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Dayan B Goodenowe - One of the best experts on this subject based on the ideXlab platform.
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oral bioavailability of the Ether Lipid plasmalogen precursor ppi 1011 in the rabbit a new therapeutic strategy for alzheimer s disease
Lipids in Health and Disease, 2011Co-Authors: Paul L. Wood, Amin M Khan, Greg Ehrmantraut, Nina Lane, Tara C Smith, Dayan B GoodenoweAbstract:Introduction: Docosahexaenoic acid (DHA) and DHA-containing ethanolamine plasmalogens (PlsEtn) are decreased in the brain, liver and the circulation in Alzheimer’s disease. Decreased supply of plasmalogen precursors to the brain by the liver, as a result of peroxisomal deficits is a process that probably starts early in the AD disease process. To overcome this metabolic compromise, we have designed an orally bioavailable DHA-containing Ether Lipid precursor of plasmalogens. PPI-1011 is an alkyl-diacyl plasmalogen precursor with palmitic acid at sn-1, DHA at sn-2 and lipoic acid at sn-3. This study outlines the oral pharmacokinetics of this precursor and its conversion to PlsEtn and phosphatidylethanolamines (PtdEtn). Methods: Rabbits were dosed orally with PPI-1011 in hard gelatin capsules for time-course and dose response studies. Incorporation into PlsEtn and PtdEtn was monitored by LC-MS/MS. Metabolism of released lipoic acid was monitored by GC-MS. To monitor the metabolic fate of different components of PPI-1011, we labeled the sn-1 palmitic acid, sn-2 DHA and glycerol backbone with 13 C and monitored their metabolic fates by LC-MS/MS. Results: PPI-1011 was not detected in plasma suggesting rapid release of sn-3 lipoic acid via gut lipases. This conclusion was supported by peak levels of lipoic acid metabolites in the plasma 3 hours after dosing. While PPI1011 did not gain access to the plasma, it increased circulating levels of DHA-containing PlsEtn and PtdEtn. Labeling experiments demonstrated that the PtdEtn increases resulted from increased availability of DHA released via remodeling at sn-2 of phosphoLipids derived from PPI-1011. This release of DHA peaked at 6 hrs while increases in phosphoLipids peaked at 12 hr. Increases in circulating PlsEtn were more complex. Labeling experiments demonstrated that increases in the target PlsEtn, 16:0/22:6, consisted of 2 pools. In one pool, the intact precursor received a sn-3 phosphoethanolamine group and desaturation at sn-1 to generate the target plasmalogen. The second pool, like the PtdEtn, resulted from increased availability of DHA released during remodeling of sn-2. In the case of sn-1 18:0 and 18:1 plasmalogens with [ 13 C3]DHA at sn-2, labeling was the result of increased availability of [ 13 C3]DHA from Lipid remodeling. Isotope and repeated dosing (2 weeks) experiments also demonstrated that plasmalogens and/or plasmalogen precursors derived from PPI-1011 are able to cross both the blood-retinal and blood-brain barriers. Conclusions: Our data demonstrate that PPI-1011, an Ether Lipid precursor of plasmalogens is orally bioavailable in the rabbit, augmenting the circulating levels of unesterified DHA and DHA-containing PlsEtn and PtdEtn. Other ethanolamine plasmalogens were generated from the precursor via Lipid remodeling (de-acylation/re-acylation reactions at sn-2) and phosphatidylethanolamines were generated via de-alkylation/re-acylation reactions at sn-1. Repeated oral dosing for 2 weeks with PPI-1011 resulted in dose-dependent increases in circulating DHA and DHAcontaining plasmalogens. These products and/or precursors were also able to cross the blood-retinal and bloodbrain barriers.
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oral bioavailability of the Ether Lipid plasmalogen precursor ppi 1011 in the rabbit a new therapeutic strategy for alzheimer s disease
Lipids in Health and Disease, 2011Co-Authors: Paul L. Wood, Amin M Khan, Greg Ehrmantraut, Nina Lane, Tara C Smith, Dayan B GoodenoweAbstract:Introduction Docosahexaenoic acid (DHA) and DHA-containing ethanolamine plasmalogens (PlsEtn) are decreased in the brain, liver and the circulation in Alzheimer's disease. Decreased supply of plasmalogen precursors to the brain by the liver, as a result of peroxisomal deficits is a process that probably starts early in the AD disease process. To overcome this metabolic compromise, we have designed an orally bioavailable DHA-containing Ether Lipid precursor of plasmalogens. PPI-1011 is an alkyl-diacyl plasmalogen precursor with palmitic acid at sn-1, DHA at sn-2 and lipoic acid at sn-3. This study outlines the oral pharmacokinetics of this precursor and its conversion to PlsEtn and phosphatidylethanolamines (PtdEtn).
