Hypoxia reduces the efficiency of elisidepsin by inhibiting hydroxylation and altering the structure of lipid rafts

Anna Király, Tímea Váradi, Tímea Hajdu, Ralph Rühl, Carlos M. Galmarini, J. Szöllősi, Peter Nagy

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4858-4875
Number of pages18
JournalMarine Drugs
Volume11
Issue number12
DOIs
Publication statusPublished - Dec 2013

Fingerprint

Hydroxylation
Lipids
Membranes
Cell Membrane
elisidepsin
Hypoxia
Fluorescence Polarization
Palmitic Acid
Mixed Function Oxygenases
Confocal Microscopy
Pharmaceutical Preparations
Cluster Analysis
Fatty Acids
Cell Line

Keywords

  • Cooperative binding
  • Elisidepsin
  • Fatty acid 2-hydroxylase
  • Hydroxylated lipids
  • Lipid rafts
  • Membrane permeabilization

ASJC Scopus subject areas

  • Drug Discovery

Cite this

Hypoxia reduces the efficiency of elisidepsin by inhibiting hydroxylation and altering the structure of lipid rafts. / Király, Anna; Váradi, Tímea; Hajdu, Tímea; Rühl, Ralph; Galmarini, Carlos M.; Szöllősi, J.; Nagy, Peter.

In: Marine Drugs, Vol. 11, No. 12, 12.2013, p. 4858-4875.

Research output: Contribution to journalArticle

Király, Anna ; Váradi, Tímea ; Hajdu, Tímea ; Rühl, Ralph ; Galmarini, Carlos M. ; Szöllősi, J. ; Nagy, Peter. / Hypoxia reduces the efficiency of elisidepsin by inhibiting hydroxylation and altering the structure of lipid rafts. In: Marine Drugs. 2013 ; Vol. 11, No. 12. pp. 4858-4875.
@article{c1af7cbf2d274144a3a064f01957c299,
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{\circledR}) 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.",
keywords = "Cooperative binding, Elisidepsin, Fatty acid 2-hydroxylase, Hydroxylated lipids, Lipid rafts, Membrane permeabilization",
author = "Anna Kir{\'a}ly and T{\'i}mea V{\'a}radi and T{\'i}mea Hajdu and Ralph R{\"u}hl and Galmarini, {Carlos M.} and J. Sz{\"o}llősi and Peter Nagy",
year = "2013",
month = "12",
doi = "10.3390/md11124858",
language = "English",
volume = "11",
pages = "4858--4875",
journal = "Marine Drugs",
issn = "1660-3397",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "12",

}

TY - JOUR

T1 - Hypoxia reduces the efficiency of elisidepsin by inhibiting hydroxylation and altering the structure of lipid rafts

AU - Király, Anna

AU - Váradi, Tímea

AU - Hajdu, Tímea

AU - Rühl, Ralph

AU - Galmarini, Carlos M.

AU - Szöllősi, J.

AU - Nagy, Peter

PY - 2013/12

Y1 - 2013/12

N2 - 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.

AB - 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.

KW - Cooperative binding

KW - Elisidepsin

KW - Fatty acid 2-hydroxylase

KW - Hydroxylated lipids

KW - Lipid rafts

KW - Membrane permeabilization

UR - http://www.scopus.com/inward/record.url?scp=84892417337&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892417337&partnerID=8YFLogxK

U2 - 10.3390/md11124858

DO - 10.3390/md11124858

M3 - Article

C2 - 24317474

AN - SCOPUS:84892417337

VL - 11

SP - 4858

EP - 4875

JO - Marine Drugs

JF - Marine Drugs

SN - 1660-3397

IS - 12

ER -