Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts

Abstract

Multiple myeloma (MM) is an incurable B-cell malignancy, requiring new therapeutic strategies. We have found that synthetic alkyl-lysophospholipids (ALPs) edelfosine and perifosine induced apoptosis in MM cell lines and patient MM cells, whereas normal B and T lymphocytes were spared. ALPs induced recruitment of Fas/CD95 death receptor, Fas-associated death domain-containing protein, and procaspase-8 into lipid rafts, leading to the formation of the death-inducing signaling complex (DISC) and apoptosis. TNF-related apoptosis-inducing ligand receptor-1/death receptor 4 (TRAIL-R1/DR4) and TRAIL-R2/DR5, as well as Bid, were also recruited into lipid rafts, linking death receptor and mitochondrial signaling pathways. ALPs induced mitochondrial cytochrome c release. Bcl-X(L) overexpression prevented cytochrome c release and apoptosis. A Fas/CD95-deficient MM subline expressing DR4 and DR5 was resistant to edelfosine. Fas/CD95 retrovirus transduction bestowed edelfosine sensitivity in these cells. A Fas/CD95 mutant lacking part of the intracellular domain was ineffective. Lipid raft disruption prevented ALP-induced Fas/CD95 clustering, DISC formation, and apoptosis. ALP-induced apoptosis was Fas/CD95 ligand (FasL/CD95L) independent. ALP-induced recruitment of death receptors in lipid rafts potentiated MM cell killing by FasL/CD95L and TRAIL. These data uncover a novel lipid raft-mediated therapy in MM involving concentration of death receptors in membrane rafts, with Fas/CD95 playing a major role in ALP-mediated apoptosis.

Combination of the anti-tumour cell ether lipid edelfosine with sterols abolishes haemolytic side effects of the drug

“…At variance with most conventional chemotherapeutic drugs, edelfosine does not target DNA but is rather taken up by malignant cells, triggering apoptosis in a large variety of human tumour cell lines, while normal cells are spared [3][4][5]. The apoptotic activity of edelfosine involves membrane rafts and the Fas/ CD95 death receptor [4][5][6], and the drug displays various dose-dependent effects on PKCα and PKCɛ [7].…”

Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy

“…EDLF induces apoptosis more expeditiously in leukemic cells than in solid tumor cells (Nieto-Miguel et al, 2006), through the intracellular activation of the death receptor Fas/CD95 and its recruitment, independently of its natural ligand FasL/CD95L, into lipid rafts (Gajate et al, 2000bMollinedo, 2001, 2007). EDLF accumulates in lipid rafts (van der Luit et al, 2002;Gajate et al, 2004), leading to a redistribution of proteins in these membrane domains that eventually induces cell death Zaremberg et al, 2005;Gajate and Mollinedo, 2007). EDLF was the first agent reported to promote co-clustering of Fas/CD95 and membrane rafts leading to apoptosis (Gajate et al, 2000bGajate and Mollinedo, 2001), representing a new way of killing tumor cells by targeting lipid rafts.…”

“…EDLF was the first agent reported to promote co-clustering of Fas/CD95 and membrane rafts leading to apoptosis (Gajate et al, 2000bGajate and Mollinedo, 2001), representing a new way of killing tumor cells by targeting lipid rafts. Additional antitumor drugs, including resveratrol (Delmas et al, 2003), cisplatin (Lacour et al, 2004), aplidin and perifosine (Gajate and Mollinedo, 2007), have been recently found to induce clustering of Fas/CD95 in lipid rafts. This has led to the notion that Fas/CD95 concentration in lipid rafts is a novel mode of action for anti-cancer drugs and a potential target in cancer chemotherapy .…”

Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells

“…Analysis of tumor xenografts revealed a strong reduction in ERK phosphorylation levels following perifosine treatment (data not shown), indicating that inhibition of MAPK signaling by perifosine toghether with Akt inhibition might also be involved in inducing tumor cells apoptosis and tumor growth delay. In 2007 van der Luit et al [60] reported perifosine incorporation into lipid rafts followed by inhibition of phosphatidylcholine synthesis and induction of apoptosis in lymphoma cells; in the same year Gajate and Mollinedo [61] demonstrated that perifosine induces apoptosis in multiple myeloma (MM) by recruitment of death receptors into lipid rafts and observed that the concentration of death receptors in lipid rafts following perifosine treatment rendered MM cells more sensitive to the action of death receptor ligands, such as TRAIL. Considering these previous observations, we can not exclude that perifosine sensitized TECs to CD34-TRAIL 1 cells-induced apoptosis not only by upregulating DR5 expression but also by acting on plasma membrane reorganization and causing DR5 accumulation into lipid rafts.…”