title: Polo-like kinase 1 inhibition as a new therapeutic modality in therapy of cholangiocarcinoma.
abstract: BACKGROUND
  Cholangiocarcinoma (CC) is highly resistant to chemotherapy and radiation, and is, therefore, difficult to cure. Polo-like kinases (Plks) are increasingly recognized as key regulators of mitosis, meiosis and cytokinesis. Alterations in PLK1- expression have been brought into relation with tumorigenesis, thus rendering PLK1 suppression an interesting target for tumor therapy. BI 2536, the first compound of the chemical class of dihydropteridinones, is a highly selective and potent inhibitor of PLK1.
  
  
  METHODS
  Retardation of cell proliferation by BI 2536 was tested in 14 CC cell lines by cell viability assay. Moreover, molecular activity of BI 2536 was investigated by Western blot, flow cytometry and real time- polymerase chain reaction (RT-PCR). Apposition of gemcitabine, 5-fluorouracil (5-FU) and insulin-like growth factor-1 receptor (IGF-1R) retardant NVP-AEW541 was also examined.
  
  
  RESULTS
  BI 2536 subdued proliferation in all CC cell lines, however, reaction was stronger in gallbladder carcinoma. Therapy with BI 2536 did not result in a significant change in phosphorylation of histone H3, AKT, and p42/44. However, exposure of cells to this compound caused arrest at the G(2)/M-checkpoint and a surge in apoptosis. Moreover, PLK1 and FOXM1 were concurrently present in all cell lines, proposing a role for their involvement. Use of a mixture of BI 2536 with 5-FU or NVP-AEW541 resulted in synergism, while a mixture with gemcitabine resulted in additive activity.
  
  
  CONCLUSIONS
  These experiments indicate that BI 2536 is effective against CC and increases the potency of 5-FU and NVP-AEW541.
authors.affiliation: Division of Gastroenterology and Rheumatology, University of Leipzig, Leipzig, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Thrum
authors.forename: Jana
authors.initials: J
authors.lastname: Lorenz
authors.forename: Joachim
authors.initials: J
authors.lastname: Mössner
authors.forename: Marcus
authors.initials: M
authors.lastname: Wiedmann
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D003841:Deoxycytidine; D005472:Fluorouracil; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C501177:NVP-AEW541