title: The plant decapeptide OSIP108 can alleviate mitochondrial dysfunction induced by cisplatin in human cells.
abstract: We investigated the effect of the Arabidopsis thaliana-derived decapeptide OSIP108 on human cell tolerance to the chemotherapeutic agent cisplatin (Cp), which induces apoptosis and mitochondrial dysfunction. We found that OSIP108 increases the tolerance of HepG2 cells to Cp and prevents Cp-induced changes in basic cellular metabolism. More specifically, we demonstrate that OSIP108 reduces Cp-induced inhibition of respiration, decreases glycolysis and prevents Cp-uptake in HepG2 cells. Apart from its protective action against Cp in human cells, OSIP108 also increases the yeast Saccharomyces cerevisiae tolerance to Cp. A limited yeast-based study of OSIP108 analogs showed that cyclization does not severely affect its activity, which was further confirmed in HepG2 cells. Furthermore, the similarity in the activity of the D-stereoisomer (mirror image) form of OSIP108 with the L-stereoisomer suggests that its mode of action does not involve binding to a stereospecific receptor. In addition, as OSIP108 decreases Cp uptake in HepG2 cells and the anti-Cp activity of OSIP108 analogs without free cysteine is reduced, OSIP108 seems to protect against Cp-induced toxicity only partly via complexation. Taken together, our data indicate that OSIP108 and its cyclic derivatives can protect against Cp-induced toxicity and, thus, show potential as treatment options for mitochondrial dysfunction- and apoptosis-related conditions.
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, Heverlee 3001, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Spincemaille
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, Heidelberg 69120, Germany.
authors.forename: Hamed
authors.initials: H
authors.lastname: Alborzinia
authors.affiliation: Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, Leuven 3000, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Dekervel
authors.affiliation: Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, Leuven 3000, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Windmolders
authors.affiliation: Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, Leuven 3000, Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: van Pelt
authors.affiliation: Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, Leuven 3000, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Cassiman
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Old 4072, Australia.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cheneval
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Old 4072, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.affiliation: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität, Braunschweig, Beethovenstrasse 55, Braunschweig 38106, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schur
authors.affiliation: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität, Braunschweig, Beethovenstrasse 55, Braunschweig 38106, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, Heidelberg 69120, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wölfl
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, Heverlee 3001, Belgium. bruno.cammue@biw.kuleuven.be.
authors.forename: Bruno P A
authors.initials: BP
authors.lastname: Cammue
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, Heverlee 3001, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Thevissen
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017360:Arabidopsis / Q000502:physiology*; D029681:Arabidopsis Proteins / Q000494:pharmacology*; D002945:Cisplatin / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D029681:Arabidopsis Proteins; C000594979:methionyl-leucyl-cysteinyl-valyl-leucyl-glutaminyl-glycyl-leucyl-arginyl-glutamic acid; D002945:Cisplatin