gamma-linolenic-acid and Neoplasms

The etiology of diet-related disorders is closely associated with dietary factors. A special role is attributed to intake of fat and fatty acid profile, both quantitative and qualitative. For prevention and treatment of the abovementioned diseases a proper supply of unsaturated fatty acids plays a significant role, because of their particular importance to health. γ-Linolenic acid (GLA), with three double bonds in the carbon chain, also known as all-cis 6,9,12-octadecatrienoic acid, belongs to the n-6 family of fatty acids. It plays biologically important functions in the human body, such as being a substrate for eicosanoids synthesis, involvement in the transport and oxidation of cholesterol, and being one of the components of lipid membrane. Its inadequate dietary intake or impaired formation is the cause of many inflammatory and degenerative diseases. A rich source of this fatty acid is vegetable oils, until recently used mainly in folk medicine. Nowadays, studies conducted both in animal models and in humans suggest its health-promoting properties in the prevention and treatment of atopic dermatitis, cardiovascular diseases, diabetes, cancers and rheumatoid arthritis.

Topics: Animals; Antineoplastic Agents; Arthritis, Rheumatoid; Cardiovascular Diseases; Dermatitis, Atopic; Dry Eye Syndromes; gamma-Linolenic Acid; Humans; Metabolic Diseases; Neoplasms

Studies showed that gamma-linolenic acid (GLA) and its derivatives have the potential to be anti-cancer molecules. In vitro, in vivo and limited clinical studies showed that GLA has selective tumoricidal action with little or no side effects. The mechanism of its action appears to be by inducing apoptosis of tumor cells by augmenting free radical generation only in the tumor cells but not normal cells. Intra-arterial injection of a lithium salt derivative of GLA demonstrated its ability to selectively occlude tumor-feeding vessels. Since GLA is an endogenous naturally occurring molecule and has no significant side effects, it calls for more studies to exploit its potential as a novel anti-cancer drug.

Topics: Animals; Apoptosis; Clinical Trials as Topic; gamma-Linolenic Acid; Humans; Neoplasms; Neovascularization, Pathologic

Inflammation plays an important role in health and disease. Most of the chronic diseases of modern society, including cancer, diabetes, heart disease, arthritis, Alzheimer's disease, etc. have inflammatory component. At the same time, the link between diet and disease is also being recognized. Amongst dietary constituents, fat has gained most recognition in affecting health. Saturated and trans fatty acids have been implicated in obesity, heart disease, diabetes and cancer while polyunsaturated fatty acids (PUFAs) generally have a positive effect on health. The PUFAs of omega-3 and omega-6 series play a significant role in health and disease by generating potent modulatory molecules for inflammatory responses, including eicosanoids (prostaglandins, and leukotrienes), and cytokines (interleukins) and affecting the gene expression of various bioactive molecules. Gamma linolenic acid (GLA, all cis 6, 9, 12-Octadecatrienoic acid, C18:3, n-6), is produced in the body from linoleic acid (all cis 6,9-octadecadienoic acid), an essential fatty acid of omega-6 series by the enzyme delta-6-desaturase. Preformed GLA is present in trace amounts in green leafy vegetables and in nuts. The most significant source of GLA for infants is breast milk. GLA is further metabolized to dihomogamma linlenic acid (DGLA) which undergoes oxidative metabolism by cyclooxygenases and lipoxygenases to produce anti-inflammatory eicosanoids (prostaglandins of series 1 and leukotrienes of series 3). GLA and its metabolites also affect expression of various genes where by regulating the levels of gene products including matrix proteins. These gene products play a significant role in immune functions and also in cell death (apoptosis). The present review will emphasize the role of GLA in modulating inflammatory response, and hence its potential applications as an anti-inflammatory nutrient or adjuvant.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Dietary Supplements; gamma-Linolenic Acid; Humans; Inflammation; Neoplasms

