title: Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells.
abstract: OBJECTIVE
  To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) or the novel anticancer agents sorafenib or bortezomib.
  
  
  METHODS
  Two human bile duct adenocarcinoma cell lines (EGI-1 and TFK-1) were studied. Crystal violet staining was used for detection of cell number changes. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). Apoptosis was determined by measuring the enzyme activity of caspase-3. Cell cycle status reflected by the DNA content was detected by flow cytometry.
  
  
  RESULTS
  MS-275 treatment potently inhibited the proliferation of EGI-1 and TFK-1 cholangiocarcinoma cells by inducing apoptosis and cell cycle arrest. MS-275-induced apoptosis was characterized by activation of caspase-3, up-regulation of Bax and down-regulation of Bcl-2. Cell cycle was predominantly arrested at the G(1)/S checkpoint, which was associated with induction of the cyclin-dependent kinase inhibitor p21(Waf/CIP1). Furthermore, additive anti-neoplastic effects were observed when MS-275 treatment was combined with gemcitabine or doxorubicin, while combination with the multi-kinase inhibitor sorafenib or the proteasome inhibitor bortezomib resulted in overadditive anti-neoplastic effects.
  
  
  CONCLUSIONS
  The growth of human cholangiocarcinoma cells can be potently inhibited by MS-275 alone or in combination with conventional cytostatic drugs or new, targeted anticancer agents.
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Baradari
authors.forename: Michael
authors.initials: M
authors.lastname: Höpfner
authors.forename: Alexander
authors.initials: A
authors.lastname: Huether
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Hans
authors.initials: H
authors.lastname: Scherübl
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D001549:Benzamides / Q000378:metabolism / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000378:metabolism / Q000627:therapeutic use; D001897:Boronic Acids; D000069286:Bortezomib; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D004317:Doxorubicin / Q000378:metabolism / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011480:Protease Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011719:Pyrazines; D011725:Pyridines / Q000378:metabolism / Q000627:therapeutic use; D000077157:Sorafenib; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001557:Benzenesulfonates; D001897:Boronic Acids; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D010671:Phenylurea Compounds; D011480:Protease Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D011725:Pyridines; D051028:bcl-2-Associated X Protein; D003841:Deoxycytidine; D050760:Cyclin-Dependent Kinase Inhibitor p27; C118739:entinostat; D009536:Niacinamide; D000069286:Bortezomib; D004317:Doxorubicin; D000077157:Sorafenib; D007770:L-Lactate Dehydrogenase; D000093542:Gemcitabine