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Open Access Highly Accessed Research

Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer

Christopher P Gully123, Fanmao Zhang12, Jian Chen1, James A Yeung1, Guermarie Velazquez-Torres126, Edward Wang126, Sai-Ching Jim Yeung45* and Mong-Hong Lee123*

Author Affiliations

1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

2 The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA

3 The University of Texas MD Anderson Cancer Center, Program in Genes and Development, Houston, TX 77330, USA

4 Department of General Internal Medicine, Ambulatory Treatment & Emergency Care, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

5 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

6 The University of Texas MD Anderson Cancer Center, Program in Cancer Biology, Houston, TX 77330, USA

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Molecular Cancer 2010, 9:42  doi:10.1186/1476-4598-9-42

Published: 22 February 2010

Abstract

Background

Aurora B kinase is an important mitotic kinase involved in chromosome segregation and cytokinesis. It is overexpressed in many cancers and thus may be an important molecular target for chemotherapy. AZD1152 is the prodrug for AZD1152-HQPA, which is a selective inhibitor of Aurora B kinase activity. Preclinical antineoplastic activity of AZD1152 against acute myelogenous leukemia, multiple myeloma and colorectal cancer has been reported. However, this compound has not been evaluated in breast cancer, the second leading cause of cancer deaths among women.

Results

The antineoplastic activity of AZD1152-HQPA in six human breast cancer cell lines, three of which overexpress HER2, is demonstrated. AZD1152-HQPA specifically inhibited Aurora B kinase activity in breast cancer cells, thereby causing mitotic catastrophe, polyploidy and apoptosis, which in turn led to apoptotic death. AZD1152 administration efficiently suppressed the tumor growth in a breast cancer cell xenograft model. In addition, AZD1152 also inhibited pulmonary metastatic nodule formation in a metastatic breast cancer model. Notably, it was also found that the protein level of Aurora B kinase declined after inhibition of Aurora B kinase activity by AZD1152-HQPA in a time- and dose-dependent manner. Investigation of the underlying mechanism suggested that AZD1152-HQPA accelerated protein turnover of Aurora B via enhancing its ubiquitination.

Conclusions

It was shown that AZD1152 is an effective antineoplastic agent for breast cancer, and our results define a novel mechanism for posttranscriptional regulation of Aurora B after AZD1152 treatment and provide insight into dosing regimen design for this kinase inhibitor in metastatic breast cancer treatment.