title: Inhibiting the aurora B kinase potently suppresses repopulation during fractionated irradiation of human lung cancer cell lines.
abstract: OBJECTIVE
  The use of molecular-targeted agents during radiotherapy of non-small-cell lung cancer (NSCLC) is a promising strategy to inhibit repopulation, thereby improving therapeutic outcome. We assessed the combined effectiveness of inhibiting Aurora B kinase and irradiation on human NSCLC cell lines in vitro.
  
  
  METHODS
  NSCLC cell lines were exposed to concentrations of AZD1152-hydroxyquinazoline pyrazol anilide (AZD1152-HQPA) inhibiting colony formation by 50% (IC50(clone)) in combination with single dose irradiation or different fractionation schedules using multiple 2-Gy fractions per day up to total doses of 4-40 Gy. The total irradiation dose required to control growth of 50% of the plaque monolayers (TCD50) was determined. Apoptosis, G2/M progression, and polyploidization were also analyzed.
  
  
  RESULTS
  TCD50 values after single dose irradiation were similar for the H460 and H661 cell lines with 11.4 ± 0.2 Gy and 10.7 ± 0.3 Gy, respectively. Fractionated irradiation using 3 × 2 Gy/day, 2 × 2 Gy/day, and 1 × 2 Gy/day schedules significantly increased TCD50 values for both cell lines grown as plaque monolayers with increasing radiation treatment time. This could be explained by a repopulation effect per day that counteracts 75 ± 8% and 27 ± 6% of the effect of a 2-Gy fraction in H460 and H661 cells, respectively. AZD1152-HQPA treatment concomitant to radiotherapy significantly decreased the daily repopulation effect (H460: 28 ± 5%, H661: 10 ± 4% of a 2-Gy fraction per day). Treatment with IC50(clone) AZD1152-HPQA did not induce apoptosis, prolong radiation-induced G2 arrest, or delay cell cycle progression before the spindle check point. However, polyploidization was detected, especially in cell lines without functional p53.
  
  
  CONCLUSIONS
  Inhibition of Aurora B kinase with low AZD1152-HQPA concentrations during irradiation of NSCLC cell lines affects repopulation during radiotherapy. Thus, concomitant Aurora B kinase inhibition and irradiation may be a promising strategy for fast repopulating tumors, which are difficult to cure by dose escalation based on conventional fractionation.
authors.affiliation: Department of Radiotherapy, University Hospital Essen, University Duisburg-Essen, Essen, Germany. ali.sak@uni-due.de
authors.forename: Ali
authors.initials: A
authors.lastname: Sak
authors.forename: Martin
authors.initials: M
authors.lastname: Stuschke
authors.forename: Michael
authors.initials: M
authors.lastname: Groneberg
authors.forename: Dennis
authors.initials: D
authors.lastname: Kübler
authors.forename: Christoph
authors.initials: C
authors.lastname: Pöttgen
authors.forename: Wilfried E E
authors.initials: WE
authors.lastname: Eberhardt
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology* / Q000532:radiotherapy*; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D003037:Cobalt Radioisotopes / Q000627:therapeutic use; D003131:Combined Modality Therapy / Q000379:methods; D019583:Dose Fractionation, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000532:radiotherapy*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology; D014410:Tumor Stem Cell Assay / Q000379:methods
chemical_list: D003037:Cobalt Radioisotopes; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011799:Quinazolines; C531556:AZD 1152-HQPA; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases