phospholipid ethers

Summary

Summary: Phospholipids which have an alcohol moiety in ethereal linkage with a saturated or unsaturated aliphatic alcohol. They are usually derivatives of phosphoglycerols or phosphatidates. The other two alcohol groups of the glycerol backbone are usually in ester linkage. These compounds are widely distributed in animal tissues.

Top Publications

  1. Gajate C, Mollinedo F. The antitumor ether lipid ET-18-OCH(3) induces apoptosis through translocation and capping of Fas/CD95 into membrane rafts in human leukemic cells. Blood. 2001;98:3860-3 pubmed
    ..This translocation of Fas into membrane rafts may provide a mechanism for amplifying Fas signaling by reorganization of membrane microdomains...
  2. Gajate C, Mollinedo F. Biological activities, mechanisms of action and biomedical prospect of the antitumor ether phospholipid ET-18-OCH(3) (edelfosine), a proapoptotic agent in tumor cells. Curr Drug Metab. 2002;3:491-525 pubmed
    ..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...
  3. Ruiter G, Zerp S, Bartelink H, van Blitterswijk W, Verheij M. Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway. Anticancer Drugs. 2003;14:167-73 pubmed
    ..Inhibition of the PI3K-Akt/PKB survival pathway represents a novel mode of action of ALPs that may significantly contribute to the induction of apoptosis...
  4. Na H, Chang C, Trosko J. Growth suppression of a tumorigenic rat liver cell line by the anticancer agent, ET-18-O-CH(3), is mediated by inhibition of cytokinesis. Cancer Chemother Pharmacol. 2003;51:209-15 pubmed
  5. Mollinedo F, de la Iglesia Vicente J, Gajate C, Estella Hermoso de Mendoza A, Villa Pulgarin J, Campanero M, et al. Lipid raft-targeted therapy in multiple myeloma. Oncogene. 2010;29:3748-57 pubmed publisher
    ..Our data reveal cholesterol-containing lipid rafts as a novel and efficient therapeutic target in MM, opening a new avenue in cancer treatment...
  6. Brites P, Ferreira A, da Silva T, Sousa V, Malheiro A, Duran M, et al. Alkyl-glycerol rescues plasmalogen levels and pathology of ether-phospholipid deficient mice. PLoS ONE. 2011;6:e28539 pubmed publisher
    ..This study provides evidence of the beneficial effects of treating a plasmalogen deficiency with alkyl-glycerol...
  7. Quesada E, Delgado J, Gajate C, Mollinedo F, Acuña A, Amat Guerri F. Fluorescent phenylpolyene analogues of the ether phospholipid edelfosine for the selective labeling of cancer cells. J Med Chem. 2004;47:5333-5 pubmed
    ..Fluorescence microscopy experiments show that 6 selectively labels human cancer cells, accumulating into specific domains of the plasma membrane...
  8. Estella Hermoso de Mendoza A, Campanero M, de la Iglesia Vicente J, Gajate C, Mollinedo F, Blanco Prieto M. Antitumor alkyl ether lipid edelfosine: tissue distribution and pharmacokinetic behavior in healthy and tumor-bearing immunosuppressed mice. Clin Cancer Res. 2009;15:858-64 pubmed publisher
  9. Zerp S, Vink S, Ruiter G, Koolwijk P, Peters E, van der Luit A, et al. Alkylphospholipids inhibit capillary-like endothelial tube formation in vitro: antiangiogenic properties of a new class of antitumor agents. Anticancer Drugs. 2008;19:65-75 pubmed
    ..Interference with the angiogenic process represents a novel mode of action of APLs and might significantly contribute to the antitumor effect of these compounds...

More Information

Publications62

  1. van Blitterswijk W, Verheij M. Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects. Curr Pharm Des. 2008;14:2061-74 pubmed
    ..For example, ALPs increase the cancer cell sensitivity to radiotherapy in vitro and in vivo. We highlight the clinical potential of perifosine, an orally available APL...
  2. Na H, Surh Y. The antitumor ether lipid edelfosine (ET-18-O-CH3) induces apoptosis in H-ras transformed human breast epithelial cells: by blocking ERK1/2 and p38 mitogen-activated protein kinases as potential targets. Asia Pac J Clin Nutr. 2008;17 Suppl 1:204-7 pubmed
    ..Based on these findings, it is likely that ET-18-O-CH3 inactivates ERK1/2, Akt, and NF-kappaB signaling via COX-2 induction in MCF10A-ras cells, thereby inducing apoptosis of these cells...
  3. Escobar P, Matu S, Marques C, Croft S. Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and amphotericin B. Acta Trop. 2002;81:151-7 pubmed
    ..5-37.1 microM against amastigotes. Amphotericin B deoxycholate was used as the standard drug and gave submicromolar ED(50) values in all assays; L. mexicana was the least sensitive species to this drug...
  4. Gajate C, Del Canto Jañez E, Acuña A, Amat Guerri F, Geijo E, Santos Beneit A, et al. Intracellular triggering of Fas aggregation and recruitment of apoptotic molecules into Fas-enriched rafts in selective tumor cell apoptosis. J Exp Med. 2004;200:353-65 pubmed
    ..Our data set a framework for the development of more targeted therapies leading to intracellular Fas activation and recruitment of downstream signaling molecules into Fas-enriched rafts...
  5. Naito Y, Okada M, Yagisawa H. Phospholipase C isoforms are localized at the cleavage furrow during cytokinesis. J Biochem. 2006;140:785-91 pubmed
  6. Loidl A, Sevcsik E, Riesenhuber G, Deigner H, Hermetter A. Oxidized phospholipids in minimally modified low density lipoprotein induce apoptotic signaling via activation of acid sphingomyelinase in arterial smooth muscle cells. J Biol Chem. 2003;278:32921-8 pubmed
    ..Thus, we conclude that modified phospholipids induce signaling cascades via activation of acid sphingomyelinase finally leading to apoptosis of smooth muscle cells, which is a detrimental process in the development of atherosclerosis...
  7. Chiang K, Niessen S, Saghatelian A, Cravatt B. An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling. Chem Biol. 2006;13:1041-50 pubmed
    ..The integrated molecular profiling method described herein should facilitate the functional annotation of metabolic enzymes in any living system...
  8. Zhang H, Gajate C, Yu L, Fang Y, Mollinedo F. Mitochondrial-derived ROS in edelfosine-induced apoptosis in yeasts and tumor cells. Acta Pharmacol Sin. 2007;28:888-94 pubmed
    ..To investigate whether a similar process mediates cytotoxicity of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3, edelfosine) in both yeasts and human tumor cells...
  9. Aroca J, Sánchez Piñera P, Corbalan Garcia S, Conesa Zamora P, de Godos A, Gomez Fernandez J. Correlation between the effect of the anti-neoplastic ether lipid 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine on the membrane and the activity of protein kinase Calpha. Eur J Biochem. 2001;268:6369-78 pubmed
    ..When PKC was assayed using large unilamellar vesicles a slight activation was observed at very low ET-18-OCH3 concentrations...
  10. Nieto Miguel T, Fonteriz R, Vay L, Gajate C, López Hernández S, Mollinedo F. Endoplasmic reticulum stress in the proapoptotic action of edelfosine in solid tumor cells. Cancer Res. 2007;67:10368-78 pubmed
    ..Our data also indicate that mitochondria are indispensable for this edelfosine-induced cell death initiated by ER stress...
  11. Cabrera Serra M, Valladares B, Piñero J. In vivo activity of perifosine against Leishmania amazonensis. Acta Trop. 2008;108:20-5 pubmed publisher
    ..Perifosine showed the higher activity in the in vivo assay and is showing as a new possibility within the alkyl-phospholipids group for the treatment against cutaneous leishmaniasis caused by L. amazonensis...
