title: Differential effect of 2-hydroxyoleic acid enantiomers on protein (sphingomyelin synthase) and lipid (membrane) targets.
abstract: The complex dual mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent anti-tumor compound used in membrane lipid therapy (MLT), has yet to be fully elucidated. It has been demonstrated that 2OHOA increases the sphingomyelin (SM) cell content via SM synthase (SGMS) activation. Its presence in membranes provokes changes in the membrane lipid structure that induce the translocation of PKC to the membrane and the subsequent overexpression of CDK inhibitor proteins (e.g., p21(Cip1)). In addition, 2OHOA also induces the translocation of Ras to the cytoplasm, provoking the silencing of MAPK and its related pathways. These two differential modes of action are triggered by the interactions of 2OHOA with either lipids or proteins. To investigate the molecular basis of the different interactions of 2OHOA with membrane lipids and proteins, we synthesized the R and S enantiomers of this compound. A molecular dynamics study indicated that both enantiomers interact similarly with lipid bilayers, which was further confirmed by X-ray diffraction studies. By contrast, only the S enantiomer was able to activate SMS in human glioma U118 cells. Moreover, the anti-tumor efficacy of the S enantiomer was greater than that of the R enantiomer, as the former can act through both MLT mechanisms. The present study provides additional information on this novel therapeutic approach and on the magnitude of the therapeutic effects of type-1 and type-2 MLT approaches. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.
authors.affiliation: Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, Fisciano 84084, SA, Italy. Electronic address: piotto@unisa.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Piotto
authors.affiliation: Department of Industrial Engineering, University of Salerno, via Giovanni Paolo II 132, Fisciano 84084, SA, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Concilio
authors.affiliation: Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, Fisciano 84084, SA, Italy.
authors.forename: Erminia
authors.initials: E
authors.lastname: Bianchino
authors.affiliation: Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, Fisciano 84084, SA, Italy.
authors.forename: Pio
authors.initials: P
authors.lastname: Iannelli
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Lipopharma Therapeutics, S.L., Palma, Spain.
authors.forename: David J
authors.initials: DJ
authors.lastname: López
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Lipopharma Therapeutics, S.L., Palma, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Terés
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Lipopharma Therapeutics, S.L., Palma, Spain.
authors.forename: Maitane
authors.initials: M
authors.lastname: Ibarguren
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Lipopharma Therapeutics, S.L., Palma, Spain.
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Barceló-Coblijn
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Lipopharma Therapeutics, S.L., Palma, Spain.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Martin
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Lipopharma Therapeutics, S.L., Palma, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Guardiola-Serrano
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Lipopharma Therapeutics, S.L., Palma, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Alonso-Sande
authors.affiliation: HASYLAB at Deutsches Elektronen-Synchrotron, D-22607 Hamburg, Germany.
authors.forename: Sérgio S
authors.initials: SS
authors.lastname: Funari
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Lipopharma Therapeutics, S.L., Palma, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Busquets
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Lipopharma Therapeutics, S.L., Palma, Spain.
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Escribá
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D051858:Forkhead Transcription Factors / Q000502:physiology; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D009829:Oleic Acids / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014961:X-Ray Diffraction
chemical_list: C483229:2-hydroxyoleic acid; D000970:Antineoplastic Agents; D051858:Forkhead Transcription Factors; D008051:Lipid Bilayers; D008563:Membrane Lipids; D009829:Oleic Acids; C090140:Whn protein; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase
keywords: 2-Hydroxyoleic acid; Anti-cancer drug; Membrane lipid therapy; Membrane physical state; Molecular dynamics