Superwarfarins are modified analogs of warfarin with additional lipophilic aromatic rings, up to 100-fold greater potency, and longer biological half-lives. We hypothesized that increased hydrophobicity allowed interactions with amphiphilic membranes and modulation of biological responses. We find that superwarfarins brodifacoum and difenacoum increase lactate production and cell death in neuroblastoma cells. In contrast, neither causes changes in glioma cells that have higher cholesterol content. After choleterol depletion, lactate production was increased and cell viability was reduced. Drug-membrane interactions were examined by surface X-ray scattering using Langmuir monolayers of dipalmitoylphosphatidylcholine and/or cholesterol. Specular X-ray reflectivity data revealed that superwarfarins, but not warfarin, intercalate between dipalmitoylphosphatidylcholine molecules, whereas grazing incidence X-ray diffraction demonstrated changes in lateral crystalline order of the film. Neither agent showed significant interactions with monolayers containing >20% cholesterol. These findings demonstrate an affinity of superwarfarins to biomembranes and suggest that cellular responses to these agents are regulated by cholesterol content.
|Number of pages||12|
|State||Published - Apr 26 2016|
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health grant 5U01NS083457 to D.L.F., Veterans Affairs Research Career Scientist Award to D.L.F., Veterans Affairs Merit grant to G.W. and I.R., and DARPA grant W911NF-09-1-378 to D.G.M.W.M. was supported by Argonne National Laboratory’s X-ray Science Division , Inelastic X-ray Nuclear Resonant Scattering group. Use of the Advanced Photon Source was supported by the U.S. Department of Energy under contract W-31-109-Eng-38 (I.K.).
© 2016 Biophysical Society.
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