Interactions of Alkylphosphocholines with Model Membranes—The Langmuir Monolayer Study

Abstract

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.

Interactions between Antitumor Alkylphosphocholines and Membrane Sphingolipids in Langmuir Monolayers

“…In this paper we have extended our study to mixtures with sphingolipids: sphingomyelin (SM) and ganglioside GM 1 . The isotherms for both sphingolipids [2224] as well as APCs [12] are known and our results are in a good agreement with the data already published. Namely, both investigated sphingolipids behave similarly in monolayers at the air/water interface (Figs.…”

“…Three antitumor phosphocholines (APCs), namely hexadecylphosphocholine (HePC), octadecylphosphocholine (OcPC) and erucylphosphocholine (ErPC) have already been studied alone as well as in mixtures with two main membrane lipids, i.e. cholesterol and phosphatidylcholines (DPPC and POPC) [12]. In this paper we have extended our study to mixtures with sphingolipids: sphingomyelin (SM) and ganglioside GM 1 .…”

“…malicious membrane was more rigid as it contained increased level of cholesterol. Although monolayer experiments proved strong anity of APCs to cholesterol [12], recent studies [13] revealed that cholesterol and cholesterol-to-phospholipid ratio are not major determinants of ATLs sensitivity.…”

Studies of Lipid Monolayers Prepared from Native and Model Plant Membranes in Their Interaction with Zearalenone and Its Mixture with Selenium Ions

“…On the basis of Langmuir monolayer technique, some steps in the mechanisms of physiological processes, especially those connected with the influence of hormones (Filek et al 2005; Gzyl et al 2004; Wnętrzak et al 2013), organic and non-organic ions (Gzyl-Malcher et al 2009, 2011; Rudolphi-Skórska et al 2014) have been interrelated. One of the important problems in plant physiology is to protect the cells against the mycotoxin accumulation (Diamond et al 2013).…”

Interactions of bioactive molecules & nanomaterials with Langmuir monolayers as cell membrane models

“…In this context, the simplest way was to investigate drug-membrane interactions. Edelfosine [179], miltefosine [180] and erucylphosphocholine [181] formed stable monolayers and displayed strong attractive interactions for mixtures with cholesterol [182][183][184][185], interpreted in terms of immobilizing drug molecules in the membrane [182] by forming -surface complexes‖ of 1:1 stiochiometry. These sphingomyelin [190,191] were important in membrane activity of ATLs due to weak interactions and the tendency to phase separate.…”