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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865398/ https://www.ncbi.nlm.nih.gov/pubmed/33513721 http://dx.doi.org/10.3390/ijms22031223 |
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author | Hur, Jin Ghosh, Mithun Kim, Tae Heon Park, Nahee Pandey, Kamal Cho, Young Bin Hong, Sa Deok Katuwal, Nar Bahadur Kang, Minsil An, Hee Jung Moon, Yong Wha |
author_facet | Hur, Jin Ghosh, Mithun Kim, Tae Heon Park, Nahee Pandey, Kamal Cho, Young Bin Hong, Sa Deok Katuwal, Nar Bahadur Kang, Minsil An, Hee Jung Moon, Yong Wha |
author_sort | Hur, Jin |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-7865398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-78653982021-02-07 Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer Hur, Jin Ghosh, Mithun Kim, Tae Heon Park, Nahee Pandey, Kamal Cho, Young Bin Hong, Sa Deok Katuwal, Nar Bahadur Kang, Minsil An, Hee Jung Moon, Yong Wha Int J Mol Sci Article 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. MDPI 2021-01-27 /pmc/articles/PMC7865398/ /pubmed/33513721 http://dx.doi.org/10.3390/ijms22031223 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hur, Jin Ghosh, Mithun Kim, Tae Heon Park, Nahee Pandey, Kamal Cho, Young Bin Hong, Sa Deok Katuwal, Nar Bahadur Kang, Minsil An, Hee Jung Moon, Yong Wha Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865398/ https://www.ncbi.nlm.nih.gov/pubmed/33513721 http://dx.doi.org/10.3390/ijms22031223 |
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