Sodium potassium pump (Na+/K+ ATPase) is a transmembrane protein complex found in all higher eukaryotes
acting as a key energy-consuming pump maintaining ionic and osmotic balance in cells. Recently recognized as an important
transducer and/or integrator of various signals as well as a protein-protein interaction scaffold forming receptor complexes
with signaling properties, the most prominent pharmacological role of Na+/K+ ATPase inhibitors is the increase of
myocardial contractility in pathologic conditions such as congestive heart failure. Consequently, modulators of Na+/K+
ATPase such as digoxin have been approved by regulatory authorities and are widely used in the treatment of cardiac failure
since 1975. Initiating from early observations of reduction of cancer incidence in cardiac patients taking digoxin, recent
epidemiological and other studies have consolidated the anti-cancer potential of Na+/K+ ATPase inhibitors in indications
such as prostate, breast, lung cancer or leukemia. More importantly, a new series of pharmacologically optimized
Na+/K+ ATPase inhibitors has recently shown strong anti-cancer activities in multiple preclinical assays and have reached
early clinical trials. Altogether, these results suggest that Na+/K+ ATPase is an emerging cancer target that merits further
investigation. In this review, we summarize key functional properties of the enzyme that are highly relevant for cancer cell
selectivity, review the most prominent chemical classes of Na+/K+ ATPase inhibitors and analyze their downstream effectors.
Moreover, we discuss overall development prospects of these candidate drugs on their way to becoming new effective
treatments of cancer in patients.
Keywords: Bufadienolides, bufalin, cancer therapy, cardenolides, cardiotonic steroids, digoxin, istaroxime, Na+/K+ ATPase,
sodium potassium ATPase, steroidal Na+/K+ ATPase inhibitors.
Rights & PermissionsPrintExport