title: Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease and one of the cancer entities with the lowest life expectancy. Beside surgical therapy, no effective therapeutic options are available yet. Here, we show that 4-phenylbutyrate (4-PB), a known and well-tolerable inhibitor of histone deacetylases (HDAC), induces up to 70% apoptosis in all cell lines tested (Panc 1, T4M-4, COLO 357, BxPc3). In contrast, it leads to cell cycle arrest in only half of the cell lines tested. This drug increases gap junction communication between adjacent T3M-4 cells in a concentration-dependent manner and efficiently inhibits cellular export mechanisms in Panc 1, T4M-4, COLO 357 and BxPc3 cells. Consequently, in combination with gemcitabine 4-PB shows an overadditive effect on induction of apoptosis in BxPc3 and T3M-4 cells (up to 4.5-fold compared to single drug treatment) with accompanied activation of Caspase 8, BH3 interacting domain death agonist (Bid) and poly (ADP-ribose) polymerase family, member 1 (PARP) cleavage. Although the inhibition of the mitogen-activated protein kinase-pathway has no influence on fulminant induction of apoptosis, the inhibition of the JNK-pathway by SP600125 completely abolishes the overadditive effect induced by the combined application of both drugs, firstly reported by this study.
authors.affiliation: Section Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller Strasse 7, Kiel 24105, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Ammerpohl
authors.forename: A
authors.initials: A
authors.lastname: Trauzold
authors.forename: B
authors.initials: B
authors.lastname: Schniewind
authors.forename: U
authors.initials: U
authors.lastname: Griep
authors.forename: C
authors.initials: C
authors.lastname: Pilarsky
authors.forename: R
authors.initials: R
authors.lastname: Grutzmann
authors.forename: H-D
authors.initials: HD
authors.lastname: Saeger
authors.forename: O
authors.initials: O
authors.lastname: Janssen
authors.forename: B
authors.initials: B
authors.lastname: Sipos
authors.forename: G
authors.initials: G
authors.lastname: Kloppel
authors.forename: H
authors.initials: H
authors.lastname: Kalthoff
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D053181:Caspase 8 / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010654:Phenylbutyrates / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000873:Anthracenes; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; D003841:Deoxycytidine; C432165:pyrazolanthrone; C075773:4-phenylbutyric acid; D053181:Caspase 8; D000093542:Gemcitabine