Abstract
The ether lipid edelfosine induces apoptosis selectively in tumor cells and is the prototypic molecule of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs. Cumulative evidence shows that edelfosine interacts with cholesterol-rich lipid rafts, endoplasmic reticulum (ER) and mitochondria. Edelfosine induces apoptosis in a number of hematological cancer cells by recruiting death receptors and downstream apoptotic signaling into lipid rafts, whereas it promotes apoptosis in solid tumor cells through an ER stress response. Edelfosine-induced apoptosis, mediated by lipid rafts and/or ER, requires the involvement of a mitochondrial-dependent step to eventually elicit cell death, leading to the loss of mitochondrial membrane potential, cytochrome c release and the triggering of cell death. The overexpression of Bcl-2 or Bcl-xL blocks edelfosine-induced apoptosis. Edelfosine induces the redistribution of lipid rafts from the plasma membrane to the mitochondria. The pro-apoptotic action of edelfosine on cancer cells is associated with the recruitment of F1FO–ATP synthase into cholesterol-rich lipid rafts. Specific inhibition of the FO sector of the F1FO–ATP synthase, which contains the membrane-embedded c-subunit ring that constitutes the mitochondrial permeability transcription pore, hinders edelfosine-induced cell death. Taking together, the evidence shown here suggests that the ether lipid edelfosine could modulate cell death in cancer cells by direct interaction with mitochondria, and the reorganization of raft-located mitochondrial proteins that critically modulate cell death or survival. Here, we summarize and discuss the involvement of mitochondria in the antitumor action of the ether lipid edelfosine, pointing out the mitochondrial targeting of this drug as a major therapeutic approach, which can be extrapolated to other alkylphospholipid analogs. We also discuss the involvement of cholesterol transport and cholesterol-rich lipid rafts in the interactions between the organelles as well as in the role of mitochondria in the regulation of apoptosis in cancer cells and cancer therapy.
Highlights
The ether lipid edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, ET-18-OCH3 ) (Figure 1) is considered as the prototype of a family of synthetic antitumor drugs collectively known as alkylphospholipid analogs (APLs) or antitumor ether lipids (AELs) [1,2,3]
Edelfosine accumulates in the lipid rafts of a wide array of hematological cancer cells [9,27,34,52,53,54], leading to apoptosis through the reorganization of these membrane domains, especially by promoting co-clustering of lipid rafts and
The higher cholesterol level in mitochondria from tumor cells as well as in the mitochondria-associated membranes (MAMs), connecting the endoplasmic reticulum (ER) and mitochondria, together with the presence of raft domains in the mitochondria could explain the presence of edelfosine in mitochondria
Summary
The ether lipid edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, ET-18-OCH3 ) (Figure 1) is considered as the prototype of a family of synthetic antitumor drugs collectively known as alkylphospholipid analogs (APLs) or antitumor ether lipids (AELs) [1,2,3]. Miltefosine (hexadecyl 2-(trimethylazaniumyl)ethyl phosphate, known as hexadecylphosphocholine) represents the minimal structural requirement for the antitumor activity of APLs and has become the first oral drug in the treatment of visceral leishmaniasis [4,5,6], being commercialized under the trademark name of Impavido® (oral solid human pharmaceutical product; Zentaris, Frankfurt, Germany). A remarkable characteristic of the ether lipid edelfosine is its selectivity in inducing apoptosis in cancer cells, whereas non-transformed cells are spared [1,2,9,27,32]. Edelfosine (Figure 1) is an oral drug showing potent antitumor activity against different kinds of tumors in cancer animal models [34,35,40,49], and lacks toxicity in rats after edelfosine oral treatment at pharmacological relevant doses, with no cardiotoxicity, hepatotoxicity or renal toxicity [50]. MOMP is regulated by the Bcl-2 family of proteins [51]
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