The asymmetry of plasma membranes and their cholesterol content influence the uptake of cisplatin

Abstract

The composition of the plasma membrane of malignant cells is thought to influence the cellular uptake of cisplatin and to take part in developing resistance to this widespread anti-cancer drug. In this work we study the permeation of cisplatin through the model membranes of normal and cancer cells using molecular dynamics simulations. A special attention is paid to lipid asymmetry and cholesterol content of the membranes. The loss of lipid asymmetry, which is common for cancer cells, leads to a decrease in their permeability to cisplatin by one order of magnitude in comparison to the membranes of normal cells. The change in the cholesterol molar ratio from 0% to 33% also decreases the permeability of the membrane by approximately one order of magnitude. The permeability of pure DOPC membrane is 5-6 orders of magnitude higher than one of the membranes with realistic lipid composition, which makes it as an inadequate model for the studies of drug permeability.

Figure 1

Snapshots of the simulated systems for cancer and normal membrane models. DOPC is shown in blue, SM in red, DOPS in yellow and DOPE in green. For the sake of clarity cholesterol is not shown. Head groups of lipids are shown as spheres. The histograms show the relative abundance of different lipid species for inner and outer monolayers for each membrane model (normalized for each monolayer). Numbers 1 and 5 correspond to the cancer and normal models presented in this work respectively, model 2 refers to the work by Klähn and Zacharias, model 3 to the work by Ingólfsson et al., model 4 to the 1) data reported by Marquardt et al..

Figure 2

Snapshot of the simulated “normal membrane” system. The wall particles are shown as black spheres. PC lipids are blue, SM are red, PE are green and PS are yellow. Cholesterol molecules are gray. Head groups of lipids and cholesterol are shown as spheres. The central region of the bicelle which is used for analysis is shaded.

Figure 3

Number densities of the lipid head groups (A), lipid tails (B) and cholesterol (C) for different model membranes. Outer leaflet corresponds to positive distances from the membrane center.

Figure 4

Order parameter of the lipid tails for all studied phospholipid species in the inner and outer monolayers for the different membrane models.

Figure 5

Absolute distance from the center of the membrane to the peak of head groups density for different membrane models as a function of cholesterol content. The lines show linear regression of the corresponding values for inner and outer leaflets.

Figure 6

(A) The PMFs of cisplatin, W(z); (B) the local diffusion coefficient of cisplatin, D(z); (C) the local resistance of the membrane R(z) (in log scale) for different membrane models. The errors are shown as ribbons for each curve. The errors for diffusion coefficients overlap a lot thus the errors of only one curve are shown in panel B to keep the figure readable. The errors of all other diffusion coefficients curves are shown separately in the Fig. S5.