title: Histone deacetylase inhibitor augments anti-tumor effect of gemcitabine and pegylated interferon-α on pancreatic cancer cells.
abstract: BACKGROUND
  Histone deacetylase (HDAC) is strongly associated with epigenetic regulation and carcinogenesis, and its inhibitor can induce the differentiation or apoptosis of cancer cells.
  
  
  METHODS
  We investigated the anticancer effects of the HDAC inhibitor valproic acid (VPA) in combination with gemcitabine (GEM), an antimetabolic, and pegylated interferon-α2b (PEG-IFN-α2b) in a human pancreatic cancer cell line using a cell proliferation assay. The gene expressions of HDAC1, MTA1, p21(Waf1), and HIF-1 were evaluated by reverse transcription-PCR.
  
  
  RESULTS
  Valproic acid at 0.5 mM when used alone did not suppress cell proliferation. PEG-IFN-α2b at 10(2 )E/ml weakly suppressed cell proliferation in both the BxPC3 (by 28%) and SUIT-2 (by 17%) human pancreatic cancer cell lines. GEM at 5 nM when used alone suppressed cell proliferation by 36 and 61% in the BxPC3 and SUIT-2 cell lines, respectively. The combination treatment of GEM + PEG-IFN-α2b strongly suppressed cell proliferation in the SUIT-2 (82%) and BxPC3 (51%) cell lines, which was further reinforced by the addition of VPA up to 88 and 67%, respectively. The combination treatment of GEM + PEG-IFN-α2b enhanced the expression of p21(Waf1), which was also reinforced by VPA.
  
  
  CONCLUSIONS
  VPA augmented the inhibitory effects of PEG-IFN-α2b alone or in combination with PEG-IFN-α2b and GEM on cell proliferation. Such inhibitory effects may be due to the up-regulation of p21(Waf1) expression.
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima City 770-8503, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Iwahashi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Shimada
authors.forename: Tohru
authors.initials: T
authors.lastname: Utsunomiya
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morine
authors.forename: Satoru
authors.initials: S
authors.lastname: Imura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ikemoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mori
authors.forename: Jun
authors.initials: J
authors.lastname: Hanaoka
authors.forename: Koji
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Yu
authors.initials: Y
authors.lastname: Saito
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators; D014635:Valproic Acid / Q000494:pharmacology*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497442:HIF1A protein, human; D056572:Histone Deacetylase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000077190:Interferon alpha-2; D016898:Interferon-alpha; C089320:MTA1 protein, human; D011994:Recombinant Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D014635:Valproic Acid; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; C417083:peginterferon alfa-2b; D000093542:Gemcitabine