Breast cancer is the most common malignant tumor and one of the leading causes of cancer-related death in women throughout the world. This study is a parallel, randomized, double-blind, controlled, 12-week supplementation trial, investigating the anti-inflammatory effects of dietary intake of fish oil and evening primrose oil (EPO), in patients with breast cancer undergoing chemotherapy. The primary outcomes were changes in the nutritional status and inflammatory cytokines of patients during the study. The secondary outcomes were changes in hematological and biochemical parameters and fatty acid profile. Of the 32 eligible patients, half of them is randomly assigned to a treatment arm with fish oil and EPO (n = 16), or a control arm (n = 16) with mineral oil as a placebo. The intervention group was taking 2 gel capsules of fish oil and 3 gel capsules of EPO (400 mg eicosapentaenoic acid, 600 mg docosahexaenoic acid, and 351 mg gamma-linolenic acid) fish oil and evening primrose oil for 12 weeks, during their chemotherapy. The control/placebo group was taking 5 gel capsules of 1g of mineral oil. One of the patients dropped out due to discontinuation of the treatment (in the placebo group) and two did not show up at the post-treatment measurements (in the intervention group), thus, 29 women completed the study. The results showed an increase in plasma levels of docosapentaenoic acid (22:5n-3), docosahexaenoic acid (22:6n-3), total n-3PUFA, vaccenic acid (18:1n-7), and a decrease in n-6/n-3 PUFA ratio in the intervention group. An increase in the plasma level of dihomo-gamma-linolenic acid (20:3n-6) was observed in the placebo group. There was no difference in plasma levels of interleukin (IL) IL-8, IL-10, and tumor necrosis factor-alpha, while the level of IL-6 decreased in both groups and was significantly lower in the intervention group at the end of the study. In conclusion, this supplementation improved the PUFA status and decreased the level of IL-6 in breast cancer patients undergoing chemotherapy. Consequently, this treatment may help reduce cancer complications resulting from impaired lipid metabolism and inflammation. ClinicalTrials.gov Identifier: NCT03516253. Date of registration 04/05/2018.

Topics: Animals; Anti-Inflammatory Agents; Dietary Supplements; Docosahexaenoic Acids; Double-Blind Method; Fatty Acids, Omega-3; Female; Fish Oils; gamma-Linolenic Acid; Interleukin-6; Mineral Oil; Neoplasms

gamma-Linolenic acid (GLA) is known to have selective tumoricidal action. In this study, the effect of lithium salt of GLA conjugated to iodized lymphographic oil (LGIOC) was injected intra-arterially close to the origin of tumor-feeding vessel(s) was studied. Four patients with stage 4 cancer disease (2 with hepatocellular carcinoma, 1 with giant cell tumor of the bone, and one with renal cell carcinoma), were selected for the study. Angiography, radiography and computed axial tomography were performed prior to and immediately after the injection of LGIOC and at periodic intervals. All four patients tolerated the treatment well. The most significant observation was the complete occlusion of the tumor-feeding vessels after LGIOC injection. Follow-up angiograms performed in all the patients showed occlusion of the tumor-feeding vessels is more or less permanent. A significant reduction in the size of the tumor was also observed in these patients. LGIOC showed occlusion of tumor-feeding vessels after infusion, and further studies are needed to confirm these preliminary results.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Carcinoma, Renal Cell; gamma-Linolenic Acid; Giant Cell Tumor of Bone; Humans; Male; Middle Aged; Neoplasms; Radiography

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Child; Clinical Trials as Topic; Fatty Acids, Essential; Female; gamma-Linolenic Acid; Humans; Linoleic Acids; Liver Neoplasms; Male; Mesothelioma; Middle Aged; Neoplasms; Oenothera biennis; Pilot Projects; Plant Oils; Pleural Neoplasms

The cardioprotective properties of linoleic acid (LA), a major n-6 (ω-6) polyunsaturated fatty acid (PUFA), have been recognized, but less is known about its associations with other causes of death. Relatively little is also known about how the minor n-6 PUFAs-γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA)-relate to mortality risk.. We investigated the associations of serum n-6 PUFAs, an objective biomarker of exposure, with risk of death in middle-aged and older men and whether disease history modifies the associations.. We included 2480 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y at baseline in 1984-1989. The stratified analyses by baseline disease status included 1019 men with a history of cardiovascular disease (CVD), cancer, or diabetes and 1461 men without a history of disease.. During the mean follow-up of 22.4 y, 1143 deaths due to disease occurred. Of these, 575 were CVD deaths, 317 were cancer deaths, and 251 were other-cause deaths. A higher serum LA concentration was associated with a lower risk of death from any cause (multivariable-adjusted HR for the highest compared with the lowest quintile: 0.57; 95% CI: 0.46, 0.71; P-trend < 0.001) and with deaths due to CVD (extreme-quintile HR: 0.54; 95% CI: 0.40, 0.74; P-trend < 0.001) and non-CVD or noncancer causes (HR: 0.48; 95% CI: 0.30, 0.76; P-trend = 0.001). Serum AA had similar, although weaker, inverse associations. Serum GLA and DGLA were not associated with risk of death, and none of the fatty acids were associated with cancer mortality. The results were generally similar among those with or without a history of major chronic disease (P-interaction > 0.13).. Our findings showed an inverse association of a higher biomarker of LA intake with total and CVD mortality and little concern for risk, thus supporting the current dietary recommendations to increase LA intake for CVD prevention. The finding of an inverse association of serum AA with the risk of death needs replication in other populations.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Arachidonic Acid; Biomarkers; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus; Diet; Fatty Acids, Omega-6; Follow-Up Studies; gamma-Linolenic Acid; Humans; Incidence; Linoleic Acid; Male; Middle Aged; Mortality; Neoplasms; Prospective Studies; Risk Factors; Socioeconomic Factors

