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


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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  • Adams RR, Carmena M, Earnshaw WC . (2001). Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol 11: 49–54.

    Article  CAS  Google Scholar 

  • Anand S, Penrhyn-Lowe S, Venkitaraman AR . (2003). AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 3: 51–62.

    Article  CAS  Google Scholar 

  • Andrews PD . (2005). Aurora kinases: shining lights on the therapeutic horizon? Oncogene 24: 5005–5015.

    Article  CAS  Google Scholar 

  • Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B et al. (1998). A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 17: 3052–3065.

    Article  CAS  Google Scholar 

  • Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP et al. (1998). Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282: 1497–1501.

    Article  CAS  Google Scholar 

  • Carmena M, Earnshaw WC . (2003). The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 4: 842–854.

    Article  CAS  Google Scholar 

  • Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G . (2004). Cell death by mitotic catastrophe: a molecular definition. Oncogene 23: 2825–2837.

    Article  CAS  Google Scholar 

  • Chan TA, Hermeking H, Lengauer C, Kinzler KW, Vogelstein B . (1999). 14-3-3 Sigma is required to prevent mitotic catastrophe after DNA damage. Nature 401: 616–620.

    Article  CAS  Google Scholar 

  • Ditchfield C, Johnson VL, Tighe A, Ellston R, Haworth C, Johnson T et al. (2003). Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol 161: 267–280.

    Article  CAS  Google Scholar 

  • Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T . (2001). Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411: 494–498.

    Article  CAS  Google Scholar 

  • Gadea BB, Ruderman JV . (2005). Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts. Mol Biol Cell 16: 1305–1318.

    Article  CAS  Google Scholar 

  • Giet R, Petretti C, Prigent C . (2005). Aurora kinases, aneuploidy and cancer, a coincidence or a real link? Trends Cell Biol 15: 241–250.

    Article  CAS  Google Scholar 

  • Girdler F, Gascoigne KE, Eyers PA, Hartmuth S, Crafter C, Foote KM et al. (2006). Validating Aurora B as an anti-cancer drug target. J Cell Sci 119: 3664–3675.

    Article  CAS  Google Scholar 

  • Gizatullin F, Yao Y, Kung V, Harding MW, Loda M, Shapiro GI . (2006). The Aurora kinase inhibitor VX-680 induces endoreduplication and apoptosis preferentially in cells with compromised p53-dependent postmitotic checkpoint function. Cancer Res 66: 7668–7677.

    Article  CAS  Google Scholar 

  • Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T et al. (2004). VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 10: 262–267.

    Article  CAS  Google Scholar 

  • Hauf S, Cole RW, LaTerra S, Zimmer C, Schnapp G, Walter R et al. (2003). The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol 161: 281–294.

    Article  CAS  Google Scholar 

  • Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M et al. (2003). Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell 114: 585–598.

    Article  CAS  Google Scholar 

  • Jallepalli PV, Lengauer C, Vogelstein B, Bunz F . (2003). The Chk2 tumor suppressor is not required for p53 responses in human cancer cells. J Biol Chem 278: 20475–20479.

    Article  CAS  Google Scholar 

  • Kastan MB, Bartek J . (2004). Aurora-kinase inhibitors as anticancer agents. Nature 432: 316–323.

    Article  CAS  Google Scholar 

  • Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F et al. (2004). Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet 36: 55–62.

    Article  CAS  Google Scholar 

  • Keen N, Taylor S . (2004). Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 4: 927–936.

    Article  CAS  Google Scholar 

  • Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV et al. (1999). A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285: 1733–1737.

    Article  CAS  Google Scholar 

  • Meraldi P, Honda R, Nigg EA . (2004). Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr Opin Genet Dev 14: 29–36.

    Article  CAS  Google Scholar 

  • Milas L, Milas MM, Mason KA . (1999). Combination of taxanes with radiation: preclinical studies. Semin Radiat Oncol 9: 12–26.

    CAS  Google Scholar 

  • Nigg EA . (2001). Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2: 21–32.

    Article  CAS  Google Scholar 

  • Ouchi M, Fujiuchi N, Sasai K, Katayama H, Minamishima YA, Ongusaha PP et al. (2004). BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition. J Biol Chem 279: 19643–19648.

    Article  CAS  Google Scholar 

  • Pawlik TM, Keyomarsi K . (2004). Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys 59: 928–942.

    Article  Google Scholar 

  • Tao W, South VJ, Zhang Y, Davide JP, Farrell L, Kohl NE et al. (2005). Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell 8: 49–59.

    Article  CAS  Google Scholar 

  • Wilkinson RW, Odedra R, Heaton SP, Wedge SR, Keen NJ, Crafter C et al. (2007). AZD1152, a selective inhibitor of Aurora B Kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 13: 3682–3688.

    Article  CAS  Google Scholar 

  • Zhang P, Castedo M, Tao Y, Violot D, Metivier D, Deutsch E et al. (2006). Caspase independence of radio-induced cell death. Oncogene 25: 7758–7770.

    Article  CAS  Google Scholar 

  • Zhou BB, Bartek J . (2004). Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer 4: 216–225.

    Article  CAS  Google Scholar 

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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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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).

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

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