Steroidal Cardiac Na⁺/K⁺ ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo

Title:Steroidal Cardiac Na⁺/K⁺ ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo

Volume: 14 Issue: 5

Author(s): Konstantinos Dimas, Natalia Papadopoulou, Constantinos Baskakis, Kyriakos C. Prousis, Michail Tsakos, Saad Alkahtani, Sabina Honisch, Florian Lang, Theodora Calogeropoulou, Konstantinos Alevizopoulos and Christos Stournaras

Affiliation:

Keywords: Na⁺/K⁺ATPase steroidal cardiac inhibitors, multi-drug resistant cells, lung tumors, prostate tumors.

Abstract: 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.

Cite this article as:

Dimas Konstantinos, Papadopoulou Natalia, Baskakis Constantinos, Prousis C. Kyriakos, Tsakos Michail, Alkahtani Saad, Honisch Sabina, Lang Florian, Calogeropoulou Theodora, Alevizopoulos Konstantinos and Stournaras Christos, Steroidal Cardiac Na⁺/K⁺ ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo, Anti-Cancer Agents in Medicinal Chemistry 2014; 14 (5) . https://dx.doi.org/10.2174/18715206113136660338