Enhancement of radiation response by inhibition of Aurora-A kinase using siRNA or a selective Aurora kinase inhibitor PHA680632 in p53-deficient cancer cells

Br J Cancer. 2007 Dec 17;97(12):1664-72. doi: 10.1038/sj.bjc.6604083. Epub 2007 Nov 20.

Abstract

Overexpression of Aurora-A kinase has been correlated with cancer susceptibility and poor prognosis in several human cancers. In this study, we evaluated the effect of inhibition of Aurora-A kinase on cell cycle progression and tumour cell survival after exposure to ionising radiation (IR). Combined IR and Aurora-A inhibition by short interfering RNA (siRNA) or by PHA680632 (a selective Aurora kinase inhibitor with submicromolar activity against Aurora-A) prior to IR led to an enhancement of radiation-induced annexin V positive cells, micronuclei formation, and Brca1 foci formation only in cells with deficient p53. However, the drug brought about additive to sub-additive interaction with radiation with regard to in vitro clonogenic survival. Cell cycle analysis revealed a high >4N DNA content 24 h after PHA680632 exposure. DNA content >4N was reduced dramatically when cells were irradiated combined with PHA680632 simultaneously. In vivo xenografts (p53-/- HCT116) of a mice study showed enhanced tumour growth delay (TGD) after the PHA680632-IR combinatorial treatment compared with IR alone. These results demonstrate that PHA680632 in association with radiation leads to an additive effect in cancer cells, especially in the p53-deficient cells, but does not act as a radiosensitiser in vitro or in vivo.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneugens / pharmacology
  • Animals
  • Aurora Kinase A
  • Aurora Kinases
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Genes, p53*
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasms / genetics*
  • Neoplasms / radiotherapy*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrazoles / pharmacology*
  • Pyrroles / pharmacology*
  • RNA, Small Interfering / pharmacology*
  • Radiation-Sensitizing Agents / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Aneugens
  • PHA 680632
  • Pyrazoles
  • Pyrroles
  • RNA, Small Interfering
  • Radiation-Sensitizing Agents
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases