Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152

Oncogene. 2008 May 22;27(23):3244-55. doi: 10.1038/sj.onc.1210990. Epub 2007 Dec 17.

Abstract

Overexpression of the Aurora-B kinase correlates with oncogenic transformation and poor prognosis. We evaluated the effects of the bona fide Aurora-B kinase inhibitor AZD1152 on tumor responses to ionizing radiation (IR). When p53(wt) HCT116 and A549 cells were pretreated with AZD1152-HQPA prior to IR, additive effects were observed. Interestingly, more pronounced tumoricidal effects were observed in p53-deficient HCT116 and HT29 cells, as well as A549 cells treated with the p53 inhibitor cyclic pifithrin-alpha. In vivo studies on xenografted mice confirmed enhanced tumor growth delay after the combination of IR plus AZD1152-IR as compared to IR alone. Again, this effect was more pronounced with p53-/- HCT116 and p53-mutant xenografts. The AZD1152-mediated radiosensitization was mimicked by knockdown of Aurora-B with a short interference RNA or by inhibition of Aurora-B by transfection with an inducible kinase-dead Aurora-B. The radiosensitizing effect of AZD1152 was lost in CHK2-/- and 14-3-3-/- HCT116 cells. Altogether, these data indicate that AZD1152 can radiosensitize tumor cell lines in vitro and in vivo, the fact that these effects are exacerbated in p53-deficient cancer cells is of potential interest for further clinical development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aurora Kinase B
  • Aurora Kinases
  • Cell Cycle / drug effects
  • Cell Cycle / radiation effects
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Checkpoint Kinase 2
  • Dose-Response Relationship, Drug
  • Female
  • Genes, p53* / physiology
  • HCT116 Cells
  • HT29 Cells
  • HeLa Cells
  • Humans
  • Infrared Rays
  • Mice
  • Mice, Nude
  • Models, Biological
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Organophosphates / pharmacology*
  • Prodrugs / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Quinazolines / pharmacology*
  • Radiation-Sensitizing Agents / pharmacology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
  • Organophosphates
  • Prodrugs
  • Quinazolines
  • Radiation-Sensitizing Agents
  • AZD 1152-HQPA
  • Checkpoint Kinase 2
  • AURKB protein, human
  • Aurkb protein, mouse
  • Aurora Kinase B
  • Aurora Kinases
  • CHEK2 protein, human
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases