TY - JOUR
T1 - Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer
AU - Gully, Christopher P.
AU - Zhang, Fanmao
AU - Chen, Jian
AU - Yeung, James A.
AU - Velazquez-Torres, Guermarie
AU - Wang, Edward
AU - Yeung, Sai Ching J.
AU - Lee, Mong Hong
N1 - Funding Information:
We thank Dr. K Mundt and Dr. E Anderson of Astra Zeneca Pharmaceuticals for providing AZD1152 (prodrug) and AZD1152-HQPA. This study was supported by grants from the National Institutes of Health 5P30CA016672-29 and National Cancer Institute CA16672, CA089266. CG is the recipient of an NIH training grant fellowship T32 CA009299. GVM is supported with a cancer prevention fellowship by the National Cancer Institute grant R25T CA57730. Additional thanks to C-H Su, R Zhao, Y-S Feng, B Chen, and L Phan for technical support and to SWG for editing.
PY - 2010/2/22
Y1 - 2010/2/22
N2 - 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.
AB - 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.
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U2 - 10.1186/1476-4598-9-42
DO - 10.1186/1476-4598-9-42
M3 - Article
C2 - 20175926
AN - SCOPUS:77649305739
SN - 1476-4598
VL - 9
JO - Molecular cancer
JF - Molecular cancer
M1 - 42
ER -