Abstract
Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) is an anti-tumour cell ether lipid with surface-active properties. Pure edelfosine can be dispersed in aqueous media in the form of micelles. One important, negative side effect of edelfosine is that it is highly haemolytic. In this paper, we show that edelfosine can be co-dispersed in water with certain lipids (particularly cholesterol, campesterol or β-sitosterol) so that it gives rise to liposomes. Surface pressure measurements demonstrate that edelfosine is slowly released from these liposomes. In liposomal form, edelfosine remains apoptogenic for a variety of leukemia cell lines, while its haemolytic effect is abolished. The phenomenon is explained on the basis of the complementarity of the molecular geometries of sterols and edelfosine.
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References
Gajate C, Mollinedo F (2002) Biological activities, mechanism of action and biomedical prospect of the antitumour ether phospholipid ET-18-OCH(3) (edelfosine), a proapoptotic agent in tumor cells. Curr Drug Metab 3:491–525
Mollinedo F, Gajate C, Martin-Santamaria S et al (2004) ET-18-OCH3 (edelfosine): a selective antitumour lipid targeting apoptosis through intracellular activation of Fas/CD95 death receptor. Curr Med Chem 11:3163–3184
Mollinedo F, Fernandez-Luna JL, Gajate C et al (1997) Selective induction of apoptosis in cancer cells by the ether lipid ET-18-OCH3 (edelfosine):molecular structure requirements, cellular uptake, and protection by Bcl-2 and Bcl-X(L). Cancer Res 57:1320–1328
Gajate C, del Canto-Jañez E, Acuña AU et al (2004) Intracellular triggering of Fas aggregation and recruitment of apoptotic molecules into Fas-enriched rafts in selective tumor cell apoptosis. J Exp Med 200:353–365
Gajate C, Mollinedo F (2007) Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood 109:711–719
Gajate C, Mollinedo F (2001) 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 98:3860–3863
Conesa-Zamora P, Mollinedo F, Corbalán-García S et al (2005) A comparative study of the effect of the antineoplastic ether lipid 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine and some homologous compounds on PKC alpha and PKC epsilon. Biochim Biophys Acta 1687:110–119
Busto JV, Sot J, Goñi FM et al (2007) Surface-active properties of the antitumour ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (edelfosine). Biochim Biophys Acta 1768:1855–1860
Torrecillas A, Aroca-Aguilar JD, Aranda FJ et al (2006) Effects of the anti-neoplastic agent ET-18-OCH(3) and some analogs on the biophysical properties of model membranes. Int J Pharm 318:28–40
Ahmad I, Filep JJ, Franklin JC et al (1997) Enhanced therapeutic effects of liposome-associated 1-O-Octadecyl-2-O-methyl-sn-glycero-3-phosphocholine. Cancer Res 57:1915–1921
Israelachvili JN, Marcelja S, Horn RG (1980) Physical principles of membrane organization. Q Rev Biophys 13:121–200
Gajate C, Santos-Beneit AM, Macho A et al (2000) Involvement of mitochondria and caspase-3 in ET-18-OCH3-induced apoptosis of human leukemic cells. Int J Cancer 86:208–218
Tardi PG, Gallagher RC, Johnstone S et al (2007) Coencapsulation of irinotecan and floxuridine into low cholesterol-containing liposomes that coordinate drug release in vivo. Biochim Biophys Acta 1768:678–687
Volodkin D, Mohwald H, Voegel JC et al (2007) Coating of negatively charged liposomes by polylysine: drug release study. J Control Release 117:111–120
Castresana J, Nieva JL, Rivas E et al (1992) Partial dehydration of phosphatidylethanolamine phosphate groups during hexagonal phase formation, as seen by i.r. spectroscopy. Biochem J 282:467–70
Szule JA, Fuller NL, Rand RP (2002) The effects of acyl chain length and saturation of diacylglycerols and phosphatidylcholines on membrane monolayer curvature. Biophys J 83:977–984
Kooijman EE, Chupin V, Fuller NL et al (2005) Spontaneous curvature of phosphatidic acid and lysophosphatidic acid. Biochemistry 44:2097–2102
Alonso A, Goñi FM, Buckley JT (2000) Lipids favoring inverted phase enhance the ability of aerolysin to permeabilize liposome bilayers. Biochemistry 39:14019–14024
Ahyayauch H, Villar AV, Alonso A et al (2005) Modulation of PI-specific phospholipase C by membrane curvature and molecular order. Biochemistry 44:11592–11600
Heczková B, Slotte JP (2006) Effect of anti-tumor ether lipids on ordered domains in model membranes. FEBS Lett 580:2471–2476
Acknowledgements
This work was supported in part by grants from the Spanish Ministerio de Educación y Ciencia (BFU2005-06095 to A.A.; SAF2005-04293 to F.M.), the Basque Government (IT-461-07 to F.M.G.) and by grant RD06/0020/1037 (to F.M.) from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Ministerio de Sanidad of Spain. J.V.B. was a predoctoral student supported by the Basque Government.
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Busto, J.V., del Canto-Jañez, E., Goñi, F.M. et al. Combination of the anti-tumour cell ether lipid edelfosine with sterols abolishes haemolytic side effects of the drug. J Chem Biol 1, 89–94 (2008). https://doi.org/10.1007/s12154-008-0009-z
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DOI: https://doi.org/10.1007/s12154-008-0009-z