ArticleInternational journal of molecular sciences2021
Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer.
Article in International journal of molecular sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 35 citations in OpenAlex.
- ATR kinase inhibitors induce mitochondrial fission in CD8bioRxiv : the preprint server for biology · 2026Article
- Comprehensive machine learning analysis of PANoptosis signatures in multiple myeloma identifies prognostic and immunotherapy biomarkers.Scientific reports · 2025Article
- Diagnostic and therapeutic advances for HER2-expressing or amplified gynecologic cancers.Gynecologic oncology · 2025Review
- Distinct effects of sacituzumab govitecan and berzosertib on DNA damage response in ovarian cancer.iScience · 2024Article
- Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes.International journal of molecular sciences · 2024Review
- Indigofera suffruticosa aerial parts extract induce G2/M arrest and ATR/CHK1 pathway in Jurkat cells.BMC complementary medicine and therapies · 2024Article
- The schedule of ATR inhibitor AZD6738 can potentiate or abolish antitumor immune responses to radiotherapy.JCI insight · 2023Article
- DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities.Cancers · 2023Review
- Elafin is related to immune infiltration and could predict the poor prognosis in ovarian cancer.Frontiers in endocrinology · 2023Article
- Recent updates on nano-phyto-formulations based therapeutic intervention for cancer treatment.Oncology research · 2023Review
- System analysis based on the T cell exhaustion‑related genes identifies CD38 as a novel therapy target for ovarian cancer.Oncology research · 2023Article
- ATR Inhibitors in Platinum-Resistant Ovarian Cancer.Cancers · 2022Review
- Targeting the DNA Damage Response Machinery for Lung Cancer Treatment.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Breaking the Bottleneck in Anticancer Drug Development: Efficient Utilization of Synthetic Biology.Molecules (Basel, Switzerland) · 2022Review
- Targeting DUSP Activity as a Treatment for High-Grade Serous Ovarian Carcinoma.Molecular cancer therapeutics · 2022Article
- Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR).Molecules (Basel, Switzerland) · 2022Review
- Ataxia telangiectasia and Rad3-related inhibition by AZD6738 enhances gemcitabine-induced cytotoxic effects in bladder cancer cells.PloS one · 2022Article
- Breast Cancer Predisposition Genes and Synthetic Lethality.International journal of molecular sciences · 2021Review
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
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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