title: Histone deacetylase inhibitor enhances the anti-tumor effect of gemcitabine: a special reference to gene-expression microarray analysis.
abstract: Histone deacetylase (HDAC) is strongly associated with epigenetic regulation and carcinogenesis, and its inhibitors induce the differentiation or apoptosis of cancer cells. Valproic acid (VPA) is one of the clinically available HDAC inhibitors. We investigated the anticancer effects of VPA in combination with gemcitabine (GEM) in the human cholangiocarcinoma cell line HuCCT1, and explored the mechanisms of the anticancer effects using microarray analysis. The anticancer effects of VPA or gemcitabine (GEM), and the effects of VPA combined with GEM, were studied by a cell proliferation assay. A microarray analysis was performed and the genes were picked up using GeneSpring GX11.5, followed by Ingenuity Pathways Analysis (IPA) and determination of gene expression by RT-PCR. GEM (5 nM) and VPA (0.5 mM) reduced proliferation by 23%, which significantly augmented the anticancer effect of GEM alone or VPA alone (P<0.01). Using microarray analysis, 43 genes were identified with the comparison between the GEM group and the GEM plus VPA combination group. Interactions were identified between genes of the 'Cellular Development' network relevant to the differentiation of cancer cells using IPA. Furthermore, GEM combined with VPA up-regulated the HLA-DRA expression compared to the single agents (P<0.01). VPA augmented the effects of GEM by enhancing the gene network mainly including HLA-DRA, possibly through the modification of cancer cell differentiation.
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 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: Yu
authors.initials: Y
authors.lastname: Saito
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D057890:Epigenomics; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000096:biosynthesis / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D046228:Microarray Analysis; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D000093542:Gemcitabine
chemical_list: D056572:Histone Deacetylase Inhibitors; D003841:Deoxycytidine; D014635:Valproic Acid; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D000093542:Gemcitabine