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Inhibition of Aurora Kinase A Synergistically Enhances Cytotoxicity in Ovarian Clear Cell Carcinoma Cell Lines Induced by Cisplatin
- Source :
- International Journal of Gynecological Cancer. 27:1666-1674
- Publication Year :
- 2017
- Publisher :
- BMJ, 2017.
-
Abstract
- Objective This study aims to clarify the incidence of Aurora kinase A (Aurora-A) protein expression and its correlation with clinical parameters in ovarian clear cell carcinoma (OCCC) tumor tissues. In addition, we assessed the efficacy of ENMD-2076, a novel selective Aurora-A inhibitor, in combination with chemotherapeutic agents for the treatment of OCCC. Methods/Materials Aurora-A protein expression was determined by immunohistochemical staining of OCCC specimens from 56 patients to evaluate its correlation with clinical outcomes in OCCC. In the in vitro study, 6 OCCC cell lines were exposed to ENMD-2076 in combination with cisplatin, SN38, doxorubicin, or paclitaxel, and cell proliferation, cell cycle distribution, and apoptosis were assessed. Results The 5-year survival rates of International Federation of Gynecology and Obstetrics stages IC3 to IV patients with intermediate or strong Aurora-A expression were significantly lower than those of patients with negative or weak Aurora-A expression. Increased Aurora-A expression was associated with significantly worse overall survival of International Federation of Gynecology and Obstetrics stages IC3 to IV patients (21% vs 77%). Multivariate analysis revealed that Aurora-A expression was an independent prognostic factor for stages IC3 to IV OCCC patients. Furthermore, synergistic effects were observed with ENMD-2076 in combination with cisplatin or SN-38 in 4 of the 6 tested cell lines. ENMD-2076 dramatically enhanced apoptosis and cell cycle arrest at the G2/M phase induced by cisplatin. Conclusions Aurora-A is a promising biomarker that is predictive of patient outcomes and a potential target for OCCC. The results suggested that chemotherapy, including ENMD-2076 in combination with cisplatin, is a potential treatment modality for patients with OCCC.
- Subjects :
- 0301 basic medicine
Oncology
Cell cycle checkpoint
medicine.medical_treatment
Apoptosis
chemistry.chemical_compound
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
Aurora Kinase A
Ovarian Neoplasms
Obstetrics and Gynecology
Drug Synergism
Middle Aged
Cell cycle
Prognosis
Immunohistochemistry
G2 Phase Cell Cycle Checkpoints
Paclitaxel
030220 oncology & carcinogenesis
Clear cell carcinoma
Female
medicine.drug
Adult
medicine.medical_specialty
Irinotecan
03 medical and health sciences
Cell Line, Tumor
Internal medicine
Biomarkers, Tumor
medicine
Humans
Doxorubicin
Protein Kinase Inhibitors
Aged
Cisplatin
Chemotherapy
business.industry
Cell growth
Ki-67 Antigen
Pyrimidines
030104 developmental biology
chemistry
Tissue Array Analysis
M Phase Cell Cycle Checkpoints
Pyrazoles
Camptothecin
business
Adenocarcinoma, Clear Cell
Subjects
Details
- ISSN :
- 1048891X
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- International Journal of Gynecological Cancer
- Accession number :
- edsair.doi.dedup.....306006f95f8e939655a736eda1a7e0e1
- Full Text :
- https://doi.org/10.1097/igc.0000000000001081