title: BH3-mimetic drugs prevent tumour onset in an orthotopic mouse model of hepatoblastoma.
abstract: Drug resistance and metastasis remain major challenges in the treatment of high-risk hepatoblastoma (HB) and require the development of alternative therapeutic strategies. Modulation of apoptosis in HB cells enhances the sensitivity of these cells towards various drugs and has been discussed to enforce treatment. We investigated the impact of apoptosis sensitisers, BH3-mimetics, on the interaction between the host and HB to reduce tumour growth and dissemination while enhancing immunity. BH3-mimetics, such as obatoclax and ABT-737, enhanced the apoptosis-inducing effect of TRAIL and TNF-α resistant HB cells (HepT1 and HUH6). Tumour cell migration was inhibited by ABT-737 and more markedly by obatoclax. In an orthotopic model of HB, tumour uptake was reduced when the cells were pretreated with low concentrations of obatoclax. Only 1 of 7 mice developed HB in the liver, compared with an incidence of 0.8 in the control group. In summary, our study showed that apoptosis sensitisers had broader effects on HB cells than expected including migration and susceptibility to cytokines in addition to the known effects on drug sensitization. Sensitising HB to apoptosis may also allow resistant HB to be targeted by immune cells and prevent tumour cell dissemination.
authors.affiliation: University Children's Hospital, Department of Pediatric Surgery and Pediatric Urology, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany. Electronic address: justus.lieber@med.uni-tuebingen.de.
authors.forename: Justus
authors.initials: J
authors.lastname: Lieber
authors.affiliation: University Children's Hospital, Department of Pediatric Surgery and Pediatric Urology, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany. Electronic address: verena.ellerkamp@med.uni-tuebingen.de.
authors.forename: Verena
authors.initials: V
authors.lastname: Ellerkamp
authors.affiliation: University Children's Hospital, Department of Pediatric Surgery and Pediatric Urology, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany. Electronic address: fabianvogt@gmx.net.
authors.forename: Fabian
authors.initials: F
authors.lastname: Vogt
authors.affiliation: University Children's Hospital, Department of Pediatric Surgery and Pediatric Urology, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany. Electronic address: julia.wenz@med.uni-tuebingen.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Wenz
authors.affiliation: University Children's Hospital, Department of Pediatric Surgery and Pediatric Urology, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany. Electronic address: steven.warmann@med.uni-tuebingen.de.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Warmann
authors.affiliation: University Children's Hospital, Department of Pediatric Surgery and Pediatric Urology, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany. Electronic address: joerg.fuchs@med.uni-tuebingen.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Fuchs
authors.affiliation: University Children's Hospital, Department of Pediatric Surgery and Pediatric Urology, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany. Electronic address: sorin.armeanu-ebinger@med.uni-tuebingen.de.
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D018197:Hepatoblastoma / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007211:Indoles; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D008822:Mice, Transgenic; D009596:Nitrophenols / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C501332:ABT-737; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; D007211:Indoles; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D013449:Sulfonamides; C520962:obatoclax
keywords: ABT-737; BH3-mimetic drugs; High-risk hepatoblastoma; Obatoclax; Orthotopic HB model; Paediatric solid tumours; TNF-α; TRAIL; Tumour cell migration