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

Oncogene volume 27, pages 3244–3255 (2008)Cite this article

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 p53wt 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-α. 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.

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Acknowledgements

We thank Dr Kisten Mundt, AstraZeneca UK, for her help in the preparation of this article. We also thank AstraZeneca for kindly providing us with AZD1152 and AZD1152-HQPA for experimental studies and Stephen S Taylor, University of Manchester, for kindly providing us with HEK293 cells for experimental studies and for his help in editing this article. We are extremely grateful to Dr Bert Vogelstein, John Hopkins University, for kindly providing us the wild-type, p53−/− CHK2−/− and 14-3-3 σ−/− HCT116 cell lines. We also thank Lorna Saint Ange for editing. This study was supported by grants from Ligue nationale contre le cancer, Agence Nationale de Recherche, Institut National contre le Cancer (INCa), Cancéropôle Ile-de-France and European Commission (Active p53, ChemoRes, RIGHT; to GK), as well as by a grant from Association pour la Recherche sur le Cancer (to MC and ED).

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Authors and Affiliations

  1. Laboratory UPRES EA27-10 Radiosensitivity of tumors and normal tissues, Villejuif, France

    Y Tao, P Zhang, V Frascogna, J Bourhis & E Deutsch

  2. Université de Paris 11(Paris-Sud), Kremlin-Bicêtre, France

    Y Tao, J Bourhis & G Kroemer

  3. Cancer Hospital, Fu Dan University, Shanghai, China

    Y Tao

  4. Faculty of Life Sciences, University of Manchester, Manchester, UK

    F Girdler

  5. INSERM, U848, Villejuif, France

    M Castedo & G Kroemer

  6. Institut Gustave-Roussy, Villejuif, France

    Y Tao, P Zhang, V Frascogna, M Castedo, J Bourhis, G Kroemer & E Deutsch

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  1. Y Tao
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Correspondence to E Deutsch.

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Tao, Y., Zhang, P., Girdler, F. et al. Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152. Oncogene 27, 3244–3255 (2008). https://doi.org/10.1038/sj.onc.1210990

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  • DOI: https://doi.org/10.1038/sj.onc.1210990

Keywords

  • cell cycle
  • checkpoints
  • AZD1152 Aurora-B
  • ionizing radiation
  • p53

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