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Treatment effects of the multikinase inhibitor sorafenib on hepatoblastoma cell lines and xenografts in NMRI ‐ Foxn1 nu mice
Author(s) -
Eicher Carmen,
Dewerth Alexander,
Kirchner Bettina,
Warmann Steven W.,
Fuchs Joerg,
ArmeanuEbinger Sorin
Publication year - 2012
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2011.02729.x
Subject(s) - hepatoblastoma , sorafenib , medicine , cancer research , cell culture , oncology , hepatocellular carcinoma , pharmacology , biology , genetics
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 Aims 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 ( HUH 6 and HepT 1) after treatment with sorafenib using MTT and Caspase 3 activation assay. Extracellular signal‐regulated kinase ( ERK ) phosphorylation was investigated using W estern blot. In addition, sorafenib (30 mg/kg) was administered orally to NMRI mice bearing subcutaneous HUH 6 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 CD 31 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 HepT 1 and HUH 6 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). CD 31 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. Conclusion 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.