Selective killing of human cancer cells by polyunsaturated fatty acids (original) (raw)
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Effects of polyunsaturated fatty acids on the growth of gastric cancer cells in vitro
Lipids in Health and Disease, 2013
Polyunsaturated fatty acids (PUFAs) have tumoricidal action, though the exact mechanism of their action is not clear. The results of the present study showed that of all the fatty acids tested, linoleic acid (LA) and α-linolenic acid (ALA) were the most effective in suppressing the growth of normal gastric cells (GES1) at 180 and 200 μM, while gastric carcinoma cells (MGC and SGC) were inhibited at 200 μM. Arachidonic acid (AA) suppressed the growth of GES1, MGC and SGC cells and lower concentrations (120 and 160 μM) of AA were more effective against gastric carcinoma (MGC and SGC) cells compared to normal gastric cells (GES1). Paradoxically, both eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids though are more unsaturated than AA, were less effective compared with LA, ALA and AA in suppressing the growth of both normal and cancer cells. At the concentration used, methotrexate showed much less growth suppressive action compared to all the fatty acids tested. PUFAs-treated cells showed accumulation of lipid droplets. A close association was noted between apoptosis and lipid peroxides formed compared to the ability of normal and tumor cells to generate ROS (reactive oxygen species) and induce SOD (superoxide dismutase activity) in response to fatty acids tested and methotrexate. Both normal and tumor cells generated lipoxin A 4 (LXA 4 ) in response to supplementation of fatty acids and methotrexate though no significant correlation was noted between their ability to induce apoptosis and LXA 4 formed. These results suggest that PUFAs induced apoptosis of normal gastric and gastric carcinoma cells could, partly, be attributed to lipid peroxidation process.
Fatty Acids and Their Analogues as Anticancer Agents
Fatty Acids, 2017
Recent research supports the beneficial effects of dietary polyunsaturated fatty acids (PUFAs) on inhibiting tumour development. Long-chain fatty acids modulate the tumour cell response to chemotherapeutic drugs. Investigators recently claimed high dietary intake of omega-6 polyunsaturated fatty acids such as linoleic acid especially in association with a low intake of omega-3 polyunsaturated fatty acids such as docosahexaenoic acid to increase risks for cancers of the breast, colon and possibly prostate. In addition to these facts, a number of investigations have demonstrated that a modified fatty acid analogues are promising molecules in cancer prevention and have potential in the treatment of cancer. Although billions of dollars have been spent on research and development on anticancer drugs, the disease remains uncontrolled. It is expected that anticancer agents preferentially kill tumour cells without causing adverse effects on normal cells. But this is rarely achieved with the existing cancer therapy. Hence, polyunsaturated fatty acids have come under the category of nutraceuticals/functional foods; their exploration in the treatment of cancer may be considered as safe. This chapter describes the effects of long-chain fatty acids and their analogues in cancer chemotherapy.
Lipids, 1998
We examined effects of polyunsaturated fatty acids (PUFA), their corresponding hydroperoxy fatty acids (hp-PUFA), as well as various pro-and antioxidants on the growth of tumor cells in culture. When cultured in RPMI 1640 medium, A-427 and WEHI clone 13 cells were both highly sensitive to hydroperoxy docosahexaenoic acid (hp-DHA), but they were far less sensitive in minimum essential medium (MEM). In contrast, A-427 cells were also sensitive to DHA in both culture media, while WEHI clone 13 cells, as well as other cell lines, tested in their respective media, were resistant. The lower sensitivity of the cell lines to hp-DHA in MEM-medium was apparently due to a more rapid reduction of hp-DHA to the corresponding hydroxy-DHA in MEM-medium. Addition of glutathione (GSH) to the culture medium abolished the effects of hp-DHA, but not the effects of DHA, while depletion of intracellular GSH levels by L-buthionine-S,R-sulfoximine strongly enhanced the cytotoxic effect of hp-DHA, but not the cytotoxic effect of DHA. α-Tocopherol protected A-427 cells against the toxic effect of DHA and abolished the induced lipid peroxidation, while it did not protect against the toxic effects of hp-DHA in A-427 or WEHI clone 13 cells. Ascorbic acid reduced the cytotoxic effect of DHA, but potentiated the toxic effect of hp-DHA while selenite essentially abolished the toxicity of both DHA and hp-DHA. These results indicate that sensitivity of tumor cell lines to PUFA and their oxidation products depends on their antioxidant defense mechanisms, as well as culture conditions, and establishes hp-DHA as a major, but probably not the sole, metabolite responsible for cytotoxicity of DHA.
