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The adrenal specific toxicant mitotane directly interacts with lipid membranes and alters membrane properties

Holger A Scheidt1, Ivan Haralampiev2, Stephan Theisgen1

  • 1University of Leipzig, Institute of Medical Physics and Biophysics, Härtelstr. 16-18, 04107 Leipzig, Germany.

Molecular and Cellular Endocrinology
|March 23, 2016
PubMed

Insights

Mitotane, a cancer drug, disrupts cell membranes by inserting into the lipid-water interface. This interaction increases membrane permeability, potentially explaining its therapeutic effects and side effects.

Area of Science:

  • Biophysics
  • Cell Biology
  • Pharmacology

Background:

  • Mitotane (o,p'.-DDD) is an orphan drug for adrenocortical carcinoma.
  • Its precise mechanisms of action are not fully understood.
  • Interaction with cellular membranes is a hypothesized mechanism.

Purpose of the Study:

  • To characterize the interaction of mitotane and its metabolite o,p'-DDA with lipid membranes.
  • To elucidate the impact of mitotane on membrane structure and dynamics.

Main Methods:

  • Biophysical approaches including nuclear magnetic resonance (NMR) spectroscopy.
  • Electron spin resonance (ESR) spectroscopy.
  • Fluorescence spectroscopy.

Main Results:

  • Mitotane and o,p'-DDA bind to lipid membranes at the lipid-water interface.
  • Mitotane, but not o,p'-DDA, disturbs bilayer structure and increases membrane permeability.
  • Mitotane's effects on membrane integrity depend on phosphatidylethanolamine and cholesterol.

Conclusions:

  • This study provides the first detailed characterization of mitotane's impact on lipid membranes.
  • Findings may enhance understanding of mitotane's therapeutic effects and side effects in adrenocortical carcinoma treatment.
Keywords:
Fluorescent lipidLipid vesiclesLipid–drug interactionMembrane structureMitotaneOrder parameterSpin-labeled lipid

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