Structural Insights into the Interactions of Digoxin and Na+/K+-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation

Digoxin is a cardiac glycoside long used to treat congestive heart failure and found recently to show antitumor potential. The hydroxy groups connected at the C-12, C-14, and C-3 ' a positions; the C-17 unsaturated lactone unit; the conformation of the steroid core; and the C-3 saccharide moiety have been demonstrated as being important for digoxin's cytotoxicity and interactions with Na+/K+-ATPase. The docking profiles for digoxin and several derivatives and Na+/K+-ATPase were investigated; an additional small Asn130 side pocket was revealed, which could be useful in the design of novel digoxin-like antitumor agents. In addition, the docking scores for digoxin and its derivatives were found to correlate with their cytotoxicity, indicating a potential use of these values in the prediction of the cancer cell cytotoxicity of other cardiac glycosides. Moreover, in these docking studies, digoxin was found to bind to FIH-1 and NF-kappa B but not HDAC, IAP, and PI3K, suggesting that this cardiac glycoside directly targets FIH-1, Na+/K+-ATPase, and NF-kappa B to mediate its antitumor potential. Differentially, digoxigenin, the aglycon of digoxin, binds to HDAC and PI3K, but not FIH-1, IAP, Na+/K+-ATPase, and NF-kappa B, indicating that this compound may target tumor autophagy and metabolism to mediate its antitumor propensity.

Automated summary

Digoxin, a cardiac glycoside, has been found to exhibit antitumor potential and its cytotoxicity is influenced by specific structural features and interactions with Na+/K+-ATPase. Docking studies also suggest that the docking scores of digoxin and its derivatives correlate with their cytotoxicity, indicating their potential use in predicting the cytotoxicity of other cardiac glycosides. Additionally, digoxin was found to directly target FIH-1, Na+/K+-ATPase, and NF-kappa B for its antitumor effects.