Alkylphosphocholines (APCs) belong to a class of synthetic antitumor lipids, which are new-generation anticancer agents. In contrast to traditional antitumor drugs, they do not attack the cell nucleus but, rather, the cellular membrane; however, their mechanism of action is not fully understood. This work compared the interactions of selected APCs [namely, hexadecylphosphocholine (miltefosine), octadecylphosphocholine and erucylphosphocholine] with the most important membrane lipids [cholesterol, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)] and examined their influence on a model membrane of tumor and normal cells. As a simple model of membranes, Langmuir monolayers prepared by mixing cholesterol either with a saturated phosphatidylcholine (DPPC), for a normal cell membrane, or with an unsaturated one (POPC), for a tumor cell membrane, have been applied. The APC–lipid interactions, based on experimental surface pressure (π) versus mean molecular area (A) isotherms, were analyzed qualitatively (with mean molecular area values) as well as quantitatively (with the ΔGexc function). Strong attractive interactions were observed for mixtures of APCs with cholesterol, contrary to the investigated phosphatidylcholines, for which the interactions were found to be weak with a tendency to separation of film components. In ternary monolayers it has been found that the investigated model systems (cholesterol/DPPC/APC vs cholesterol/POPC/APC) differ significantly as regards the interactions between film-forming molecules. The results demonstrate stronger interactions between the components of cholesterol/POPC/APC monolayers compared to cholesterol/POPC film, mimicking tumor cell membranes. In contrast, the interactions in cholesterol/DPPC/APC films were found to be weaker than those in the cholesterol/DPPC system, serving as a model of healthy cell membranes, thus proving that the incorporation of APCs is, from a thermodynamic point of view, unfavorable for binary cholesterol/DPPC monolayers. It can be concluded that the composition of healthy cell membranes is a natural barrier preventing the incorporation of APCs into normal cells.

In this study, 25-hydroxycholesterol (25-OH), a biamphiphilic compound with a wide range of biological activities, has been investigated at the air/water interface. We were interested in how two hydroxyl groups attached at distal positions of the 25-OH molecule (namely, at C(3) in the sterane system and at C(25) in the side chain) influence its surface behavior. Apart from traditional Langmuir monolayers, other complementary surface-sensitive techniques, such as electric surface potential measurements, Brewster angle microscopy (BAM, enabling texture visualization and film thickness measurements), and polarization modulation-infrared reflection-absorption spectroscopy (PM-IRRAS), were applied. Experimental data have been interpreted with the aid of theoretical study. Our results show that 25-OH molecules in the monomolecular layer are anchored to the water surface alternatively with C(3) or C(25) hydroxyl groups. Theoretical calculations revealed that the populations of these alternative orientations were not equal and molecules anchored with C(3) hydroxyl groups were found to be in excess. As a consequence of such an arrangement, surface films of 25-OH are of lower stability as compared to cholesterol (considered as a non-oxidized analogue of 25-OH). Moreover, it was found that, upon compression, the transition from mono- to bilayer occurred. The molecular mechanism and interactions stabilizing bilayer structure were proposed. The explanation of the observed unusual surface behavior of 25-OH may contribute to an understanding of differences in biological activity between chain- and ring-oxidized sterols.

Cyclosporin A (CsA), a hydrophobic cyclic peptide produced by the fungus Tolypocladium inflatum, is well known for its high efficiency as an immunosuppressor for transplanted organs and anti-inflammatory properties; however, it is also active as antiparasitic (antimalarial) drug. Antimalarial mechanism of CsA action lacks a detailed understanding at molecular level. Due to a high lipophilicity of CsA, it is able to interact with lipids of cellular membrane; however, molecular targets of this drug are still unknown. To get a deeper insight into the mode of antimalarial activity of CsA, it is of utmost importance to examine its interactions with membrane components. To reach this goal, the Langmuir monolayer technique, which serves as a very useful, easy to handle and controllable model of biomembranes, has been employed. In this work, the interactions between CsA and main membrane lipids, i.e., cholesterol (Chol), 2-oleoyl-1-palmitoyl-3-phosphocholine (POPC), and sphingomyelin (SM), have been investigated. Attractive interactions are observed only for CsA mixtures with SM, while repulsive forces occur in systems containing remaining membrane lipids. Taking into consideration mutual interactions between membrane lipids (Chol–SM; Chol–POPC and SM–POPC), the behavior of CsA in model erythrocyte membrane of normal and infected cells has been analyzed. Our results prove strong affinity of CsA to SM in membrane environment. Since normal and parasitized erythrocytes differ significantly in the level of SM, this phospholipid may be considered as a molecular target for antimalarial activity of CsA.Electronic supplementary materialThe online version of this article (doi:10.1007/s00232-015-9814-9) contains supplementary material, which is available to authorized users.