Biological Activities, Mechanisms of Action and Biomedical Prospect of the Antitumor Ether Phospholipid ET-18-OCH3 (Edelfosine), A Proapoptotic Agent in Tumor Cells

Abstract

The antitumor ether lipid ET-18-OCH(3) (edelfosine) is the prototype of a new class of antineoplastic agents, synthetic analogues of lysophosphatidylcholine, that shows a high metabolic stability, does not interact with DNA and shows a selective apoptotic response in tumor cells, sparing normal cells. Unlike currently used antitumor drugs, ET-18-OCH(3) does not act directly on the formation and function of the replication machinery, and thereby its effects are independent of the proliferative state of target cells. Because of its capacity to modulate cellular regulatory and signaling events, including those failing in cancer cells, like defective apoptosis, ET-18-OCH(3), beyond its putative clinical importance, is an interesting model compound for the development of more selective drugs for cancer therapy. Although ET-18-OCH(3) enhances host defense mechanisms against tumors, its major antitumor action lies in a direct effect on cancer cells, inhibiting phosphatidylcholine biosynthesis and inducing apoptosis in tumor cells. Recent progress has allowed unraveling the molecular mechanism underlying the apoptotic action of ET-18-OCH(3), leading to the notion that ET-18-OCH(3) is selectively incorporated into tumor cells and induces cell death by intracellular activation of the cell death receptor Fas/CD95. This intracellular Fas/CD95 activation is a novel mechanism of action for an antitumor drug and represents a new way to target tumor cells in cancer chemotherapy that can be of interest as a new framework in designing novel antitumor drugs. ET-18-OCH(3) and some analogues are pleiotropic agents that affect additional biomedical important diseases, including parasitic and autoimmune diseases, suggesting new therapeutic indications for these compounds.

Lipid raft involvement in yeast cell growth and death

“…Edelfosine has been reported to have affinity for cholesterol, and for cholesterol-rich membranes such as rafts (Ausili et al, 2008; Busto et al, 2008), because of the complementarity of the molecular geometrics of sterols and edelfosine (Busto et al, 2008). Edelfosine induces apoptotic cell death in a wide number of human cancer cells (Mollinedo et al, 1997, 2004, 2010a,b; Gajate and Mollinedo, 2002, 2007; Gajate et al, 2012) through raft reorganization and redistribution of the raft protein content (Gajate and Mollinedo, 2001, 2007; Gajate et al, 2004, 2009a). In human hematopoietic cancer cells, edelfosine treatment leads to the recruitment of apoptotic molecules into raft platforms, thus leading to the emerging concept of an apoptotic “liquid-ordered” plasma membrane platform named as “cluster of apoptotic signaling molecule-enriched rafts” (CASMERs; Gajate and Mollinedo, 2005; Gajate et al, 2009b; Mollinedo and Gajate, 2010a,b).…”

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

“…Edelfosine (1- O -octadecyl-2- O -methyl- rac -glycero-3-phosphocholine, ET-18-OCH 3 ) is a promising antitumor ether lipid drug [28]–[30], which is not mutagenic and acts by activating apoptosis through its interaction with cell membranes [31]–[34]. In addition to its antitumor activity, edelfosine has been shown to exert in vitro antiparasitic activity against different species of Leishmania parasites [35]–[37].…”

Involvement of lipid rafts in the localization and dysfunction effect of the antitumor ether phospholipid edelfosine in mitochondria

“…3, 4, 5 This group of compounds also includes miltefosine, marketed under the trade name of Miltex (Baxter Oncology GmbH, Halle/Westfalen, Germany) as a topical drug for the palliative treatment of cutaneous metastases from breast cancer, and perifosine, currently in phase II clinical trials. 6 Edelfosine shows affinity for cholesterol, 7, 8 and has been reported to kill a wide variety of tumor cells through its accumulation in lipid rafts, 9, 10, 11, 12 which are membrane microdomains enriched in cholesterol and sphingolipids.…”