title: 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.
  
  
  CONCLUSIONS
  Sorafenib together with inhibitors of the β-catenin pathway might be an effective tool in the treatment of pediatric HCC.
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, University Children׳s Hospital Tuebingen, Hoppe-Seyler-Street 3, 72076 Tuebingen, Germany. Electronic address: carmeneicher@gmx.de.
authors.forename: Carmen
authors.initials: C
authors.lastname: Nagel
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, University Children׳s Hospital Tuebingen, Hoppe-Seyler-Street 3, 72076 Tuebingen, Germany.
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, University Children׳s Hospital Tuebingen, Hoppe-Seyler-Street 3, 72076 Tuebingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dewerth
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, University Children׳s Hospital Tuebingen, Hoppe-Seyler-Street 3, 72076 Tuebingen, Germany.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Warmann
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, University Children׳s Hospital Tuebingen, Hoppe-Seyler-Street 3, 72076 Tuebingen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Fuchs
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D009536:Niacinamide; D000077157:Sorafenib
keywords: HC-AFW1; Pediatric hepatocellular carcinoma; Sorafenib; Xenograft; pHCC; β-catenin