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

Authors
  • Tao, Y
  • Zhang, P
  • Frascogna, V
  • Lecluse, Y
  • Auperin, A
  • Bourhis, J
  • Deutsch, E
Type
Published Article
Journal
British journal of cancer
Publication Date
Dec 17, 2007
Volume
97
Issue
12
Pages
1664–1672
Identifiers
PMID: 18026198
Source
Medline
License
Unknown

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.

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