ArticleJournal of the American Chemical Society2016
Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 53 citations in OpenAlex.
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- Repurposing clinically safe drugs for DNA repair pathway choice in CRISPR genome editing and synthetic lethality.Nature communications · 2025Article
- KLX ameliorates liver cancer progression by mediating ZBP1 transcription and ubiquitination and increasing ZBP1-induced PANoptosis.Acta pharmacologica Sinica · 2025Article
- A Novel 3D High-Throughput Phenotypic Drug Screening Pipeline to Identify Drugs with Repurposing Potential for the Treatment of Ovarian Cancer.Advanced healthcare materials · 2025Article
- The mechanistic role of cardiac glycosides in DNA damage response and repair signaling.Cellular and molecular life sciences : CMLS · 2023Review
- Qualitative and quantitative phytochemical screening of Nerium oleander L. extracts associated with toxicity profile.Scientific reports · 2022Article
- Synthesis and Biological Evaluation of Cardiac Glycosides for Cancer Therapy by Targeting the DNA Damage Response.ChemMedChem · 2022Article
- The botanical drug PBI-05204, a supercritical COFrontiers in pharmacology · 2022Article
- Inhibition of ATM Induces Hypersensitivity to Proton Irradiation by Upregulating Toxic End Joining.Cancer research · 2021Article
- Cardiac glycosides inhibit cancer through Na/K-ATPase-dependent cell death induction.Biochemical pharmacology · 2020Article
- Targeting UHRF1-dependent DNA repair selectively sensitizes KRAS mutant lung cancer to chemotherapy.Cancer letters · 2020Article
- Digoxin Enhances the Anticancer Effect on Non-Small Cell Lung Cancer While Reducing the Cardiotoxicity of Adriamycin.Frontiers in pharmacology · 2020Article
- Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors.Cancer research · 2019Article
- Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51.Science translational medicine · 2019Article
- Modular Total Synthesis and Cell-Based Anticancer Activity Evaluation of Ouabagenin and Other Cardiotonic Steroids with Varying Degrees of Oxygenation.Journal of the American Chemical Society · 2019Article
- ATR Inhibition Is a Promising Radiosensitizing Strategy for Triple-Negative Breast Cancer.Molecular cancer therapeutics · 2018Article
- HMG-CoA Reductase Inhibition Delays DNA Repair and Promotes Senescence After Tumor Irradiation.Molecular cancer therapeutics · 2018Article
- Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas.Molecular cancer therapeutics · 2017Article
- Non-homologous End Joining Inhibitor SCR-7 to Exacerbate Low-dose Doxorubicin Cytotoxicity in HeLa Cells.Journal of cancer prevention · 2017Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Small-molecule inhibitors of DNA repair pathways are being intensively investigated as primary and adjuvant chemotherapies. We report the discovery that cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, are potent inhibitors of DNA double-strand break (DSB) repair. Our data suggest that cardiac glycosides interact with phosphorylated mediator of DNA damage checkpoint protein 1 (phospho-MDC1) or E3 ubiquitin-protein ligase ring finger protein 8 (RNF8), two factors involved in DSB repair, and inhibit the retention of p53 binding protein 1 (53BP1) at the site of DSBs. These observations provide an explanation for the anticancer activity of this class of compounds, which has remained poorly understood for decades, and provide guidance for their clinical applications. This discovery was enabled by the development of the first high-throughput unbiased cellular assay to identify new small-molecule inhibitors of DSB repair. Our assay is based on the fully automated, time-resolved quantification of phospho-SER139-H2AX (γH2AX) and 53BP1 foci, two factors involved in the DNA damage response network, in cells treated with small molecules and ionizing radiation (IR). This primary assay is supplemented by robust secondary assays that establish lead compound potencies and provide further insights into their mechanisms of action. Although the cardiac glycosides were identified in an evaluation of 2366 small molecules, the assay is envisioned to be adaptable to larger compound libraries. The assay is shown to be compatible with small-molecule DNA cleaving agents, such as bleomycin, neocarzinostatin chromophore, and lomaiviticin A, in place of IR.
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