The sodium pump, 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 its aberrant expression and activity are implicated in the development and progression of different cancers. Cardiotonic steroids, known ligands of the sodium pump have been widely used for the treatment of heart failure. However, early epidemiological evaluations and subsequent demonstration of anti-cancer activity in vitro and in vivo have indicated the possibility of developing this class of compound as chemotherapeutic agents in oncology. Their development to date as anti-cancer agents has however been impaired by a narrow therapeutic margin resulting from their potential to induce cardiovascular side-effects. The review will thus discuss (i) sodium pump structure, function, expression in diverse cancers and its chemical targeting and that of its sub-units, (ii) reported in vitro and in vivo anti-cancer activity of cardiotonic steroids, (iii) managing the toxicity of these compounds and the limitations of existing preclinical models to adequately predict the cardiotoxic potential of new molecules in man and (iv) the potential of chemical modification to reduce the cardiovascular side-effects and improve the anti-cancer activity of new molecules.
Effects of one or more kinase inhibitors on ouabain- or digoxin-induced [Ca 2+ ] i oscillations. Cells were prepared as described in Fig. 2 . Data are the mean ± SEM of the percentage of cells oscillating from at least three independent experiments, and the figure shows a representative recording of both the control and cells pretreated with different concentrations (25 and/or 50 μ m ) of inhibitor. (A) Ouabain-induced Ca 2+ oscillations are significantly suppressed by the Src kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-( t -butyl)pyrazolo[3,4- d ]pyrimidine (PP2), but not by its inactive equivalent 4-amino-7-phenylpyrazol[3,4- d ]pyrimidine (B) or the ERK 1/2 inhibitor 2′-amino-3′-methoxyflavone (PD98059) (C). (D) Digoxin-induced Ca 2+ oscillations are significantly suppressed by PP2.