gamma-linolenic-acid and Brain-Neoplasms

Gamma-linolenic acid (GLA) induced apoptosis of tumor cells without harming normal cells. Both cyclo-oxygenase (COX) and lipoxygenase (LO) inhibitors did not inhibit the selective tumoricidal action of GLA in some, but not all, tumor cells suggesting that GLA by itself is active. In contrast, anti-oxidants such as vitamin E blocked the tumoricidal action of GLA. GLA-treated tumor but not normal cells produced a 2-3-fold increase in free radicals and lipid peroxides. GLA decreased the anti-oxidant content of tumor cells, expression of oncogenes ras, and Bcl-2, enhanced the activity of p53, protected normal cells and tissues from the toxic actions of radiation and anti-cancer drugs, enhanced the cytotoxic action of anti-cancer drugs and reversed tumor cell drug resistance. In the animal glioma model, GLA induced tumor regression and preserved the surrounding normal brain tissue. In three open-label clinical studies, intra-tumoral injection of GLA induced significant reduction of glioma without any significant side effects. The low neurotoxicity of GLA to normal brain neurons and selective activity against tumor cells suggests that it could be an effective anti-glioma molecule.

Topics: Animals; Antioxidants; Apoptosis; Brain Neoplasms; Cyclooxygenase Inhibitors; Free Radicals; gamma-Linolenic Acid; Glioma; HeLa Cells; HL-60 Cells; Humans; Lipid Peroxides; Lipoxygenase Inhibitors; Mice; Vitamin E

Glioblastoma multiforme (GBM) is the most malignant astrocytoma, the main treatments consist of surgical resection followed by radiotherapy and chemotherapy. Patients, after diagnosed, have a survival rate of one year. GBM cells have an invasive, proliferative and migratory characteristic, also they do not respond properly for usual cancer treatment (radiotherapy, chemotherapy). Fatty acids have been studied as an adjuvant cancer treatment in breast, colorectal and GBM. The fatty acid can alter tumoural cell metabolism causing a modification of eicosanoids production. This study has observed some cellular aspects modified by fatty acid treatment in vitro, using GBM cells (human and rat). Modifications in cell behaviour were analyzed like cell proliferation, apoptosis, migration and invasion cell capacity after treatment with fatty acid (gamma-linolenic acid). The treatment suggested in this study showed an increased number of apoptotic cells and a decreased number of proliferative and migratory cells. These data recognize that gamma-linolenic acid could be used as an alternative treatment for glioblastoma.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Movement; Cell Proliferation; gamma-Linolenic Acid; Glioblastoma; Humans; Rats; Tumor Cells, Cultured

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

Arachidonic acid (AA) and Gamma linolenic acid have been shown to limit glioma cell growth, stimulate apoptosis and lipid peroxidation. However, brain tumours are characterised by cellular heterogeneity and responding cell populations have not been identified. Brain tumour samples from patients were disaggregated. In cell preparations from 7 gliomas, reactive oxygen species (ROS), morphology and plasma membrane integrity were monitored +/-18-36 microM AA for 15-120 min using flow cytometry. Basal oxidative activity related to cell size/morphology, small granular cells showed lower activity. AA stimulation of ROS formation depended on cell size/morphology. Large, less granular cells showed greater AA stimulation. In 17 gliomas, GFAP immunofluorescence was demonstrated in larger cell populations. The large GFAP positive cell population with low side scatter was the highest responding cell population, suggesting selective tumour cell sensitivity to AA induced ROS formation. ROS may have a role in AA induced cell death and anti-tumour activity of AA in glioma.

Topics: Antineoplastic Agents; Arachidonic Acid; Brain Neoplasms; Cell Death; Cell Division; gamma-Linolenic Acid; Glioma; Humans; In Vitro Techniques; Oxidation-Reduction; Reactive Oxygen Species

Highly unsaturated fatty acids (HUFAs) are naturally occurring anti-tumour agents. HUFAs act as intracellular signalling molecules in cell proliferation and death. In human glioma, HUFAs may stimulate tumour regression and apoptosis. An implantation glioma model, using the C6 glioma cell line, was used to investigate the bioactivity of locally infused n-6 HUFA gamma linolenic acid (GLA). Rat brains (15 normal and 37 C6 tumour bearing) were infused with vehicle or GLA 200 microM-2 mM. The most active local concentration of GLA for anti-tumour activity was 2 mM, infused at 1 microl/h over 7 days. Tumour regression, increased apoptosis and decreased proliferation were observed in tumours of rats infused with this concentration of GLA. Little effect on normal neuronal tissue was detected. The intraparenchymal route was an effective method of GLA administration in the treatment of glioma. These studies provide further insights into the potential role of HUFAs as anti-glioma agents.

