Inhibiting the aurora B kinase potently suppresses repopulation during fractionated irradiation of human lung cancer cell lines

Int J Radiat Oncol Biol Phys. 2012 Oct 1;84(2):492-9. doi: 10.1016/j.ijrobp.2011.12.021. Epub 2012 Feb 28.

Abstract

Purpose: 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 and materials: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Aurora Kinase B
  • Aurora Kinases
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Non-Small-Cell Lung / radiotherapy*
  • Cell Culture Techniques
  • Cell Cycle / physiology
  • Cell Cycle / radiation effects*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cell Survival / radiation effects
  • Cobalt Radioisotopes / therapeutic use
  • Combined Modality Therapy / methods
  • Dose Fractionation, Radiation
  • Enzyme Inhibitors / pharmacology
  • G2 Phase / drug effects
  • Humans
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / radiotherapy*
  • Neoplasm Proteins / antagonists & inhibitors*
  • Polyploidy
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Quinazolines / pharmacology
  • Tumor Stem Cell Assay / methods

Substances

  • Cobalt Radioisotopes
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Quinazolines
  • AZD 1152-HQPA
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases