AZD1152, an
Aurora kinase inhibitor with selectivity for
Aurora B kinase, can enhance the effect of ionizing radiation (IR). The aim of this study was to evaluate and to mechanistically explore scheduling effects of
AZD1152 on
tumor responses to IR, in three different settings: neoadjuvant (
AZD1152 before IR), adjuvant (IR before
AZD1152), or concomitant treatments (
AZD1152 plus one single IR dose). A more pronounced
tumor growth delay was observed in the neoadjuvant and adjuvant schedules as compared to the concomitant schedule. However,
AZD1152 enhanced the efficacy of IR when concomitant IR was fractionated over several days. Histopathological examination revealed that
AZD1152 + IR induced
polyploidy, multinucleation and micronuclei in vivo. Time-lapse videomicroscopy confirmed that cell death induced by
AZD1152 + IR was preceded by multinucleation and the formation of micronuclei, which both are hallmarks of mitotic catastrophe.
Caspase inhibition or removal of the
pro-apoptotic protein Bax did not ameliorate the long-term cell survival of AZD1152-treated
cancer cells. In contrast, a chemical inhibitor of CHK1, Chir124, sensitized
cancer cells to the lethal effect of
AZD1152. Altogether, these data support the contention that
AZD1152 mediates radiosensitization in vivo by enhancing mitotic catastrophe, which can be used as a
biomarker of treatment efficacy.