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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.

SUBMITTER: Rivel T

PROVIDER: S-EPMC6449338 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Rivel Timothée T Ramseyer Christophe C Yesylevskyy Semen S

Scientific reports 20190404 1

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 ...[more]

PMID: 30948733

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Project description:A uniquely sensitive method for ceramide domain detection allowed us to study in detail cholesterol-ceramide interactions in lipid bilayers with low (physiological) ceramide concentrations, ranging from low or no cholesterol (a situation similar to intracellular membranes, such as endoplasmic reticulum) to high cholesterol (similar to mammalian plasma membrane). Diverse fluorescence spectroscopy and microscopy experiments were conducted showing that for low cholesterol amounts ceramide segregates into gel domains that disappear upon increasing cholesterol levels. This was observed in different raft (sphingomyelin/cholesterol-containing) and non-raft (sphingomyelin-absent) membranes, i.e. mimicking different types of cell membranes. Cholesterol-ceramide interactions have been described mainly as raft sphingomyelin-dependent. Here sphingomyelin independence is demonstrated. In addition, ceramide-rich domains re-appear when either cholesterol is converted by cholesterol oxidase to cholestenone or the temperature is decreased. Ceramide is more soluble in cholesterol-rich fluid membranes than in cholesterol-poor ones, thereby increasing the chemical potential of cholesterol. Ceramide solubility depends on the average gel-fluid transition temperature of the remaining membrane lipids. The inability of cholestenone-rich membranes to dissolve ceramide gel domains shows that the cholesterol ordering and packing properties are fundamental to the mixing process. We also show that the solubility of cholesterol in ceramide domains is low. The results are rationalized by a ternary phospholipid/ceramide/cholesterol phase diagram, providing the framework for the better understanding of biochemical phenomena modulated by cholesterol-ceramide interactions such as cholesterol oxidase activity, lipoprotein metabolism, and lipid targeting in cancer therapy. It also suggests that the lipid compositions of different organelles are such that ceramide gel domains are not formed unless a stress or pathological situation occurs.

Project description:This study examines the relationship between cellular sphingomyelin content and the distribution of unesterified cholesterol between the plasma-membrane pool and the putative intracellular regulatory pool. The sphingomyelin content of cultured human skin fibroblasts was reduced by treatment of intact cells with extracellularly added neutral sphingomyelinase, and subsequent changes in the activities of cholesterol-metabolizing enzymes were determined. Exposure of fibroblasts to 0.1 unit of sphingomyelinase/ml for 60 min led to the depletion of more than 90% of the cellular sphingomyelin, as determined from total lipid extracts. In a time-course study, it was found that within 10 min of the addition of sphingomyelinase to cells, a dramatic increase in acyl-CoA:cholesterol acyltransferase activity could be observed, whether measured from the appearance of plasma membrane-derived [3H]cholesterol or exogenously added [14C]oleic acid, in cellular cholesteryl esters. In addition, the cholesteryl ester mass was significantly higher in sphingomyelin-depleted fibroblasts at 3 h after exposure to sphingomyelinase compared with that in untreated fibroblasts [7.1 +/- 0.4 nmol of cholesterol/mg equivalents of esterified cholesterol compared with 4.2 +/- 0.1 nmol of cholesterol/mg equivalents of cholesteryl ester in control cells (P less than 0.05)]. The sphingomyelin-depleted cells also showed a reduction in the rate of endogenous synthesis of cholesterol, as measured by incorporation of sodium [14C]acetate into [14C]cholesterol. These results are consistent with a rapid movement of cholesterol from sphingomyelin-depleted plasma membranes to the putative intracellular regulatory pool of cholesterol. This mass movement of cholesterol away from the plasma membranes presumably resulted from a decreased capacity of the plasma membranes to solubilize cholesterol, since sphingomyelin-depleted cells also had a decreased capacity to incorporate nanomolar amounts of [3H]cholesterol from the extracellular medium, as compared with control cells. These findings confirm previous assumptions that the membrane sphingomyelin content is an important determinant of the overall distribution of cholesterol within intact cells.

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

Publications

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

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