Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Abstract

Synthetic alkyl lipids, such as the ether lipids edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) and ohmline (1-O-hexadecyl-2-O-methyl-rac-glycero-3-β-lactose), are forming a class of antitumor agents that target cell membranes to induce apoptosis and to decrease cell migration/invasion, leading to the inhibition of tumor and metastasis development. In this review, we present the structure-activity relationship of edelfosine and ohmline, and we point out differences and similarities between these two amphiphilic compounds. We also discuss the mechanisms of action of these synthetic alkyl ether lipids (involving, among other structures and molecules, membrane domains, Fas/CD95 death receptor signaling, and ion channels), and highlight a key role for lipid rafts in the underlying process. The reorganization of lipid raft membrane domains induced by these alkyl lipids affects the function of death receptors and ion channels, thus leading to apoptosis and/or inhibition of cancer cell migration. The possible therapeutic use of these alkyl lipids and the clinical perspectives for these lipids in prevention or/and treatment of tumor development and metastasis are also discussed.

Effect of Erufosine on Membrane Lipid Order in Breast Cancer Cell Models

“…It is therefore tempting to assume that the changes in membrane order (observed by using Di-4-ANEPPDQH rather than Laurdan) might be connected to alterations in membrane compositions brought about by EPC3. This hypothesis is in agreement with the observation that certain APLs might influence lipid metabolism and lipid-mediated signaling cascades (1,2,43). Also EPC3 can reduce the synthesis of key raft-associated phospholipids, such as PC and SM ((44) and Tzoneva R., unpublished data).…”

7‐Dehydrocholesterol (7‐DHC), But Not Cholesterol, Causes Suppression of Canonical TGF‐β Signaling and Is Likely Involved in the Development of Atherosclerotic Cardiovascular Disease (ASCVD)

“…This results from the predominant localization of TbR-I and TbR-II in lipid rafts/caveolae in these cells [Ren et al, 2011]. We hypothesize that high-level accumulation (10-2,000-fold normal) of 7-DHC, which varies in severity in SLOS patients and SLOS tissues, results in lipid raft/caveolae dysfunction, turnover, and down-regulation of the many resident membrane proteins in lipid rafts/caveolae, including TGF-b receptors [Huang and Huang, 2005;Chen et al, 2007Chen et al, , 2008Chen et al, , 2009Chen et al, , 2011, neurotrophin receptors [Sebastião et al, 2011;Zhang et al, 2013;Gou-F abregas et al, 2016], G protein-coupled receptors (GPCRs) (neurological receptors) [Bj€ ork and Svenningsson, 2011], ion channels [Jaffr es et al, 2016], receptor protein kinases (RTKs) (e.g., growth factor receptors) [Basu et al, 2008] and growth hormone receptor [Yang et al, 2004]. Down-regulation of these important membrane proteins in tissues during embryonic development may result in prenatal and postnatal growth retardation, microcephaly, intellectual disability, multiple external malformations (e.g., cleft palate), internal anomalies, and mental retardation characteristic of SLOS.…”

Micellar curcumin improves the antibacterial activity of the alkylphosphocholines erufosine and miltefosine against pathogenicStaphyloccocus aureusstrains

“…In the light of the emerging bacterial resistance to broad-spectrum antibiotics, the efforts of many scientists are focused on the development of new active chemical structures or drug repurposing. Alkylphosphocholines (APC) are a promising class of drugs with pleiotropic pharmacological effects [1][2][3]. They originate from membrane ether lipids and structurally represent phosphocholine esters of aliphatic long-chain alcohols with amphiphilic chemical properties.…”