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.
Highlights
Aurora-B is one of the chromosomal passenger proteins that are essential for a number of processes during mitosis
Polyploidy has been shown to correlate with Aurora kinases inhibition (Harrington et al, 2004), and we used it as a surrogate of PHA680632 efficacy on Aurora kinases
When 6 Gy irradiation was performed after 1 h PHA680632 exposure, the 44N DNA content cell accumulation (44N cells percentage) reduced dramatically in the p53wt HCT116 cell line when compared to the same cells exposed to PHA680632 without irradiation P 1⁄4 0.0068
Summary
Aurora-B is one of the chromosomal passenger proteins that are essential for a number of processes during mitosis. Amplification of Aurora genes, as well as mRNA and protein overexpression, has frequently been reported in many human cancer cell lines: colon – rectum, breast, pancreas, and ovary. Their genetic localisations (Aurora-A, 20q13; Aurora-B, 17q13) map to chromosomal loci frequently altered in tumours. Overexpression of Aurora-A is likely to induce a low level of genetic instability, through abnormal centrosome duplication and the generation of aneuploidy. These properties make the Aurora kinases attractive targets for anticancer therapy; the first inhibitors have been tested in the clinical setting. The effect of combining Aurora-A inhibition with IR is unknown, and the aim of this study was to evaluate the influence of inhibition of Aurora-A kinase of tumour radio-sensitivity by either a genetic inhibition using short interfering RNA (siRNA) targeting Aurora-A or a pharmacological approach using a selective inhibitor PHA680632 (Soncini et al, 2006)
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