title: The HDACi Panobinostat Shows Growth Inhibition Both In Vitro and in a Bioluminescent Orthotopic Surgical Xenograft Model of Ovarian Cancer.
abstract: BACKGROUND
  In most epithelial ovarian carcinomas (EOC), epigenetic changes are evident, and overexpression of histone deacetylases (HDACs) represents an important manifestation. In this study, we wanted to evaluate the effects of the novel HDAC inhibitor (HDACi) panobinostat, both alone and in combination with carboplatin, on ovarian cancer cell lines and in a murine bioluminescent orthotopic surgical xenograft model for EOC.
  
  
  METHODS
  The effects of panobinostat, both alone and in combination with carboplatin, on proliferation and apoptosis in ovarian cancer cell lines, were evaluated using colony and WST-1 assays, Hoechst staining and flow cytometry analysis. In addition, mechanisms were characterised by western blotting and phosphoflow analysis. Immuno-deficient mice were engrafted orthotopically with SKOV-3luc+ cells and serial bioluminescence imaging monitored the effects of treatment with panobinostat and/or carboplatin and/or surgery. Survival parameters were also measured.
  
  
  RESULTS
  Panobinostat treatment reduced cell growth and diminished cell viability, as shown by the induced cell cycle arrest and apoptosis in vitro. We observed increased levels of cleaved PARP and caspase-3, downregulation of cdc2 protein kinase, acetylation of H2B and higher pH2AX expression. The combined administration of carboplatin and panobinostat synergistically increased the anti-tumour effects compared to panobinostat or carboplatin treatment alone. In our novel ovarian cancer model, the mice showed significantly higher rates of survival when treated with panobinostat, carboplatin or a combination of both, compared to the controls. Panobinostat was as efficient as carboplatin regarding prolongation of survival. No significant additional effect on survival was observed when surgery was combined with carboplatin/panobinostat treatment.
  
  
  CONCLUSIONS
  Panobinostat demonstrates effective in vitro growth inhibition in ovarian cancer cells. The efficacy of panobinostat and carboplatin was equal in the orthotopic EOC model used. We conclude that panobinostat is a promising therapeutic alternative that needs to be further assessed for the treatment of EOC.
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Jonas Liesvei 72, 5058 Bergen, Norway.|Department of Clinical Science, University of Bergen, PB 7804, 5020 Bergen, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Helland
authors.affiliation: KinN Therapeutics, Laboratoriebygget, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Popa
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Jonas Liesvei 72, 5058 Bergen, Norway.|Department of Clinical Science, University of Bergen, PB 7804, 5020 Bergen, Norway.
authors.forename: Katharina
authors.initials: K
authors.lastname: Bischof
authors.affiliation: Department of Clinical Science, University of Bergen, PB 7804, 5020 Bergen, Norway.|Department of Internal Medicine, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway.|Centre for Cancer Biomarkers (CCBIO), University of Bergen, 5020 Bergen, Norway.
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.affiliation: Department of Clinical Science, University of Bergen, PB 7804, 5020 Bergen, Norway.|Department of Internal Medicine, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway.
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Jonas Liesvei 72, 5058 Bergen, Norway.|Department of Clinical Science, University of Bergen, PB 7804, 5020 Bergen, Norway.|Centre for Cancer Biomarkers (CCBIO), University of Bergen, 5020 Bergen, Norway.
authors.forename: Line
authors.initials: L
authors.lastname: Bjørge
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D000077767:Panobinostat; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D016190:Carboplatin; D011065:Poly(ADP-ribose) Polymerases; D016203:CDC2 Protein Kinase; D053148:Caspase 3