Ether Lipid 1-O-Octadecyl-2-O-Methoxy-Rac
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Lipid Raft-Mediated Akt Signaling As a Therapeutic Target in Mantle Cell Lymphoma
OPEN Citation: Blood Cancer Journal (2013) 3, e118; doi:10.1038/bcj.2013.15 & 2013 Macmillan Publishers Limited All rights reserved 2044-5385/13 www.nature.com/bcj ORIGINAL ARTICLE Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma M Reis-Sobreiro1, G Roue´ 2, A Moros2, C Gajate1, J de la Iglesia-Vicente1, D Colomer2 and F Mollinedo1 Recent evidence shows that lipid raft membrane domains modulate both cell survival and death. Here, we have found that the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is present in the lipid rafts of mantle cell lymphoma (MCL) cells, and this location seems to be critical for full activation and MCL cell survival. The antitumor lipids (ATLs) edelfosine and perifosine target rafts, and we found that ATLs exerted in vitro and in vivo antitumor activity against MCL cells by displacing Akt as well as key regulatory kinases p-PDK1 (phosphatidylinositol-dependent protein kinase 1), PI3K and mTOR (mammalian TOR) from lipid rafts. This raft reorganization led to Akt dephosphorylation, while proapoptotic Fas/CD95 death receptor was recruited into rafts. Raft integrity was critical for Ser473 Akt phosphorylation. ATL-induced apoptosis appeared to correlate with the basal Akt phosphorylation status in MCL cell lines and primary cultures, and could be potentiated by the PI3K inhibitor wortmannin, or inhibited by the Akt activator pervanadate. Classical Akt inhibitors induced apoptosis in MCL cells. Microenvironmental stimuli, such as CD40 ligation or stromal cell contact, did not prevent ATL-induced apoptosis in MCL cell lines and patient-derived cells. These results highlight the role of raft-mediated PI3K/Akt signaling in MCL cell survival and chemotherapy, thus becoming a new target for MCL treatment. -
Membrane Lipid Therapy: Modulation of the Cell Membrane Composition and Structure As a Molecular Base for Drug Discovery and New Disease Treatment
Progress in Lipid Research 59 (2015) 38–53 Contents lists available at ScienceDirect Progress in Lipid Research journal homepage: www.elsevier.com/locate/plipres Review Membrane lipid therapy: Modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment Pablo V. Escribá a, Xavier Busquets a, Jin-ichi Inokuchi b, Gábor Balogh c, Zsolt Török c, Ibolya Horváth c, ⇑ ⇑ John L. Harwood d, , László Vígh c, a Department of Biology, University of the Balearic Islands, E-07122 Palma de Mallorca, Spain b Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Japan c Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary d School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK article info abstract Article history: Nowadays we understand cell membranes not as a simple double lipid layer but as a collection of Received 28 January 2015 complex and dynamic protein–lipid structures and microdomains that serve as functional platforms Received in revised form 10 April 2015 for interacting signaling lipids and proteins. Membrane lipids and lipid structures participate directly Accepted 29 April 2015 as messengers or regulators of signal transduction. In addition, protein–lipid interactions participate in Available online 9 May 2015 the localization of signaling protein partners to specific membrane microdomains. Thus, lipid alterations Dedicated to the memory of our late change cell signaling that are associated with a variety of diseases including cancer, obesity, neurodegen- colleague and friend, Professor John E. erative disorders, cardiovascular pathologies, etc. This article reviews the newly emerging field of mem- Halver. -
Epirubicin Enhances TRAIL-Induced Apoptosis in Gastric Cancer Cells by Promoting Death Receptor Clustering in Lipid Rafts
MOLECULAR MEDICINE REPORTS 4: 407-411, 2011 Epirubicin enhances TRAIL-induced apoptosis in gastric cancer cells by promoting death receptor clustering in lipid rafts LING XU, XIUJUAN QU, YING LUO, YE ZHANG, JING LIU, JINGLEI QU, LINGYUN ZHANG and YUNPENG LIU Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, P.R. China Received December 16, 2010; Accepted February 4, 2011 DOI: 10.3892/mmr.2011.439 Abstract. Gastric cancer cells are usually insensitive to tumor induce apoptosis in many cancer cells without causing signifi- necrosis factor-related apoptosis-inducing ligand (TRAIL). cant toxicity to normal cells. TRAIL triggers apoptosis upon In the present study, in MGC803 cells treated with 100 ng/ml engagement of two receptors named death receptor 4 (DR4) TRAIL for 24 h, the inhibition rate of cell proliferation was and death receptor 5 (DR5). In response to TRAIL, death 9.76±2.39% and the rate of cell apoptosis was only 4.37±1.45%. receptors recruit the Fas-associated death domain (FADD) Treatment with epirubicin (1.18 µg/ml, IC50 dose for 24 h) and and procaspase-8 and -10, hence forming the macromolecular TRAIL (100 ng/ml for 24 h) led to a marked increase in the complex, termed the death-inducing signaling complex (DISC). inhibition rate of cell proliferation and apoptosis compared to Within this complex, procaspase-8 and -10 are activated treatment with epirubicin or TRAIL alone (P<0.05). Moreover, and initiate the caspase cascade, leading to apoptosis (3,4). even more notable cleavage of caspase-3 and 8 was detected However, previous studies including our own have reported with the combination of epirubicin and TRAIL. -
Chemistry and Physics of Lipids Effects of Ether Vs. Ester Linkage On
Chemistry and Physics of Lipids 160 (2009) 33–44 Contents lists available at ScienceDirect Chemistry and Physics of Lipids journal homepage: www.elsevier.com/locate/chemphyslip Effects of ether vs. ester linkage on lipid bilayer structure and water permeability S. Deren Guler a, D. Dipon Ghosh b, Jianjun Pan a, John C. Mathai c, Mark L. Zeidel c, John F. Nagle a,b, Stephanie Tristram-Nagle a,∗ a Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA b Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA c Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Cambridge, MA 02139, USA article info abstract Article history: The structure and water permeability of bilayers composed of the ether-linked lipid, dihexadecylphos- Received 29 January 2009 phatidylcholine (DHPC), were studied and compared with the ester-linked lipid, dipalmitoylphosphadit- Received in revised form 29 March 2009 dylcholine (DPPC). Wide angle X-ray scattering on oriented bilayers in the fluid phase indicate that the Accepted 26 April 2009 area per lipid A is slightly larger for DHPC than for DPPC. Low angle X-ray scattering yields A = 65.1 Å2 for Available online 3 May 2009 ◦ −13 DHPC at 48 C. LAXS data provide the bending modulus, KC = 4.2 × 10 erg, and the Hamaker parame- ter H =7.2× 10−14 erg for the van der Waals attractive interaction between neighboring bilayers. For the Keywords: low temperature phases with ordered hydrocarbon chains, we confirm the transition from a tilted L Ether lipid ◦ gel phase to an untilted, interdigitated LI phase as the sample hydrates at 20 C. -
Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS As Anti-Cancer Agents † # ‡ # § # † § Valentina Piano, , Daniel I
Articles pubs.acs.org/acschemicalbiology Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents † # ‡ # § # † § Valentina Piano, , Daniel I. Benjamin, , Sergio Valente, , Simone Nenci, Biagina Marrocco, § ∥ ⊥ ‡ † Antonello Mai, , Alessandro Aliverti, Daniel K. Nomura,*, and Andrea Mattevi*, † Department of Biology and Biotechnology, University of Pavia, via Ferrata 9, 27100 Pavia, Italy ‡ Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California 94720, United States § Department of Drug Chemistry and Technologies, University “La Sapienza”, P. le A. Moro 5, Roma 00185, Italy ∥ Pasteur Institute, Cenci Bolognetti Foundation, P.le A. Moro 5, Roma 00185, Italy ⊥ Department of Biosciences, University of Milano, Via Festa del Perdono, 7, 20122 Milano, Italy *S Supporting Information ABSTRACT: Dysregulated ether lipid metabolism is an important hallmark of cancer cells. Previous studies have reported that lowering ether lipid levels by genetic ablation of the ether lipid-generating enzyme alkyl-glycerone phosphate synthase (AGPS) lowers key structural and oncogenic ether lipid levels and alters fatty acid, glycerophospholipid, and eicosanoid metabolism to impair cancer pathogenicity, indicating that AGPS may be a potential therapeutic target for cancer. In this study, we have performed a small-molecule screen to identify candidate AGPS inhibitors. We have identified several lead AGPS inhibitors and have structurally characterized their interactions with the enzyme and show that these inhibitors bind to distinct portions of the active site. We further show that the lead AGPS inhibitor 1a selectively lowers ether lipid levels in several types of human cancer cells and impairs their cellular survival and migration. We provide here the first report of in situ-active pharmacological tools for inhibiting AGPS, which may provide chemical scaffolds for future AGPS inhibitor development for cancer therapy. -
Phosphoinositide Phosphatase SHIP-1 Regulates Apoptosis Induced by Edelfosine, Fas Ligation and DNA Damage in Mouse Lymphoma Cells Maaike C
Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells Maaike C. Alderliesten, Jeffrey B. Klarenbeek, Arnold H. van der Luit, Menno van Lummel, David R Jones, Shuraila Zerp, Nullin Divecha, Marcel Verheij, Wim J van Blitterswijk To cite this version: Maaike C. Alderliesten, Jeffrey B. Klarenbeek, Arnold H. van der Luit, Menno van Lummel, David R Jones, et al.. Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells. Biochemical Journal, Portland Press, 2011, 440 (1), pp.127-135. 10.1042/BJ20110125. hal-00642836 HAL Id: hal-00642836 https://hal.archives-ouvertes.fr/hal-00642836 Submitted on 19 Nov 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Biochemical Journal Immediate Publication. Published on 27 Jul 2011 as manuscript BJ20110125 Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells Maaike C. ALDERLIESTEN*, Jeffrey B. KLARENBEEK*, Arnold H. VAN DER ‡ LUIT*2, Menno VAN LUMMEL*3, David R. JONES , Shuraila ZERP*†, Nullin ‡ DIVECHA , Marcel VERHEIJ† and Wim J. VAN BLITTERSWIJK*1 *Division of Cell Biology (B5) and †Department of Radiotherapy, The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The ‡ Netherlands, Paterson Institute for Cancer Research, Inositide laboratory, The University of Manchester, Wilmslow Road, M20 4BX Manchester, UK. -
Akt Inhibitors in Cancer Treatment: the Long Journey from Drug Discovery to Clinical Use (Review)
INTERNATIONAL JOURNAL OF ONCOLOGY 48: 869-885, 2016 Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review) GeORGe MIHAI NITUleSCU1, DeNISA MARGINA1, PeTRAS JUzeNAS2, QIAN PeNG2, OctavIAN TUDORel OlARU1, eMMANOUIl SAlOUSTROS3, CONCETTINA FENGA4, DeMeTRIOS Α. Spandidos5, MASSIMO lIBRA6 and ARISTIDIS M. Tsatsakis7 1Faculty of Pharmacy, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020956, Romania; 2Department of Pathology, Radiumhospitalet, Oslo University Hospital, 0379 Oslo, Norway; 3Oncology Unit, General Hospital of Heraklion ‘venizelio’, Heraklion 71409, Greece; 4Section of Occupational Medicine, University of Messina, I‑98125 Messina, Italy; 5Department of virology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece; 6Department of Biomedical and Biotechnological Sciences, General and Clinical Pathology and Oncology Section, University of Catania, I‑95124 Catania, Italy; 7Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece Received November 17, 2015; Accepted December 24, 2015 DOI: 10.3892/ijo.2015.3306 Abstract. Targeted cancer therapies are used to inhibit the importance of each chemical scaffold. We explore the pipeline growth, progression, and metastasis of the tumor by interfering of Akt inhibitors and their preclinical and clinical examina- with specific molecular targets and are currently the focus of tion status, presenting the potential clinical application of these anticancer drug development. -
A Functional Genomic Screen in Saccharomyces Cerevisiae Reveals Divergent Mechanisms of Resistance to Different Alkylphosphochol
