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Inhibition of Aurora Kinase A Synergistically Enhances Cytotoxicity in Ovarian Clear Cell Carcinoma Cell Lines Induced by Cisplatin

Authors :
Toru Sugiyama
Yasuko Suga
Yohei Chiba
Daisuke Fukagawa
Tamotsu Sugai
Hiroaki Itamochi
Naoto Yoshino
Hideki Kawamura
Atsumi Kojima-Chiba
Yasushi Muraki
Seiya Sato
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.

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