Concentration- and time-dependent effects of γ-linolenic acid supplementation to tumor cells in culture (original) (raw)
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Biochemical and Biophysical Research Communications, 1996
We examined the effect of gamma-linolenic acid (GLA) supplementation on the growth and fatty acid composition of three human tumor cell lines (the neuroblastoma CHP-212, the tubal carcinoma TG, and the colon carcinoma SW-620), in order to evaluate the relationship between GLA-induced tumor cell death and the distribution of fatty acids in tumor cells. At the highest GLA concentrations (10 and 20 mg/ml), the DNA synthesis was completely abolished; at 5 mg/ml GLA only SW-620 cells did not proliferate, while CHP-212 and TG cells showed a residual [ 3 H]-thymidine incorporation. GLA levels were very low in cells grown in control medium; GLA supplementation caused a significant incorporation of GLA itself in all the cell lines at each concentration. In TG and CHP-212 cells, GLA was metabolized, although to a different extent, to dihomo-gamma linolenic acid and arachidonic acid. SW-620 cells neither elongated nor desaturated the incorporated GLA. The highest cytostatic effect was reached when GLA was not transformed into its metabolites, suggesting that the GLA toxicity to tumor cells is not dependent on metabolites but is due to GLA itself. ᭧
International Journal of Cancer, 2004
Both n-6 and n-3 polyunsaturated fatty acids are dietary fats important for cell function, being involved in several physiologic and pathologic processes, such as tumorigenesis. Linoleic acid and conjugated linoleic acid, its geometrical and positional stereoisomer, were tested on several human tumor cell lines originating from different tissues and with different degrees of malignancy. This was to provide the widest possible view of the impact of dietary lipids on tumor development. While linoleic acid exerted different effects, ranging from inhibitory to neutral, even promoting growth, conjugated linoleic acid inhibited growth in all lines tested and was particularly effective against the more malignant cells, with the exception of mammary tumor cells, in which behavior was the opposite, the more malignant cell line being less affected. The inhibitory effect of conjugated linoleic acid on growth may be accompanied by different contributions from apoptosis and necrosis. The effects of conjugated linoleic acid on growth or death involved positive or negative variations in PPARs. The important observation is that a big increase of PPAR␣ protein occurred in cells undergoing strong induction of apoptosis, whereas PPAR/␦ protein decreased. Although PPAR␣ and PPAR/␦ seem to be correlated to execution of the apoptotic program, the modulation of PPAR␥ appears to depend on the type of tumor cell, increasing as protein content, when inhibition of cell proliferation occurred. In conclusion, CLA may be regarded as a component of the diet that exerts antineoplastic activity and its effect may be antiproliferative or pro-apoptotic.
Biochimica et biophysica acta, 2014
Conjugated linoleic acid (CLA) is thought to exert anticarcinogenic, antiatherogenic, anti-inflammatory and weight loss effects. The impact on eicosanoid biosynthesis may be one of the mechanisms of its action. The aim of this study was to establish whether CLA mixture supplemented daily after administration of carcinogen (7, 12-dimethylbenz[a]anthracene, DMBA) influenced the concentration of linoleic and arachidonic acid metabolites: 13- or 9-hydroxyoctadecadienoic acids (13-, 9-HODE) and 15-, 12- or 5-hydroxyeicosatetraenoic acids (15-, 12- or 5-HETE) and prostaglandin E2 (PGE2) in rat serum and DMBA-induced tumours. The correlations between polyunsaturated fatty acids (PUFA) and HETE and HODE contents in serum were also investigated. Female Sprague-Dawley rats divided into three groups according to the diet (1% Bio-C.L.A., 2% Bio-C.L.A. and plant oil in the control group) were used in the study. On the 50th day of life some of the animals in every dietary group were administered ...
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2017
The objective of the study was to assess the influence of conjugated linoleic acid (CLA) daily supplementation prior and after carcinogenic agent on the concentrations of eicosanoidsmetabolites of arachidonic acid (15-, 12-or 5-hydroxyeicosatetraenoic acids (15-, 12-, 5-HETE), prostaglandin E 2 (PGE 2)) and linoleic acid (13-or 9hydroxyoctadecadienoic acids (13-, 9-HODE)) in rat serum and 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumors. Female rats were randomised into six groups, receiving 1% or 2% Bio-C.L.A or plant oil since the 37th day of life throughout the whole experiment. Some rats (50-day-old) were administered DMBA to induce tumors. Eicosanoids were analyzed with LC-MS/MS. The study indicated that CLA supplemented daily to rats prior and after carcinogen administration affected concentrations of arachidonic and linoleic acid metabolites in rat serum and induced tumors. However, ratios of eicosanoids exerting opposite activities (e.g. 12-HETE/15-HETE) appear to act as more precise factors reflecting pathological changes in an organism than individual compounds.
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.
