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

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

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 14 , Issue 5 , 2014

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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.

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

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Article Details

VOLUME: 14
ISSUE: 5
Year: 2014
Page: [762 - 770]
Pages: 9
DOI: 10.2174/18715206113136660338
Price: $58

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