title: Effect of sorafenib combined with cytostatic agents on hepatoblastoma cell lines and xenografts.
abstract: BACKGROUND
  Sorafenib has recently been shown to reduce tumour growth in hepatoblastoma (HB) xenografts. The effect of a combined administration with cytostatic agents was now investigated.
  
  
  METHODS
  Cell viability after treatment with sorafenib and different cytostatic agents was evaluated in two HB cell lines (HUH6 and HepT1) using MTT assay. ERK signalling was investigated by western blot, NOXA expression by rt-PCR, and formation of DNA adducts using immunocytology. NMRI mice bearing subcutaneous HUH6-derived tumours were treated with sorafenib alone or in combination with cisplatin. Tumour progression, viability, apoptosis, and vascularisation were monitored by tumour volume, AFP levels, TUNEL assay, and CD31 immunostaining, respectively.
  
  
  RESULTS
  The combination of sorafenib and cisplatin led to a remarkable decrease in cell viability. The cisplatin-induced enhanced ERK1/2 activation, but not NOXA expression and the formation of DNA adducts was partly abrogated by sorafenib. In HB xenografts, both, sorafenib and alternated application of sorafenib and cisplatin significantly reduced tumour growth (P<0.05). Levels of AFP were lower in both treated groups (P=0.08). Relative apoptotic areas were increased (P=0.003). Mean vascular density was the lowest in the sorafenib/CDDP group (P=0.02).
  
  
  CONCLUSIONS
  The combination of sorafenib with cisplatin might be a promising treatment option for high risk or recurrent HB.
authors.affiliation: Department of Pediatric Surgery and Urology, University Children's Hospital, Hoppe-Seyler-Strasse 3, 72076 Tuebingen, Germany. carmen.eicher@med.uni-tuebingen.de
authors.forename: C
authors.initials: C
authors.lastname: Eicher
authors.forename: A
authors.initials: A
authors.lastname: Dewerth
authors.forename: J
authors.initials: J
authors.lastname: Thomale
authors.forename: V
authors.initials: V
authors.lastname: Ellerkamp
authors.forename: S
authors.initials: S
authors.lastname: Hildenbrand
authors.forename: S W
authors.initials: SW
authors.lastname: Warmann
authors.forename: J
authors.initials: J
authors.lastname: Fuchs
authors.forename: S
authors.initials: S
authors.lastname: Armeanu-Ebinger
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D054697:Cytostatic Agents / Q000627:therapeutic use*; D018736:DNA Adducts / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D054697:Cytostatic Agents; D018736:DNA Adducts; C498702:PMAIP1 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D009536:Niacinamide; D000077157:Sorafenib; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002945:Cisplatin