bioRxiv preprint doi: https://doi.org/10.1101/2020.10.16.343244; this version posted October 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. A functional genomic screen in Saccharomyces cerevisiae reveals divergent mechanisms of resistance to different alkylphosphocholine chemotherapeutic agents. Jacquelin M. Garcia*,3, Michael J. Schwabe*,4, Dennis R. Voelker†, and Wayne R. Riekhof* *School of Biological Sciences, University of Nebraska – Lincoln, Lincoln, NE, USA; †Department of Medicine, National Jewish Health, Denver, CO, USA Current address: 3Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO, USA; 4Department of Surgery, Creighton University School of Medicine, Omaha, NE, USA 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.10.16.343244; this version posted October 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract The alkylphosphocholine (APC) class of antineoplastic and antiprotozoal drugs, such as edelfosine and miltefosine, are structural mimics of lyso-phosphatidylcholine (lyso-PC), and are inhibitory to the yeast Saccharomyces cerevisiae at low micromolar concentrations. Cytotoxic effects related to inhibition of phospholipid synthesis, induction of an unfolded protein response, inhibition of oxidative phosphorylation, and disruption of lipid rafts have been attributed to members of this drug class, however the molecular mechanisms of action of these drugs remain incompletely understood. -
Antiprotozoal Activities of Phospholipid Analogues Simon L
Molecular & Biochemical Parasitology 126 (2003) 165–172 Review Antiprotozoal activities of phospholipid analogues Simon L. Croft a,∗, Karin Seifert a, Michael Ducheneˆ b a Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK b Division of Specific Prophylaxis and Tropical Medicine, Department of Pathophysiology, AKH, Währinger Gürtel 18-20, A-1090 Vienna, Austria Received 3 June 2002; received in revised form 8 August 2002; accepted 13 August 2002 Abstract The antiprotozoal activity of phospholipid analogues, originally developed as anti-cancer drugs, has been determined in the past decade. The most susceptible parasites are Leishmania spp. and Trypanosoma cruzi with activity also shown against Trypanosoma brucei spp., Entamoeba histolytica and Acanthamoeba spp. Miltefosine, an alkylphosphocholine, was registered for the oral treatment of visceral leishmaniasis (VL) in India in March 2002. This review will focus on the biological activities of phospholipid analogues. Biochemical and molecular targets and mechanism(s) of action have been studied extensively in tumor cells but have not been determined in protozoa. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Phospholipid analogues; Miltefosine; Protozoa 1. Introduction hexadecylphosphocholine (HPC, miltefosine) for the top- ical treatment of skin metastases was approved in Au- Interest in phospholipid analogues as chemotherapeutic gust 1992. The discovery of the ether-lipid structure of agents resulted from the work of Munder and co-workers platelet-activating factor (PAF) also prompted further in- [1] following their investigation of the immunomodula- terest in the synthesis and activity of phospholipids [8,9] tory activity of lysophosphatidylcholine (LPC). As LPC (Fig. -
Sensitivity of K562 and HL-60 Cells to Edelfosine, an Ether Lipid Drug, Correlates with Production of Reactive Oxygen Species1
[CANCER RESEARCH 58, 2809-2K16. July I. 1998] Sensitivity of K562 and HL-60 Cells to Edelfosine, an Ether Lipid Drug, Correlates with Production of Reactive Oxygen Species1 Brett A. Wagner, Garry R. Buettner, Larry W. Oberley, and C. Patrick Burns2 Departments of Medicine ¡B.A. W., C. P. B.¡and Radiology/Radiation Research Laboratory ¡G.R. B., L W. O.I. and the Electron Spin Resonance Facilin ¡C.R. B.j, The University of Iowa College of Medicine, The University of Iowa Cancer Center. Iowa City. Iowa 52242 ABSTRACT Such information could be helpful in the understanding of the mech anism of ether lipid cytotoxicity. Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine; I, I -18-( )( 'II, i, a membrane-targeting anticancer ether lipid drug has been The difference in cytotoxicity between the two cell lines is not due to drug metabolism (8). We have demonstrated previously that the shown previously in vitro to be capable of initiating oxidative processes in cells. Here we study two human leukemia cell lines (HL-60 and K562) that ether lipids are capable of enhancing lipid peroxidative damage (9) and free radical events in cells. In L1210 cells, ether lipids augment have different sensitivities to edelfosine; HL-60 cells are more sensitive generation of L¿3 (10, 11). The generation of Ld' under various than K562 cells. To determine whether edelfosine alters the sensitivity of these lines to an oxidative stress, cells were subjected to the oxidative oxidative conditions correlates directly with oxygen consumption (11, stress of iron(II) plus ascorbate and then monitored for free radical 12), extent of cellular polyunsaturation (10, 11, 13), and depletion of formation, membrane integrity, and cytotoxicity. -
