Steroidal Cardiac Na+/K+ ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo
Konstantinos Dimas, Natalia Papadopoulou, Constantinos Baskakis, Kyriakos C. Prousis, Michail Tsakos, Saad Alkahtani, Sabina Honisch, Florian Lang, Theodora Calogeropoulou, Konstantinos Alevizopoulos and Christos Stournaras
Pages 762-770 (9)
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.
Na+/K+ATPase steroidal cardiac inhibitors, multi-drug resistant cells, lung tumors, prostate tumors.
Department of Biochemistry, University of Crete Medical School, GR-71110, Heraklion, Greece.