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in vitro and in vivo plasmalogen replacement evaluations in rhizomelic chrondrodysplasia punctata and pelizaeus merzbacher disease using ppi 1011 an Ether Lipid plasmalogen precursor
Lipids in Health and Disease, 2011Co-Authors: Paul L. Wood, Amin M Khan, Greg Ehrmantraut, Nancy Braverman, Tara C Smith, Dayan B GoodenoweAbstract:Background Childhood peroxisomal disorders and leukodystrophies are devastating diseases characterized by dysfunctional Lipid metabolism. Plasmalogens (Ether glycerophosphoethanolamine Lipids) are decreased in these genetic disorders. The biosynthesis of plasmalogens is initiated in peroxisomes but completed in the endoplasmic reticulum. We therefore undertook a study to evaluate the ability of a 3-substituted, 1-alkyl, 2-acyl glyceryl Ether Lipid (PPI-1011) to replace plasmalogens in rhizomelic chrondrodysplasia punctata type 1 (RCDP1) and rhizomelic chrondrodysplasia punctata type 2 (RCDP2) lymphocytes which possess peroxisomal mutations culminating in deficient plasmalogen synthesis. We also examined plasmalogen synthesis in Pelizaeus-Merzbacher disease (PMD) lymphocytes which possess a proteoLipid protein-1 (PLP1) missense mutation that results in abnormal PLP1 folding and it's accumulation in the endoplasmic reticulum (ER), the cellular site of the last steps in plasmalogen synthesis. In vivo incorporation of plasmalogen precursor into tissue plasmalogens was also evaluated in the Pex7 mouse model of plasmalogen deficiency.
Fabian Dorninger - One of the best experts on this subject based on the ideXlab platform.
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Ether Lipid Deficiency in Mice Produces a Complex Behavioral Phenotype Mimicking Aspects of Human Psychiatric Disorders
International journal of molecular sciences, 2019Co-Authors: Fabian Dorninger, Gerhard Zeitler, Anna Gundacker, Daniela D. Pollak, Johannes BergerAbstract:Ether Lipids form a specialized subgroup of phosphoLipids that requires peroxisomes to be synthesized. We have previously detected that deficiency in these Lipids leads to a severe disturbance of neurotransmitter homeostasis and release as well as behavioral abnormalities, such as hyperactivity, in a mouse model. Here, we focused on a more detailed examination of the behavioral phenotype of Ether Lipid-deficient mice (Gnpat KO) and describe a set of features related to human psychiatric disorders. Gnpat KO mice show strongly impaired social interaction as well as nestlet shredding and marble burying, indicating disturbed execution of inborn behavioral patterns. Also, compromised contextual and cued fear conditioning in these animals suggests a considerable memory deficit, thus potentially forming a connection to the previously determined Ether Lipid deficit in human patients with Alzheimer’s disease. Nesting behavior and the preference for social novelty proved normal in Ether Lipid-deficient mice. In addition, we detected task-specific alterations in paradigms assessing depression- and anxiety-related behavior. The reported behavioral changes may be used as easy readout for the success of novel treatment strategies against Ether Lipid deficiency in ameliorating nervous system-associated symptoms. Furthermore, our findings underline that Ether Lipids are paramount for brain function and demonstrate their relevance for cognitive, social, and emotional behavior. We hereby substantially extend previous observations suggesting a link between deficiency in Ether Lipids and human mental illnesses, particularly autism and attention-deficit hyperactivity disorder.
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Disturbed neurotransmitter homeostasis in Ether Lipid deficiency.
