title: Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin.
abstract: The human pathology Wilson disease (WD) is characterized by toxic copper (Cu) accumulation in brain and liver, resulting in, among other indications, mitochondrial dysfunction and apoptosis of hepatocytes. In an effort to identify novel compounds that can alleviate Cu-induced toxicity, we screened the Pharmakon 1600 repositioning library using a Cu-toxicity yeast screen. We identified 2 members of the drug class of Angiotensin II Type 1 receptor blockers (ARBs) that could increase yeast tolerance to Cu, namely Candesartan and Losartan. Subsequently, we show that specific ARBs can increase yeast tolerance to Cu and/or the chemotherapeutic agent cisplatin (Cp). The latter also induces mitochondrial dysfunction and apoptosis in mammalian cells. We further demonstrate that specific ARBs can prevent the prevalence of Cu-induced apoptotic markers in yeast, with Candesartan Cilexetil being the ARB which demonstrated most pronounced reduction of apoptosis-related markers. Next, we tested the sensitivity of a selection of yeast knockout mutants affected in detoxification of reactive oxygen species (ROS) and Cu for Candesartan Cilexetil rescue in presence of Cu. These data indicate that Candesartan Cilexetil increases yeast tolerance to Cu irrespectively of major ROS-detoxifying proteins. Finally, we show that specific ARBs can increase mammalian cell tolerance to Cu, as well as decrease the prevalence of Cu-induced apoptotic markers. All the above point to the potential of ARBs in preventing Cu-induced toxicity in yeast and mammalian cells.
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Spincemaille
authors.affiliation: Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster, Germany.
authors.forename: Gursimran
authors.initials: G
authors.lastname: Chandhok
authors.affiliation: Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster, Germany.
authors.forename: Andree
authors.initials: A
authors.lastname: Zibert
authors.affiliation: Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Verbeek
authors.affiliation: CISTIM Leuven vzw, Bio-Incubator 2, Wetenschapspark Arenberg, Gaston Geenslaan 2, 3001 Heverlee, Belgium. ; Centre for Drug Design and Discovery (CD3), KU Leuven R&D, Waaistraat 6, Box 5105, 3000 Leuven.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chaltin
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee, Belgium. ; Department of Plant Systems Biology, VIB, Technologiepark 927, 9052, Ghent, Belgium.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Cammue
authors.affiliation: Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Cassiman
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Thevissen
keywords: cisplatin; copper; drug repositioning; sartans