title: The aurora B kinase inhibitor AZD1152 sensitizes cancer cells to fractionated irradiation and induces mitotic catastrophe.
abstract: 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.
authors.affiliation: UPRES EA27-10 Laboratoire Radiosensibilité des Tumeurs et Tissus Sains, Villejuif, France.
authors.forename: Yungan
authors.initials: Y
authors.lastname: Tao
authors.forename: Céline
authors.initials: C
authors.lastname: Leteur
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.forename: Fiona
authors.initials: F
authors.lastname: Girdler
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Valérie
authors.initials: V
authors.lastname: Frascogna
authors.forename: Mariana
authors.initials: M
authors.lastname: Varna
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D010755:Organophosphates / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D011839:Radiation, Ionizing; D014183:Transplantation, Heterologous
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D020169:Caspases