2. Academic Validation
  3. The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells

The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells

  • Oncotarget. 2016 Jan 5;7(1):745-58. doi: 10.18632/oncotarget.6378.
Christian Mayr 1 2,  Andrej Wagner 1,  Magdalena Loeffelberger 2,  Daniela Bruckner 3,  Martin Jakab 4,  Frieder Berr 2,  Pietro Di Fazio 5,  Matthias Ocker 6 7 8,  Daniel Neureiter 8,  Martin Pichler 9,  Tobias Kiesslich 1 2
Affiliations

Affiliations

  • 1 Department of Internal Medicine I, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria.
  • 2 Laboratory for Tumor Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
  • 3 Research Program for Experimental Ophthalmology and Glaucoma Research, University Clinic of Ophthalmology and Optometry, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria.
  • 4 Laboratory of Functional and Molecular Membrane Physiology, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
  • 5 Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany.
  • 6 Institute for Surgical Research, Philipps-University Marburg, Marburg, Germany.
  • 7 Present address: Experimental Medicine Oncology, Bayer Pharma AG, Berlin, Germany.
  • 8 Present address: Department of Gastroenterology, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany.
  • 9 Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria.
PMID: 26623561 DOI: 10.18632/oncotarget.6378
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.

Keywords

BMI1; PRC1; PTC-209; biliary tract cancer; cell cycle arrest.

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