Abstract 3331: Cluster of apoptotic signaling molecule-enriched rafts (CASMER) as a new target in the mechanism of action of the antitumor alkylphospholipid analogue edelfosine and cancer chemotherapy.
Authors: Mollinedo Faustino , Gajate Consuelo , Gonzalez-Camacho Fernando , Reis-Sobreiro Mariana 
Published: August 2014

Abstract
Lipid rafts are cholesterol- and sphingolipid-rich liquid ordered microdomains that float within the liquid disordered bilayer in cell membranes, and can coalesce upon clustering of their components. Proteins located in rafts are limited in their ability to freely diffuse over the plasma membrane. Thus, lipid rafts can form concentrating platforms for signaling molecules. Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) is the prototype molecule of a family of unnatural lipids, collectively known as synthetic alkylphospholipid analogs, which promotes apoptosis in a variety of tumor cells. Our in vitro and in vivo studies showed the preferential uptake of edelfosine by tumor cells, accumulating in lipid rafts, and promoting the intracellular activation of Fas/CD95 death receptor and its recruitment, together with downstream signaling molecules, in lipid rafts (1,2). This led us to define the concept of CASMER (cluster of apoptotic signaling molecule-enriched rafts) (3), which functions as a novel supramolecular entity in the triggering of apoptosis. Clusters of rafts, containing recruited Fas/CD95, FADD, and procaspase-8, forming the so-called death-inducing signaling complex (DISC), were shown to be involved in edelfosine-induced apoptosis of human T-cell leukemia Jurkat cells through genetic, biochemical and ultrastructural approaches. Co-immunoprecipitation and electron microscopy analyses revealed that edelfosine induced the clustering of DISC-containing rafts (4). Edelfosine-induced apoptosis in hematologic cancer cells involved both extrinsic and intrinsic pathways of apoptosis (5), as follows: drug accumulation in rafts → raft reorganization → Fas/CD95 recruitment in rafts → DISC → Bid cleavage → mitochondrial cytochrome c release → cell death. We have further extended the involvement of lipid rafts in the anticancer activity of additional antitumor agents, including resveratrol (6). Altogether, our data reveal that cholesterol-containing lipid rafts are a novel and efficient therapeutic target in blood malignancies, opening a new avenue in cancer treatment. These data also identify edelfosine as the first raft-targeted antitumor drug, thus behaving as a lead compound in the search of new agents for this raft-targeted therapy. These results provide the proof-of-principle and rationale for further clinical evaluation of edelfosine as well as of this new raft-targeted therapy to improve patient outcome in cancer.
Citation Format: Faustino Mollinedo, Consuelo Gajate, Fernando Gonzalez-Camacho, Mariana Reis-Sobreiro. Cluster of apoptotic signaling molecule-enriched rafts (CASMER) as a new target in the mechanism of action of the antitumor alkylphospholipid analogue edelfosine and cancer chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3331. doi:10.1158/1538-7445.AM2013-3331