title: Hypoxia reduces the efficiency of elisidepsin by inhibiting hydroxylation and altering the structure of lipid rafts.
abstract: The mechanism of action of elisidepsin (PM02734, Irvalec®) is assumed to involve membrane permeabilization via attacking lipid rafts and hydroxylated lipids. Here we investigate the role of hypoxia in the mechanism of action of elisidepsin. Culturing under hypoxic conditions increased the half-maximal inhibitory concentration and decreased the drug's binding to almost all cell lines which was reversed by incubation of cells with 2-hydroxy palmitic acid. The expression of fatty acid 2-hydroxylase was strongly correlated with the efficiency of the drug and inversely correlated with the effect of hypoxia. Number and brightness analysis and fluorescence anisotropy experiments showed that hypoxia decreased the clustering of lipid rafts and altered the structure of the plasma membrane. Although the binding of elisidepsin to the membrane is non-cooperative, its membrane permeabilizing effect is characterized by a Hill coefficient of ~3.3. The latter finding is in agreement with elisidepsin-induced clusters of lipid raft-anchored GFP visualized by confocal microscopy. We propose that the concentration of elisidepsin needs to reach a critical level in the membrane above which elisidepsin induces the disruption of the cell membrane. Testing for tumor hypoxia or the density of hydroxylated lipids could be an interesting strategy to increase the efficiency of elisidepsin.
authors: Department of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, Hungary. nagyp@med.unideb.hu.
authors: Anna
authors: A
authors: Király
authors: Tímea
authors: T
authors: Váradi
authors: Tímea
authors: T
authors: Hajdu
authors: Ralph
authors: R
authors: Rühl
authors: Carlos M
authors: CM
authors: Galmarini
authors: János
authors: J
authors: Szöllősi
authors: Peter
authors: P
authors: Nagy
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D003412:Cricetulus; D047630:Depsipeptides / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects / Q000502:physiology*; D000860:Hypoxia / Q000503:physiopathology*; D008055:Lipids / Q000502:physiology*; D061986:MCF-7 Cells; D021962:Membrane Microdomains / Q000187:drug effects / Q000502:physiology*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology
chemical_list: D047630:Depsipeptides; D008055:Lipids; C522358:elisidepsin; D019308:Palmitic Acid; D006899:Mixed Function Oxygenases; C019081:fatty acid alpha-hydroxylase