Pancreatic Cancer Research Today is a free monthly online journal that collates and summarizes the latest research about Pancreatic Cancer, including details on symptoms, causes, treatment, information.

Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells.

Ammerpohl O, Trauzold A, Schniewind B, Griep U, Pilarsky C, Grutzmann R, Saeger HD, Janssen O, Sipos B, Kloppel G, Kalthoff H

Section Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller Strasse 7, Kiel 24105, Germany.

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.

Published 10 January 2007 in Br J Cancer, 96(1): 73-81.
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