gamma-linolenic-acid and Glioblastoma

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

Polyunsaturated fatty acids (PUFAs) such as γ-linolenic acid (GLA), arachidonic acid (AA) and docosahexaenoic acid (DHA) have cytotoxic action on glioma cells.. We evaluated the cytotoxic action of GLA, AA and DHA on glioma cells with specific reference to the expression of miRNAs. Relative expression of miRNAs were assessed by using high throughput nanocapillary real-time PCR. Most of the miRNA target genes that showed altered expression could be classified as apoptotic genes and were up-regulated by PUFA or temozolomide treatment, while similar treatments resulted in repression of the corresponding mRNAs, such as cox2, irs1, irs2, ccnd1, itgb3, bcl2, sirt1, tp53inp1 and k-ras.. Our results highlight involvement of miRNAs in the induction of apoptosis in glioma cells by fatty acids and temozolomide.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Apoptosis Regulatory Proteins; Arachidonic Acid; Cell Line, Tumor; Dacarbazine; Docosahexaenoic Acids; Down-Regulation; gamma-Linolenic Acid; Glioblastoma; Glioma; Humans; MicroRNAs; Neoplasm Proteins; Osmolar Concentration; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Temozolomide; Up-Regulation

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

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