Abstract |
Overexpression of Aurora-A kinase has been correlated with cancer susceptibility and poor prognosis in several human cancers. In this study, we evaluated the effect of inhibition of Aurora-A kinase on cell cycle progression and tumour cell survival after exposure to ionising radiation (IR). Combined IR and Aurora-A inhibition by short interfering RNA ( siRNA) or by PHA680632 (a selective Aurora kinase inhibitor with submicromolar activity against Aurora-A) prior to IR led to an enhancement of radiation-induced annexin V positive cells, micronuclei formation, and Brca1 foci formation only in cells with deficient p53. However, the drug brought about additive to sub-additive interaction with radiation with regard to in vitro clonogenic survival. Cell cycle analysis revealed a high >4N DNA content 24 h after PHA680632 exposure. DNA content >4N was reduced dramatically when cells were irradiated combined with PHA680632 simultaneously. In vivo xenografts (p53-/- HCT116) of a mice study showed enhanced tumour growth delay (TGD) after the PHA680632-IR combinatorial treatment compared with IR alone. These results demonstrate that PHA680632 in association with radiation leads to an additive effect in cancer cells, especially in the p53-deficient cells, but does not act as a radiosensitiser in vitro or in vivo.
|
Authors | Y Tao, P Zhang, V Frascogna, Y Lecluse, A Auperin, J Bourhis, E Deutsch |
Journal | British journal of cancer
(Br J Cancer)
Vol. 97
Issue 12
Pg. 1664-72
(Dec 17 2007)
ISSN: 0007-0920 [Print] England |
PMID | 18026198
(Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Aneugens
- PHA 680632
- Pyrazoles
- Pyrroles
- RNA, Small Interfering
- Radiation-Sensitizing Agents
- Aurka protein, mouse
- Aurora Kinase A
- Aurora Kinases
- Protein Serine-Threonine Kinases
|
Topics |
- Aneugens
(pharmacology)
- Animals
- Aurora Kinase A
- Aurora Kinases
- Cell Survival
(drug effects, radiation effects)
- Genes, p53
- HCT116 Cells
- HT29 Cells
- Humans
- Mice
- Mice, Nude
- Neoplasms
(genetics, radiotherapy)
- Protein Serine-Threonine Kinases
(antagonists & inhibitors)
- Pyrazoles
(pharmacology)
- Pyrroles
(pharmacology)
- RNA, Small Interfering
(pharmacology)
- Radiation-Sensitizing Agents
(pharmacology)
- Xenograft Model Antitumor Assays
|