2-hydroxy-9-cis-octadecenoic-acid and Glioma

2-hydroxy-9-cis-octadecenoic-acid has been researched along with Glioma* in 7 studies

Reviews

1 review(s) available for 2-hydroxy-9-cis-octadecenoic-acid and Glioma

ArticleYear
Regulation of the cancer cell membrane lipid composition by NaCHOleate: effects on cell signaling and therapeutical relevance in glioma.
    Biochimica et biophysica acta, 2014, Volume: 1838, Issue:6

    This review summarizes the cellular bases of the effects of NaCHOleate (2-hydroxyoleic acid; 2OHOA; Minerval) against glioma and other types of tumors. NaCHOleate, activates sphingomyelin synthase (SGMS) increasing the levels of cell membrane sphingomyelin (SM) and diacylglycerol (DAG) together with reductions of phosphatidylethanolamine (PE) and phosphatidylcholine (PC). The increases in the membrane levels of NaCHOleate itself and of DAG induce a translocation and overexpression of protein kinase C (PKC) and subsequent reductions of Cyclin D, cyclin-dependent kinases 4 and 6 (CDKs 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of E2F1 and knockdown of dihydrofolate reductase (DHFR) impairing DNA synthesis. In addition in some cancer cells, the increases in SM are associated with Fas receptor (FasR) capping and ligand-free induction of apoptosis. In glioma cell lines, the increases in SM are associated with the inhibition of the Ras/MAPK and PI3K/Akt pathways, in association with p27Kip1 overexpression. Finally, an analysis of the Repository of Molecular Brain Neoplasia Data (REMBRANDT) database for glioma patient survival shows that the weight of SM-related metabolism gene expression in glioma patients' survival is similar to glioma-related genes. Due to its low toxicity and anti-tumoral effect in cell and animal models its status as an orphan drug for glioma treatment by the European Medicines Agency (EMA) was recently acknowledged and a phase 1/2A open label, non-randomized study was started in patients with advanced solid tumors including malignant glioma. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

    Topics: Animals; Cell Membrane; Glioma; Humans; Membrane Lipids; Oleic Acids; Signal Transduction

2014

Other Studies

6 other study(ies) available for 2-hydroxy-9-cis-octadecenoic-acid and Glioma

ArticleYear
Differential effect of 2-hydroxyoleic acid enantiomers on protein (sphingomyelin synthase) and lipid (membrane) targets.
    Biochimica et biophysica acta, 2014, Volume: 1838, Issue:6

    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.

    Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Membrane; Cell Proliferation; Forkhead Transcription Factors; Glioma; Humans; Lipid Bilayers; Lung Neoplasms; Male; Membrane Lipids; Mice; Mice, Nude; Models, Chemical; Molecular Dynamics Simulation; Oleic Acids; Signal Transduction; Stereoisomerism; Transferases (Other Substituted Phosphate Groups); Tumor Cells, Cultured; X-Ray Diffraction

2014
Sustained activation of sphingomyelin synthase by 2-hydroxyoleic acid induces sphingolipidosis in tumor cells.
    Journal of lipid research, 2013, Volume: 54, Issue:5

    The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor drug, involves the rapid and specific activation of sphingomyelin synthase (SMS), leading to a 4-fold increase in SM mass in tumor cells. In the present study, we investigated the source of the ceramides required to sustain this dramatic increase in SM. Through radioactive and fluorescent labeling, we demonstrated that sphingolipid metabolism was altered by a 24 h exposure to 2OHOA, and we observed a consistent increase in the number of lysosomes and the presence of unidentified storage materials in treated cells. Mass spectroscopy revealed that different sphingolipid classes accumulated in human glioma U118 cells after exposure to 2OHOA, demonstrating a specific effect on C16-, C20-, and C22-containing sphingolipids. Based on these findings, we propose that the demand for ceramides required to sustain the SMS activation (ca. 200-fold higher than the basal level) profoundly modifies both sphingolipid and phospholipid metabolism. As the treatment is prolonged, tumor cells fail to adequately metabolize sphingolipids, leading to a situation resembling sphingolipidosis, whereby cell viability is compromised.

    Topics: Cell Line, Tumor; Cell Survival; Ceramides; Glioma; Humans; Oleic Acids; Sphingolipidoses; Sphingolipids; Transferases (Other Substituted Phosphate Groups)

2013
2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy.
    Proceedings of the National Academy of Sciences of the United States of America, 2012, May-29, Volume: 109, Issue:22

    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.

    Topics: Animals; Antineoplastic Agents; Autophagy; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Cell Survival; Dacarbazine; Dose-Response Relationship, Drug; Glioma; Humans; Male; MAP Kinase Signaling System; Membrane Lipids; Mice; Mice, Nude; Microscopy, Confocal; Oleic Acids; Phosphatidylinositol 3-Kinases; Protein Transport; Proto-Oncogene Proteins c-akt; ras Proteins; Temozolomide; Time Factors; Xenograft Model Antitumor Assays

2012
Normalization of sphingomyelin levels by 2-hydroxyoleic acid induces autophagic cell death of SF767 cancer cells.
    Autophagy, 2012, Volume: 8, Issue:10

