ArticleJournal of experimental & clinical cancer research : CR2017
Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine.
Article in Journal of experimental & clinical cancer research : CR, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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The trial behind it
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Who cites it
19 citing papers in PubMed, 81 citations in OpenAlex.
- Review
- Guarding against digestive-system cancers: Unveiling the role of Chk2 as a potential therapeutic target.Genes & diseases · 2025Review
- Pan-cancer analysis of oncogenic role of CEP55 and experiment validation in clear cell renal cell carcinoma.Scientific reports · 2024Article
- SIRT3-dependent mitochondrial redox homeostasis mitigates CHK1 inhibition combined with gemcitabine treatment induced cardiotoxicity in hiPSC-CMs and mice.Archives of toxicology · 2023Article
- Review
- Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide.Medical oncology (Northwood, London, England) · 2022Article
- Targeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus.Nature communications · 2022Article
- Emerging strategies for the improvement of chemotherapy in bladder cancer: Current knowledge and future perspectives.Journal of advanced research · 2022Review
- Ataxia telangiectasia and Rad3-related inhibition by AZD6738 enhances gemcitabine-induced cytotoxic effects in bladder cancer cells.PloS one · 2022Article
- Article
- Radiosensitization of NSCLC cells to X-rays and carbon ions by the CHK1/CHK2 inhibitor AZD7762, Honokiol and Tunicamycin.Radiation and environmental biophysics · 2020Article
- A Tiered Female Ovarian Toxicity Screening Identifies Toxic Effects of Checkpoint Kinase 1 Inhibitors on Murine Growing Follicles.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.Molecular oncology · 2020Article
- Loss of CHEK2 Predicts Progression in Stage pT1 Non-Muscle-Invasive Bladder Cancer (NMIBC).Pathology oncology research : POR · 2020Article
- Targeting SREBP1 chemosensitizes colorectal cancer cells to gemcitabine by caspase-7 upregulation.Bioengineered · 2019Article
- Checkpoint kinase inhibitor AZD7762 enhance cisplatin-induced apoptosis in osteosarcoma cells.Cancer cell international · 2019Article
- Integrated proteomic and phosphoproteomic analyses of cisplatin-sensitive and resistant bladder cancer cells reveal CDK2 network as a key therapeutic target.Cancer letters · 2018Article
- Combined inhibition of BET proteins and class I HDACs synergistically induces apoptosis in urothelial carcinoma cell lines.Clinical epigenetics · 2018Article
- DNA Repair Pathway Alterations in Bladder Cancer.Cancers · 2017Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMore effective chemotherapies are urgently needed for bladder cancer, a major cause of morbidity and mortality worldwide. We therefore explored the efficacy of the combination of gemcitabine and AZD7762, a checkpoint kinase 1/2 (CHK1/2) inhibitor, for bladder cancer.
methodsViability, clonogenicity, cell cycle distribution and apoptosis were assessed in urothelial cancer cell lines and various non-malignant urothelial cells treated with gemcitabine and AZD7762. DNA damage was assessed by γH2A.X and 53-BP1 staining and checkpoint activation was followed by Western blotting. Pharmacological inhibition of CHK1 and CHK2 was compared to downregulation of either CHK1 or CHK2 using siRNAs.
resultsCombined use of gemcitabine and AZD7762 synergistically reduced urothelial carcinoma cell viability and colony formation relative to either single treatment. Non-malignant urothelial cells were substantially less sensitive to this drug combination. Gemcitabine plus AZD7762 inhibited cell cycle progression causing cell accumulation in S-phase. Moreover, the combination induced pronounced levels of apoptosis as indicated by an increase in the fraction of sub-G1 cells, in the levels of cleaved PARP, and in caspase 3/7 activity. Mechanistic investigations showed that AZD7762 treatment inhibited the repair of gemcitabine-induced double strand breaks by interference with CHK1, since siRNA-mediated depletion of CHK1 but not of CHK2 mimicked the effects of AZD7762.
conclusionsAZD7762 enhanced sensitivity of urothelial carcinoma cells to gemcitabine by inhibiting DNA repair and disturbing checkpoints. Combining gemcitabine with CHK1 inhibition holds promise for urothelial cancer therapy.
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