title: The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma.
abstract: BACKGROUND
  The primary goal of current chemotherapy in hepatoblastoma (HB) is reduction of tumour volume and vitality to enable complete surgical resection and reduce risk of recurrence or metastatic disease. Drug resistance remains a major challenge for HB treatment. In some malignancies inhibition of anti-apoptotic pathways using small BH3 mimetic molecules like ABT-737 shows synergistic effects in combination with cystotoxic agents in vitro. Now we analysed toxicology and synergistic effects of this approach in HB cells and HB xenografts.
  
  
  METHODS
  Viability was monitored in HB cells (HUH6 and HepT1) and fibroblasts treated with paclitaxel, ABT-737 and a combination of both in a MTT assay. HUH6 xenotransplants in NOD/LtSz-scid IL2Rγnull mice (NSG) were treated accordingly. Tumour volume and body weight were monitored. Xenografted tumours were analysed by histology and immunohistochemistry (Ki-67 and TUNEL assay).
  
  
  RESULTS
  ABT-737 reduced viability in HUH6 and HepT1 cells cultures at concentrations above 1 μM and also enhanced the cytotoxic effect of paclitaxel when used in combination. Thereby paclitaxel could be reduced tenfold to achieve similar reduction of viability of tumour cells. In contrast no toxicity in fibroblasts was observed at the same regiments. Subcutaneous HB (HUH6) treated with paclitaxel (12 mg/kg body weight, n = 7) led to delayed tumour growth in the beginning of the experiment. However, tumour volume was similar to controls (n = 5) at day 25. Combination treatment with paclitaxel and ABT-737 (100 mg/kg, n = 8) revealed significantly 10 fold lower relative tumour volumes compared to control and paclitaxel groups. Paclitaxel dependent toxicity was observed in this mice strain.
  
  
  CONCLUSIONS
  Our results demonstrate enhancement of chemotherapy by using modulators of apoptosis. Further analyses should include improved pharmacological formulations of paclitaxel and BH3 mimetics in order to reduce toxicological effects. Sensitising HB to apoptosis may also render resistant HB susceptible to established chemotherapy regimens.
authors.affiliation: Department of Paediatric Surgery and Paediatric Urology, University Children's Hospital, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany.
authors.forename: Justus
authors.initials: J
authors.lastname: Lieber
authors.forename: Carmen
authors.initials: C
authors.lastname: Eicher
authors.forename: Julia
authors.initials: J
authors.lastname: Wenz
authors.forename: Bettina
authors.initials: B
authors.lastname: Kirchner
authors.forename: Steven W
authors.initials: SW
authors.lastname: Warmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Fuchs
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D018197:Hepatoblastoma / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D017239:Paclitaxel