linoleic-acid and Brain-Neoplasms

In vitro and in vivo studies have shown that gamma-linoleic acid (GLA), arachidonic acid (AA) and eicosapentaenoic acid (EPA) can selectively kill tumor cells. In a clinical trial, the effectiveness of intratumoral administration of GLA in patients with gliomas was studied. Of the 6 patients treated, all showed substantial response to GLA as documented by computerized tomography. There were no acute side-effects due to the therapy. This report demonstrates that intratumoral administration of GLA is a possible approach to the treatment of human glial tumors.

Topics: Adolescent; Adult; Antineoplastic Agents; Brain Neoplasms; Glioma; Humans; Injections, Intraventricular; Linoleic Acid; Linoleic Acids; Male; Middle Aged

The mitochondrial phospholipid cardiolipin (CL) has been implicated with mitochondrial morphology, function, and cell proliferation. Changes in CL are often paralleled by changes in the lipid environment of mitochondria that may contribute to mitochondrial function and proliferation. This study aimed to separate the effects of CL content and CL composition from cellular free fatty acid distribution on bioenergetics and proliferation in C6 glioma cells. To this end, cardiolipin synthase and the CL remodelling enzyme, tafazzin, were knocked-down by siRNA in C6 cells. After 72 h of cultivation, we analysed CL composition by means of LC/MS/MS, distribution of cellular fatty acids by means of gas chromatography, and determined oxygen consumption and proliferation. Knock-down of cardiolipin synthase affected the cellular CL content in the presence of linoleic acid (LA) in the culture medium. Knock-down of tafazzin had no consequence with respect to the pattern of cellular fatty acids but caused a decrease in cell proliferation. It significantly changed the distribution of molecular CL species, increased CL content, decreased oxygen consumption, and decreased cell proliferation when cultured in the presence of linoleic acid (LA). The addition of linoleic acid to the culture medium caused significant changes in the pattern of cellular fatty acids and the composition of molecular CL species. These data suggest that tafazzin is required for efficient bioenergetics and for proliferation of glioma cells. Supplementation of fatty acids can be a powerful tool to direct specific changes in these parameters.

Topics: Acyltransferases; Animals; Brain Neoplasms; Cardiolipins; Cell Line, Tumor; Cell Proliferation; Citrate (si)-Synthase; Gene Knockdown Techniques; Glioma; Linoleic Acid; Membrane Proteins; Mitochondria; Rats; RNA, Messenger; RNA, Small Interfering; Transcription Factors; Transferases (Other Substituted Phosphate Groups)

Embelin is a potent dual inhibitor of 5-lipoxigenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1 that suppresses proliferation of human glioma cells and induces apoptosis by inhibiting XIAP and NF-κB signaling pathway. Synthetic structural modification yielded the derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id), an embelin constrained analogue, with improved efficiency against 5-LOX in human neutrophils and anti-inflammatory activity in vivo. Taking into account that lipoxygenase (LOX) metabolites, from arachidonic acid and linoleic acid, have been implicated in tumor progression, here, we determined whether RF-Id was able to hinder glioblastoma (GBM) cancer cell growth and the related mechanisms.. U87MG and LN229 cells were plated in 96-wells and treated with increasing concentrations of RF-Id. Cell viability was evaluated by MTT assay. The effects of the compounds on cell cycle, apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array and evaluating caspase cascade and NFκB pathway by western blotting technique.. Here, we found that RF-Id induced a stronger inhibition of GBM cell growth than treatment with embelin. Flow cytometry analysis showed that RF-Id induced about 30 % apoptosis and a slight increase of autophagy after 72 h on U87-MG cells. Moreover, the compound induced an increase in the percentage of cells in G2 and S phase that was paralleled by an increase of p21 and p27 expression but no significant changes of the mitochondrial membrane potential; array analysis showed a significant upregulation of CASP8 and a downregulation of IAP family and NFκB genes in cells treated with RF-Id. RF-Id induced a significant cleavage of caspases 8, 9, 3 and 7, blocked c-IAP2/XIAP interaction by inducing XIAP degradation and inhibited NFκB pathway.. RF-Id induced a caspase-dependent apoptosis in GBM cells by inhibiting IAP family proteins and NFκB pathway and represents a promising lead compound for designing a new class of anti-cancer drugs with multiple targets.