  12. Gajate C, Gonzalez Camacho F, Mollinedo F. Lipid raft connection between extrinsic and intrinsic apoptotic pathways. Biochem Biophys Res Commun. 2009;380:780-4 pubmed publisher
  13. Pushkareva M, Janoff A, Mayhew E. Inhibition of cell division but not nuclear division by 1-O- octadecyl-2-O-methyl-Sn-glycero-3-phosphocholine. Cell Biol Int. 1999;23:817-28 pubmed
    ..2000). Furthermore, treatment of cells with ET-18-OCH(3)results in the accumulation of apoptotic cells in time- and dose-dependent manner. It is possible that inhibition of cytokinesis may be related to cytoskeletal effects...
  14. Tsutsumi T, Tokumura A, Kitazawa S. Undifferentiated HL-60 cells internalize an antitumor alkyl ether phospholipid more rapidly than resistant K562 cells. Biochim Biophys Acta. 1998;1390:73-84 pubmed
    ..c) 1998 Elsevier Science B.V...
  15. Gajate C, Mollinedo F. Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood. 2007;109:711-9 pubmed
    ..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...
  16. Jan C, Wu S, Tseng C. The ether lipid ET-18-OCH3 increases cytosolic Ca2+ concentrations in Madin Darby canine kidney cells. Br J Pharmacol. 1999;127:1502-10 pubmed
    ..Phospholipase D and phospholipase A2, but not phospholipase C, might be involved in mediating the capacitative Ca2+ entry. La3+ abolished the ET-18-OCH3-induced [Ca2+]i rise presumably by inhibiting PAF receptors...
  17. Qin J, Testai F, Dawson S, Kilkus J, Dawson G. Oxidized phosphatidylcholine formation and action in oligodendrocytes. J Neurochem. 2009;110:1388-99 pubmed publisher
    ..We concluded that OxPC initially activated NSMase and converted sphingomyelin into ceramide to mediate a series of downstream pro-apoptotic events in oligodendrocytes...
  18. Pérez Victoria F, Gamarro F, Ouellette M, Castanys S. Functional cloning of the miltefosine transporter. A novel P-type phospholipid translocase from Leishmania involved in drug resistance. J Biol Chem. 2003;278:49965-71 pubmed
  19. Mollinedo F, Fernandez M, Hornillos V, Delgado J, Amat Guerri F, Acuña A, et al. Involvement of lipid rafts in the localization and dysfunction effect of the antitumor ether phospholipid edelfosine in mitochondria. Cell Death Dis. 2011;2:e158 pubmed publisher
    ..These observations unveil a new framework in cancer chemotherapy that involves a link between lipid rafts and mitochondria in the mechanism of action of an antitumor drug, thus opening new avenues for cancer treatment...
  20. Mollinedo F, Gajate C, Martin Santamaria S, Gago F. ET-18-OCH3 (edelfosine): a selective antitumour lipid targeting apoptosis through intracellular activation of Fas/CD95 death receptor. Curr Med Chem. 2004;11:3163-84 pubmed
    ..This novel mechanism of action represents a new way to target tumour cells in cancer chemotherapy and can be of interest as a new framework in designing novel and more selective proapoptotic antitumour drugs...
  21. Torrecillas A, Aroca Aguilar J, Aranda F, Gajate C, Mollinedo F, Corbalan Garcia S, et al. Effects of the anti-neoplastic agent ET-18-OCH3 and some analogs on the biophysical properties of model membranes. Int J Pharm. 2006;318:28-40 pubmed
  22. Tokumura A, Tsutsumi T, Nishioka Y, Tsukatani H. Exogenously added alkylmethylglycerophosphocholine and alkylmethylcarbamylglycerophosphocholine accumulate in plasma membranes more than in intracellular membranes of rabbit platelets. Chem Phys Lipids. 1997;86:75-83 pubmed
  23. Pegorier S, Stengel D, Durand H, Croset M, Ninio E. Oxidized phospholipid: POVPC binds to platelet-activating-factor receptor on human macrophages. Implications in atherosclerosis. Atherosclerosis. 2006;188:433-43 pubmed
    ..Thus, we suggest, that POVPC signals in mature macrophages only in part through the PAF-R, a part of its effects may involve other receptors...
