Na+/K+-ATPase Revisited: On Its Mechanism of Action, Role in Cancer, and Activity Modulation

Abstract

Maintenance of Na+ and K+ gradients across the cell plasma membrane is an essential process for mammalian cell survival. An enzyme responsible for this process, sodium-potassium ATPase (NKA), has been currently extensively studied as a potential anticancer target, especially in lung cancer and glioblastoma. To date, many NKA inhibitors, mainly of natural origin from the family of cardiac steroids (CSs), have been reported and extensively studied. Interestingly, upon CS binding to NKA at nontoxic doses, the role of NKA as a receptor is activated and intracellular signaling is triggered, upon which cancer cell death occurs, which lies in the expression of different NKA isoforms than in healthy cells. Two major CSs, digoxin and digitoxin, originally used for the treatment of cardiac arrhythmias, are also being tested for another indication—cancer. Such drug repositioning has a big advantage in smoother approval processes. Besides this, novel CS derivatives with improved performance are being developed and evaluated in combination therapy. This article deals with the NKA structure, mechanism of action, activity modulation, and its most important inhibitors, some of which could serve not only as a powerful tool to combat cancer, but also help to decipher the so-far poorly understood NKA regulation.

Cardiac Glycosides as Immune System Modulators

“…This transport is ensured by energy from adenosine triphosphate (ATP) cleavage and it is crucial for the maintenance of the cell plasma membrane potential. The CG binding to NKA impedes this function, which leads to the accumulation of Na + ions in the cytosol [ 32 ]. As a consequence, the Na + /Ca 2+ exchanger is activated and the intracellular concentration of Ca 2+ increases ( Figure 1 ).…”

“…The aforementioned inhibition of NKA pumping activity occurs at high therapeutic concentrations of CGs (hundreds of nM) [ 32 ]. However, when lower CG concentrations of the compounds are used, a complex signalosome is formed with NKA in its center.…”

“…In addition to this complex mechanism of action of CGs, great variability of their biological actions comes also from NKA itself. Different isoforms of NKA subunits are expressed in different tissues [ 32 ] and CGs have different affinities for the particular isoforms. For example, digoxin and digitoxin are more selective to α2 and α3 than to α1 NKA isoform.…”

Quo vadis Cardiac Glycoside Research?

“…The next part was devoted to the CG structure concerning their ability to interact with NKA. This research is connected with the study of CGs as anticancer drugs [ 144 , 145 ]. The therapeutic window of these compounds is very narrow, which complicates their use in clinical practice not only in the field of cardiology but also as potential anticancer drugs.…”

Autophagy Induction by Trichodermic Acid Attenuates Endoplasmic Reticulum Stress-Mediated Apoptosis in Colon Cancer Cells

“…In recent years, natural products have aroused people’s interest in the development of new anticancer therapeutic drugs [ 61 , 62 , 63 ], because most of them show good potential of medicinal significance, which can be used as alternative drugs for the treatment of various diseases (including cancer) with few side effects relatively [ 64 , 65 ]. TDA is a newly discovered octahydronaphthalene derivative, isolated from the secondary metabolites of plant endophytic fungi, and has shown anticancer activity in a variety of cancers [ 12 , 13 ].…”