Antitumour ether lipids: proapoptotic agents with multiple therapeutic indications

Abstract

Synthetic ether-linked analogues of phosphatidylcholine, collectively referred to as antitumour ether lipids or synthetic antitumour lipids (ATLs), are a versatile class of structurally-related and pharmacologically active alkylphospholipids with manifold biomedical applications that are able to kill tumour cells and protozoan parasites. This cytotoxic action of ATLs relies on their ability to affect signalling processes, inducing apoptosis in the target cell. ATLs comprise two subfamilies of compounds, namely: i) the so-called alkyl-lysophospholipid analogues or alkyl ether phospholipids, exemplified by edelfosine, which shows a selective antitumour action through a unique mechanism of action by intracellular activation of Fas/CD95 death receptor and its co-clustering with membrane rafts; and ii) the alkylphosphocholines (APCs), exemplified by miltefosine, which has become the first orally-effective treatment for visceral leishmaniasis. New clinically promising APC members include perifosine and erucylphosphocholine. Additional ATL therapeutic indications include multiple sclerosis, autoimmune and inflammatory diseases, as well as psoriasis and viral infections. This review summarises the evidence and patented information supporting major ATL biomedical uses.