In vitro and In vivo Selective Antitumor Activity of Edelfosine against Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Involving Lipid Rafts

Abstract

Purpose: Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) remain B-cell malignancies with limited therapeutic options. The present study investigates the in vitro and in vivo effect of the phospholipid ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) in MCL and CLL.Experimental Design: Several cell lines, patient-derived tumor cells, and xenografts in severe combined immunodeficient mice were used to examine the anti-MCL and anti-CLL activity of edelfosine. Furthermore, we analyzed the mechanism of action and drug biodistribution of edelfosine in MCL and CLL tumor-bearing severe combined immunodeficient mice.Results: Here, we have found that the phospholipid ether edelfosine was the most potent alkyllysophospholipid analogue in killing MCL and CLL cells, including patient-derived primary cells, while sparing normal resting lymphocytes. Alkyl-lysophospholipid analogues ranked edelfosine > perifosine ≫ erucylphosphocholine ≥ miltefosine in their capacity to elicit apoptosis in MCL and CLL cells. Edelfosine induced coclustering of Fas/CD95 death receptor and rafts in MCL and CLL cells. Edelfosine was taken up by malignant cells, whereas normal resting lymphocytes hardly incorporated the drug. Raft disruption by cholesterol depletion inhibited drug uptake, Fas/CD95 clustering, and edelfosine-induced apoptosis. Edelfosine oral administration showed a potent in vivo anticancer activity in MCL and CLL xenograft mouse models, and the drug accumulated dramatically and preferentially in the tumor.Conclusions: Our data indicate that edelfosine accumulates and kills MCL and CLL cells in a rather selective way, and set coclustering of Fas/CD95 and lipid rafts as a new framework in MCL and CLL therapy. Our data support a selective antitumor action of edelfosine. Clin Cancer Res; 16(7); 2046-54. ©2010 AACR.Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are two major B-cell-derived neoplasias for which current therapy is not satisfactory, leading in most cases to relapse and eventually to a fatal outcome. This lack of efficient therapy underscores the need for a continued search for novel chemotherapeutic agents. CLL is the most common adult leukemia and is characterized by the progressive accumulation of mature CD5 + B lymphocytes in the peripheral blood, bone marrow, and secondary lymphoid organs. New treatment combinations have incorporated the use of purine analogue (fludarabine)-based regimens together with monoclonal antibodies rituximab (anti-CD20) and alemtuzumab (anti-CD52), leading to improved complete response rates and prolonged progression-free survival, but a long-term survival benefit has not been shown (1, 2). MCL is characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in the overexpression of cyclin D1 in mature B

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

“…3A). Alkyl-lysophospholipid analogs (e.g., edelfosine and, to a lesser extent, perifosine) incorporate into lipid rafts, modify their organization, and can selectively induce programmed cell death in CLL and lymphoma cells (17,18). We found that edelfosine (and, to a much lesser extent, perifosine) significantly reduced aggregation upon prolonged incubation with CLL cells (Fig.…”

“…CLL cells (1 3 10 6 ) were separately mixed in the presence or in the absence of the following: 25 or 50 mg/ml anti-human CD21 (clone Bu32), 2.5 mg/ml anti-human CD62L (clone DREG-56), and 40 mg/ml anti-human b 2 integrin (clone P4H9-A11), all for 30 min; 10 mM MbCD for 5, 10, and 30 min; 20 mM cytochalasin B for 30 min; 10, 20, or 50 mM Syk inhibitor II, 70 mM genistein, 3 mM herbimycin A, or 1, 5, or 10 mM edelfosine or perifosine for 1 or 24 h; and 1, 5, 10, or 20 mM PP2 for 15 min or 2 h. These concentrations were established according to previous publications (17)(18)(19)(20)(21)(22)(23) and were titrated in this study to obtain a maximal effect without killing the cells. Controls used included Abs as isotype controls.…”

Edelfosine lipid nanosystems overcome drug resistance in leukemic cell lines

“…Edelfosine (ET) (1-O-octadecyl-2-O-methyl-snglycero-3-phosphocholine) is the prototype of a promising class of anticancer drugs known as synthetic alkyl-lysophospholipids (ALPs), which selectively target tumor cells sparing healthy ones [5]. ET is active against several tumor cell lines [5][6][7]. The exact mechanism of action of ET still remains to be fully elucidated, but it has been proved that it accumulates in membrane lipid rafts by recruiting and promoting clustering of Fas/CD95 receptors [6,[8][9][10].…”

Silencing of anti-apoptotic transmembrane protein lifeguard sensitizes solid tumor cell lines MCF-7 and SW872 to perifosine-induced cell death activation

“…activity (10). Although different types of alkylphospholipids depend on the same modes of cellular uptake, it appears that observed differences in kinetics and efficiencies may depend on variations in the importance of singular pathways, e.g., raft-mediated endocytosis via ATP-dependent translocase activity (15,16).…”

“…Various studies have shown that perifosine accumulates in lipid rafts in a manner sensitive to raft disruption by cholesterol depletion (9)(10)(11). Subsequently, it was suggested that LFG, an anti-apoptotic protein with subcellular localization in lipid rafts, may interfere with perifosine-induced apoptosis.…”