Topics: Acetyl-CoA Carboxylase; Animals; Antineoplastic Agents; ATP Citrate (pro-S)-Lyase; Biosynthetic Pathways; Fatty Acid Synthases; Fatty Acids; Humans; Lipogenesis; Models, Chemical; Molecular Structure; Neoplasms

Unsaturated fatty acids (UFAs) exhibit in vitro cytotoxicity against many malignant cell lines and yield decreased cancer incidence and reduced tumor growth in animal models. But clinical and animal studies to date have achieved response using only localized delivery methods such as intratumoral infusion. To explore possibilities for enhanced clinical efficacy, fresh surgical explants of tumors from 22 patients with five malignancies were exposed to gamma-linolenic acid (GLA) and alpha-linolenic acid (ALA) and analyzed with an in vitro chemosensitivity testing system, the Fluorescent Cytoprint Assay (FCA). A total of 282 micro-organ cultures derived from these malignant tumors were exposed to GLA and ALA at different concentrations.. GLA and ALA exhibited greater than 90% cytotoxicity at a sharp concentration threshold between 500 microM and 1 mM against all but two malignant micro-organ cultures tested in 5-10% serum. In tests using 30-40% serum, GLA and ALA killed tumor at concentrations of 2 mM and above.. The concentration threshold of 500 microM to 2 mM exhibited for antitumor activity by GLA and ALA is much higher than that observed in most previously reported cell culture studies but consistent with physiological concentrations found to kill tumor clinically and in animals. A mechanism of antitumor activity by unsaturated fatty acids through selective destabilization of the malignant plasma membrane is considered. An oral regimen is proposed for phase I clinical testing that could push the area under the curve for serum concentration of unbound unsaturated fatty acids over time to much higher levels than previously achieved for systemic administration and into the range that could yield antitumor response.

Topics: alpha-Linolenic Acid; Cell Death; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; gamma-Linolenic Acid; Humans; Neoplasms; Serum; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Synergism; gamma-Linolenic Acid; Genes, erbB-2; Humans; Neoplasms; Transcription, Genetic; Trastuzumab

The omega-6 polyunsaturated fatty acid gamma-linolenic acid (GLA; 18:3n-6), which is found in several plant oils and is used as an herbal medicine, has antitumor activity in vitro. We examined the effect of GLA on the expression of the Her-2/neu (erbB-2) oncogene, which is involved in development of numerous types of human cancer. Flow cytometric and immunoblotting analyses demonstrated that GLA treatment substantially reduced Her-2/neu protein levels in the Her-2/neu-overexpressing cell lines BT-474, SK-Br3, and MDA-MB-453 (breast cancer), SK-OV3 (ovarian cancer), and NCI-N87 (gastrointestinal tumor derived). GLA exposure led to a dramatic decrease in Her-2/neu promoter activity and a concomitant increase in the levels of polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/neu, in these cell lines. In transient transfection experiments, a Her-2/neu promoter bearing a PEA3 site-mutated sequence was not subject to negative regulation by GLA in Her-2/neu-overexpressing cell lines. Concurrent treatments of Her-2/neu-overexpressing cancer cells with GLA and the anti-Her-2/neu antibody trastuzumab led to synergistic increases in apoptosis and reduced growth and colony formation.

Topics: Analysis of Variance; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Drug Synergism; Female; Flow Cytometry; gamma-Linolenic Acid; Gastrointestinal Neoplasms; Genes, erbB-2; Humans; Immunoblotting; Neoplasms; Ovarian Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors; Transcription, Genetic; Trastuzumab

Gamma linolenic acid (GLA) has been recently shown to inhibit tumour-induced angiogenesis. The present study investigated the effects of GLA on the HUVEC-specific adhesion. After treatment with GLA, HUVECs decreased the amounts of Triton soluble and insoluble VE-cadherin and beta-catenin and reduced tube formation in matrix in a concentration-dependent manner. An anti-VE-cadherin antibody dissociated HUVECs' colonies and exerted similar inhibitory effects on tube formation of HUVECs. These data indicate that the VE-cadherin/catenins complex is essential for formation and maintenance of new capillaries. It is concluded, therefore, that GLA inhibits tumour-induced angiogenesis partly via the decrease in the expression of VE-cadherin and beta-catenin.

Topics: Antigens, CD; beta Catenin; Cadherins; Cells, Cultured; Cytoskeletal Proteins; Endothelium, Vascular; Fluorescent Antibody Technique; gamma-Linolenic Acid; Humans; Neoplasms; Neovascularization, Pathologic; Trans-Activators

Desmosomes are key structures in cell-cell adhesion. In this study we examined the effect of n-6 essential fatty acids on the expression of desmoglein (Dsg), desmosomal cadherin and the formation of desmosomes in E-cadherin negative human breast, colon and lung cancer cells and melanoma cells. Electron microscopy revealed that cells cultured with gamma linolenic acid (GLA) showed increased cell-cell adhesion together with an increase in the formation of desmoglein-containing desmosomes. Western blotting studies of cellular proteins demonstrated that, following culture with fatty acids, Dsg expression was modified, with the greatest increase seen after GLA treatment. Other fatty acids increased Dsg expression, but to a lesser extent. It is concluded that GLA regulates desmosome-mediated cell-cell adhesion in human cancer cells, particularly in cells without E-cadherin.

Topics: Cadherins; Cell Adhesion; Cell Movement; Cytoskeletal Proteins; Desmogleins; Desmoplakins; Desmosomes; gamma-Linolenic Acid; Humans; Neoplasms; Tumor Cells, Cultured

Inhibition of angiogenesis shows considerable promise as a strategy for treating solid malignancies. Induction of collagenase by protein kinase C plays an important role in the angiogenic process as well as in metastasis. Lipoxygenase products are required for endothelial cell mitosis, and also promote collagenase production. By down-regulating hormonal activation of protein kinase C and modulating eicosanoid metabolism, ingestion of omega-3-rich fish oils may impede angiogenesis and reduce tumor invasiveness-thus rationalizing the growth-retardant and anti-metastatic effects of fish oil feeding almost invariably seen in animal tumour models. Certain other anti-inflammatory agents-including cromolyn (an inhibitor of protein kinase C activation) and gamma-linolenic acid (which indirectly inhibits lipoxygenase) may have analogous tumour-retardant activity. Clinical application of supplemental fish oil in cancer therapy is long overdue.

Topics: Animals; Down-Regulation; Eicosanoids; Fish Oils; gamma-Linolenic Acid; Humans; Lipoxygenase Inhibitors; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Protein Kinase C

E-cadherin is a cell to cell adhesion molecule which acts as a suppressor of metastasis. This study examined the effect of gamma-linolenic acid (GLA), a n-6 polyunsaturated fatty acid, on the expression of E-cadherin in human cancer cells. Western blotting studies demonstrated that treatment of cells with GLA for 24 h increased the expression of E-cadherin in lung, colon, breast, melanoma, and liver cancer cells, but not in endothelial cells and fibroblasts. The results were confirmed by immunocytochemistry. In contrast, two other n-6 fatty acids, linoleic acid and arachidonic acid, failed to induce these changes. The increased expression of E-cadherin was correlated with reduced in vitro invasion and increased aggregation, indicating that the increased E-cadherin expression induced by GLA was biologically active. These data add GLA to the short list of E-cadherin up-regulatory factors. The up-regulation of E-cadherin expression in human cancer cells may contribute to the anticancer properties of GLA.

Topics: Antineoplastic Agents; Arachidonic Acid; Blotting, Western; Cadherins; Cell Aggregation; gamma-Linolenic Acid; Humans; Immunohistochemistry; Linoleic Acid; Linoleic Acids; Neoplasm Invasiveness; Neoplasms; Tumor Cells, Cultured

This hypothesis proposes that the essential fatty acids (EFAs), linoleic acid (LA) and gamma-linolenic acid (GLA), play important roles in cancer treatment. Oxidation of LA by lipoxidase especially increases tumour cell death, whilst GLA inhibits urokinase-type plasminogen activator (uPA) activity. Increased uPA activity is: firstly, responsible for cancer invasion and metastasis and secondly, responsible for proteolysis of lipoxidase which favours a decrease in cancer cell death. Addition of LA and GLA to available therapeutic regimens may be worth considering in cancer treatment.

