ECE2015 Eposter Presentations Endocrine tumours (69 abstracts)
Mitotane directly interacts with lipid membranes and alters membrane structure and dynamics
Peter Müller 1 , Stephan Theisgen 2 , Andreas Schirbel 3 , Silviu Sbiera 3 , Ivan Haralampiev 1 , Martin Fassnacht 3, , Daniel Huster 2 & Matthias Kroiss 3,
1Humboldt University, Berlin, Germany; 2Institute of Medical Physics and Biophysics, Leipzig, Germany; 3University Hospital Würzburg, Würzburg, Germany; 4Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
Context: Mitotane (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]ethane) is the only drug approved for treatment of adrenocortical carcinoma (ACC). Mitotane counteracts both tumor growth and tumoural steroid hormone production but treatment is severely hampered by unfavorable pharmacokinetics and serious side effects. Mitotane is a lipophilic compound and treatment emergent alterations of lipid metabolism are frequently observed. This raises the question whether mitotane directly interacts with lipids.
Objective: To investigate the impact of mitotane on lipid membranes using biophysical techniques.
Methods: We used nuclear magnetic resonance (NMR), electron spin resonance (ESR) and fluorescence spectroscopy as well as fluorescence microscopy to determine whether mitotane interacts with lipid membranes. We aimed at determining the impact of mitotane on membrane structure and dynamics by assessing its influence on membrane integrity and on the formation of lateral membrane domains in lipid vesicles (large unilamellar vesicles, giant unilamellar vesicles).
Results: We demonstrate that mitotane intercalates into lipid membranes. This binding influences the mobility of spin-labeled lipids within membranes and disturbs membrane integrity in a dose-dependent manner. The presence of cholesterol in the membrane appears to modulate these effects.
Conclusion: Mitotane directly binds to and interacts with lipid membranes thereby altering membrane structure and dynamics. This interaction may contribute to the biological effects of mitotane impacting both on efficacy and adverse effects.
Disclosure: This work was supported by the Deutsche Forschungsgemeinschaft (grant FA 466/4-1 to M.F. and KR 4371/1-1 to M.K.) and a fellowship of the Comprehensive Cancer Center Mainfranken to M.K.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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