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

Abstract

BACKGROUND:

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.

• Authors: Carmen Nagel, Sorin Armeanu-Ebinger, Alexander Dewerth, Steven W Warmann, Jörg Fuchs
• Journal: Experimental cell research (Exp Cell Res) Vol. 331 Issue 1 Pg. 97-104 (Feb 01 2015) ISSN: 1090-2422 [Electronic] United States
• PMID: 25447203 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 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)
• Sorafenib
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• beta Catenin (metabolism)