Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer
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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-01-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/3/1223 |
| _version_ | 1797406951132364800 |
|---|---|
| author | Jin Hur Mithun Ghosh Tae Heon Kim Nahee Park Kamal Pandey Young Bin Cho Sa Deok Hong Nar Bahadur Katuwal Minsil Kang Hee Jung An Yong Wha Moon |
| author_facet | Jin Hur Mithun Ghosh Tae Heon Kim Nahee Park Kamal Pandey Young Bin Cho Sa Deok Hong Nar Bahadur Katuwal Minsil Kang Hee Jung An Yong Wha Moon |
| author_sort | Jin Hur |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T03:34:12Z |
| format | Article |
| id | doaj.art-13b0e8b7f60442c281f63afc64f029a1 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T03:34:12Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-13b0e8b7f60442c281f63afc64f029a12023-12-03T14:49:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-01223122310.3390/ijms22031223Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian CancerJin Hur0Mithun Ghosh1Tae Heon Kim2Nahee Park3Kamal Pandey4Young Bin Cho5Sa Deok Hong6Nar Bahadur Katuwal7Minsil Kang8Hee Jung An9Yong Wha Moon10Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaHematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaDepartment of Pathology, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaHematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaHematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaHematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaHematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaHematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaHematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaDepartment of Pathology, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaHematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, KoreaEpithelial 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.https://www.mdpi.com/1422-0067/22/3/1223chemotherapy-resistant ovarian cancerbelotecanataxia telangiectasia and Rad3-related inhibitor |
| spellingShingle | Jin Hur Mithun Ghosh Tae Heon Kim Nahee Park Kamal Pandey Young Bin Cho Sa Deok Hong Nar Bahadur Katuwal Minsil Kang Hee Jung An Yong Wha Moon Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer International Journal of Molecular Sciences chemotherapy-resistant ovarian cancer belotecan ataxia telangiectasia and Rad3-related inhibitor |
| title | Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer |
| title_full | Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer |
| title_fullStr | Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer |
| title_full_unstemmed | Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer |
| title_short | Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer |
| title_sort | synergism of azd6738 an atr inhibitor in combination with belotecan a camptothecin analogue in chemotherapy resistant ovarian cancer |
| topic | chemotherapy-resistant ovarian cancer belotecan ataxia telangiectasia and Rad3-related inhibitor |
| url | https://www.mdpi.com/1422-0067/22/3/1223 |
| work_keys_str_mv | AT jinhur synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer AT mithunghosh synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer AT taeheonkim synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer AT naheepark synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer AT kamalpandey synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer AT youngbincho synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer AT sadeokhong synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer AT narbahadurkatuwal synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer AT minsilkang synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer AT heejungan synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer AT yongwhamoon synergismofazd6738anatrinhibitorincombinationwithbelotecanacamptothecinanalogueinchemotherapyresistantovariancancer |