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
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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
Christos Stournaras, e-mail: firstname.lastname@example.org
Konstantinos Alevizopoulos, e-mail: email@example.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
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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