title: The green tea catechin epigallocatechin gallate induces cell cycle arrest and shows potential synergism with cisplatin in biliary tract cancer cells.
abstract: BACKGROUND
  The green tea catechin epigallocatechin gallate (EGCG) was shown to effectively inhibit tumor growth in various types of cancer including biliary tract cancer (BTC). For most BTC patients only palliative therapy is possible, leading to a median survival of about one year. Chemoresistance is a major problem that contributes to the high mortality rates of BTC. The aim of this study was to investigate the cytotoxic effect of EGCG alone or in combination with cisplatin on eight BTC cell lines and to investigate the cellular anti-cancer mechanisms of EGCG.
  
  
  METHODS
  The effect of EGCG treatment alone or in combination with the standard chemotherapeutic cisplatin on cell viability was analyzed in eight BTC cell lines. Additionally, we analyzed the effects of EGCG on caspase activity, cell cycle distribution and gene expression in the BTC cell line TFK-1.
  
  
  RESULTS
  EGCG significantly reduced cell viability in all eight BTC cell lines (p < 0.05 or p < 0.01, respectively, for most cell lines and EGCG concentrations > 5 μM). Combined EGCG and cisplatin treatment showed a synergistic cytotoxic effect in five cell lines and an antagonistic effect in two cell lines. Furthermore, EGCG reduced the mRNA levels of various cell cycle-related genes, while increasing the expression of the cell cycle inhibitor p21 and the apoptosis-related death receptor 5 (p < 0.05). This observation was accompanied by an increase in caspase activity and cells in the sub-G1 phase of the cell cycle, indicating induction of apoptosis. EGCG also induced a down-regulation of expression of stem cell-related genes and genes that are associated with an aggressive clinical character of the tumor, such as cd133 and abcg2.
  
  
  CONCLUSIONS
  EGCG shows various anti-cancer effects in BTC cell lines and might therefore be a potential anticancer drug for future studies in BTC. Additionally, EGCG displays a synergistic cytotoxic effect with cisplatin in most tested BTC cell lines. Graphical abstract Summary illustration.
authors.affiliation: Department of Internal Medicine I, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria. ch.mayr@salk.at.|Laboratory for Tumour Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria. ch.mayr@salk.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Mayr
authors.affiliation: Department of Internal Medicine I, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria. and.wagner@salk.at.
authors.forename: Andrej
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Institute of Pathology, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria. d.neureiter@salk.at.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. mpichler@mdanderson.org.
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.affiliation: Laboratory for Functional and Molecular Membrane Physiology, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria. martin.jakab@pmu.ac.at.
authors.forename: Martin
authors.initials: M
authors.lastname: Jakab
authors.affiliation: Institute of Pathology, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria. r.illig@salk.at.
authors.forename: Romana
authors.initials: R
authors.lastname: Illig
authors.affiliation: Laboratory for Tumour Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria. frieder.berr@pmu.ac.at.
authors.forename: Frieder
authors.initials: F
authors.lastname: Berr
authors.affiliation: Department of Internal Medicine I, Salzburger Landeskliniken - SALK, Paracelsus Medical University, Salzburg, Austria. t.kiesslich@salk.at.|Laboratory for Tumour Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria. t.kiesslich@salk.at.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kiesslich
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001661:Biliary Tract Neoplasms; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D002392:Catechin; C045651:epigallocatechin gallate; D002945:Cisplatin