Human molecular genetics, 2019Co-Authors: Fabian Dorninger, Theresa König, Petra Scholze, Michael L. Berger, Gerhard Zeitler, Christoph Wiesinger, Anna Gundacker, Daniela D. Pollak, Sigismund Huck, Wilhelm W JustAbstract:Plasmalogens, the most prominent Ether (phospho)Lipids in mammals, are structural components of most cellular membranes. Due to their physicochemical properties and abundance in the central nervous system, a role of plasmalogens in neurotransmission has been proposed, but conclusive data are lacking. Here, we targeted this issue in the glyceronephosphate O-acyltransferase (Gnpat) KO mouse, a model of complete deficiency in Ether Lipid biosynthesis. Throughout the study, focusing on adult male animals, we found reduced brain levels of various neurotransmitters. In the dopaminergic nigrostriatal tract, synaptic endings but not neuronal cell bodies were affected. Neurotransmitter turnover was altered in Ether Lipid-deficient murine as well as human post-mortem brain tissue. A generalized loss of synapses did not account for the neurotransmitter deficits, since the levels of several presynaptic proteins appeared unchanged. However, reduced amounts of vesicular monoamine transporter indicate a compromised vesicular uptake of neurotransmitters. As exemplified by norepinephrine, the release of neurotransmitters from Gnpat KO brain slices was diminished in response to strong electrical and chemical stimuli. Finally, addressing potential phenotypic correlates of the disturbed neurotransmitter homeostasis, we show that Ether Lipid deficiency manifests as hyperactivity and impaired social interaction. We propose that the lack of Ether Lipids alters the properties of synaptic vesicles leading to reduced amounts and release of neurotransmitters. These features likely contribute to the behavioral phenotype of Gnpat KO mice, potentially modeling some human neurodevelopmental disorders like autism or attention deficit hyperactivity disorder.
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Reduced muscle strength in Ether Lipid‐deficient mice is accompanied by altered development and function of the neuromuscular junction
Journal of neurochemistry, 2017Co-Authors: Fabian Dorninger, Gerhard Zeitler, Ruth Herbst, Bojana Kravic, Bahar Z. Camurdanoglu, Igor Macinkovic, Sonja Forss-petter, Siegfried Strack, Muzamil Majid Khan, Hans R. WaterhamAbstract:Inherited deficiency in Ether Lipids, a subgroup of phosphoLipids whose biosynthesis needs peroxisomes, causes the fatal human disorder rhizomelic chondrodysplasia punctata. The exact roles of Ether Lipids in the mammalian organism and, therefore, the molecular mechanisms underlying the disease are still largely enigmatic. Here, we used the glyceronephosphate O-acyltransferase knockout (Gnpat KO) mouse to study the consequences of complete inactivation of Ether Lipid biosynthesis and documented substantial deficits in motor performance and muscle strength of these mice. We hypothesized that, probably in addition to previously described cerebellar abnormalities and myelination defects in the peripheral nervous system, an impairment of neuromuscular transmission contributes to the compromised motor abilities. Structurally, a morphologic examination of the neuromuscular junction (NMJ) in diaphragm muscle at different developmental stages revealed aberrant axonal branching and a strongly increased area of nerve innervation in Gnpat KO mice. Postsynaptically, acetylcholine receptor (AChR) clusters colocalized with nerve terminals within a widened endplate zone. In addition, we detected atypical AChR clustering, as indicated by decreased size and number of clusters following stimulation with agrin, in vitro. The turnover of AChRs was unaffected in Ether Lipid-deficient mice. Electrophysiological evaluation of the adult diaphragm indicated that, whereas evoked potentials were unaltered in Gnpat KO mice, Ether Lipid deficiency leads to fewer spontaneous synaptic vesicle fusion events but, conversely, an increased postsynaptic response to spontaneous vesicle exocytosis. We conclude from our findings that Ether Lipids are essential for proper development and function of the NMJ and may, therefore, contribute to motor performance. This article is protected by copyright. All rights reserved.