Topics: Animals; Apoptosis; Biological Availability; Brain; Brain Neoplasms; Cell Division; Disease Models, Animal; Fatty Acids, Unsaturated; gamma-Linolenic Acid; Glioma; In Situ Nick-End Labeling; Male; Rats; Rats, Wistar; Signal Transduction

The highly unsaturated fatty acids (HUFA) of the n-6 and n-3 series are involved in cell signalling in normal and transformed cells and have recently been associated with pathways leading to tumour cell death. The antitumour activity of three HUFA (arachidonic acid, gamma linolenic acid and eicosapentaenoic acid) were studied in glioma cells and tissue. Using five glioma models, including primary cell suspensions prepared from 46 human glioma samples and an in vivo rat C6 glioma model, we obtained evidence that, following exposure to HUFA, either administered into the medium surrounding human glioma cells or in 16 preparations of multicellular spheroids derived from human and rodent glioma cell lines (C6, MOG, U87, U373) or administered intra-tumourally by infusion using osmotic mini-pumps in 48 rats, glioma regression and apoptosis were detected. Additionally, synergy between gamma irradiation and HUFA administration was observed in 13 experiments analyzing C6 glioma cell apoptosis in vitro. These pro-apoptotic and antiproliferative activities were observed using both C18 and C20 fatty acids of the n-6 and n-3 series, but not when saturated and monounsaturated C18 and C20 fatty acid preparations were used. In the glioma infusion model, in addition to the apoptosis detected in glioma tissue infused with HUFA for 3-7 days, preservation of normal neural tissue and vasculature in adjacent brain was observed. Also, there was little evidence of acute inflammatory infiltration in regressing tumours. Our findings suggest that intraparenchymal infusion of HUFA may be effective in stimulating glioma regression.

Topics: Animals; Apoptosis; Arachidonic Acid; Brain Neoplasms; Cell Division; Fatty Acids, Unsaturated; gamma-Linolenic Acid; Glioma; Humans; In Situ Nick-End Labeling; Rats; Reactive Oxygen Species; Tumor Cells, Cultured; X-Rays

Gamma linoleic acid (GLA) salts may exert a direct antiproliferative activity on tumor cells. The cytotoxicity is linked to the generation of conjugated dienes, peroxyl radicals and superoxide radicals. Lithium gammalinolenate (LiGLA) and meglumine gammalinolenate (MeGLA) have been recently developed for enhancing the water solubility of these compounds. MeGLA or LiGLA (10(-5) to 10(-4) mol/l) and fotemustine (Fote) (2 x 10(-6) to 2 x 10(-4) mol/l) were applied, alone or in combination, for up to 9 days to two human glioblastoma cell lines A172 and U373MG. Fote was applied first followed by LiGLA and/or MeGLA. Cytotoxicity was evaluated by the MTT test, and the effects of drug combinations were analyzed by the isobolographic representation according to the Chou and Talalay method (combination indexes). For both GLA salts, cytotoxicity was manifested after 4 days of cell exposure and with very sharp dose-response curves. Comparison of IC50 values indicated that MeGLA was more active than LiGLA. There was a constant reduction in IC50 values following an increase in exposure time for A172 cells: between 4 and 9 days of cell exposure, IC50 changed from 73 to 46 microM for LiGLA and from 49 to 31 microM for MeGLA (p<0.05). With U373MG cells, there was no influence of exposure duration on IC50 values. Combination index values indicated that association between Fote and GLA salts globally resulted in slightly antagonistic effects. These results may be useful for further development of GLA salts at the clinical level.

