{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:12:36Z","timestamp":1790507556232,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T00:00:00Z","timestamp":1611705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health &amp; Welfare, Republic of Korea","award":["HI16C1559"],"award-info":[{"award-number":["HI16C1559"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Epithelial ovarian cancer remains the leading cause of mortality among all gynecologic malignancies owing to recurrence and ultimate development of chemotherapy resistance in the majority of patients. In the chemotherapy-resistant ovarian cancer preclinical model, we investigated whether AZD6738 (an ataxia telangiectasia and Rad3-related (ATR) inhibitor) could synergize with belotecan (a camptothecin analog and topoisomerase I inhibitor). In vitro, both chemotherapy-resistant and chemotherapy-sensitive ovarian cancer cell lines showed synergistic anti-proliferative activity with a combination treatment of belotecan and AZD6738. The combination also demonstrated synergistic tumor inhibition in mice with a chemotherapy-resistant cell line xenograft. Mechanistically, belotecan, a DNA-damaging agent, increased phospho-ATR (pATR) and phospho-Chk1 (pChk1) in consecutive order, indicating the activation of the DNA repair system. This consequently induced G2\/M arrest in the cell cycle analysis. However, when AZD6738 was added to belotecan, pATR and pChk1 induced by belotecan alone were suppressed again. A cell cycle analysis in betotecan showed a sub-G1 increase as well as a G2\/M decrease, representing the release of G2\/M arrest and the induction of apoptosis. In ascites-derived primary cancer cells from both chemotherapy-sensitive and -resistant ovarian cancer patients, this combination was also synergistic, providing further support for our hypothesis. The combined administration of ATR inhibitor and belotecan proved to be synergistic in our preclinical model. This combination warrants further investigation in a clinical trial, with a particular aim of overcoming chemotherapy resistance in ovarian cancer.<\/jats:p>","DOI":"10.3390\/ijms22031223","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T06:10:54Z","timestamp":1611727854000},"page":"1223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer"],"prefix":"10.3390","volume":"22","author":[{"given":"Jin","family":"Hur","sequence":"first","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"},{"name":"Department of Biomedical Science, The Graduate School, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mithun","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"},{"name":"Department of Biomedical Science, The Graduate School, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Heon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahee","family":"Park","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2144-0577","authenticated-orcid":false,"given":"Kamal","family":"Pandey","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Bin","family":"Cho","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa Deok","family":"Hong","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"},{"name":"Department of Biomedical Science, The Graduate School, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7648-8044","authenticated-orcid":false,"given":"Nar Bahadur","family":"Katuwal","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"},{"name":"Department of Biomedical Science, The Graduate School, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minsil","family":"Kang","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Jung","family":"An","sequence":"additional","affiliation":[{"name":"Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7943-974X","authenticated-orcid":false,"given":"Yong Wha","family":"Moon","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Marsden, D.E., Friedlander, M., and Hacker, N.F. 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