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from peroxisomal disorders to common neurodegenerative diseases the role of Ether phosphoLipids in the nervous system
FEBS Letters, 2017Co-Authors: Fabian Dorninger, Sonja Forsspetter, Johannes BergerAbstract:The emerging diverse roles of Ether (phospho)Lipids in nervous system development and function in health and disease are currently attracting growing interest. Plasmalogens, a subgroup of Ether Lipids, are important membrane components involved in vesicle fusion and membrane raft composition. They store polyunsaturated fatty acids and may serve as antioxidants. Ether Lipid metabolites act as precursors for the formation of glycosyl-phosphatidyl-inositol anchors; others, like platelet-activating factor, are implicated in signaling functions. Consolidating the available information, we attempt to provide molecular explanations for the dramatic neurological phenotype in Ether Lipid-deficient human patients and mice by linking individual functional properties of Ether Lipids with pathological features. Furthermore, recent publications have identified altered Ether Lipid levels in the context of many acquired neurological disorders including Alzheimer's disease (AD) and autism. Finally, current efforts to restore Ether Lipids in peroxisomal disorders as well as AD are critically reviewed.
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reduced muscle strength in Ether Lipid deficient mice is accompanied by altered development and function of the neuromuscular junction
Journal of Neurochemistry, 2017Co-Authors: Fabian Dorninger, Gerhard Zeitler, Sonja Forsspetter, Ruth Herbst, Bojana Kravic, Bahar Z. Camurdanoglu, Igor Macinkovic, Siegfried Strack, Muzamil Majid Khan, Hans R. WaterhamAbstract:Inherited deficiency in Ether Lipids, a subgroup of phosphoLipids whose biosynthesis needs peroxisomes, causes the fatal human disorder rhizomelic chondrodysplasia punctata. The exact roles of Ether Lipids in the mammalian organism and, therefore, the molecular mechanisms underlying the disease are still largely enigmatic. Here, we used the glyceronephosphate O-acyltransferase knockout (Gnpat KO) mouse to study the consequences of complete inactivation of Ether Lipid biosynthesis and documented substantial deficits in motor performance and muscle strength of these mice. We hypothesized that, probably in addition to previously described cerebellar abnormalities and myelination defects in the peripheral nervous system, an impairment of neuromuscular transmission contributes to the compromised motor abilities. Structurally, a morphologic examination of the neuromuscular junction (NMJ) in diaphragm muscle at different developmental stages revealed aberrant axonal branching and a strongly increased area of nerve innervation in Gnpat KO mice. Postsynaptically, acetylcholine receptor (AChR) clusters colocalized with nerve terminals within a widened endplate zone. In addition, we detected atypical AChR clustering, as indicated by decreased size and number of clusters following stimulation with agrin, in vitro. The turnover of AChRs was unaffected in Ether Lipid-deficient mice. Electrophysiological evaluation of the adult diaphragm indicated that, whereas evoked potentials were unaltered in Gnpat KO mice, Ether Lipid deficiency leads to fewer spontaneous synaptic vesicle fusion events but, conversely, an increased postsynaptic response to spontaneous vesicle exocytosis. We conclude from our findings that Ether Lipids are essential for proper development and function of the NMJ and may, therefore, contribute to motor performance. This article is protected by copyright. All rights reserved.
Christophe Vandier - One of the best experts on this subject based on the ideXlab platform.
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digalactosyl glycero Ether Lipid synthetic approaches and evaluation as sk3 channel inhibitor
Organic and Biomolecular Chemistry, 2013Co-Authors: Charlotte M Sevrain, Maxime Guéguinou, Marie Potiercartereau, Jeanpierre Haelters, Helene Couthongourves, Aurelie Chantome, Christophe VandierAbstract:The recent discoveries of the involvement of SK3 channel in some cell motility mechanisms occurring in cancer disease have opened up the way to the synthesis of inhibitors that could reduce metastasis formation. On the basis of our recent previous works showing that both lactose-glycero-Ether Lipid (Ohmline) and some phosphate analogues (GPGEL) were efficient compounds to modulate SK3 channel activity, the present study, which found its inspiration in the structure of the natural glycoLipid DiGalactosylDiacylGlycerol (DGDG), reports the incorporation of a digalactosyl moiety (α-galactopyranosyl-(1→6)-β-galactopyranosyl-) as the polar head of a glycero Ether Lipid. For the construction of the digalactosyl fragment, two synthetic approaches were compared. The standard strategy which is based on the use of the benzyl protecting group to produce 1→6 disaccharide unit, was compared with a second method that made use of the trimethylsilyl moiety as a protecting group. This second strategy, which is applied for the first time to the synthesis of (1→6)-disaccharide unit, presents a net advantage in terms of efficacy (better global yield) and cost. Finally, compound 16, which is characterized by a (1→6) DiGalactosyl unit (DG) as the polar head of the amphiphilic structure, was tested as a modulator of the SK3 channel activity. Patch-clamp experiments have shown that compound 16 reduced SK3 currents (−28.2 ± 2.0% at 5 μM) and cell migration assays performed at 300 nM have shown a reduction of cell migration (SK3 + HEK293T) by 19.6 ± 2.7%.
