title: Treatment effects of the multikinase inhibitor sorafenib on hepatoblastoma cell lines and xenografts in NMRI-Foxn1 nu mice.
abstract: BACKGROUND
  Multidrug resistance is a major reason for poor treatment results in advanced hepatoblastoma (HB). Several alternative treatment options are currently under investigation to improve the prognosis of affected patients
  
  
  OBJECTIVE
  This study aimed to analyse the impact of sorafenib on the viability of HB cells and xenotransplanted HB tumours.
  
  
  METHODS
  Cell viability and apoptosis were evaluated in two HB cell lines (HUH6 and HepT1) after treatment with sorafenib using MTT and Caspase 3 activation assay. Extracellular signal-regulated kinase (ERK) phosphorylation was investigated using Western blot. In addition, sorafenib (30 mg/kg) was administered orally to NMRI mice bearing subcutaneous HUH6 derived tumours. Tumour progression and viability were monitored by tumour volume and α-fetoprotein (AFP) levels, and apoptosis was assessed using TUNEL assay. Tumour angiogenesis and mean vascular density (MVD) was determined using CD31 staining, ERK phosphorylation was detected using indirect immunofluorescence.
  
  
  RESULTS
  Treatment with sorafenib led to decreased ERK phosphorylation, reduced cell viability and induction of apoptosis in HepT1 and HUH6 cells. In HB xenografts, sorafenib significantly reduced tumour growth compared with control (P < 0.05). AFP levels were lower in the sorafenib group (P = 0.07). Relative apoptotic areas detected using TUNEL assay were increased (P = 0.003). CD31 staining revealed inhibition of angiogenesis, and mean vascular density was lower in the sorafenib group (P = 0.02). ERK phosphorylation was reduced in tumours tissues after sorafenib treatment.
  
  
  CONCLUSIONS
  Treatment with sorafenib led to a potent inhibition of cell viability, tumour progression and angiogenesis. Sorafenib might therefore also be a promising treatment option for high risk or recurrent HB.
authors.affiliation: Department of Pediatric Surgery and Urology, University Children's Hospital, Tuebingen, Germany. carmen.eicher@med.uni-tuebingen.de
authors.forename: Carmen
authors.initials: C
authors.lastname: Eicher
authors.forename: Alexander
authors.initials: A
authors.lastname: Dewerth
authors.forename: Bettina
authors.initials: B
authors.lastname: Kirchner
authors.forename: Steven W
authors.initials: SW
authors.lastname: Warmann
authors.forename: Joerg
authors.initials: J
authors.lastname: Fuchs
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D001557:Benzenesulfonates / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D053148:Caspase 3; D045744:Cell Line, Tumor; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D051858:Forkhead Transcription Factors / Q000235:genetics; D018197:Hepatoblastoma / Q000188:drug therapy*; D020287:In Situ Nick-End Labeling; D051379:Mice; D009389:Neovascularization, Pathologic / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D000077157:Sorafenib; D013778:Tetrazolium Salts; D013844:Thiazoles; D014183:Transplantation, Heterologous; D019737:Transplants; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D051858:Forkhead Transcription Factors; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013778:Tetrazolium Salts; D013844:Thiazoles; C090140:Whn protein; D000509:alpha-Fetoproteins; D009536:Niacinamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; C022616:thiazolyl blue