoblastoma cells

Pediatr Surg Int. 2013 Feb;29(2):141-9. doi: 10.1007/s00383-012-3237-9. Epub 2012 Dec 25.

Abstract

Purpose: 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.

Conclusion: 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.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Celecoxib
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Etodolac / pharmacology
  • Hepatoblastoma / drug therapy*
  • Hepatoblastoma / metabolism
  • Hepatoblastoma / pathology
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / pharmacology
  • Pyrimidinones / pharmacology
  • Sulfonamides / pharmacology
  • Tissue Distribution
  • Tumor Cells, Cultured
  • beta Catenin / antagonists & inhibitors*
  • beta Catenin / metabolism

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • ICG 001
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidinones
  • Sulfonamides
  • beta Catenin
  • Etodolac
  • Celecoxib
  • Cisplatin