| 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 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. |
| Authors | Y Tao, P Zhang, F Girdler, V Frascogna, M Castedo, J Bourhis, G Kroemer, E Deutsch
(Affiliation: Laboratory UPRES EA27-10 Radiosensitivity of tumors and normal tissues, Villejuif, France.)
|
| Journal | Oncogene
(Oncogene)
Vol. 27
Issue 23
Pg. 3244-55
(May 22 2008)
ISSN: 1476-5594 England |
| PMID | 18084327
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- 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
- AZD 1152-HQPA
- Phosphoric Acid Esters
- Prodrugs
- Quinazolines
- Radiation-Sensitizing Agents
- aurora kinase
- checkpoint kinase 2
- Protein-Serine-Threonine Kinases
|
| Topics |
- Animals
- Cell Cycle
(drug effects, radiation effects)
- Cell Survival
(drug effects, radiation effects)
- Dose-Response Relationship, Drug
- Female
- Genes, p53
(physiology)
- HCT116 Cells
- HT29 Cells
- Hela Cells
- Humans
- Infrared Rays
- Mice
- Mice, Nude
- Models, Biological
- Neoplasms
(genetics, pathology)
- Phosphoric Acid Esters
(pharmacology)
- Prodrugs
(pharmacology)
- Protein-Serine-Threonine Kinases
(antagonists & inhibitors, genetics)
- Quinazolines
(pharmacology)
- Radiation-Sensitizing Agents
(pharmacology)
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
|