  24. Horowitz L, Hirdes W, Suh B, Hilgemann D, Mackie K, Hille B. Phospholipase C in living cells: activation, inhibition, Ca2+ requirement, and regulation of M current. J Gen Physiol. 2005;126:243-62 pubmed
    ..In each test, the suppression of KCNQ current closely paralleled the expected fall of PIP2. The results are described by a kinetic model...
  25. Ausili A, Torrecillas A, Aranda F, Mollinedo F, Gajate C, Corbalan Garcia S, et al. Edelfosine is incorporated into rafts and alters their organization. J Phys Chem B. 2008;112:11643-54 pubmed publisher
    ..The conclusion is that molecular ways of action of edelfosine in cells may involve the modification of the structure of rafts...
  26. Vrablic A, Albright C, Craciunescu C, Salganik R, Zeisel S. Altered mitochondrial function and overgeneration of reactive oxygen species precede the induction of apoptosis by 1-O-octadecyl-2-methyl-rac-glycero-3-phosphocholine in p53-defective hepatocytes. FASEB J. 2001;15:1739-44 pubmed
  27. van der Luit A, Vink S, Klarenbeek J, Perrissoud D, Solary E, Verheij M, et al. A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells. Mol Cancer Ther. 2007;6:2337-45 pubmed
    ..Overall, our results suggest that lipid rafts are critical membrane portals for cellular entry of alkylphospholipids depending on SMS1 activity and, therefore, are potential targets for alkylphospholipid anticancer therapy...
  28. Vink S, van Blitterswijk W, Schellens J, Verheij M. Rationale and clinical application of alkylphospholipid analogues in combination with radiotherapy. Cancer Treat Rev. 2007;33:191-202 pubmed
    ..The preclinical results on molecular targeting underlying this approach will be reviewed, concluded with first clinical data on combined treatment of radiotherapy with perifosine...
  29. Watson A, Leitinger N, Navab M, Faull K, Horkko S, Witztum J, et al. Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo. J Biol Chem. 1997;272:13597-607 pubmed
    ..Overall, these studies suggest that specific oxidized derivatives of arachidonic acid-containing phospholipids may be important initiators of atherogenesis...
  30. van Blitterswijk W, Hilkmann H, Storme G. Accumulation of an alkyl lysophospholipid in tumor cell membranes affects membrane fluidity and tumor cell invasion. Lipids. 1987;22:820-3 pubmed
    ..The extent of AMG-PC incorporation and fluidity change was not strictly correlated with the degree to which tumor cell invasion was inhibited...
  31. Al Shawaf E, Naylor J, Taylor H, Riches K, Milligan C, O Regan D, et al. Short-term stimulation of calcium-permeable transient receptor potential canonical 5-containing channels by oxidized phospholipids. Arterioscler Thromb Vasc Biol. 2010;30:1453-9 pubmed publisher
    ..Stimulation of calcium-permeable TRPC5-containing channels may be an early event in cellular responses to oxidized phospholipids that couples to cell migration and requires an unidentified G protein-coupled receptor. ..
  32. Hanson P, Malone L, Birchmore J, Nichols J. Lem3p is essential for the uptake and potency of alkylphosphocholine drugs, edelfosine and miltefosine. J Biol Chem. 2003;278:36041-50 pubmed
    ..These data demonstrate a requirement for Lem3p expression for normal phosphatidylcholine and alkylphosphocholine drug transport across the plasma membrane of yeast...
  33. Mollinedo F, de la Iglesia Vicente J, Gajate C, Estella Hermoso de Mendoza A, Villa Pulgarin J, de Frias M, et al. In vitro and In vivo selective antitumor activity of Edelfosine against mantle cell lymphoma and chronic lymphocytic leukemia involving lipid rafts. Clin Cancer Res. 2010;16:2046-54 pubmed publisher
    ..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...
  34. Mollinedo F, Gajate C. Fas/CD95 death receptor and lipid rafts: new targets for apoptosis-directed cancer therapy. Drug Resist Updat. 2006;9:51-73 pubmed
    ..These findings set a novel framework for the development of more targeted therapies leading to intracellular Fas activation and recruitment of downstream signaling molecules into Fas-enriched lipid rafts...
  35. Komljenovic D, Sandhoff R, Teigler A, Heid H, Just W, Gorgas K. Disruption of blood-testis barrier dynamics in ether-lipid-deficient mice. Cell Tissue Res. 2009;337:281-99 pubmed publisher
    ..These results suggest that ELs are essential for cyclic BTB dynamics ensuring the sluice mechanism for leptotene translocation into the adluminal compartment...
  36. Subbanagounder G, Leitinger N, Schwenke D, Wong J, Lee H, Rizza C, et al. Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position. Arterioscler Thromb Vasc Biol. 2000;20:2248-54 pubmed
  37. Rosenberger T, Oki J, Purdon A, Rapoport S, Murphy E. Rapid synthesis and turnover of brain microsomal ether phospholipids in the adult rat. J Lipid Res. 2002;43:59-68 pubmed
    ..The short half-lives of microsomal ether phospholipids and the rapid transfer to synaptosomes are consistent with evidence of the marked involvement of these lipids in brain signal transduction and synaptic function...
  38. Zaremberg V, Gajate C, Cacharro L, Mollinedo F, McMaster C. Cytotoxicity of an anti-cancer lysophospholipid through selective modification of lipid raft composition. J Biol Chem. 2005;280:38047-58 pubmed
    ..This study points to a novel mode of action for an anti-cancer drug through modification of plasma membrane lipid composition resulting in the displacement of an essential protein from lipid rafts...
  39. Teigler A, Komljenovic D, Draguhn A, Gorgas K, Just W. Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum. Hum Mol Genet. 2009;18:1897-908 pubmed publisher
    ..Common molecular mechanisms that may underlie these phenotypes are discussed...
  40. Thai T, Rodemer C, Jauch A, Hunziker A, Moser A, Gorgas K, et al. Impaired membrane traffic in defective ether lipid biosynthesis. Hum Mol Genet. 2001;10:127-36 pubmed
    ..The data suggest that plasmalogens, analogous to cholesterol, are essential for correct membrane functioning and their deficiency results in impaired membrane trafficking...
  41. Stemmer U, Ramprecht C, Zenzmaier E, Stojcic B, Rechberger G, Kollroser M, et al. Uptake and protein targeting of fluorescent oxidized phospholipids in cultured RAW 264.7 macrophages. Biochim Biophys Acta. 2012;1821:706-18 pubmed publisher
    ..The respective proteins are involved in apoptosis, stress response, lipid metabolism and transport. The identified target proteins may be considered primary signaling platforms of the oxidized phospholipid...
  42. Styger R, Wiesmann U, Honegger U. Plasmalogen content and beta-adrenoceptor signalling in fibroblasts from patients with Zellweger syndrome. Effects of hexadecylglycerol. Biochim Biophys Acta. 2002;1585:39-43 pubmed
    ..In vivo, this may contribute to the clinical manifestations of the disease...
  43. Santa Rita R, Henriques Pons A, Barbosa H, de Castro S. Effect of the lysophospholipid analogues edelfosine, ilmofosine and miltefosine against Leishmania amazonensis. J Antimicrob Chemother. 2004;54:704-10 pubmed
    ..Analysis of the effect of edelfosine, ilmofosine and miltefosine on Leishmania amazonensis and of potential targets of these lysophospholipid analogues...