Topics: Arachidonate 5-Lipoxygenase; Arachidonic Acid; Autophagy; Benzoquinones; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Inhibitor of Apoptosis Proteins; Linoleic Acid; Oxidative Stress; Signal Transduction

Considering the observations that linoleic acid conjugated with paclitaxel (CLA-PTX) possesses antitumor activity against brain tumors, is able to cross the blood-brain barrier, but has poor water solubility, the purpose of this study was to prepare a novel CLA-PTX microemulsion and evaluate its activity against brain tumors in vitro and in vivo.. The in vitro cytotoxicity of a CLA-PTX microemulsion was investigated in C6 glioma cells. The in vivo antitumor activity of the CLA-PTX microemulsion was evaluated in tumor-bearing nude mice and rats. The pharmacokinetics of the CLA-PTX microemulsion were investigated in rats, and its safety was also evaluated in mice.. The average droplet size of the CLA-PTX microemulsion was approximately 176.3 ± 0.8 nm and the polydispersity index was 0.294 ± 0.024. In vitro cytotoxicity results showed that the IC(50) of the CLA-PTX microemulsion was 1.61 ± 0.83 μM for a C6 glioma cell line, which was similar to that of free paclitaxel and CLA-PTX solution (P > 0.05). The antitumor activity of the CLA-PTX microemulsion against brain tumors was confirmed in our in vivo C6 glioma tumor-bearing nude mice as well as in a rat model. In contrast, Taxol(®) had almost no significant antitumor effect in C6 glioma tumor-bearing rats, but could markedly inhibit growth of C6 tumors in C6 glioma tumor-bearing nude mice. The pharmacokinetic results indicated that CLA-PTX in solution has a much longer circulation time and produces higher drug plasma concentrations compared with the CLA-PTX microemulsion. The results of the acute toxicity study showed that the LD(50) of CLA-PTX solution was 103.9 mg/kg. In contrast, the CLA-PTX microemulsion was well tolerated in mice when administered at doses up to 200 mg/kg.. CLA-PTX microemulsion is a novel formulation with significant antitumor efficacy in the treatment of brain tumors, and is safer than CLA-PTX solution.

Topics: Animals; Antineoplastic Agents, Phytogenic; Brain Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Emulsions; Glioma; Lethal Dose 50; Linoleic Acid; Mice; Nanocapsules; Paclitaxel; Treatment Outcome

Docosahexaenoic acid (DHA) may have potential anticarcinogenic effect. In the present study, effect of DHA on rat C6 glioma was tested. In vitro, cytotoxic effect of 50-400 microM DHA on C6 cells was evaluated and compared with linoleic acid (LA). In vivo, adult female Wistar rats implanted with C6 tumor, fed 1 ml of DHA oil (containing 73% DHA, 36 rats) or LA oil (containing 72-77% LA, 41 rats) daily, starting one week prior to tumor implantation until death or if survived, until 30 days after implantation. Another group of tumor bearing rats was treated with chloroethyl-cyclohexyl-nitrosourea (CCNU, 30 mg/kg, 31 rats) at day 8 post implantation to show if the result of oil supplementation is comparable to single agent chemotherapy. mRNA expression of p21 and p27 was determined in vitro at 100 and 150 microM of fatty acids and in tumors of rats supplemented with LA or DHA oils. In vitro, DHA, but not LA, had cytotoxic effect on C6 cells at 200 and 400 microM and DHA increased mRNA expression of p21 at 150 microM (p < 0.05). In rat glioma model, although a non-significant trend towards better survival was observed in DHA oil relative to LA oil group, the difference was not significant (p = 0.20). p21 and p27 mRNA expression in tumors of DHA oil group did not differ with LA oil group. Single dose of CCNU increased survival when compared to LA oil group (p < 0.001). In conclusion, intake of DHA at the dose or duration employed in the present study might be insufficient to bring about its cytotoxic action on rat's C6 brain tumor.

Topics: Animals; Antineoplastic Agents; Body Weight; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase Inhibitor p27; Diet; Docosahexaenoic Acids; Eating; Fatty Acids; Female; Glioma; Linoleic Acid; Neoplasm Transplantation; p21-Activated Kinases; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Analysis

Experimental studies indicate that gamma linolenic acid (GLA) and docosahexaenoic acid (DHA) may inhibit glioma cells growth but effects of oral consumption of these fatty acids on brain tumor fatty acid composition have not been determined in vivo.. GLA oil (GLAO; 72% GLA), DHA oil (DHAO; 73% DHA) were fed to adult wistar rats (1 mL/rat/day) starting one week prior to C6 glioma cells implantation and continued for two weeks after implantation. Control group were fed same amount of high linoleic acid safflower oil (74-77% linoleic acid). Fatty acid composition of tumor samples was determined in a set of 8-12 animals in each group and serum fatty acid in 6 animals per each group. Gene expression of tumor fatty acid binding protein 7 (FABP7), epidermal growth factor receptor (EGFR), peroxisome proliferator activated receptor gamma (PPAR-gamma) and retinoid x receptor-alpha (RXR-alpha) were determined in a set of 18 animals per group.. DHAO feeding increased EPA of brain tumors and decreased ratio of n-6/n-3 fatty acids. Serum levels of EPA were also increased in DHAO group. A similar trend in serum and tumor levels of DHA were observed in DHAO group but it did not achieve statistical significance. GLAO increased serum concentration of GLA but had no significant effect on tumor GLA or dihomo-gamma linolenic acid (DGLA) concentrations. Gene expression of FABP7 was up-regulated in tumors of DHAO group but no other significant effects were observed on EGFR, PPAR-gamma or RXR-alpha expression, and expression of these genes in tumors of GLAO were not different from SFO group.. Dietary supplementation of DHA containing oil could be an effective way to increase levels of long chain n-3 fatty acids in brain tumors and this increase may be mediated partly by up-regulation of FABP7 expression.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Chromatography, Gas; Docosahexaenoic Acids; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Fatty Acids; Female; gamma-Linolenic Acid; Gene Expression; Genes, erbB-1; Glioma; Linoleic Acid; Lipid Metabolism; Nerve Tissue Proteins; PPAR gamma; Rats; Rats, Wistar; Retinoid X Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction

In this study, the role of exogenous fatty acids in the regulation of proteolipid protein (PLP) gene expression was investigated using the following model culture system: C6 glioma cells expressing the green-fluorescent protein (eGFP) driven by different segments of PLP promoter. Eicosapentanoic acid (EPA; 20:5 n-3), but not arachidonic acid (AA; 20:4 n-6), induced a significant increase in medium fluorescence intensity (MFI) determined by fluorescence-activated cell sorting (FACS). The induction of PLP promoter was time-dependent showing maximal activity between 24 and 48 h after EPA exposure. PLP promoter activation was dependent on fatty acid concentration, with maximum activation at 200 microM. Northern blot analysis confirmed the fluorescence data in C6 cells incubated with EPA. Furthermore, this treatment increased the adenylyl cyclase-cyclic AMP (cAMP) levels and the mitogen-activated protein kinase (MAPK) activation in C6 cells. PLP promoter activity was inhibited by pre-treatment with H89 (protein kinase A (PKA) inhibitor), but not with PD98059 (MAPK inhibitor), suggesting that EPA stimulates the expression of PLP via cAMP-mediated pathways.

Topics: alpha-Linolenic Acid; Animals; Arachidonic Acid; Blotting, Northern; Blotting, Western; Brain Neoplasms; Cell Line, Tumor; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Glioma; Green Fluorescent Proteins; Linoleic Acid; Luminescent Proteins; Mitogen-Activated Protein Kinases; Myelin Proteolipid Protein; Rats; RNA, Messenger; Stimulation, Chemical; Transfection

Topics: Astrocytoma; Biopsy; Brain Neoplasms; Fatty Acids; Glioblastoma; Humans; Linoleic Acid

The effect of arachidonic acid (AA, 20:4) was analyzed in vitro by employment of C6 glioma cells and astrocytes from primary culture. The cells were suspended in an incubation chamber under continuous control of pH, pO2, and temperature. Cell swelling was quantified by flow cytometry. After a control period, the suspension was added with AA at concentrations of 0.01 to 1.0 mM. Administration of AA induced an immediate, dose dependent swelling in C6 glioma cells or astrocytes. AA-concentrations of 0.01 mM led to an increase of the glial cell volume to 103.0 +/- 1.0% of control, 0.1 mM to 110.0 +/- 1.5%, and 1.0 mM to 118.8 +/- 1.5% within 10 min. The swelling response to linoleic acid (18:2) was only about half of what was found when AA was administered at a concentration of 0.1 mM, whereas stearic acid (18:0) did not induce any cell volume changes. Inhibition of the cyclo- and lipoxygenase pathway by BW 755C did not prevent glial swelling from AA, whereas it was reduced by SOD, or almost completely abolished by the aminosteroid U-74389F, an antagonist of lipid peroxidation. Replacement of Na(+)- and Cl- -ions in the suspension medium by choline chloride was also associated with complete abolishment of cell swelling from AA. The results demonstrate an impressive efficacy of arachidonic acid to induce glial swelling which might be attributable to activation of lipid peroxidation by the fatty acid, leading to an increased Na(+)-permeability and subsequent influx of water into the cells.

Topics: Animals; Arachidonic Acid; Astrocytes; Brain Neoplasms; Cell Line; Cell Membrane Permeability; Dose-Response Relationship, Drug; Flow Cytometry; Glioma; Intracellular Fluid; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Neuroglia; Neurons; Rats; Sodium; Tumor Cells, Cultured; Water-Electrolyte Balance

Topics: Brain Neoplasms; Cholesterol; Chromatography; Chromatography, Gas; Ependymoma; Fatty Acids; Glioma; Glycerides; Linoleic Acid; Mice; Neoplasm Transplantation; Oleic Acid; Palmitic Acid; Phospholipids; Research; Stearic Acids