Checkpoint kinase inhibitor AZD7762 overcomes cisplatin resistance in clear cell carcinoma of the ovary
| Autor: | Jun Naniwa, Tasuku Harada, Nao Oumi, Seiya Sato, Tetsuro Oishi, Junzo Kigawa, Shinya Sato, Akiko Kudoh, Misaki Kato, Hiroaki Itamochi, Mayumi Nishimura, Muneaki Shimada |
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| Rok vydání: | 2013 |
| Předmět: |
Small interfering RNA
Mice Nude Antineoplastic Agents Thiophenes Mice Checkpoint Kinase Inhibitor AZD7762 Cell Line Tumor Cytotoxic T cell Medicine Animals Urea Protein Kinase Inhibitors Cisplatin Ovarian Neoplasms business.industry Obstetrics and Gynecology Drug Synergism Cell cycle Xenograft Model Antitumor Assays Oncology Cell culture Drug Resistance Neoplasm Clear cell carcinoma Cancer research Female business Clear cell medicine.drug Adenocarcinoma Clear Cell |
| Zdroj: | International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 24(1) |
| ISSN: | 1525-1438 |
| Popis: | ObjectiveCheckpoint 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.MethodsFour 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.ResultsSynergistic 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.ConclusionsThe present study indicates that chemotherapy with AZD7762 and cisplatin should be explored as a treatment modality for women with ovarian clear cell carcinoma. |
| Databáze: | OpenAIRE |
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