Cardiotonic steroids: Revealed by cardiology, hoped for potential in oncology

624 Cardiotonic steroids (CSs: comprising cardenolides and bufadienolides) are characterised by their abundance in nature, diversity of structure, potential for chemical modification and wide use in cardiology for heart failure management. Epidemiological data have for some time also indicated lower mortality rates in cancer patients who were on digitalis at time of first diagnosis, compared to patients not on digitalis therapy. However, the inherent high toxicity and poor therapeutic margin of the commonly used CSs have prevented their development as anti-cancer agents. By binding to the sodium pump (Na + /K + -ATPase), CSs elicit several downstream signalling cascades affecting a number of different targets. The sodium pump could thus 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. There are currently more than 1000 papers investigating CSs in cancer, however it seems that the wider scientific community is still not sufficiently intrigued by the idea of CS use in oncology. In fact, there is a huge discrepancy between the number of reports dealing with the identification and isolation of new CSs with in vitro anti-tumour activity, and those concerned with the further investigation of these compounds. In this study, we present the in vitro and in vivo anti-cancer activity of different CSs and the potential of chemical modification to reduce the cardiovascular side-effects and improve the anti-cancer activity of new molecules. Indeed, the use of medicinal chemistry to target CSs towards specific sodium pump subunits over-expressed in certain cancers may improve both anti-tumour activity and reduce cardiotoxicity, the limiting toxicity for this class of compound. This strategy has in part been demonstrated with the hemi-synthetic analogue UNBS1450 derived from the naturally occurring CS: 2”-oxovoruscharin. Adverse effects have always been the companions of effective chemotherapeutics in oncology and the benefits contributed to patients have had to be counterbalanced by cumulative toxicity. In the absence of totally appropriate preclinical cardiotoxic models, the search for totally clean non-toxic anti-cancer CSs could prevent the development of some promising compounds with original mechanisms of action overcoming major chemoresistance pathways responsible for the failure of chemotherapy.