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Survival; Drug Interactions; Drug Screening Assays, Antitumor; gamma-Linolenic Acid; Glioblastoma; Humans; Lithium Compounds; Meglumine; Nitrosourea Compounds; Organophosphorus Compounds; Tumor Cells, Cultured

Intracranial infusions of gamma-linolenic acid (GLA), an essential fatty acid, have been used as an adjuvant therapy following malignant glioma resection; however, little is known about the dose response of glioma cells to this therapy. In this in vitro study the authors address this important pharmacological question.. Glioma spheroids derived from U87, U373, MOG-G-CCM, and C6 cell lines were grown in collagen gel and exposed to a range of GLA concentrations (0-1 mM) for 5 days. The diameter of glioma spheroids was measured, the apoptotic index was assessed using both the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique and cell morphological testing, and the levels of proliferating cell nuclear antigen were also measured.. The dose-response patterns were similar for all four glioma spheroids. Low concentrations of GLA (<100 microM) increased both apoptosis and proliferation with a net increase in tumor growth and invasion, whereas high-dose GLA (>100 microM) significantly impaired spheroid cell growth. The proliferative effects of low-dose GLA could be a hazard in the clinical treatment of malignant glioma; however, because of the low toxicity of GLA against normal cells, local delivery of millimolar doses of GLA could significantly reduce tumor size.

Topics: Animals; Apoptosis; Astrocytoma; Brain Neoplasms; Cell Division; Dose-Response Relationship, Drug; gamma-Linolenic Acid; Glioblastoma; Humans; Neoplasm Invasiveness; Spheroids, Cellular; Tumor Cells, Cultured

This study compares the effect of gamma-linolenic acid (GLA) and its precursor linoleic acid (LA) on survival of 36B10 malignant rat astrocytoma cells and 'normal' rat astrocytes. GLA was cytotoxic to 36B10 cells but not to astrocytes. By contrast, LA supplementation did not affect the survival of either cell types. There were minor differences in the uptake, distribution and use of radiolabelled GLA and LA by the 36B10 cells and astrocytes. GLA and LA supplementation increased the total polyunsaturated fatty acid (PUFA) content of the cells indicating increased oxidative potential. However, elevated levels of 8-isoprostane, an indicator of increased oxidative stress, were only observed in the GLA supplemented 36B10 cells. Addition of the antioxidant trolox to GLA-enriched 36B10 cells blocked the cytotoxic effect. Further, GLA enhanced the radiation sensitivity of the astrocytoma cells but not the astrocytes; trolox blocked the GLA-mediated increase in astrocytoma cell radiosensitivity. LA did not affect the radiation response of either cell type. While cyclo-oxygenase inhibitors did not affect GLA cytotoxicity, they blocked the enhanced radiation response of GLA-supplemented cells. The lipoxygenase inhibitor NDGA did not affect the toxicity produced by GLA. Thus, GLA is toxic to the neoplastic astrocytoma cells but not to normal astrocytes.

Topics: alpha-Linolenic Acid; Animals; Antineoplastic Agents; Antioxidants; Astrocytes; Astrocytoma; Brain Neoplasms; Cell Death; Chromans; Cyclooxygenase Inhibitors; Dinoprost; F2-Isoprostanes; gamma-Linolenic Acid; Ibuprofen; Indomethacin; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured; Vitamin E

gamma-Linolenic acid (GLA) has been shown to have selective tumoricidal action both in vitro and in vivo. Earlier, in a limited clinical study, we have demonstrated that intra-tumoral administration of GLA can induce regression of human gliomas. In an extension of this study, we evaluated the effect of intra-cerebral injection of GLA on normal dog brain and in 15 patients with malignant gliomas. Histopathological examination revealed that GLA is not cytotoxic to the normal dog brain cells. Administration of 10 mg of GLA via a cerebral reservoir placed in the tumour bed, at the rate of 1 mg/day over a period of 10 days, revealed that GLA is not only safe and non-toxic but can also regress cerebral gliomas as evaluated by computerised tomography and increased survival of the patients by 1.5-2 years. Based on these results and our earlier in vitro study, we suggest that GLA is a safe anti-tumour agent and recommend its use in the management of human gliomas.

Topics: Adult; Aged; Aged, 80 and over; Animals; Astrocytoma; Brain Neoplasms; Dogs; Female; gamma-Linolenic Acid; Glioblastoma; Glioma; Humans; Injections, Intralesional; Male; Middle Aged; Tomography, X-Ray Computed