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DiGalactosyl-Glycero-Ether Lipid: synthetic approaches and evaluation as SK3 channel inhibitor.
Organic and Biomolecular Chemistry, 2013Co-Authors: Charlotte M Sevrain, Maxime Guéguinou, Jeanpierre Haelters, Aurelie Chantome, Christophe Vandier, Hélène Couthon, Marie Potier-cartereau, Paul-alain JaffresAbstract:The recent discoveries of the involvement of SK3 channel in some cell motility mechanisms occurring in cancer disease have opened up the way to the synthesis of inhibitors that could reduce metastasis formation. On the basis of our recent previous works showing that both lactose-glycero-Ether Lipid () and some phosphate analogues () were efficient compounds to modulate SK3 channel activity, the present study, which found its inspiration in the structure of the natural glycoLipid DiGalactosylDiacylGlycerol (DGDG), reports the incorporation of a digalactosyl moiety (α-galactopyranosyl-(1→6)-β-galactopyranosyl-) as the polar head of a glycero Ether Lipid. For the construction of the digalactosyl fragment, two synthetic approaches were compared. The standard strategy which is based on the use of the benzyl protecting group to produce 1→6 disaccharide unit, was compared with a second method that made use of the trimethylsilyl moiety as a protecting group. This second strategy, which is applied for the first time to the synthesis of (1→6)-disaccharide unit, presents a net advantage in terms of efficacy (better global yield) and cost. Finally, compound , which is characterized by a (1→6) DiGalactosyl unit (DG) as the polar head of the amphiphilic structure, was tested as a modulator of the SK3 channel activity. Patch-clamp experiments have shown that compound reduced SK3 currents (-28.2 ± 2.0% at 5 μM) and cell migration assays performed at 300 nM have shown a reduction of cell migration (SK3 + HEK293T) by 19.6 ± 2.7%.
Faustino Mollinedo - One of the best experts on this subject based on the ideXlab platform.
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Combination of the anti-tumour cell Ether Lipid edelfosine with sterols abolishes haemolytic side effects of the drug
Journal of Chemical Biology, 2008Co-Authors: Jon V Busto, Faustino Mollinedo, Felix M Goni, Esther Del Canto-jañez, Alicia AlonsoAbstract: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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surface active properties of the antitumour Ether Lipid 1 o octadecyl 2 o methyl rac glycero 3 phosphocholine edelfosine
Biochimica et Biophysica Acta, 2007Co-Authors: Jon V Busto, Faustino Mollinedo, Jesus Sot, Felix M Goni, Alicia AlonsoAbstract:Abstract The surface activity and interaction with Lipid monolayers and bilayers of the antitumour Ether Lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (edelfosine) have been studied. Edelfosine is a surface-active soluble amphiphile, with critical micellar concentrations at 3.5 μM and 19 μM in water. When the air–water interface is occupied by a phosphoLipid, edelfosine becomes inserted in the phosphoLipid monolayer, increasing surface pressure. This increase is dose-dependent, and reaches a plateau at ca. 2 μM edelfosine bulk concentration. The Ether Lipid can become inserted in phosphoLipid monolayers with initial surface pressures of up to 33 mN/m, which ensures its capacity to become inserted into cell membranes. Upon interaction with phosphoLipid vesicles, edelfosine exhibits a weak detergent activity, causing release of vesicle contents to a low extent (
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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.
