title: 2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy.
abstract: Despite recent advances in the development of new cancer therapies, the treatment options for glioma remain limited, and the survival rate of patients has changed little over the past three decades. Here, we show that 2-hydroxyoleic acid (2OHOA) induces differentiation and autophagy of human glioma cells. Compared to the current reference drug for this condition, temozolomide (TMZ), 2OHOA combated glioma more efficiently and, unlike TMZ, tumor relapse was not observed following 2OHOA treatment. The novel mechanism of action of 2OHOA is associated with important changes in membrane-lipid composition, primarily a recovery of sphingomyelin (SM) levels, which is markedly low in glioma cells before treatment. Parallel to membrane-lipid regulation, treatment with 2OHOA induced a dramatic translocation of Ras from the membrane to the cytoplasm, which inhibited the MAP kinase pathway, reduced activity of the PI3K/Akt pathway, and downregulated Cyclin D-CDK4/6 proteins followed by hypophosphorylation of the retinoblastoma protein (RB). These regulatory effects were associated with induction of glioma cell differentiation into mature glial cells followed by autophagic cell death. Given its high efficacy, low toxicity, ease of oral administration, and good distribution to the brain, 2OHOA constitutes a new and potentially valuable therapeutic tool for glioma patients.
authors.affiliation: Molecular Cell Biomedicine, Department of Biology-Institut Universitari d'Investigacions en Ciències de la Salut, University of the Balearic Islands, 07122 Palma de Mallorca, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Terés
authors.forename: Victoria
authors.initials: V
authors.lastname: Lladó
authors.forename: Mónica
authors.initials: M
authors.lastname: Higuera
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Barceló-Coblijn
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Martin
authors.forename: Maria Antònia
authors.initials: MA
authors.lastname: Noguera-Salvà
authors.forename: Amaia
authors.initials: A
authors.lastname: Marcilla-Etxenike
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García-Verdugo
authors.forename: Mario
authors.initials: M
authors.lastname: Soriano-Navarro
authors.forename: Carlos
authors.initials: C
authors.lastname: Saus
authors.forename: Ulises
authors.initials: U
authors.lastname: Gómez-Pinedo
authors.forename: Xavier
authors.initials: X
authors.lastname: Busquets
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Escribá
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009829:Oleic Acids / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077204:Temozolomide; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism
chemical_list: C483229:2-hydroxyoleic acid; D000970:Antineoplastic Agents; D008563:Membrane Lipids; D009829:Oleic Acids; D003606:Dacarbazine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins; D000077204:Temozolomide