Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells.
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.
Ammerpohl
O
O
Section Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller Strasse 7, Kiel 24105, Germany.
Trauzold
A
A
Schniewind
B
B
Griep
U
U
Pilarsky
C
C
Grutzmann
R
R
Saeger
H-D
HD
Janssen
O
O
Sipos
B
B
Kloppel
G
G
Kalthoff
H
H
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
D000873:Anthracenes; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; D003841:Deoxycytidine; C432165:pyrazolanthrone; C075773:4-phenylbutyric acid; D053181:Caspase 8; D000093542:Gemcitabine