The Na+/K+-ATPase (NKA), the sodium pump, or the sodium potassium pump, is the first P-type ion-translocating ATPase, an energy-transducing ion pump in mammalian cell membranes. It moves Na+ and K+ ions in opposite directions and restores Na+ and K+ electrochemical gradients to drive ions and metabolic substrates across the plasma membrane. Thus, NKA plays a key role in the regulation of intracellular Ca2+, which is responsible for modulating numerous cellular processes. For example, NKA is differentially expressed and regulated by the cardiovascular system, of which inhibition can prevent the exit of Na+ ions followed by a decreased release of Ca2+ from cells and thus has been used widely for the treatment of congestive heart failure. Also, NKA inhibition can induce Ca2+ accumulation that results in increased reactive oxygen species and activates signal transduction pathways to lead to cell apoptosis. Thus, NKA has become a molecular target for the treatment of cancer. Interestingly, NKA is also the major target related to the toxicity and other biological activities observed for the use of its inhibitors, indicating that therapeutic effects of these inhibitors can be improved by targeting NKA.

Digitalis species are well known for their cardiac glycoside secondary metabolites, of which digoxin, digitoxin, and gitoxin have been identified as promising agents for the potential treatment of cardiovascular diseases and cancer. These cardiac glycosides bind differentially to NKA and inhibit its activity to show potent cytotoxicity against various human cancer cells, for which the C-3 saccharide moiety, the hydroxy substituents at the C-12 and C-15 positions, the C-17 lactone unit, and the conformation of the entire molecules all play an important role. Molecular docking investigations suggest that these structural characteristics defined to be important for their anticancer potential also play a critical role in their binding to NKA. Thus, the potential anticancer activity of cardiac glycosides could be improved by modification of the molecules and their interaction with NKA. This Research Topic aims to investigate the historical journey of NKA and cardiac glycosides, tracing their use from traditional medicine to modern oncology. By reviewing past and current synthetic methodologies, the role of structural variations, such as hydroxy group positioning and aglycone modifications, that influence their interaction with Na+/K+-ATPase and other antitumor targets, such as KEAP1 and MDM2, will be addressed. This will be helpful for the discovery of novel NKA-targeted anticancer cardiac glycosides. In addition, advances in computational organic chemistry, particularly molecular docking studies, will be explored to characterize some novel active binding pockets of NKA, which will be supportive of prediction and enhancement of the antitumor potential of cardiac glycosides. Furthermore, discussed herein will guide the synthesis of novel derivatives of cardiac glycosides with optimized therapeutic profiles, which will enrich understanding of cardiac glycosides to support the development of new anticancer agents, aligning with the mission of advancing fundamental and applied organic chemistry knowledge.

We welcome Original Research, Review, Mini Review and Perspective articles on themes including, but not limited to:
• Structural biology for the enzyme, Na+/K+-ATPase
• Structural insight into cardiac glycosides
• Medicinal chemistry for synthetic modifications on cardiac glycosides
• Oncology biology for anticancer activity of cardiac glycosides
• Molecular biology for molecular targets of cardiac glycosides

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Cardiac Glycosides: From Heart Remedies to Cancer Fighters