title: Identification of new P-glycoprotein inhibitors derived from cardiotonic steroids.
abstract: P-glycoprotein (ABCB1, MDR1) is capable of extruding chemotherapeutics outside the cell and its overexpression in certain cancer cells may cause failure of chemotherapy. Many attempts were carried out to identify potent inhibitors of this transporter and numerous compounds were shown to exert inhibitory effects in vitro, but so far none were able to make their way to the clinic due to serious complications. Natural compounds represent a great source of therapeutics, which are believed to be safe and effective. Therefore, we have screened a large library of naturally occurring cardiotonic steroids and their derivatives using high throughput flow cytometry. We were able to identify six compounds capable of modulating P-glycoprotein activity. By using P-glycoprotein ATPase assays, molecular docking in silico studies and resazurin reduction assays, the outcome of this high throughput screening platform has been validated. These novel compounds may serve as candidates to reverse doxorubicin resistance in leukemia cells.
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Maen
authors.initials: M
authors.lastname: Zeino
authors.affiliation: St. Mary's, Respiratory Infections NHLI, Flow Cytometry Core Facility, Imperial College, London, Great Britain.
authors.forename: Malte S
authors.initials: MS
authors.lastname: Paulsen
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria; Departments of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Zehl
authors.affiliation: Departments of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Ernst
authors.initials: E
authors.lastname: Urban
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kopp
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany. Electronic address: efferth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002301:Cardiac Glycosides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002301:Cardiac Glycosides; D004317:Doxorubicin
keywords: Cardiotonic steroids; Chemotherapy; Multidrug resistance reversal; P-glycoprotein