Hot Topics in Neural Membrane Lipidology
A.A. Farooqui Hot Topics in Neural Membrane Lipidology ▶ Focuses exclusively on lipid mediators and neurological disorders Not only do glycerophospholipid, sphingolipid, and cholesterol-derived lipid mediators facilitate the transfer of messages from one cell to another, they also facilitate communication among subcellular organelles. Hot Topics in Neural Membrane Lipidology provides readers with a cutting-edge, comprehensive review of these lipid mediators, their roles and association with neurological disorders, and the future direction of research on the topic. This monograph provides readers with critical data and is particularly accessible to neuroscience graduate students, teachers, and researchers. It can be used as a supplemental text for a range of neuroscience courses. Clinicians and pharmacologists will find this book useful for understanding molecular aspects of lipid mediators in acute neural trauma like stroke, spinal cord trauma, head injury, and neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease. 2009, XXIV, 408 p. 62 illus. About the Author: Printed book Akhlaq A. Farooqui is a leader in the field of brain phospholipases A2, bioactive ether lipid metabolism, and glutamate-mediated neurotoxicity. He has discovered the stimulation of Hardcover plasmalogen-selective phospholipase A2 activity in brains from patients with Alzheimer ▶ 199,99 € | £179.99 | $249.99 disease, and published cutting edge research on the generation and identification of ▶ *213,99 € (D) | 219,99 € (A) | CHF 236.00 glycerophospholipid, sphingolipid, and cholesterol-derived lipid mediators in kainic acid neurotoxicity. Dr. Farooqui has authored three monographs: Glycerophospholipids eBook in Brain: Phospholipase A2 in Neurological Disorders (2007); Neurochemical Aspects of Excitotoxicity (2008); and Metabolism and Functions of Bioactive Ether Lipids in Brain Available from your bookstore or (2008). -
Effect of Erufosine on Membrane Lipid Order in Breast Cancer Cell Models
biomolecules Article Effect of Erufosine on Membrane Lipid Order in Breast Cancer Cell Models 1, 1, 2 1 Rumiana Tzoneva y, Tihomira Stoyanova y, Annett Petrich , Desislava Popova , Veselina Uzunova 1 , Albena Momchilova 1 and Salvatore Chiantia 2,* 1 Bulgarian Academy of Sciences, Institute of Biophysics and Biomedical Engineering, 1113 Sofia, Bulgaria; [email protected] (R.T.); [email protected] (T.S.); [email protected] (D.P.); [email protected] (V.U.); [email protected] (A.M.) 2 Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Street 24-25, 14476 Potsdam, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-331-9775872 These author contribute equally to this work. y Received: 2 April 2020; Accepted: 19 May 2020; Published: 22 May 2020 Abstract: Alkylphospholipids are a novel class of antineoplastic drugs showing remarkable therapeutic potential. Among them, erufosine (EPC3) is a promising drug for the treatment of several types of tumors. While EPC3 is supposed to exert its function by interacting with lipid membranes, the exact molecular mechanisms involved are not known yet. In this work, we applied a combination of several fluorescence microscopy and analytical chemistry approaches (i.e., scanning fluorescence correlation spectroscopy, line-scan fluorescence correlation spectroscopy, generalized polarization imaging, as well as thin layer and gas chromatography) to quantify the effect of EPC3 in biophysical models of the plasma membrane, as well as in cancer cell lines. Our results indicate that EPC3 affects lipid–lipid interactions in cellular membranes by decreasing lipid packing and increasing membrane disorder and fluidity. As a consequence of these alterations in the lateral organization of lipid bilayers, the diffusive dynamics of membrane proteins are also significantly increased.