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Membrane Cholesterol Modulates Superwarfarin Toxicity
- Source :
- Biophysical journal. 110(8)
- Publication Year :
- 2015
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Programmed cell death
1,2-Dipalmitoylphosphatidylcholine
Biophysics
01 natural sciences
Cell membrane
03 medical and health sciences
chemistry.chemical_compound
Cell Line, Tumor
0103 physical sciences
Amphiphile
medicine
Animals
Humans
Viability assay
010306 general physics
Membranes
Dose-Response Relationship, Drug
Cholesterol
Cell Membrane
4-Hydroxycoumarins
Rats
030104 developmental biology
Membrane
medicine.anatomical_structure
chemistry
Biochemistry
Dipalmitoylphosphatidylcholine
Toxicity
Subjects
Details
- ISSN :
- 15420086
- Volume :
- 110
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Biophysical journal
- Accession number :
- edsair.doi.dedup.....7cab10749e2a6594e721183f1ef9b60a