Digoxin as a Novel Anti-Cancer Agent: Molecular Mechanisms and Therapeutic Potential

Research has revealed promising therapeutic potential for digoxin, a cardiac glycoside traditionally used in treating heart conditions, as a novel anti-cancer agent. Through multiple molecular mechanisms, digoxin demonstrates remarkable capabilities in targeting cancer cells while potentially enhancing conventional treatment outcomes. This cardiac glycoside operates through several key pathways, including the inhibition of Na+/K+-ATPase, suppression of hypoxia-inducible factors, and modulation of cellular calcium levels, all of which contribute to its anti-cancer properties:

1. Inhibition of Na+/K+-ATPase: Digoxin inhibits Na+/K+-ATPase, increasing intracellular calcium and activating apoptotic pathways.
2. Suppression of Hypoxia-Inducible Factor-1α (HIF-1α): Digoxin reduces HIF-1α levels, inhibiting tumor growth and angiogenesis under hypoxic conditions.
3. Induction of apoptosis: Digoxin triggers apoptosis by modulating Bcl-2 family proteins, activating caspases, and increasing intracellular calcium and ROS.
4. Inhibition of cancer cell proliferation: Digoxin inhibits the proliferation of various cancer cell lines, including prostate, breast, and lung cancer.
5. Anti-angiogenic effects: Digoxin inhibits angiogenesis by reducing the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors.
6. Improving immune response: Digoxin enhances anti-tumor immunity by promoting the activation of dendritic cells and T cells.
7. Inhibition of cancer stem cells: Digoxin targets cancer stem cells by disrupting their self-renewal pathways.
8. Synergistic effects with chemotherapy: Digoxin enhances the efficacy of chemotherapy agents by sensitizing cancer cells to apoptosis and reducing drug resistance.
9. Inhibition of Nuclear Factor-κB (NF-κB) pathway: Digoxin suppresses the NF-κB pathway, which is involved in inflammation, cell survival, and tumor progression.
10. Reduction of tumor metastasis: Digoxin inhibits the migration and invasion of cancer cells, reducing metastasis.
11. Increase in Reactive Oxygen Species (ROS): Digoxin increases ROS levels, leading to oxidative stress and apoptosis in cancer cells.
12. Increase in cytosolic calcium: Digoxin elevates cytosolic calcium levels, disrupting mitochondrial function and activating apoptotic pathways.
13. Disruption of mitochondrial function: Digoxin-induced calcium overload disrupts mitochondrial membrane potential, leading to ROS production and apoptosis.

Digoxin can be toxic and has a narrow therapeutic index. Based on a study by Li X et al. of hemodialysis patients with compromised kidney function, intermittent low-dose digoxin administration offered safety and therapeutic benefits. While the standard digoxin maintenance dose ranges from 125-250 μg daily, this study demonstrated that administering just 62.5 μg every other day prevented toxicity from drug accumulation while maintaining the therapeutic benefits needed for heart failure management.

The extensive research surrounding digoxin’s anti-cancer properties presents compelling evidence for its potential role in cancer therapy. While its narrow therapeutic index necessitates careful dosing considerations, as demonstrated by successful low-dose protocols in hemodialysis patients, the multi-faceted mechanisms through which digoxin affects cancer cells make it a promising candidate for further clinical investigation. Its ability to work synergistically with existing chemotherapy agents and its effects on cancer stem cells and tumor microenvironment suggests that digoxin could become a valuable addition to the anticancer therapeutic arsenal. Future research focusing on optimal dosing strategies and specific cancer-type applications will be crucial in fully realizing digoxin’s potential in cancer treatment.