Biochimica et biophysica acta, 2005Co-Authors: Pablo Conesa-zamora, Faustino Mollinedo, Senena Corbalán-garcía, Juan C Gómez-fernándezAbstract:The effects of the anti-neoplastic Ether Lipid ET-18-OCH3 and some structural homologues on the activity of protein kinase C alpha (PKC alpha) were studied and compared with the effects the same had on the activity of PKC epsilon. ET-18-OCH3 progressively inhibited the activity of PKC alpha as the concentration was increased up to 30 mol% of the total Lipid, above which the effect was one of activation. The experiments carried out with the homologues showed that the methoxy group bound at the sn-2 position of the glycerol of ET-18-OCH3 is essential for both the initial inhibitory effect and the subsequent activation effect. On the other hand, variations in the type of bond linking substitutions in the sn-1 position, Ether or ester, do not seem to play an important role in determining the activity of the enzyme. The effects were different on PKC epsilon since ET-18-OCH3 had a triphasic effect, activating the enzyme at low concentrations, inhibiting it at slightly higher concentrations and then activating it again at higher concentrations. In this case, when the homologues were used, it was observed that the presence of the methoxy group linked to the sn-2 position of glycerol and the type of bond linking substitutions to the sn-1 position were important for activating the enzyme, so that only homologues with ester bonds as LPC and PAPC were able to induce the initial activation step in a way similar to ET-18-OCH3. Substitution of the phosphocholine group of ET-18-OCH3 by phosphoserine led to a greater activation of PKC alpha, an effect that comes from the Ca(2+)-phosphoLipid binding site probably because of the specific interaction of this site with the phosphoserine group. The action of ET-18-OCH3 and its homologues, as demonstrated in this paper, may permit the selective inhibition or activation of PKC alpha and PKC epsilon by using the most suitable range of concentrations.
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the antitumor Ether Lipid et 18 och3 induces apoptosis through translocation and capping of fas cd95 into membrane rafts in human leukemic cells
Blood, 2001Co-Authors: Consuelo Gajate, Faustino MollinedoAbstract:The antitumor Ether Lipid ET-18-OCH3 promotes apoptosis in tumor cells through intracellular activation of Fas/CD95. Results of this study showed that ET-18-OCH3 induces cocapping of Fas and membrane rafts, specialized plasma membrane regions involved in signaling, before the onset of apoptosis in human leukemic cells. Patches of membrane rafts accumulated Fas clusters in leukemic cells treated with ET-18-OCH3. Sucrose gradient centrifugation of Triton X-100 cell lysates showed that Fas translocated into membrane rafts following ET-18-OCH3 treatment of T-leukemic Jurkat cells. Disruption of membrane raft integrity by methyl-β-cyclodextrin or filipin inhibited ET-18-OCH3-induced apoptosis in leukemic primary cells and cell lines. Fas clustering was also inhibited by methyl-β-cyclodextrin. These data indicate that ET-18-OCH3 reorganizes membrane rafts to trigger apoptosis in human leukemic cells, and that Fas coaggregation with membrane rafts is required for ET-18-OCH3–induced apoptosis. This translocation of Fas into membrane rafts may provide a mechanism for amplifying Fas signaling by reorganization of membrane microdomains.
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intracellular triggering of fas independently of fasl as a new mechanism of antitumor Ether Lipid induced apoptosis
International Journal of Cancer, 2000Co-Authors: Consuelo Gajate, Faustino Mollinedo, Rosalba I Fonteriz, Christelle Cabaner, Granada Alvareznoves, Ysmael Alvarezrodriguez, Manuel ModolellAbstract:Antitumor Ether Lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH(3); edelfosine) induces apoptosis in cancer cells, sparing normal cells. We have found that the apoptotic action of ET-18-OCH(3) required drug uptake and Fas in the target cell. Failure to accomplish one of these requirements prevents cell killing by the Ether Lipid. In human lymphoid leukemic cells, ET-18-OCH(3) does not promote Fas or FasL expression and ET-18-OCH(3)-induced apoptosis is not inhibited by pre-incubation with an anti-Fas blocking antibody that abrogates cell killing mediated by Fas/FasL interactions. ET-18-OCH(3)-resistant normal human Fas-positive fibroblasts do not incorporate ET-18-OCH(3), but undergo apoptosis upon ET-18-OCH(3) microinjection. Murine fibroblasts L929 and L929-Fas, stably transfected with human Fas cDNA, do not incorporate ET-18-OCH(3) and are resistant to its action when added exogenously. Microinjection of ET-18-OCH(3) induces apoptosis in L929-Fas cells, but not in wild-type L929 cells. Confocal laser scanning microscopy shows that ET-18-OCH(3) induces Fas clustering and capping during triggering of ET-18-OCH(3)-induced apoptosis. Microinjection-induced apoptosis and Fas clustering are specific for the molecular structure of ET-18-OCH(3). Our data indicate that ET-18-OCH(3) induces apoptosis via Fas after the Ether Lipid is inside the cell, and this Fas activation is independent of the interaction of Fas with its natural ligand FasL. This explains the selective action of ET-18-OCH(3) on tumors since only cancer cells incorporate sufficient amounts of the drug.
