Anti-tumor Mechanism of Cardiac Glycosides, a Traditional Drug for Treating Heart Disease

Cardiac glycosides (CGs), traditionally used for the treatment of cardiac diseases, have recently garnered widespread attention due to their unique antitumor effects, making them important candidates for drug repurposing strategies. This review systematically illustrates the diverse mechanisms of action of CGs in antitumor activities, including inhibition of Na/K-ATPase-mediated signaling, downregulation of key transcription factors such as HIF-1, and induction of G2/M cell cycle arrest. Studies have shown that CGs exhibit minimal cytotoxicity against normal cells at therapeutic concentrations (0.52.0 nM) and exhibit excellent selectivity against various tumor cell types. Clinical data demonstrate a 20%30% reduction in cancer incidence in patients receiving long-term digoxin therapy. Furthermore, the combination of CGs with chemotherapeutic agents significantly enhances tumor inhibition and reduces cardiotoxicity. Chemical modification and nanoformulation optimization have further enhanced the anticancer efficacy of CGs, such as by reducing the IC50 of fluorinated digoxin against MCF-7 cells to one-third of the original drug. Combination with anti-PD-1 antibodies has also demonstrated enhanced immunotherapy synergy. In summary, CGs are expected to serve as an important part of comprehensive tumor treatment and provide new treatment options for cancer patients.