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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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