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

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)

Volume 17, 14 Issues, 2017

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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Institut de Chimie de Clermont-Ferrand
Université Clermont Auvergne

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Research Article

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, 14(5): 762-770.

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: Department of Biochemistry, University of Crete Medical School, GR-71110, Heraklion, Greece.


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<sup> </sup>/K<sup> </sup>ATPase steroidal cardiac inhibitors, multi-drug resistant cells, lung tumors, prostate tumors.

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Article Details

Volume: 14
Issue Number: 5
First Page: 762
Last Page: 770
Page Count: 9
DOI: 10.2174/18715206113136660338
Price: $58
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