Sodium potassium pump (Na+/K+ATPase) is a validated pharmacological target for the treatment of congestive heart failure.
Recent data with inotropic drugs such as digoxin & digitoxin (digitalis) suggest a potent anti-cancer action of these drugs and promote
Na+/K+ATPase as a novel therapeutic target in cancer. However, digitalis have narrow therapeutic indices, are pro-arrhythmic and are
considered non-developable drugs by the pharmaceutical industry. On the contrary, a series of recently-developed steroidal inhibitors
showed better pharmacological properties and clinical activities in cardiac patients. Their anti-cancer activity however, remained
unknown. In this study, we synthesized seventeen steroidal cardiac inhibitors and explored for the first time their anti-cancer activity in
vitro and in vivo. Our results indicate potent anti-cancer actions of steroidal cardiac inhibitors in multiple cell lines from different tumor
panels including multi-drug resistant cells. Furthermore, the most potent compound identified in our studies, the 3-[(R)-3-
pyrrolidinyl]oxime derivative 3, showed outstanding potencies (as measured by GI50, TGI and LC50 values) in most cells in vitro, was
selectively cytotoxic in cancer versus normal cells showing a therapeutic index of 31.7 and exhibited significant tumor growth inhibition
in prostate and lung xenografts in vivo. Collectively, our results suggest that previously described cardiac Na+/K+ATPase inhibitors have
potent anti-cancer actions and may thus constitute strong re-purposing candidates for further cancer drug development.