Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin
Authors:Pieter Spincemaille1,+, Gursimran Chandhok2,+, Andree Zibert2, Hartmut Schmidt2, Jef Verbeek3, Patrick Chaltin4,5, Bruno P.A. Cammue1,6,#, David Cassiman3, Karin Thevissen1,#
1 Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee, Belgium.
2 Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster, Germany.
3 Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
4 CISTIM Leuven vzw, Bio-Incubator 2, Wetenschapspark Arenberg, Gaston Geenslaan 2, 3001 Heverlee, Belgium.
5 Centre for Drug Design and Discovery (CD3), KU Leuven R&D, Waaistraat 6, Box 5105, 3000 Leuven.
6 Department of Plant Systems Biology, VIB, Technologiepark 927, 9052, Ghent, Belgium.
+ Both authors contributed equally to this work.
# Authors coordinated equally.
Keywords:
sartans, copper, cisplatin, drug repositioning.
Abbreviations:
aSMase - acid sphingomyelinase,
Cp - cisplatin,
Cu - copper,
ROS - reactive oxygen species,
SL - sphingolipid.
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Conflict of interest statement:
The authors declare no conflict of interest.
Please cite this article as:
Pieter Spincemaille, Gursimran Chandhok, Andree Zibert, Hartmut Schmidt, Jef Verbeek, Patrick Chaltin, Bruno P.A. Cammue, David Cassiman, Karin Thevissen (2014). Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin. Microbial Cell 1(11): 352-364.
© 2014 Spincemaille et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
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.
doi: 10.15698/mic2014.11.175
Volume 1, pp. 352 to 364, published 24/10/2014.