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Anti-tumor activity of sorafenib in a model of a pediatric hepatocellular carcinoma.

AbstractBACKGROUND:
Treatment outcome of children with pediatric hepatocellular carcinoma (pHCC) is poor. Therefore, we evaluated the tyrosine kinase inhibitor sorafenib in a model of pHCC.
METHODS:
Cell viability after treatment with sorafenib was evaluated in HC-AFW1 cells (pHCC) using MTT assay and compared to an adult HCC (aHCC) and two hepatoblastoma (HB) cell lines. ERK, pERK, E-cadherin, and vimentin expression were investigated using Western Blot. Sorafenib (60 mg/kg) was administered orally to NOD.Cg-Prkdcscid-IL2rgtmWjl/Sz mice bearing subcutaneous HC-AFW1-derived tumors. Tumor progression, viability, and vascularization were monitored by tumor volume, AFP levels, and CD31 immunostaining, respectively. Sensitization to sorafenib was evaluated using the β-catenin inhibitor ICG001.
RESULTS:
Sorafenib reduced cell viability in HC-AFW1 (IC50: 8 µM), comparable to HB cells, however less pronounced in aHCC cells (IC50: 23 µM). Sorafenib inhibited ERK signaling in both, HC-AFW1 cells and -xenografts. In vivo, sorafenib treatment only led to a moderate tumor growth inhibition, although significant reduction of vascularization and tumor growth kinetics was observed. Long-term treatment with sorafenib decreased E-cadherin, but showed no induction of vimentin expression. Combining sorafenib with a β-catenin inhibitor led to an additional reduction of cell viability.
CONCLUSION:
Sorafenib together with inhibitors of the β-catenin pathway might be an effective tool in the treatment of pediatric HCC.
AuthorsCarmen Nagel, Sorin Armeanu-Ebinger, Alexander Dewerth, Steven W Warmann, Jörg Fuchs
JournalExperimental cell research (Exp Cell Res) Vol. 331 Issue 1 Pg. 97-104 (Feb 1 2015) ISSN: 1090-2422 [Electronic] United States
PMID25447203 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Inc. All rights reserved.
Chemical References
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • beta Catenin
  • Niacinamide
  • sorafenib
Topics
  • Adult
  • Animals
  • Blotting, Western
  • Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
  • Cell Proliferation (drug effects)
  • Child
  • Epithelial-Mesenchymal Transition
  • Female
  • Humans
  • Liver Neoplasms (drug therapy, metabolism, pathology)
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neovascularization, Pathologic (drug therapy)
  • Niacinamide (analogs & derivatives, therapeutic use)
  • Phenylurea Compounds (therapeutic use)
  • Protein Kinase Inhibitors (therapeutic use)
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • beta Catenin (metabolism)

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