ArticlePloS one2014
21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up-regulates Na,K-ATPase and epithelial tight junctions.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- Impact of Time, Temperature, and Conformational Changes on the Characterization of Cardiotonic Steroid-NaThe Journal of membrane biology · 2026Review
- Anoikis: To Die or Not to Die?International journal of molecular sciences · 2026Review
- Evaluation and investigation of the cardiotoxicity of the potential anti-cholangiocarcinoma drug lanatoside C.Frontiers in toxicology · 2026Article
- Na,K-ATPase mediated and cardiotonic induced signaling in health and disease.Frontiers in physiology · 2025Review
- Digoxin and its NaBioorganic & medicinal chemistry · 2024Review
- NaInternational journal of molecular sciences · 2024Review
- PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma.Frontiers in molecular biosciences · 2023Article
- Cytotoxic effect of carbohydrate derivatives of digitoxigenin involves modulation of plasma membrane CaJournal of cellular biochemistry · 2021Article
- Implications of Synthetic Modifications of the Cardiotonic Steroid Lactone Ring on Cytotoxicity.The Journal of membrane biology · 2021Article
- Evaluation of Cardiotonic Steroid Modulation of Cellular Cholesterol and Phospholipid.The Journal of membrane biology · 2021Article
- Clinical significance of P-class pumps in cancer.Oncology letters · 2021Review
- Structural Insights into the Interactions of Digoxin and NaMolecules (Basel, Switzerland) · 2021Article
- The γ-Benzylidene Digoxin Derivative BD-15 Increases the α3-Na, K-ATPase Activity in Rat Hippocampus and Prefrontal Cortex and no Change on Heart.The Journal of membrane biology · 2021Article
- NaMolecules (Basel, Switzerland) · 2021Review
- NaJournal of natural products · 2020Article
- 21-Benzylidene digoxin decreases proliferation by inhibiting the EGFR/ERK signaling pathway and induces apoptosis in HeLa cells.Steroids · 2020Article
- Ouabain Enhances Cell-Cell Adhesion Mediated by βInternational journal of molecular sciences · 2019Article
- Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Cancer mortality does not differ by antiarrhythmic drug use: A population-based cohort of Finnish men.Scientific reports · 2018Article
- Digoxin reduces the mutagenic effects of Mitomycin C in human and rodent cell lines.Cytotechnology · 2017Article
Corrections and comments
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Authors and funding
24 authors at 7 institutions in 3 countries.
Funding
Abstract
Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biological effects depend on the binding to their receptor, Na,K-ATPase, through which, they inhibit Na+ and K+ ion transport and activate of several intracellular signaling pathways. In this study, we added a styrene group to the lactone ring of the cardiotonic steroid digoxin, to obtain 21-benzylidene digoxin (21-BD), and investigated the effects of this synthetic cardiotonic steroid in different cell models. Molecular modeling indicates that 21-BD binds to its target Na,K-ATPase with low affinity, adopting a different pharmacophoric conformation when bound to its receptor than digoxin. Accordingly, 21-DB, at relatively high µM amounts inhibits the activity of Na,K-ATPase α1, but not α2 and α3 isoforms. In addition, 21-BD targets other proteins outside the Na,K-ATPase, inhibiting the multidrug exporter Pdr5p. When used on whole cells at low µM concentrations, 21-BD produces several effects, including: 1) up-regulation of Na,K-ATPase expression and activity in HeLa and RKO cancer cells, which is not found for digoxin, 2) cell specific changes in cell viability, reducing it in HeLa and RKO cancer cells, but increasing it in normal epithelial MDCK cells, which is different from the response to digoxin, and 3) changes in cell-cell interaction, altering the molecular composition of tight junctions and elevating transepithelial electrical resistance of MDCK monolayers, an effect previously found for ouabain. These results indicate that modification of the lactone ring of digoxin provides new properties to the compound, and shows that the structural change introduced could be used for the design of cardiotonic steroid with novel functions.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.