Oncotarget

Research Papers:

Functional characterization and anti-cancer action of the clinical phase II cardiac Na+/K+ ATPase inhibitor istaroxime: in vitro and in vivo properties and cross talk with the membrane androgen receptor

Konstantinos Alevizopoulos, Konstantinos Dimas, Natalia Papadopoulou, Eva-Maria Schmidt, Anna Tsapara, Saad Alkahtani, Sabina Honisch, Kyriakos C. Prousis, Saud Alarifi, Theodora Calogeropoulou, Florian Lang and Christos Stournaras _

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Oncotarget. 2016; 7:24415-24428. https://doi.org/10.18632/oncotarget.8329

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Abstract

Konstantinos Alevizopoulos1, Konstantinos Dimas2, Natalia Papadopoulou3, Eva-Maria Schmidt4,7, Anna Tsapara3, Saad Alkahtani5, Sabina Honisch4, Kyriakos C. Prousis6, Saud Alarifi5, Theodora Calogeropoulou6, Florian Lang4,*, Christos Stournaras3,4,*

1Pharmacellion Ltd, CH61 9PN, Wirral, United Kingdom

2Laboratory of Pharmacology, Faculty of Medicine, University of Thessaly, Larissa, Greece

3Department of Biochemistry, University of Crete Medical School, Heraklion, Greece

4Department of Physiology, University of Tübingen, Tübingen, Germany

5Department of Zoology, Science College, King Saud University, Riyadh, Saudi Arabia

6Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece

7Department of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany

*These authors contributed equally to this work

Correspondence to:

Christos Stournaras, e-mail: cstourn@med.uoc.gr

Konstantinos Alevizopoulos, e-mail: kalevizo@gmail.com

Keywords: Na+/K+ ATPase, istaroxime, prostate cancer, actin cytoskeleton, membrane androgen receptor

Received: November 03, 2015     Accepted: March 06, 2016     Published: March 24, 2016

ABSTRACT

Sodium potassium pump (Na+/K+ ATPase) is a validated pharmacological target for the treatment of various cardiac conditions. Recent published data with Na+/K+ ATPase inhibitors suggest a potent anti-cancer action of these agents in multiple indications. In the present study, we focus on istaroxime, a Na+/K+ ATPase inhibitor that has shown favorable safety and efficacy properties in cardiac phase II clinical trials. Our experiments in 22 cancer cell lines and in prostate tumors in vivo proved the strong anti-cancer action of this compound. Istaroxime induced apoptosis, affected the key proliferative and apoptotic mediators c-Myc and caspase-3 and modified actin cystoskeleton dynamics and RhoA activity in prostate cancer cells. Interestingly, istaroxime was capable of binding to mAR, a membrane receptor mediating rapid, non-genomic actions of steroids in prostate and other cells. These results support a multi-level action of Na+/K+ ATPase inhibitors in cancer cells and collectively validate istaroxime as a strong re-purposing candidate for further cancer drug development.


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