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

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,...

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Published in:Oncotarget 2016-04, Vol.7 (17), p.24415-24428
Main Authors: Alevizopoulos, Konstantinos, Dimas, Konstantinos, Papadopoulou, Natalia, Schmidt, Eva-Maria, Tsapara, Anna, Alkahtani, Saad, Honisch, Sabina, Prousis, Kyriakos C, Alarifi, Saud, Calogeropoulou, Theodora, Lang, Florian, Stournaras, Christos
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Cell Line
Cell Line, Tumor
Cell Proliferation - drug effects
Clinical Trials, Phase II as Topic
Etiocholanolone - analogs & derivatives
Etiocholanolone - metabolism
Etiocholanolone - pharmacology
Female
HCT116 Cells
Humans
Male
MCF-7 Cells
Mice, Inbred NOD
Mice, SCID
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - metabolism
Protein Binding
Receptors, Androgen - metabolism
Research Paper
Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors
Sodium-Potassium-Exchanging ATPase - metabolism
Tumor Burden - drug effects
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.8329