Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer.
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.
Gully
Christopher P
CP
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Zhang
Fanmao
F
Chen
Jian
J
Yeung
James A
JA
Velazquez-Torres
Guermarie
G
Wang
Edward
E
Yeung
Sai-Ching Jim
SC
Lee
Mong-Hong
MH
D000782:Aneuploidy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009362:Neoplasm Metastasis; D010755:Organophosphates / Q000494:pharmacology / Q000627:therapeutic use*; D011123:Polyploidy; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay; D054875:Ubiquitination / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000970:Antineoplastic Agents; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D025821:Polyubiquitin; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex