title: Synergistic activity of histone deacetylase and proteasome inhibition against pancreatic and hepatocellular cancer cell lines.
abstract: OBJECTIVE
  To determine the phenotypic effects of belinostat (bel) and bortezomib (bor) against pancreatic cancer (PC) and hepatocellular cancer (HCC) cell lines.
  
  
  METHODS
  Antiproliferative effects were assessed using a sulforhodamine B assay. Synergy was evaluated using the Chou and Talalay method. Apoptosis was measured by caspase-3/-7 activity and PARP cleavage. Downstream effector proteins were detected via immunoblotting. Quantitative nuclear magnetic resonance (NMR)-based metabolomics analysis was performed.
  
  
  RESULTS
  There were single-agent antiproliferative effects against PC and HCC cell lines; the combination of bel and bor (bel+bor) had a synergistic effect. There was up to a 45-fold induction of apoptosis over the control. Post-treatment cell death was associated with p21 up-regulation, more pronounced with treatment with bel+bor. Treatment with bel+bor enhanced hyperacetylation of histone H3 over single-agent bel. A metabolic signature was established for treatments with bor and bel+bor.
  
  
  CONCLUSIONS
  The combination of bel+bor displayed significant antiproliferative activity against PC and HCC cell lines, with exhibiting synergistic antiproliferative and proapoptotic patterns even at suboptimal single-agent doses.
authors.affiliation: Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada. jennifer.spratlin@albertahealthservices.ca
authors.forename: J L
authors.initials: JL
authors.lastname: Spratlin
authors.forename: T M
authors.initials: TM
authors.lastname: Pitts
authors.forename: G N
authors.initials: GN
authors.lastname: Kulikowski
authors.forename: M P
authors.initials: MP
authors.lastname: Morelli
authors.forename: J J
authors.initials: JJ
authors.lastname: Tentler
authors.forename: N J
authors.initials: NJ
authors.lastname: Serkova
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D013449:Sulfonamides
chemical_list: D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D013449:Sulfonamides; D000069286:Bortezomib; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; C487081:belinostat