title: PLK1-inhibition can cause radiosensitization or radioresistance dependent on the treatment schedule.
abstract: OBJECTIVE
  PLK1-inhibitors are emerging as new potential anticancer agents. It is therefore important to explore the combined effects of PLK1-inhibitors with conventional therapies. Based on the functional roles of PLK1 in both mitosis and the G2 checkpoint, we hypothesized that the treatment schedule might influence the combined effects of PLK1-inhibiton and radiation.
  
  
  METHODS
  Human osteosarcoma U2OS and colorectal cancer HT29 and SW620 cells were treated with the PLK1-inhibitor BI2536 before or after X-ray irradiation (0-6 Gy). Clonogenic assays, flow cytometry, immunofluorescence and mCherry-53BP1 time-lapse imaging were used to assay cell survival, cell cycle progression and DNA damage repair.
  
  
  RESULTS
  Treatment with the PLK1-inhibitor for 24h before radiation caused cells to accumulate in G2/M and resulted in increased radiosensitivity. In contrast, the cytotoxic effects of the two treatments were less-than-additive when cells were treated with the PLK1-inhibitor for 24h after radiation. This resistance was associated with a prolonged G2 checkpoint causing enhanced repair of the radiation-induced damage and decreased BI2536-mediated mitotic damage.
  
  
  CONCLUSIONS
  PLK1-inhibitors need to be administrated several hours before radiation to achieve radiosensitization. If PLK1-inhibitors are given after radiation, cell killing is reduced due to the prolonged G2 checkpoint.
authors: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway.
authors: Christin
authors: C
authors: Lund-Andersen
authors: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway.
authors: Sebastian
authors: S
authors: Patzke
authors: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway.
authors: Viola
authors: V
authors: Nähse-Kumpf
authors: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway. Electronic address: randi.syljuasen@rr-research.no.
authors: Randi G
authors: RG
authors: Syljuåsen
mesh_terms: D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D004249:DNA Damage; D004260:DNA Repair; D005434:Flow Cytometry; D019073:HT29 Cells; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536
keywords: Cancer; Combined treatment; DNA damage; G2 checkpoint; Ionizing radiation; Mitosis; PLK1-inhibitors