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: Silvia Terés, Victoria Lladó, Mónica Higuera, Gwendolyn Barceló-Coblijn, Maria Laura Martin, Maria Antònia Noguera-Salvà, Amaia Marcilla-Etxenike, José Manuel García-Verdugo, Mario Soriano-Navarro, Carlos Saus, Ulises Gómez-Pinedo, Xavier Busquets, Pablo V Escribá
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 22 Pg. 8489-94 (May 29 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22586083 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-hydroxyoleic acid
• Antineoplastic Agents
• Membrane Lipids
• Oleic Acids
• Dacarbazine
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• ras Proteins
• Temozolomide

Topics

• Animals
• Antineoplastic Agents (metabolism, pharmacology)
• Autophagy (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Membrane (chemistry, drug effects, metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dacarbazine (analogs & derivatives, pharmacology)
• Dose-Response Relationship, Drug
• Glioma (drug therapy, metabolism, pathology)
• Humans
• MAP Kinase Signaling System (drug effects)
• Male
• Membrane Lipids (chemistry, metabolism)
• Mice
• Mice, Nude
• Microscopy, Confocal
• Oleic Acids (metabolism, pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Transport (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Temozolomide
• Time Factors
• Xenograft Model Antitumor Assays
• ras Proteins (metabolism)