Topics: Antineoplastic Agents, Phytogenic; Cell Death; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Linoleic Acid; Linoleic Acids; Lipoxygenase; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Oxidation-Reduction; Plant Oils; Urokinase-Type Plasminogen Activator

We hypothesize that a relative deficiency in gamma-linolenic and eicosapentaenoic acids and in their derivatives may contribute to the development of AIDS. These polyunsaturated fatty acids (PUFAs) may be the source of natural endogenous agents against AIDS by preventing the spread of viral infection due to their ability to destroy enveloped viruses, by controlling cancer development either directly due to their cytostatic and cytotoxic effects on cancer cells or indirectly by modulating the immune response and by protecting from genetic damage. Supplementation of these dietary PUFAs in the prevention, and possibly in the treatment of AIDS, is considered.

Topics: Acquired Immunodeficiency Syndrome; Dietary Fats; Disease Susceptibility; Eicosapentaenoic Acid; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Immunity; Linolenic Acids; Models, Biological; Neoplasms; Virus Diseases

Polyunsaturated fatty acids killed incubated human breast, lung and prostate cancer cells at concentrations which had no adverse effects on normal human fibroblasts or on normal animal cell lines. The most consistent and selective effects were obtained with fatty acids containing 3, 4 and 5 double bonds. When human cancer cells and normal human fibroblasts were co-cultured in the absence of polyunsaturated fatty acids, the malignant cells overgrew the normal ones. When eicosapentaenoic acid (EPA, 20:5n-3), gamma-linolenic acid (GLA, 18:3n-6) or arachidonic acid (AA, 20:4n-6) were added to the co-cultures, the normal cells outgrew the malignant ones. These observations suggest that treatment of malignancy with polyunsaturated fatty acids may have considerable potential while being associated with a high level of safety.

Topics: alpha-Linolenic Acid; Animals; Breast Neoplasms; Cell Division; Cell Line; Cell Survival; Dogs; Fatty Acids, Unsaturated; Female; Fibroblasts; gamma-Linolenic Acid; Humans; Linolenic Acids; Lung Neoplasms; Male; Neoplasms; Prostatic Neoplasms

Recently, addition of gamma linolenic acid (GLA) which is a precursor of prostaglandin E1 (PGE1) to cell cultures, has been shown to inhibit growth of various carcinoma cells (1,2,3,4). These findings are consistent with Horrobin's proposal that some of the metabolic abnormalities of malignant cells may be due to deficiencies of certain prostanoids. To determine whether the observed effects of GLA are in fact mediated by increasing levels of its metabolites, this study investigated the influence of various inhibitors and stimulants of prostaglandin (PG) synthesis on the effects of GLA on carcinoma cells in vitro. Most of the agents used (aspirin, imidazole, lithium carbonate and ascorbic acid) produced results consistent with the idea that elevation of levels of thromboxane A2 (TxA2) and/or PGE1 may be important as regards the actions of GLA. In sharp contrast was the result obtained with indomethacin. This drug, which could be expected to block conversion of GLA to PGE1 and therefore protect cells against the effects of GLA, actually exaggerated the effects of this fatty acid, thereby causing cell death and desquamation.

Topics: Alprostadil; Aspirin; Cell Division; Cell Line; Cell Survival; gamma-Linolenic Acid; Humans; Imidazoles; Indomethacin; Linolenic Acids; Neoplasms; Prostaglandins; Prostaglandins E; Thromboxane A2; Thromboxanes

Recent studies on the effects of the essential fatty acid metabolic intermediate, gamma-linolenic acid, on the growth of cancer cells in culture and on induced mammary cancer tumours in rats, strongly suggest that the metabolic defect in the cancer cells studied is simply a metabolic block involving the enzyme delta-6-desaturase. The latter enzyme is responsible for the conversion of linoleic acid to gamma-linolenic acid. These observations would suggest that cancer in the cell lines studied could be a relatively simple metabolic disease.

Topics: 8,11,14-Eicosatrienoic Acid; Alprostadil; Animals; Carcinoma, Hepatocellular; Cell Line; Cells, Cultured; Esophageal Neoplasms; Fatty Acid Desaturases; gamma-Linolenic Acid; Humans; Linolenic Acids; Liver Neoplasms; Melanoma; Metabolic Diseases; Mice; Neoplasms; Prostaglandins E; Scurvy