Abstract | BACKGROUND: 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:
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Authors | Christopher P Gully, Fanmao Zhang, Jian Chen, James A Yeung, Guermarie Velazquez-Torres, Edward Wang, Sai-Ching Jim Yeung, Mong-Hong Lee |
Journal | Molecular cancer
(Mol Cancer)
Vol. 9
Pg. 42
(Feb 22 2010)
ISSN: 1476-4598 [Electronic] England |
PMID | 20175926
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- 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
- Antineoplastic Agents
- Organophosphates
- Protein Kinase Inhibitors
- Quinazolines
- Polyubiquitin
- AURKB protein, human
- Aurkb protein, mouse
- Aurora Kinase B
- Aurora Kinases
- Protein Serine-Threonine Kinases
- Proteasome Endopeptidase Complex
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Topics |
- Aneuploidy
- Animals
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Apoptosis
(drug effects)
- Aurora Kinase B
- Aurora Kinases
- Breast Neoplasms
(drug therapy, enzymology, pathology)
- Cell Proliferation
(drug effects)
- Female
- G2 Phase
(drug effects)
- Humans
- Mice
- Mitosis
(drug effects)
- Neoplasm Metastasis
- Organophosphates
(pharmacology, therapeutic use)
- Polyploidy
- Polyubiquitin
(metabolism)
- Proteasome Endopeptidase Complex
(metabolism)
- Protein Kinase Inhibitors
(pharmacology, therapeutic use)
- Protein Processing, Post-Translational
(drug effects)
- Protein Serine-Threonine Kinases
(antagonists & inhibitors, metabolism)
- Quinazolines
(pharmacology, therapeutic use)
- Tumor Stem Cell Assay
- Ubiquitination
(drug effects)
- Xenograft Model Antitumor Assays
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