title: 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.
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.
authors.affiliation: Pharmacellion Ltd, CH61 9PN, Wirral, United Kingdom.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Alevizopoulos
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Thessaly, Larissa, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Dimas
authors.affiliation: Department of Biochemistry, University of Crete Medical School, Heraklion, Greece.
authors.forename: Natalia
authors.initials: N
authors.lastname: Papadopoulou
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.|Department of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Schmidt
authors.affiliation: Department of Biochemistry, University of Crete Medical School, Heraklion, Greece.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsapara
authors.affiliation: Department of Zoology, Science College, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Saad
authors.initials: S
authors.lastname: Alkahtani
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Sabina
authors.initials: S
authors.lastname: Honisch
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Kyriakos C
authors.initials: KC
authors.lastname: Prousis
authors.affiliation: Department of Zoology, Science College, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Saud
authors.initials: S
authors.lastname: Alarifi
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Theodora
authors.initials: T
authors.lastname: Calogeropoulou
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.affiliation: Department of Biochemistry, University of Crete Medical School, Heraklion, Greece.|Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Christos
authors.initials: C
authors.lastname: Stournaras
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D005043:Etiocholanolone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D011944:Receptors, Androgen; D005043:Etiocholanolone; D000254:Sodium-Potassium-Exchanging ATPase; C468128:Istaroxime
keywords: Na+/K+ ATPase; actin cytoskeleton; istaroxime; membrane androgen receptor; prostate cancer