Cytotoxic action of cis-unsaturated fatty acids on human cervical carcinoma (HeLa) cells in vitro
Prostaglandins, Leukotrienes and Essential Fatty Acids, 1995
The effect of n-3 and n-6 fatty acids (FAs) on the growth of human cervical carcinoma (HeLa) cells was studied. Of all the FAs tested, docosahexaenoic acid (DHA, 22:6 n-3) and eicosapentaenoic acid (EPA, 20:5 n-3) were found to be the most potent in their cytotoxic action on HeLa cells and the potency of various fatty acids with regard to their cytotoxic action was as follows: DHA > EPA > dihomo-gamma-linolenic acid (DGLA) = gamma-linolenic acid (GLA) > linoleic acid (LA) > arachidonic acid (AA) > alpha-linolenic acid (ALA). The cycloxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguaretic acid (NDGA), the antioxidants vitamin E, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT), the superoxide anion quencher superoxide dismutase (SOD), the hydroxyl and hydrogen peroxide quenchers mannitol and catalase, respectively, and the calmodulin antagonists trifluoperazine (TFP) and chlorpromazine (CPZ) could all block the cytotoxic action of GLA, which was used as a representative cytotoxic FA, on HeLa cells. On the other hand, copper and iron salts and buthionine sulfoxamine, a glutathione (GSH) depletor, potentiated the cytotoxic action of suboptimal doses of GLA. GLA-induced radical generation and lipid peroxidation in HeLa cells could be blocked by indomethacin, NDGA and calmodulin antagonists. The cytotoxic action of cisunsaturated fatty acids (c-UFAs) is not dependent on the alteration in the protein kinase C levels since no alteration in the diacylglycerol levels was observed. Hydroxy and hydroperoxy products of GLA were found to be toxic to HeLa cells, whereas prostaglandin (PG)E1, PGF2a, and prostacyclin stimulated cell growth. From these results, it is evident that radicals are the modulators of the cytotoxic action of c-UFAs, that their formation is a calmodulin-dependent process, and that lipoxygenase products may mediate the tumoricidal action of FAs.
Journal of Nutrition, 2000
We showed previously that dietary eicosapentaenoic acid [EPA, 20:5(n-3)] is antitumorigenic in the Apc Min/ϩ mouse, a genetic model of intestinal tumorigenesis. Only a few studies have evaluated the effects of dietary fatty acids, including EPA and docosahexaenoic acid [DHA, 22:6(n-3)], in this animal model and none have evaluated the previously touted antitumorigenicity of ␣-linolenic acid [ALA, 18:3(n-3)], conjugated linoleic acid [CLA, 77% 18:2(n-7)], or ␥-linolenic acid [GLA, 18:3(n-6)]. Stearidonic acid [SDA, 18:4(n-3)], the ⌬6-desaturase product of ALA, which is readily metabolized to EPA, has not been evaluated previously for antitumorigenic efficacy. This study was undertaken to evaluate the antitumorigenicity of these dietary fatty acids (ALA, SDA, EPA, DHA, CLA and GLA) compared with oleic acid [OA, 18:1(n-9)] at a level of 3 g/100 g in the diets of Apc Min/ϩ mice and to determine whether any alterations in tumorigenesis correspond to alterations in prostaglandin biosynthesis. Tumor multiplicity was significantly lower by ϳ50% in mice fed SDA or EPA compared with controls, whereas less pronounced effects were observed in mice fed DHA (P ϭ 0.15). ALA, CLA and GLA were ineffective at the dose tested. Although lower tumor numbers coincided with significantly lower prostaglandin levels in SDA-and EPA-fed mice, ALA and DHA supplementation resulted in equally low prostaglandin levels, despite proving less efficacious with regard to tumor number. Prostaglandin levels did not differ significantly in the CLA and GLA groups compared with controls. These results suggest that SDA and EPA attenuate tumorigenesis in this model and that this effect may be related in part to alterations in prostaglandin biosynthesis.
