title: Cytotoxicity of cardiotonic steroids in sensitive and multidrug-resistant leukemia cells and the link with Na(+)/K(+)-ATPase.
abstract: Cardiotonic steroids have long been in clinical use for treatment of heart failure and are now emerging as promising agents in various diseases, especially cancer. Their main target is Na(+)/K(+)-ATPase, a membrane protein involved in cellular ion homeostasis. Na(+)/K(+)-ATPase has been implicated in cancer biology by affecting several cellular events and signaling pathways in both sensitive and drug-resistant cancer cells. Hence, we investigated the cytotoxic activities of 66 cardiotonic steroids and cardiotonic steroid derivatives in sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. Data were then subjected to quantitative structure-activity relationship analysis (QSAR) and molecular docking into Na(+)/K(+)-ATPase, which both indicated a possible differential expression of the pump in the mentioned cell lines. This finding was confirmed by western blotting, intracellular potassium labeling and next generation sequencing which showed that Na(+)/K(+)-ATPase was less expressed in multidrug-resistant than in sensitive cells.
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors: Maen
authors: M
authors: Zeino
authors: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors: Ruth
authors: R
authors: Brenk
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors: Lisa
authors: L
authors: Gruber
authors: Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria; Department of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors: Martin
authors: M
authors: Zehl
authors: Department of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors: Ernst
authors: E
authors: Urban
authors: Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors: Brigitte
authors: B
authors: Kopp
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany. Electronic address: efferth@uni-mainz.de.
authors: Thomas
authors: T
authors: Efferth
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002018:Bufanolides / Q000737:chemistry / Q000494:pharmacology; D002301:Cardiac Glycosides / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004077:Digoxin / Q000737:chemistry / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D062105:Molecular Docking Simulation; D061251:Primary Cell Culture; D021281:Quantitative Structure-Activity Relationship; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014700:Verapamil / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D002301:Cardiac Glycosides; D004077:Digoxin; D004317:Doxorubicin; D014700:Verapamil; D000254:Sodium-Potassium-Exchanging ATPase; C022777:bufalin
keywords: Cardiotonic steroids; Multidrug resistance; Na(+)/K(+)-ATPase signalosome; Next generation sequencing