Copyright
©The Author(s) 2023.
World J Gastroenterol. Mar 28, 2023; 29(12): 1824-1837
Published online Mar 28, 2023. doi: 10.3748/wjg.v29.i12.1824
Published online Mar 28, 2023. doi: 10.3748/wjg.v29.i12.1824
Table 1 Summary of the main findings from key original articles investigating non-cardiac applications of digoxin and other cardiac glycosides
Manuscript title | Publication year | Main biomedical/molecular findings | Main histological findings | Ref. |
Cardiac glycosides inhibit p53 synthesis by a mechanism relieved by Src or MAPK inhibition | 2009 | Activation of Src/MAPK signaling pathways, resulting in reduction of p53 protein synthesis | NA | [72] |
Human cytomegalovirus inhibition by cardiac glycosides: Evidence for involvement of the HERG gene | 2012 | CG reduced expression of the potassium channel gene, hERG, and reduced NF-κB levels | NA | [85] |
Digoxin Suppresses HIV-1 Replication by Altering Viral RNA Processing | 2013 | Reduction in HIV-1 viral mRNAs encoding structural proteins, with reduced synthesis of HIV-1 structural protein; altered viral RNA splice site use leading to loss of essential viral factor Rev; changed activity of CLK family of SR protein kinases and modification of SR proteins | NA | [91] |
A novel cell-based high-throughput screen for inhibitors of HIV-1 gene expression and budding identifies the cardiac glycosides | 2014 | Na-K ATPase- dependent but intracellular Ca2+-independent inhibition of HIV-1 gene expression at the post-integration stage of the viral life cycle | NA | [90] |
Digoxin Suppresses Tumor Malignancy through Inhibiting Multiple Src-Related Signaling Pathways in Non-Small Cell Lung Cancer | 2015 | Inhibition of proliferation, invasion, migration, and colony formation of A549 lung cancer cells; suppression of Src and related protein activity; reduced EGFR and STAT3 activity | NA | [75] |
Synergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma | 2016 | Inhibition of the ATP1A1 Na+/K+ pump, which is highly expressed in melanoma, resulting in selective toxicity to melanoma cells. Digoxin was also additive or synergistic with MEK inhibitor and/or BRAF inhibitor to induce cell death in melanoma cells; increased intracellular acidification, mitochondrial calcium dysregulation, and ATP depletion in melanoma cells | NA | [79] |
Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan | 2017 | Activated TFEB, conferred hepatoprotection against diet-induced steatosis in mice, and extended lifespan of Caenorhabditis elegans | Amelioration of high-fat diet-induced steatosis, reversal of hepatocyte p62/SQSTM1 accumulation, suggesting enhanced autophagic flux | [62] |
Targeting Intracellular Ion Homeostasis for the Control of Respiratory Syncytial Virus | 2018 | Findings suggested digoxin-mediated inhibition of RSV transcription and/or replication, likely dependent on changes in intracellular Na+ and K+ | NA | [82] |
Digoxin Suppresses PKM2 Promoted HIF-1α Transactivation in Steatohepatitis | 2018 | Binding of PKM2 by digoxin downregulated HIF-1α transactivation to decrease sterile inflammation in the liver. Digoxin suppressed ROS production both in vivo and in vitro from hepatocytes and immune cells | Reduction in hepatic damage, steatosis, and inflammation induced by endotoxin, high fat diet, or alcohol | [27] |
Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation | 2019 | Digoxin downregulated PKM2-PKM2-HIF-1α axis and attenuated inflammasome activity in macrophages and hepatic oxidative stress response | Reduction of high fat diet-induced hepatic damage, steatosis, and liver inflammation | [28] |
