title: Interactions between ABC-transport proteins and the secondary Fusarium metabolites enniatin and beauvericin.
abstract: Enniatins (ENN) and beauvericin (BEA) exert cytotoxic properties. Here, we observed that their impact on Ca(2+)-homeostasis can be reversed by exogenous ATP. Thus, we investigated whether membrane-located ATP-binding cassette (ABC) transporters influence ENNs- and BEA-induced cytotoxicity. In short-term exposure assays breast cancer resistance protein (ABCG2)-overexpression weakly but significantly reduced the cytotoxic activity of BEA but not ENNs. In contrast, multidrug resistance-associated protein-1 (ABCC1)- and P-glycoprotein (ABCB1)-overexpression was not protective under identical conditions. ABCG2-mediated resistance against BEA was reversible by ABCG2 modulators. In long-term exposure assays, ABCG2 and ABCB1 significantly protected against ENNs- and to a lesser extent BEA-induced cytotoxicity. Moreover, both fusariotoxins potently inhibited the ABCG2- and ABCB1-mediated efflux of specific fluorescent substrates, with BEA being more effective. Additionally, ATPase and photoaffinity-labelling assays proofed interaction of both substances with ABCG2 and ABCB1. Remarkably, 2 years selection of KB-3-1 cells against both fusariotoxins resulted only in two-fold ENNs but negligible BEA resistance. Interestingly, the selected sublines displayed upregulation of multidrug resistance proteins and crossresistance to other chemotherapeutics. Summarizing, ABCG2 and ABCB1 slightly but significantly protect human cells against ENNs- and BEA-induced cytotoxicity. However, both mycotoxins potently interact with ABCB1 and ABCG2 transport functions suggesting influences on bioavailability of xenobiotics and pharmaceuticals.
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.
authors.forename: Rita
authors.initials: R
authors.lastname: Dornetshuber
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Michael
authors.initials: M
authors.lastname: Sulyok
authors.forename: Rainer
authors.initials: R
authors.lastname: Schumacher
authors.forename: Peter
authors.initials: P
authors.lastname: Chiba
authors.forename: Stephan
authors.initials: S
authors.lastname: Kopp
authors.forename: Gunda
authors.initials: G
authors.lastname: Koellensperger
authors.forename: Michael
authors.initials: M
authors.lastname: Micksche
authors.forename: Rosa
authors.initials: R
authors.lastname: Lemmens-Gruber
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm; D005670:Fusarium / Q000472:pathogenicity*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D009183:Mycotoxins / Q000633:toxicity*; D009363:Neoplasm Proteins / Q000502:physiology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002118:Calcium; D047630:Depsipeptides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009183:Mycotoxins; D009363:Neoplasm Proteins; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C100264:enniatins; C004456:beauvericin; C421109:multidrug resistance-associated protein 1