1. ¹Laboratory UPRES EA27-10 Radiosensitivity of tumors and normal tissues, University Paris XI, Institut Gustave-Roussy, Villejuif, France
2. ²Department of Radiation Oncology of Cancer Hospital, Fu Dan University, Shanghai, China
3. ³Institut Gustave-Roussy, Villejuif, France
4. ⁴Department of Biostatistics and Epidemiology, Institut Gustave-Roussy, Villejuif, France

Correspondence: Dr E Deutsch, Laboratory UPRES EA27-10 Radiosensitivity of tumors and normal tissues, University Paris XI, Institut Gustave-Roussy, 39 Rue Camille-Desmoulins, Villejuif 94805, France. E-mail: deutsch@igr.fr

Received 6 September 2007; Revised 10 October 2007; Accepted 12 October 2007; Published online 20 November 2007.

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.