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Checkpoint Kinase Inhibitor AZD7762 Overcomes Cisplatin Resistance in Clear Cell Carcinoma of the Ovary

Itamochi, Hiroaki MD, PhD*; Nishimura, Mayumi PhD; Oumi, Nao PhD; Kato, Misaki PhD; Oishi, Tetsuro MD, PhD*; Shimada, Muneaki MD, PhD*; Sato, Shinya MD, PhD*; Naniwa, Jun MD, PhD*; Sato, Seiya MD, PhD*; Kudoh, Akiko MD*; Kigawa, Junzo MD, PhD; Harada, Tasuku MD, PhD*

International Journal of Gynecological Cancer: January 2014 - Volume 24 - Issue 1 - p 61–69
doi: 10.1097/IGC.0000000000000014
Ovarian Cancer

Objective: Checkpoint kinase (Chk) inhibitors are thought to increase the cytotoxic effects of DNA-damaging agents and are undergoing clinical trials. The present study was aimed to assess the potential to use the Chk1 and Chk2 inhibitor, AZD7762, with other anticancer agents in chemotherapy to treat ovarian clear cell carcinoma.

Methods: Four ovarian clear cell carcinoma cell lines were used in this study. We treated the cells with AZD7762 and anticancer agents, then assessed cell viability, cell cycle distribution, apoptosis, and the expression of protein in apoptotic pathways and molecules downstream of the Chk signaling pathways. We also investigated the effects of these drug combinations on tumor growth in a nude mouse xenograft model.

Results: Synergistic effects from the combination of AZD7762 and cisplatin were observed in all 4 cell lines. However, we observed additive effects when AZD7762 was combined with paclitaxel on all cell lines tested. AZD7762 effectively suppressed the Chk signaling pathways activated by cisplatin, dramatically enhanced expression of phosphorylated H2A.X, cleaved caspase 9 and PARP, decreased the proportion of cells in the gap 0/ gap 1 phase and the synthesis-phase fraction, and increased apoptotic cells. Combinations of small interfering RNA against Chk 1 and small interfering RNA against Chk2 enhanced the cytotoxic effect of cisplatin in both RMG-I and KK cells. Finally, treating mice-bearing RMG-I with AZD7762 and cisplatin significantly suppressed growth of tumors in a xenograft model.

Conclusions: The present study indicates that chemotherapy with AZD7762 and cisplatin should be explored as a treatment modality for women with ovarian clear cell carcinoma.

*Department of Obstetrics and Gynecology, Tottori University School of Medicine, and †Tottori University Hospital Cancer Center, Yonago, Japan.

The authors declare no conflicts of interest.

Address correspondence and reprint requests to Hiroaki Itamochi, MD, PhD, Department of Obstetrics and Gynecology, Tottori University School of Medicine, 36-1 Nishicho, Yonago 683-8504, Japan. E-mail: itamochi@med.tottori-u.ac.jp.

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (24592517 to H. Itamochi).

Received August 6, 2013

Accepted August 29, 2013

© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.