Maxime Guéguinou - One of the best experts on this subject based on the ideXlab platform.
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digalactosyl glycero Ether Lipid synthetic approaches and evaluation as sk3 channel inhibitor
Organic and Biomolecular Chemistry, 2013Co-Authors: Charlotte M Sevrain, Maxime Guéguinou, Marie Potiercartereau, Jeanpierre Haelters, Helene Couthongourves, Aurelie Chantome, Christophe VandierAbstract:The recent discoveries of the involvement of SK3 channel in some cell motility mechanisms occurring in cancer disease have opened up the way to the synthesis of inhibitors that could reduce metastasis formation. On the basis of our recent previous works showing that both lactose-glycero-Ether Lipid (Ohmline) and some phosphate analogues (GPGEL) were efficient compounds to modulate SK3 channel activity, the present study, which found its inspiration in the structure of the natural glycoLipid DiGalactosylDiacylGlycerol (DGDG), reports the incorporation of a digalactosyl moiety (α-galactopyranosyl-(1→6)-β-galactopyranosyl-) as the polar head of a glycero Ether Lipid. For the construction of the digalactosyl fragment, two synthetic approaches were compared. The standard strategy which is based on the use of the benzyl protecting group to produce 1→6 disaccharide unit, was compared with a second method that made use of the trimethylsilyl moiety as a protecting group. This second strategy, which is applied for the first time to the synthesis of (1→6)-disaccharide unit, presents a net advantage in terms of efficacy (better global yield) and cost. Finally, compound 16, which is characterized by a (1→6) DiGalactosyl unit (DG) as the polar head of the amphiphilic structure, was tested as a modulator of the SK3 channel activity. Patch-clamp experiments have shown that compound 16 reduced SK3 currents (−28.2 ± 2.0% at 5 μM) and cell migration assays performed at 300 nM have shown a reduction of cell migration (SK3 + HEK293T) by 19.6 ± 2.7%.
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DiGalactosyl-Glycero-Ether Lipid: synthetic approaches and evaluation as SK3 channel inhibitor.
Organic and Biomolecular Chemistry, 2013Co-Authors: Charlotte M Sevrain, Maxime Guéguinou, Jeanpierre Haelters, Aurelie Chantome, Christophe Vandier, Hélène Couthon, Marie Potier-cartereau, Paul-alain JaffresAbstract:The recent discoveries of the involvement of SK3 channel in some cell motility mechanisms occurring in cancer disease have opened up the way to the synthesis of inhibitors that could reduce metastasis formation. On the basis of our recent previous works showing that both lactose-glycero-Ether Lipid () and some phosphate analogues () were efficient compounds to modulate SK3 channel activity, the present study, which found its inspiration in the structure of the natural glycoLipid DiGalactosylDiacylGlycerol (DGDG), reports the incorporation of a digalactosyl moiety (α-galactopyranosyl-(1→6)-β-galactopyranosyl-) as the polar head of a glycero Ether Lipid. For the construction of the digalactosyl fragment, two synthetic approaches were compared. The standard strategy which is based on the use of the benzyl protecting group to produce 1→6 disaccharide unit, was compared with a second method that made use of the trimethylsilyl moiety as a protecting group. This second strategy, which is applied for the first time to the synthesis of (1→6)-disaccharide unit, presents a net advantage in terms of efficacy (better global yield) and cost. Finally, compound , which is characterized by a (1→6) DiGalactosyl unit (DG) as the polar head of the amphiphilic structure, was tested as a modulator of the SK3 channel activity. Patch-clamp experiments have shown that compound reduced SK3 currents (-28.2 ± 2.0% at 5 μM) and cell migration assays performed at 300 nM have shown a reduction of cell migration (SK3 + HEK293T) by 19.6 ± 2.7%.