    The very high mortality rate of gliomas reflects the unmet therapeutic need associated with this type of brain tumor. We have discovered that the plasma membrane fulfills a critical role in the propagation of tumorigenic signals, whereby changes in membrane lipid content can either activate or silence relevant pathways. We have designed a synthetic fatty acid, 2-hydroxyoleic acid (2OHOA), that specifically activates sphingomyelin synthase (SGMS), thereby modifying the lipid content of cancer cell membranes and restoring lipid levels to those found in normal cells. In reverting, the structure of the membrane by activating SGMS, 2OHOA inhibits the RAS-MAPK pathway, which in turn fails to activate the CCND (Cyclin D)-CDK4/CDK6 and PI3K-AKT1 pathways. The overall result in SF767 cancer cells, a line that is resistant to apoptosis, is the sequential induction of cell cycle arrest, cell differentiation and autophagy. Such effects are not observed in normal cells (MRC-5) and thus, this specific activation of programmed cell death infers greater efficacy and lower toxicity to 2OHOA than that associated with temozolomide (TMZ), the reference drug for the treatment of glioma.

    Topics: Autophagy; Cell Cycle; Cell Line, Tumor; Endoplasmic Reticulum Stress; Glioma; Humans; Models, Biological; Oleic Acids; Signal Transduction; Sphingomyelins

2012
2-Hydroxyoleic acid induces ER stress and autophagy in various human glioma cell lines.
    PloS one, 2012, Volume: 7, Issue:10

    2-Hydroxyoleic acid is a synthetic fatty acid with potent anti-cancer activity which does not induce undesired side effects. However, the molecular and cellular mechanisms by which this compound selectively kills human glioma cancer cells without killing normal cells is not fully understood. The present study was designed to determine the molecular bases underlying the potency against 1321N1, SF-767 and U118 human glioma cell lines growth without affecting non cancer MRC-5 cells.. The cellular levels of endoplasmic reticulum (ER) stress, unfolded protein response (UPR) and autophagy markers were determined by quantitative RT-PCR and immunoblotting on 1321N1, SF-767 and U118 human glioma cells and non-tumor MRC-5 cells incubated in the presence or absence of 2OHOA or the ER stress/autophagy inducer, palmitate. The cellular response to these agents was evaluated by fluorescence microscopy, electron microscopy and flow cytometry. We have observed that 2OHOA treatments induced augments in the expression of important ER stress/UPR markers, such as phosphorylated eIF2α, IRE1α, CHOP, ATF4 and the spliced form of XBP1 in human glioma cells. Concomitantly, 2OHOA led to the arrest of 1321N1 cells in the G(2)/M phase of the cell cycle, with down-regulation of cyclin B1 and Cdk1/Cdc2 proteins in the three glioma cell lines studied. Finally, 2OHOA induced autophagy in 1321N1, SF-767 and U118 cells, with the appearance of autophagic vesicles and the up-regulation of LC3BI, LC3BII and ATG7 in 1321N1 cells, increases of LC3BI, LC3BII and ATG5 in SF-767 cells and up-regulation of LC3BI and LC3BII in U118 cells. Importantly, 2OHOA failed to induce such changes in non-tumor MRC-5 cells.. The present results demonstrate that 2OHOA induces ER stress/UPR and autophagy in human glioma (1321N1, SF-767 and U118 cell lines) but not normal (MRC-5) cells, unraveling the molecular bases underlying the efficacy and lack of toxicity of this compound.

    Topics: Antineoplastic Agents; Autophagy; Brain Neoplasms; Cell Line; Cell Line, Tumor; Cell Survival; Endoplasmic Reticulum; Fatty Acids; Fibroblasts; Glioma; Humans; Lung; Oleic Acids; Signal Transduction; Tetrazolium Salts; Thiazoles

2012
Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy.
    Proceedings of the National Academy of Sciences of the United States of America, 2011, Dec-06, Volume: 108, Issue:49

    The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-fold), restoring the levels found in MRC-5 cells, while a loss of phosphatidylethanolamine and phosphatidylcholine is observed (57 and 30%, respectively). The increased SM mass was due to a rapid and highly specific activation of SM synthases (SMS). This effect appeared to be specific against cancer cells as it did not affect nontumor MRC-5 cells. Therefore, low SM levels are associated with the tumorigenic transformation that produces cancer cells. SM accumulation occurred at the plasma membrane and caused an increase in membrane global order and lipid raft packing in model membranes. These modifications would account for the observed alteration by 2OHOA in the localization of proteins involved in cell apoptosis (Fas receptor) or differentiation (Ras). Importantly, SMS inhibition by D609 diminished 2OHOA effect on cell cycle. Therefore, we propose that the regulation of SMS activity in tumor cells is a critical upstream event in 2OHOA antitumor mechanism, which also explains its specificity for cancer cells, its potency, and the lack of undesired side effects. Finally, the specific activation of SMS explains the ability of this compound to trigger cell cycle arrest, cell differentiation, and autophagy or apoptosis in cancer cells.

    Topics: Apoptosis; Bridged-Ring Compounds; Cell Cycle Checkpoints; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Survival; Cell Transformation, Neoplastic; Cells; fas Receptor; Gene Expression Regulation, Enzymologic; Glioma; Humans; Immunoblotting; Jurkat Cells; Membrane Microdomains; Membrane Proteins; Nerve Tissue Proteins; Norbornanes; Oleic Acids; Phosphodiesterase Inhibitors; ras Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sphingomyelins; Thiocarbamates; Thiones; Transferases (Other Substituted Phosphate Groups)

2011