The expression of Na+,K+-ATPase isoforms can be altered by pathological conditions. For instance, in several cardiac diseases, the Na+,K+-ATPase isoform composition of the heart is modified [32]. Numerous studies have reported changes in Na+,K+-ATPase subunit expression and activity in the course of malignant transformation [33-36], including gliomas [37], with evidence that these occur at the very early stages of tumorigenesis [35]. Moreover, it was previously shown that both non-small cell lung and prostate cancer overexpress Na+,K+-ATPase ��1 compared with healthy tissues [35, 36, 38], while reduced expression of the ��1 isoform is commonly observed in carcinoma and is associated with events involved in cancer progression [39].
Recent studies show that in addition to pumping ions, Na+,K+-ATPase interacts with neighboring membrane proteins and organized cytosolic cascades of signaling proteins to send messages to the intracellular organelles [40, 41]. Moreover, it seems that two pools of sodium pumps exist, i.e., one broadly distributed in the plasma membrane directly involved in ion exchange, and another (the one located in caveolae) implicated in the signal transduction in couple with tyrosine kinase Src and epidermal growth factor receptor and functions as a signal-transducing receptor for cardiotonic steroids [36, 38, 40, 41]. These data support the view that Na+,K+-ATPase could be an important target for the development of anti-cancer drugs as it serves as a versatile signal transducer, it is a key player in cell adhesion and the aberrant expression of Na+,K+-ATPase and activity are implicated in the development and progression of different cancers [35-38].
The sodium pump is specifically inhibited by a series of naturally occurring cardiac glycosides, a family of compounds that includes cardenolides and cardiotonic steroids. The ouabain like specific inhibitors of sodium pump activity primarily bind to extracellular domains of �� subunits [42]. Since cardiotonic steroids are the natural ligands and specific inhibitors of the sodium pump [43], this supports the possibility of their development as anticancer agents targeting overexpressed Na+,K+-ATPase �� subunits [35-38, 44].However, the activity of Na+,K+-ATPase may be affected by various endogenous and exogenous factors [42-54].
The regulation of Na+,K+-ATPase activity in various tissues is under the control of a number of circulating hormones that impart both short- and long-term control over its activity [44, 45]. Also, the activity of the enzyme is dependent Batimastat on the lipid status of the membrane [46]. Although the mechanism of the toxic effect of various Na+,K+-ATPase activity modulators has not been completely understood yet, this enzyme can be taken as meaningful index of cellular activity and represents a useful toxicological tool [54].