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 p53(wt) 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-alpha. 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.
Tao
Y
Y
Laboratory UPRES EA27-10 Radiosensitivity of tumors and normal tissues, Villejuif, France.
Zhang
P
P
Girdler
F
F
Frascogna
V
V
Castedo
M
M
Bourhis
J
J
Kroemer
G
G
Deutsch
E
E
D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D004305:Dose-Response Relationship, Drug; D005260:Female; D016158:Genes, p53 / Q000502:physiology; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007259:Infrared Rays; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D010755:Organophosphates / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
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; D011355:Prodrugs; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; C531556:AZD 1152-HQPA; D064447:Checkpoint Kinase 2; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases