Synergism of AZD6738, an ATR Inhibitor, in Combination with Belotecan, a Camptothecin Analogue, in Chemotherapy-Resistant Ovarian Cancer

Autor: Young Bin Cho, Kamal Pandey, Min Sil Kang, Jin Hur, Nar Bahadur Katuwal, Tae Heon Kim, Mithun Ghosh, Yong Wha Moon, Sa Deok Hong, Hee Jung An, Nahee Park
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Indoles
Apoptosis
Ataxia Telangiectasia Mutated Proteins
Carcinoma
Ovarian Epithelial
Camptothecin Analogue
lcsh:Chemistry
Mice
Antineoplastic Combined Chemotherapy Protocols
Phosphorylation
lcsh:QH301-705.5
Spectroscopy
Ovarian Neoplasms
Mice
Inbred BALB C
Sulfonamides
Cell Cycle
Drug Synergism
General Medicine
Cell cycle
Immunohistochemistry
Computer Science Applications
G2 Phase Cell Cycle Checkpoints
Sulfoxides
Female
ataxia telangiectasia and Rad3-related inhibitor
Cell Survival
DNA repair
Morpholines
Mice
Nude
Antineoplastic Agents
belotecan
Topoisomerase-I Inhibitor
Article
Catalysis
Inorganic Chemistry
chemotherapy-resistant ovarian cancer
Cell Line
Tumor
medicine
Animals
Humans
Physical and Theoretical Chemistry
Molecular Biology
Cell Proliferation
business.industry
Organic Chemistry
medicine.disease
Antineoplastic Agents
Phytogenic
Xenograft Model Antitumor Assays
Pyrimidines
lcsh:Biology (General)
lcsh:QD1-999
Cell culture
Checkpoint Kinase 1
Ataxia-telangiectasia
Cancer research
Camptothecin
Ovarian cancer
business
Zdroj: International Journal of Molecular Sciences
Volume 22
Issue 3
International Journal of Molecular Sciences, Vol 22, Iss 1223, p 1223 (2021)
ISSN: 1422-0067
DOI: 10.3390/ijms22031223
Popis: 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.
Databáze: OpenAIRE
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