Effects of etherlipid analogs on cell membrane functions

Abstract

Hexadecylphosphocholine and other etherlipid-derived substances show a pronounced antiproliferative activity on neoplastic cells and a broad spectrum of other biological effects on many cell types in vitro and in vivo. Though the precise molecular mechanism by which these etherlipid analogs act still remains unresolved, it seems clear that it most probably involves some essential function of the cell membrane. We investigated the effect of different etherlipids with and without cytotoxic activity in etherlipid-susceptible and -resistant tumor cell lines on three important membrane functions. We observed various inhibitory activities on endocytosis and the uptake of small precursor molecules as sugars, amino acids, and alcohols by toxic and nontoxic substances in resistant as well as susceptible cells. There was no correlation between the antiproliferative characteristics of the compounds and the effects on these membrane transport functions. Furthermore, the substances reduced the number of membrane tumor necrosis factor-alpha receptors regardless of their antiproliferative properties. The results of these investigations suggest that etherlipid analogs may interfere with many membrane functions in an unspecific manner. Therefore, many of the previously reported biological effects of etherlipids have to be viewed under a different light. Future investigation on these compounds should always contain appropriate control substances and cell models to really prove the specificity of the observed effects.

Miltefosine enhances phagocytosis but decreases nitric oxide production by peritoneal macrophages of C57BL/6 mice

“…It is possible that miltefosine improved phagocytosis through the increment in fluidity of the membrane of the macrophage that occurs by the inhibition of the de novo synthesis of phosphatidylcholine, a major component of biological membranes [32], consequently improving chemotaxis, motility, adherence of the macrophage and phagocytosis [20,22,[33][34][35][36][37][38]. Our data agree with the enhanced phagocytosis of L. donovani by macrophages of hamsters treated per os with miltefosine for 5 days [39].…”

Lysosomal and mitochondrial pathways in miltefosine-induced apoptosis in U937 cells

“…Moreover, miltefosine has extensive indications, being also registered as the first effective and safe oral treatment (Impavido r ) for Indian visceral leishmaniasis and cutaneous leishmaniasis [7,8]. In contrast to most currently available chemotherapeutic drugs, ATLs do not directly target DNA, but exert their action at the plasma membrane level where they interfere with mitogenic signal transduction pathways [9][10][11]. Whereas malignant cells are highly sensitive to the lethal action of ATLs, normal cells remain relatively unaffected, illustrating a selective antitumor property [12,13].…”

Hexadecylphosphocholine interferes with the intracellular transport of cholesterol in HepG2 cells

“…Other authors have also demonstrated that this movement of cholesterol from the plasma membrane to the ER can be inhibited under different experimental conditions, such as in the presence of hydrophobic amines [29] or progesterone [21], and by the disruption of the cytoskeleton or of the acidic compartments [10,30]. We also analysed the movement of newly synthesized cholesterol to the plasma membrane by using [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]acetate as a cholesterogenic precursor and (2-hydroxypropyl)-b-cyclodextrin as a cholesterol acceptor, as described by Yamauchi et al [31]. Our data showed that HePC treatment does not modify cholesterol transport from the ER to the plasma membrane (i.e.…”

“…Owing to its amphiphilic properties, HePC interacts with the cell membrane and rapidly reaches other subcellular membranes [5], thus being able to affect cell metabolism at different levels. We reported, in a previous study, that HePC interferes with phosphatidylcholine (PtdCho) synthesis in HepG2 cells via both cytidine 5¢-diphosphocholine [6] and phosphatidylethanolamine methylation [7].…”