References:

1. Elbaz HA, Stueckle TA, Tse W, Rojanasakul Y, Dinu CZ. Digitoxin and its analogs as novel cancer therapeutics. Exp Hematol Oncol. 2012 Apr 5;1(1):4.
2. Haux J. Digitoxin is a potential anticancer agent for several types of cancer. Med Hypotheses. 1999 Dec;53(6):543-8.
3. Lee DH, Cheul Oh S, Giles AJ, Jung J, Gilbert MR, Park DM. Cardiac glycosides suppress the maintenance of stemness and malignancy via inhibiting HIF-1α in human glioma stem cells. Oncotarget. 2017 Jun 20;8(25):40233-40245.
4. Li X, Ao X, Liu Q, et al. Intermittent low-dose digoxin may be effective and safe in patients with chronic heart failure undergoing maintenance hemodialysis. Exp Ther Med. 2014;8(6):1689-1694.
5. Lin SY, Chang HH, Lai YH, Lin CH, Chen MH, Chang GC, Tsai MF, Chen JJ. Digoxin Suppresses Tumor Malignancy through Inhibiting Multiple Src-Related Signaling Pathways in Non-Small Cell Lung Cancer. PLoS One. 2015 May 8;10(5):e0123305.
6. Menger L, Vacchelli E, Adjemian S, Martins I, Ma Y, Shen S, Yamazaki T, Sukkurwala AQ, Michaud M, Mignot G, Schlemmer F, Sulpice E, Locher C, Gidrol X, Ghiringhelli F, Modjtahedi N, Galluzzi L, André F, Zitvogel L, Kepp O, Kroemer G. Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci Transl Med. 2012 Jul 18;4(143):143ra99.
7. Newman RA, Yang P, Pawlus AD, Block KI. Cardiac glycosides as novel cancer therapeutic agents. Mol Interv. 2008 Feb;8(1):36-49.
8. Prassas I, Karagiannis GS, Batruch I, Dimitromanolakis A, Datti A, Diamandis EP. Digitoxin-induced cytotoxicity in cancer cells is mediated through distinct kinase and interferon signaling networks. Mol Cancer Ther. 2011 Nov;10(11):2083-93.
9. Reddy D, Kumavath R, Barh D, Azevedo V, Ghosh P. Anticancer and Antiviral Properties of Cardiac Glycosides: A Review to Explore the Mechanism of Actions. Molecules. 2020 Aug 7;25(16):3596.
10. Ren Y, Anderson AT, Meyer G, Lauber KM, Gallucci JC, Douglas Kinghorn A. Digoxin and its Na⁺/K⁺-ATPase-targeted actions on cardiovascular diseases and cancer. Bioorg Med Chem. 2024 Nov 15;114:117939.
11. Slingerland M, Cerella C, Guchelaar HJ, Diederich M, Gelderblom H. Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials. Invest New Drugs. 2013 Aug;31(4):1087-94.
12. Vetter M, Ngyuen-Sträuli BD, Krol I, Ring A, Kohler A, Castro-Giner F, Vogel M, Grasic Kuhar C, Schwab F, Heinzelmann-Schwarz V, Kuster Pfister G, Weber W, Kurzeder C, Aceto N. Abstract PO5-18-04: Effect of Digoxin on clusters of circulating tumor cells in patients with metastatic breast cancer (DICCT). Cancer Res. 2024 May 1;84(9_Suppl):PO5-18-04.
13. Wang T, Xu P, Wang F, Zhou D, Wang R, Meng L, Wang X, Zhou M, Chen B, Ouyang J. Effects of digoxin on cell cycle, apoptosis and NF-κB pathway in Burkitt’s lymphoma cells and animal model. Leuk Lymphoma. 2017 Jul;58(7):1673-1685.
14. Wang Y, Ma Q, Zhang S, Liu H, Zhao B, Du B, Wang W, Lin P, Zhang Z, Zhong Y, Kong D. Digoxin Enhances the Anticancer Effect on Non-Small Cell Lung Cancer While Reducing the Cardiotoxicity of Adriamycin. Front Pharmacol. 2020 Feb 28;11:186.
15. Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R, Dang CV, Liu JO, Semenza GL. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19579-86.
16. Zhao YT, Yan JY, Han XC, Niu FL, Zhang JH, Hu WN. Anti-proliferative effect of digoxin on breast cancer cells via inducing apoptosis. Eur Rev Med Pharmacol Sci. 2017 Dec;21(24):5837-5842.
17. Zhou Y, Zhou Y, Yang M, Wang K, Liu Y, Zhang M, Yang Y, Jin C, Wang R, Hu R. Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway. Redox Biol. 2019 Apr;22:101131.