Clinical & Translational Oncology, 2002
The dietary fat hypothesis postulates that dietary or exogenously derived fatty acids play an important role in the carcinogenesis, evolution and/or progression of breast cancer. In order to reveal possible underlying mechanisms of this hypothesis, we studied the influence of ω- 3 polyunsaturated fatty acids (PUFAs) -α-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA)-, ω-6 PUFAs-linoleic (LA), γ-linolenic (GLA) and arachidonic (ARA)- and monounsaturated ω- 9 oleic acid (OA) on the proliferation, adhesion and metastatic potential of human breast cancer cells in culture. GLA and the ω-3 PUFAs, ALA and DHA, inhibited significantly the cell growth of MCF-7 and MDA-MB-231 breast cancer cell lines, while EPA has less marked inhibitory effects. ω-6 PUFAs, LA and ARA, or ω- 9 OA had either no effect or caused a slight increase of proliferation. The attachment of breast cancer cells to the extracellular matrix components (type IV collagen, fibronectin and Matrigel) was significantly inhibited by ω-6 GLA and ω-3 PUFAs ALA, DHA and EPA. At concentrations which had no effect on cell growth over the duration of experiments the ω-6 PUFAs, LA and GLA, and the ω-3 PUFAs, ALA, DHA and EPA, had the ability to inhibit both cellular migration and invasion into type IV collagen and Matrigel. In summary, our findings indicate important differences in the ability of ω-3, ω-6 and ω-9 fatty acids to modulate prolif eration, attachment to extracellular matrix components, mo-tility and invasiveness of human breast carcinoma cells in vitro, with the GLA and all ω-3 PUFAs being the most effective inhibitors. Our data are consistent with the view that the type rather than the amount of dietary fatty acids is be more important in breast cancer development and progression. Los ácidos grasos exógenos o procedentes de la dieta podrían jugar un papel importante en la carcinogénesis, evolución y/o progresión del cáncer de mama. Para estudiar los posibles mecanismos que subyacen a esta hipótesis hemos estudiado en cultivo, la influencia de los ácidos grasos poliinsaturados (PUFAs) ω-3 -α-linolénico (ALA), eicosapentaenoico (EPA) y docosahexaenoico (DHA)-, los PUFAs ω-6 -linoleico (LA), γ-linolénico (GLA) y araquidónico (ARA)- y el ácido graso monoinsaturado ω-9 ácido oleico (OA) en la proliferación, adhesión y potencial metastásico de las células humanas de cáncer de mama. El GLA y los PUFAs ω-3 ALA y DHA inhibieron significativamente el crecimiento de las células de cáncer de mama, mientras que los efectos inhibidores del EPA fueron menos marcados. Los PUFAs ω-6, LA y ARA, o el ω-9 OA no modificaron o produjeron un débil incremento de la proliferación. La adhesión de las células de cáncer de mama a componentes de la matriz extracelular (colágeno tipo IV, fibronectina y Matrigel) fue inhibida significativamente por el ω-6 GLA y por los PUFAs ω-3 ALA, DHA y EPA. A las concentraciones que no afectó el crecimiento celular durante el transcurso de los experimentos, los PUFAs ω-6 LA y GLA y los PUFAs ω-3 ALA, DHA y EPA inhibieron la migración e invasión celulares en el colágeno tipo IV y el Matrigel. En resumen, nuestros resultados indican que existen diferencias importantes en la capacidad de los ácidos grasos ω-3, ω-6 y ω-9 para modular in vitro la proliferación, adhesión a componentes de la matriz extracelular, motilidad e invasividad de las células humanas de cáncer de ma-ma, siendo el GLA y los PUFAs ω-3 los inhibidores más efectivos. Los resultados son consistentes con la opinión de que, más que la cantidad total, es el tipo de ácido graso en la dieta el factor más importante en el desarrollo y progresión del cáncer de mama.
Breast Cancer Research and Treatment, 1997
Numerous studies have shown dietary fatty acids to influence the progression of several types of cancers. The purpose of the present investigation was to examine the influence of various types of fatty acids, including ω-3 fatty acids and a new class of hypolipidemic peroxisome proliferating fatty acid analogues, namely the 3-thia fatty acids, on MCF-7 human breast cancer cell growth. 3-thia fatty acids represent non-β-oxidizable fatty acid analogues in which a sulphur atom substitutes for the β-methylene group (3-position) in the saturated and unsaturated fatty acids.