title: The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells.
abstract: BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up-regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 µM). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC.
authors.affiliation: Department of Internal Medicine I, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria.|Laboratory for Tumor Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Mayr
authors.affiliation: Department of Internal Medicine I, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Andrej
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Laboratory for Tumor Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Loeffelberger
authors.affiliation: Research Program for Experimental Ophthalmology and Glaucoma Research, University Clinic of Ophthalmology and Optometry, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bruckner
authors.affiliation: Laboratory of Functional and Molecular Membrane Physiology, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Jakab
authors.affiliation: Laboratory for Tumor Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Frieder
authors.initials: F
authors.lastname: Berr
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany.
authors.forename: Pietro
authors.initials: P
authors.lastname: Di Fazio
authors.affiliation: Institute for Surgical Research, Philipps-University Marburg, Marburg, Germany.|Present address: Experimental Medicine Oncology, Bayer Pharma AG, Berlin, Germany.|Present address: Department of Gastroenterology, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ocker
authors.affiliation: Present address: Department of Gastroenterology, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.affiliation: Department of Internal Medicine I, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria.|Laboratory for Tumor Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kiesslich
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001661:Biliary Tract Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D006574:Heterocyclic Compounds, 2-Ring; C586999:PTC-209; D013844:Thiazoles; D063150:Polycomb Repressive Complex 1; D002945:Cisplatin
keywords: BMI1; PRC1; PTC-209; biliary tract cancer; cell cycle arrest