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The Investigational Aurora Kinase A Inhibitor MLN8237 Induces Defects in Cell Viability and Cell-Cycle Progression in Malignant Bladder Cancer Cells In Vitro and In Vivo
- Source :
- Clinical Cancer Research. 19:1717-1728
- Publication Year :
- 2013
- Publisher :
- American Association for Cancer Research (AACR), 2013.
-
Abstract
- Purpose: Despite more than 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluated Aurora kinase A, identified as an upregulated candidate molecule in bladder cancer, as a potential therapeutic target. Experimental Design: Gene expression in human bladder cancer samples was evaluated using RNA microarray and quantitative reverse transcriptase PCR. Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cell dynamics in malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells were evaluated in vitro and in vivo in a mouse xenograft model. Results: A set of 13 genes involved in the mitotic spindle checkpoint, including Aurora kinases A and B, were upregulated in human urothelial carcinoma compared with normal urothelium. The Aurora kinase A inhibitor MLN8237 induced cell-cycle arrest, aneuploidy, mitotic spindle failure, and apoptosis in the human bladder cancer cell lines T24 and UM-UC-3. MLN8237 also arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model. Finally, in vitro sequential administration of MLN8237 with either paclitaxel or gemcitabine resulted in synergistic cytotoxic effects in T24 cells. Conclusions: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma and can be exploited with pharmacologic Aurora A inhibition. Given our demonstration of the ability of the Aurora A inhibitor MLN8237 to inhibit growth of bladder cancer in vitro and in vivo, we conclude that Aurora kinase inhibitors warrant further therapeutic investigation in bladder cancer. Clin Cancer Res; 19(7); 1717–28. ©2013 AACR.
- Subjects :
- Cancer Research
Pathology
medicine.medical_specialty
Cell cycle checkpoint
Paclitaxel
Cell Survival
Aurora inhibitor
Gene Expression
Apoptosis
Protein Serine-Threonine Kinases
Biology
urologic and male genital diseases
Deoxycytidine
Article
Mice
Aurora kinase
Aurora Kinases
Cell Line, Tumor
medicine
Animals
Cluster Analysis
Humans
Neoplasm Invasiveness
Aurora Kinase A
Bladder cancer
Gene Expression Profiling
Cell Cycle
Cancer
Drug Synergism
Azepines
Cell Cycle Checkpoints
Aneuploidy
Mitotic spindle checkpoint
medicine.disease
Xenograft Model Antitumor Assays
Gemcitabine
Tumor Burden
Spindle apparatus
Phenotype
Pyrimidines
Urinary Bladder Neoplasms
Oncology
Cancer research
M Phase Cell Cycle Checkpoints
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....54bb3963f75ed0bc0857d5af45d6b62d