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Inhibition of Aurora Kinase A Synergistically Enhances Cytotoxicity in Ovarian Clear Cell Carcinoma Cell Lines Induced by Cisplatin: A Potential Treatment Strategy
  1. Yohei Chiba, MD*,
  2. Seiya Sato, MD, PhD*,
  3. Hiroaki Itamochi, MD, PhD*,
  4. Naoto Yoshino, MD, PhD,
  5. Daisuke Fukagawa, MD,
  6. Hideki Kawamura, MD*,,
  7. Yasuko Suga, MD, PhD*,
  8. Atsumi Kojima-Chiba, MD, PhD*,
  9. Yasushi Muraki, MD, PhD,
  10. Tamotsu Sugai, MD, PhD and
  11. Toru Sugiyama, MD, PhD*
  1. *Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Uchimaru, Morioka-City;
  2. Division of Infectious Diseases and Immunology, Department of Microbiology, Iwate Medical University School of Medicine, Nishitokuta, Yahaba; and
  3. Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Uchimaru, Morioka-City, Iwate, Japan.
  1. Address correspondence and reprint requests to Hiroaki Itamochi, MD, PhD, Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka-City, Iwate, 020-8505, Japan. E-mail: itamochi@iwate-med.ac.jp.

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.

  • Aurora-A
  • clear cell
  • ovarian cancer
  • targeted therapy
  • tissue microarray

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Footnotes

  • This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (16K11151 to H. Itamochi).

  • The authors declare no conflicts of interest.

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