Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer

Molecular Cancer

Research

Sai-Ching Jim Yeung¹  James A Yeung²  Jian Chen²  Fanmao Zhang³  Edward Wang⁴  Guermarie Velazquez-Torres⁴  Christopher P Gully⁵  Mong-Hong Lee⁵ 

[1] Department of General Internal Medicine, Ambulatory Treatment & Emergency Care, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;The University of Texas Graduate School of Biomedical Sciences at Houston, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;The University of Texas Graduate School of Biomedical Sciences at Houston, 77030, Houston, TX, USA;The University of Texas MD Anderson Cancer Center, Program in Cancer Biology, 77330, Houston, TX, USA;Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;The University of Texas Graduate School of Biomedical Sciences at Houston, 77030, Houston, TX, USA;The University of Texas MD Anderson Cancer Center, Program in Genes and Development, 77330, Houston, TX, USA;

关键词: Breast Cancer;    Breast Cancer Cell;    Human Breast Cancer Cell;    Human Breast Cancer Cell Line;    Aurora Kinase;   

DOI  :  10.1186/1476-4598-9-42

 received in 2009-10-20, accepted in 2010-02-22,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundAurora 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.ResultsThe 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.ConclusionsIt 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.

【 授权许可】

Unknown   
© Gully et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.