Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts
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-maxim...
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MDPI AG
2013-12-01
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| Series: | Marine Drugs |
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| Online Access: | http://www.mdpi.com/1660-3397/11/12/4858 |
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| author | Anna Király Tímea Váradi Tímea Hajdu Ralph Rühl Carlos M. Galmarini János Szöllősi Peter Nagy |
| author_facet | Anna Király Tímea Váradi Tímea Hajdu Ralph Rühl Carlos M. Galmarini János Szöllősi Peter Nagy |
| author_sort | Anna Király |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:07:35Z |
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| id | doaj.art-f51e71c5d41e46428207b192790bf399 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-14T07:07:35Z |
| publishDate | 2013-12-01 |
| publisher | MDPI AG |
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| series | Marine Drugs |
| spelling | doaj.art-f51e71c5d41e46428207b192790bf3992022-12-22T02:06:31ZengMDPI AGMarine Drugs1660-33972013-12-0111124858487510.3390/md11124858md11124858Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid RaftsAnna Király0Tímea Váradi1Tímea Hajdu2Ralph Rühl3Carlos M. Galmarini4János Szöllősi5Peter Nagy6Department of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, HungaryDepartment of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, HungaryDepartment of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, HungaryDepartment of Biochemistry and Molecular Biology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, HungaryCell Biology Department, PharmaMar, Avda de los Reyes 1, Pol. Ind. La Mina, Colmenar Viejo, Madrid 28770, SpainDepartment of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, HungaryDepartment of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, HungaryThe 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.http://www.mdpi.com/1660-3397/11/12/4858elisidepsinlipid raftshydroxylated lipidsfatty acid 2-hydroxylasecooperative bindingmembrane permeabilization |
| spellingShingle | Anna Király Tímea Váradi Tímea Hajdu Ralph Rühl Carlos M. Galmarini János Szöllősi Peter Nagy Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts Marine Drugs elisidepsin lipid rafts hydroxylated lipids fatty acid 2-hydroxylase cooperative binding membrane permeabilization |
| title | Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts |
| title_full | Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts |
| title_fullStr | Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts |
| title_full_unstemmed | Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts |
| title_short | Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts |
| title_sort | hypoxia reduces the efficiency of elisidepsin by inhibiting hydroxylation and altering the structure of lipid rafts |
| topic | elisidepsin lipid rafts hydroxylated lipids fatty acid 2-hydroxylase cooperative binding membrane permeabilization |
| url | http://www.mdpi.com/1660-3397/11/12/4858 |
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