||Na+/K+-ATPase as a target for cardiotonic steroids and cisplatin
Suzuki, Kuniaki ,
Deyama, Yoshiaki ,
Minamikawa, HajimeYoshimura, Yoshitaka
79 , 2017-09 , 北海道歯学会
The sodium (Na+)/potassium (K+)-ATPase is an ion pump located on the surface of all animal cells. It pumps three sodium ions out of the cell while pumping two potassium ions into the cell, hydrolyzing one ATP molecule as the driving force for the reaction. Na+/K+-ATPase forms and maintains the electrochemical gradient in cells, which provides the basis for the excitability of nerve and muscle tissues and contributes to the osmotic regulation of cell volume. In addition, the electrochemical Na+ gradient is the driving force for the secondary transport of nutrients such as amino acids, sugars, and drugs. Recently, the Na+/K+-ATPase has been studied as an important target for cancer treatment, as it has been implicated in the development and progression of many cancers. Na+/K+-ATPase forms a phosphoenzyme intermediate (EP) during ATP hydrolysis. Cardiotonic steroids have been used to treat congestive heart failure and arrhythmias, and recently their anti-cancer activities have been reported. Ouabain, a specific inhibitor of Na+/K+-ATPase, is a cardiotonic steroid that binds to EP, inhibiting its dephosphorylation and the release of inorganic phosphate. Cisplatin is one of the most potent anti-tumor agents. Many studies have examined the relationship between cisplatin and Na+/K+-ATPase from the viewpoint of cisplatin accumulation and the prevention of nephrotoxicity. It has been suggested that the transport of cisplatin into cells is mediated by the Na+/K+-ATPase and that Na+/K+-ATPase activity is inhibited by cisplatin, although the underlying mechanism remains unclear. In this review, we evaluate the mechanisms underlying inhibition of Na+/K+-ATPase by cisplatin. We also summarize the structure, function, and enzymatic reaction of Na+/K+-ATPase, as well as the potential for the pump to serve as a target for ouabain and cisplatin. Finally, we will describe experiments conducted by our group showing the mechanism of Na+/K+-ATPase inhibition by cisplatin, and the combined effects of ouabain and cisplatin on cancer cell viability.