BioPhysics & Condensed Matter Seminar: Dr. David Gidalevitz, Illiois Institute of Technology  Add To Calendar

  • Date(s): Thursday, 3/15 3:30 PM to Thursday, 3/15 4:30 PM
  • Speaker: Prof. David Gidalevitz
  • Host: Prof. Ursula Perez-Salas
Title: Membrane cholesterol reduces cellular toxicity from small hydrophobic drugs

Abstract: Hydrophobic drugs and toxins must permeate the plasma membrane barrier to carry out their specific functions. Plasma membranes of eukaryotes are primarily composed of phospholipids, proteins, and sterols. These members change in concentration and chemo type based on the function of the host cell. Here we use methyl cyclodextrin assays to deplete glioma and neuroblastoma cells of their cholesterol content and find that specific cell types survive longer prior to membrane cholesterol depletion, while the cell lines with higher membrane cholesterol content have higher survival times. Surface X-ray scattering on Langmuir lipid monolayers of characteristic phospholipid DPPC (dipalmitoylphosphatidylcholine) and cholesterol mixtures show that this relationship to membrane cholesterol extends to the molecular level. Specular X-ray reflectivity of these films before and after interaction with the superwarfarin brodifacoum show that the drug has a high affinity for monolayers of exclusively the DPPC lipid, while having no measurable effect on films entirely composed of cholesterol. Grazing incidence X-ray diffraction on the film clearly demonstrates that the ordered portion of the lipid membrane shifts from a rectangular unit cell to a hexagonal unit cell upon interaction; no changes in the cholesterol membrane diffraction were observed. Monolayers of DPPC to Cholesterol molecular ratios 1:0, 1:1, 2:1, 4:1, and 0:1 were formed to observe changes in affinity between the pure lipid cases. In molar ratios of up to 4:1 DPPC to cholesterol, no effect was observed in the lipid membrane in neither packing characteristics nor membrane affinity of the drug. Our results suggest that even a 20% ratio of membrane cholesterol could have a protective role as it pertains to the uptake and permeation of hydrophobic toxins, such as superwarfarins.