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001-es BibID:	BIBFORM050047
Első szerző:	Király Anna
Cím:	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, János Szöllősi, Peter Nagy
Dátum:	2013
Megjegyzések:	The mechanism of action of elisidepsin (PM02734, Irvalec(R)) 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
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban analysis Anisotropy article Biophysics cell biology Cell Line Cell Membrane Cells Confocal Confocal microscopy EXPRESSION Fluorescence FLUORESCENCE ANISOTROPY Hungary lipid raft LIPID RAFTS Lipids Microscopy Research Research Support Support
Megjelenés:	Marine Drugs. - 11 : 12 (2013), p. 4858-4875. -
További szerzők:	Váradi Tímea (1982-) (okleveles vegyész) Hajdu Tímea (1991-) (biomérnök) Rühl, Ralph (1969-) (vegyész) Galmarini, Carlos M. Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
Internet cím:	DOI Szerző által megadott URL Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM022510
Első szerző:	Váradi Tímea (okleveles vegyész)
Cím:	ErbB protein modifications are secondary to severe cell membrane alterations induced by elisidepsin treatment / Váradi T., Roszik J., Lisboa D., Vereb G., Molina-Guijarro J. M., Galmarini C. M., Szöllosi J., Nagy P.
Dátum:	2011
Megjegyzések:	Elisidepsin is a marine-derived anti-tumor agent with unique mechanism of action. It has been suggested to induce necrosis associated with severe membrane damage. Since indirect evidence points to the involvement of ErbB receptor tyrosine kinases and lipid rafts in the mechanism of action of elisidepsin, we investigated the effect of the drug on the distribution of ErbB proteins and systematically compared the elisidepsin sensitivity of cell lines overexpressing ErbB receptors. Stable expression of a single member of the ErbB family (ErbB1-3) or co-transfection of ErbB2 and ErbB3 did not modify the elisidepsin sensitivity of CHO and A431 cells. However, elisidepsin induced the redistribution of ErbB3 and two GPI-anchored proteins (transfected GPI-anchored eGFP and placental alkaline phosphatase) from the plasma membrane to intracellular vesicles without comparable effects on ErbB1 and ErbB2. Elisidepsin increased the binding of a conformational sensitive anti-ErbB3 antibody without modifying the binding of other ErbB2 or ErbB3 antibodies, and it decreased the homoassociation of both ErbB2 and ErbB3. We also found that elisidepsin decreased the fluorescence anisotropy of a membrane specific fluorescent probe and induced a blue shift in the emission spectrum of Laurdan pointing to significant changes in the order of the plasma membrane possibly associated with the formation of liquid ordered domains. Although the distribution of ErbB proteins is preferentially altered by elisidepsin, our data question their role in determining sensitivity to the drug. We assume that induction of liquid ordered domains is the primary action of elisidepsin leading to all the other observed changes.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban Elisidepsin ErbB proteins Liquid ordered domain FRET
Megjelenés:	European Journal of Pharmacology 667 : 1-3 (2011), p. 91-99. -
További szerzők:	Roszik János (1979-) (biofizikus) Lisboa, Duarte (1982-) (biotechnológus) Vereb György (1965-) (biofizikus, orvos) Molina-Guijarro, J. M. Galmarini, Carlos M. Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
Internet cím:	Szerző által megadott URL Intézményi repozitóriumban (DEA) tárolt változat DOI
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