Antiviral activity of digoxin and ouabain against SARS-CoV-2 infection and its implication for COVID-19 | 2020 | Inhibition of viral mRNA expression, copy number, and viral protein expression at the post entry stage of the viral life cycle | NA | [81] |
Classical Drug Digitoxin Inhibits Influenza Cytokine Storm, With Implications for COVID-19 therapy | 2020 | Suppression of levels of the cytokines TNF-α, GRO/KC, MIP2, MCP1, and IFN-γ during cytokine storm | No difference in density of immune cells in rat lung sections, comparing digitoxin-treated and control lungs | [84] |
Inhibition of the IL-17A axis in adipocytes suppresses diet-induced obesity and metabolic disorders in mice | 2021 | Digoxin inhibition of RORγT activity suppressed the IL-17A axis, thus preventing diet-induced obesity, metabolic alterations, and liver injury | Prevention of high fat diet-induced hepatic lipid accumulation, reduced fibrosis, increased browning of adipose tissue | [59] |
Table 2 Ongoing clinical trials of digoxin in non-cardiac diseases
Study title | Medication doses | Current status | Estimated study completion date | Clinical Trials.gov number | Number of participants | Country of trial |
Phase 1 | ||||||
Inhibition of Sterile Inflammation by Digoxin | Digoxin 3.00 mcg/Kg/day vs Digoxin 0.15 mcg/Kg/day vs placebo | Recruiting | July 2023 | NCT03559868 | 45 | United States |
Phase IB Trial of Metformin, Digoxin, Simvastatin in Subjects With Advanced Pancreatic Cancer and Other Advanced Solid Tumors | Metformin 850 mg po/day, Simvastatin 5 mg po/day, Digoxin 0.0625 mg po/day vs Metformin 850 mg po/day then 1700 mg po/day, Simvastatin 20 mg po/day, Digoxin 0.25 mg po/day vs Metformin 850 mg po/day then 1700 mg po/day Simvastatin 40 mg po/day, Digoxin 0.25 mg po/day then 0.375 mg po/day | Recruiting | December 2023 | NCT03889795 | 15 | United States |
Effect of Digoxin on Clusters of Circulating Tumor Cells in Breast Cancer Patients | Digoxin 0.125 mg or 0.250 mg digoxin based on renal function and target serum digoxin concentration | Recruiting | June 2022 | NCT03928210 | 9 | Switzerland |
Phase 2 | ||||||
Digoxin In Treatment of Alcohol Associated Hepatitis | Digoxin titration to goal 0.5 and 1.1 ng/mL vs no digoxin | Recruiting | August 2024 | NCT05014087 | 60 | United States |
Evaluating the Effect of Digoxin and Ursodeoxycholic Acid in Patients With Rheumatoid Arthritis | Digoxin 0.25 mg + DMARDS vs UCDA 500 mg + DMARDS vs placebo + DMARDS | Recruiting | July 2022 | NCT04834557 | 90 | Egypt |
FOLFIRINOX With Digoxin in Patients With Resectable Pancreatic Cancer | FOLFIRINOX + digoxin 0.125 or 0.250 mg for target digoxin level 0.8 to 1.2 ng/mL | Recruiting | February 2025 | NCT04141995 | 20 | United States |
Topical Ionic Contra-Viral Therapy in Actinic Keratosis | Digoxin topical gel 0.125% vs furosemide topical gel 0.125% vs digoxin and furosemide gel 0.125% vs vehicle gel | Unknown | September 2019 | NCT03684772 | 32 | Netherlands |
Phase II Multicentric Study of Digoxin Per os in Classic or Endemic Kaposi’s Sarcoma (KADIG 01) | Digoxin goal 0.6 to 1.2 ng/mL for age < 75 yr; Digoxin goal 0.5-0.8 ng/mL for age > 75 yr | Unknown | September 2019 | NCT02212639 | 17 | France |
- Citation: Jamshed F, Dashti F, Ouyang X, Mehal WZ, Banini BA. New uses for an old remedy: Digoxin as a potential treatment for steatohepatitis and other disorders. World J Gastroenterol 2023; 29(12): 1824-1837
- URL: https://www.wjgnet.com/1007-9327/full/v29/i12/1824.htm
- DOI: https://dx.doi.org/10.3748/wjg.v29.i12.1824