  44. Arthur G, Samadder P, Bittman R. ET-18-OCH3 inhibits the phosphorylation and activation of p70 S6 kinase in MCF-7 cells. Anticancer Res. 2005;25:95-100 pubmed
    ..The data suggest that the inhibition of p70S6K activation of by ET-18-OCH3 contributes to the antiproliferative effects of ALPs in MCF-7 cells...
  45. Nieto Miguel T, Gajate C, Mollinedo F. Differential targets and subcellular localization of antitumor alkyl-lysophospholipid in leukemic versus solid tumor cells. J Biol Chem. 2006;281:14833-40 pubmed
    ..These data indicate that edelfosine targets two different subcellular structures in a cell type-dependent manner, namely cell surface lipid rafts in leukemic cells and endoplasmic reticulum in solid tumor cells...
  46. Huber J, Vales A, Mitulovic G, Blumer M, Schmid R, Witztum J, et al. Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions. Arterioscler Thromb Vasc Biol. 2002;22:101-7 pubmed
    ..In addition to oxidized lipoproteins, oxidized MVs and apoptotic blebs may play an important role in chronic inflammatory diseases, such as atherosclerosis...
  47. Mollinedo F, Gajate C, Morales A, Del Canto Jañez E, Justies N, Collía F, et al. Novel anti-inflammatory action of edelfosine lacking toxicity with protective effect in experimental colitis. J Pharmacol Exp Ther. 2009;329:439-49 pubmed publisher
    ..Our data identify edelfosine as a novel anti-inflammatory drug by abating neutrophil infiltration through L-selectin shedding and may provide a new therapeutic approach for inflammatory bowel disease free from toxicity...
  48. Busto J, Sot J, Goni F, Mollinedo F, Alonso A. Surface-active properties of the antitumour ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (edelfosine). Biochim Biophys Acta. 2007;1768:1855-60 pubmed
    ..The surface-active properties of edelfosine are similar to those of other "single-chain" lipids, e.g. lysophosphatidylcholine, palmitoylcarnitine, or N-acetylsphingosine...
  49. Gajate C, Gonzalez Camacho F, Mollinedo F. Involvement of raft aggregates enriched in Fas/CD95 death-inducing signaling complex in the antileukemic action of edelfosine in Jurkat cells. PLoS ONE. 2009;4:e5044 pubmed publisher
    ..Recent evidence suggests that co-clustering of Fas/CD95 death receptor and lipid rafts plays a major role in death receptor-mediated apoptosis...
  50. Van Overloop H, Denizot Y, Baes M, Van Veldhoven P. On the presence of C2-ceramide in mammalian tissues: possible relationship to etherphospholipids and phosphorylation by ceramide kinase. Biol Chem. 2007;388:315-24 pubmed
    ..Our data indicate that C(2)-ceramide is present in mammalian tissues and can be converted to C(2)-ceramide-1-phosphate, in addition to other documented metabolic alterations, but does not seem to be linked to ether lipid metabolism...
  51. Moumtzi A, Trenker M, Flicker K, Zenzmaier E, Saf R, Hermetter A. Import and fate of fluorescent analogs of oxidized phospholipids in vascular smooth muscle cells. J Lipid Res. 2007;48:565-82 pubmed
  52. Fruhwirth G, Moumtzi A, Loidl A, Ingolic E, Hermetter A. The oxidized phospholipids POVPC and PGPC inhibit growth and induce apoptosis in vascular smooth muscle cells. Biochim Biophys Acta. 2006;1761:1060-9 pubmed
    ..Thus, the direct and indirect effects of POVPC and PGPC on cell viability may account for the detrimental actions of oxLDL on VSMC...
  53. Ruiter G, Zerp S, Bartelink H, van Blitterswijk W, Verheij M. Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. Cancer Res. 1999;59:2457-63 pubmed
    ..This type of modulation of specific signal transduction pathways in tumor cells may lead to the development of new therapeutic strategies...