Aurora kinase inhibition downregulates NF-κB and sensitises tumour cells to chemotherapeutic agents

We have identified that Aurora-A activates NF-kappa B via I kappa B alpha phosphorylation. Here, we analysed different human tumour cell types for their NF-kappa B activity. We found that there is an association between cell resistance to chemotherapeutic agents and NF-kappa B activation. A549 human lung adenocarcinoma cells and SKOV3 human ovarian cancer cells have high levels of NF-kappa B and are resistant to cytotoxic agents such as adriamycin and VP-16 (etoposide). We also found that in A549 and SKOV3 cells treated with a small molecule inhibitor towards Aurora kinases, the NF-kappa B activity was downregulated and the efficacy of cytotoxic drugs was enhanced. In addition, the transcriptional targets Bcl-X-L and Bcl-2 were downregulated. This study provides evidence for a potential mechanism of chemoresistance and may be useful for the enhancement of certain chemotherapeutics regimens. (c) 2006 Elsevier Inc. All rights reserved.