Journal of Zhejiang University Science B, 2010
Polyunsaturated fatty acids (PUFAs) possess anti-cancer action both in vitro and in vivo. In the present study, we detected cell viability with methyl thiazolyl tetrazolium (MTT) assay and cell membrane permeability with propidium iodide (PI) fluorescence dyeing, and calculated cell membrane fluidity change as fluorescence anisotropy. Fatty acid content in cells was measured by gas chromatography/mass spectroscopy (GC/MS), and the relationship between fatty acid composition and cell viability was studied. We observed that n-6 PUFA linoleic acid (LA) inhibited tumor cell growth at high concentrations (≥300 µmol/L), while low concentrations (100-200 µmol/L) seemed to promote cell proliferation. Analyses of cell membrane permeability, cell membrane fluidity, and cell fatty acid composition suggested that the anti-cancer action of LA could be related to changes in the ratio of n-6 to n-3 PUFAs. We observed that pre-incubation of cancer cells with 100 µmol/L LA for 24 h enhanced cell sensitivity to the cytotoxic action of LA, whereas undifferentiated cell line LoVo seemed to have a distinct path in LA-induced death. These results showed that one of the mechanisms by which supplementation of LA induces cancer cell death could be altering the ratio of n-6/n-3 PUFAs, and this may be related to cell differentiation status.
British Journal of Cancer, 1997
Lipid metabolism has been considered recently as a novel target for cancer therapy. In this field, lithium gamma-linolenate (LiGLA) is a promising experimental compound for use in the treatment of human tumours. In. vivo and in vitro studies allowed us to assess the metabolism of radiolabelled LiGLA by tumour tissue and different organs of the host. In vitro studies demonstrated that human pancreatic (AsPC-1), prostatic (PC-3) and mammary carcinoma (ZR-75-1) cells were capable of elongating GLA from LiGLA to dihomo-gamma-linolenic acid (DGLA) and further desaturating it to arachidonic acid (AA). AsPC-1 cells showed the lowest A5-desaturase activity on DGLA. In the in vivo studies, nude mice bearing the human carcinomas were given Li[1-14C]GLA (2.5 mg kg-') by intravenous injection for 30 min. Mice were either sacrificed after infusion or left for up to 96 h recovery before sacrifice. In general, the organs showed a maximum uptake of radioactivity 30 min after the infusion started (t = 0). Thereafter, in major organs the percentage of injected radioactivity per g of tissue declined below 1% 96 h after infusion. In kidney, brain, testes/ovaries and all three tumour tissues, labelling remained constant throughout the experiment. The ratio of radioactivity in liver to tumour tissues ranged between 16-and 24-fold at t = 0 and between 3.1-and 3.7-fold at 96 h. All tissues showed a progressive increase in the proportion of radioactivity associated with AA with a concomitant decrease in radiolabelled GLA as the time after infusion increased. DGLA declined rapidly in liver and plasma, but at a much slower rate in brain and malignant tissue. Seventy-two hours after the infusion, GLA was only detected in plasma and tumour tissue. The sum of GLA + DGLA varied among tumour tissues, but it remained 2-4 times higher than in liver and plasma. In brain, DGLA is the major contributor to the sum of these fatty acids. Data showed that cytotoxic GLA and DGLA, the latter provided either by the host or by endogenous synthesis, remained in human tumours for at least 4 days.
Linoleic acid metabolism in metastatic and nonmetastatic murine mammary tumor cells
Cancer research, 1989
The mechanism(s) by which dietary linoleic acid (18:2n-6) enhances mammary tumor growth and metastasis is not known. Since arachidonic acid (20:4n-6)-derived prostaglandins (PC) may play a role in the metastatic dissemination of tumor cells, the ability of two murine mammary tumor cell lines, 4526 (metastasis positive) and line 168 (spontaneous metastasis negative), to convert 18:2n-6 into prostaglandins was exam ined. Cells were initially incubated with |'4qi8:2n-6 and after 8-24 h the ["( '|t;illv acids were quantitated by high-performance liquid chromatography following transesterification. |'4C]18:2n-6 was metabolized primar ily to |l4C|dihomogammalinolenic acid (20:3n-6) in line 4526 cells and |"C'|20:4n-6 in line 168 cells. Examination of cellular fatty acid levels revealed a 20:3n-6/20:4n-6 ratio of 1.79 ±0.36 and 0.20 ±0.02 in line 4526 and 168 cells, respectively. These data are consistent with an inherently lower A5 desaturase activity in line 4526 relative to 168. To assess the metabolism of 18:2n-6 into eicosanoid products, the cell lines were prelabeled with [l4C]18:2n-6 or 0-40 MMnonradiolabeled 18:2n-6 overnight and subsequently stimulated with calcium ionophore A23187 for 1 h. Total PGE production, as determined by radioimmunoassay, was greater in 168 relative to 4526 cells at all 18:2n-6 concentrations. 14Cprostaglandins detected by high-performance liquid chromatography and argentation thin-layer chromatography were: PGF,„ and PGE, (derived from 20:3n-6) and PGF2„ and PGE2 (derived from 20:4n-6) from line 4526; PGE, and PGE2 from line 168. PGE,/PGE2 ratios were 1.43 ± 0.07 and 0.23 ±0.03 for 4526 and 168 lines, respectively. Neither cell line synthesized lipoxygenase products following |'4C]18:2n-6 or [3H]-20:4n-6 incubations under the conditions employed. Additional studies are warranted in order to define the biological properties of 1-and 2series cyclooxygenase products as they relate to tumor cell metastasis.
Conjugated linoleic acid (CLA) and the long-chain polyunsaturated nҀ3 fatty acids have been shown in vivo and in vitro to reduce tumor growth. Tumor growth could occur by slowing or stopping cell replication (by interfering with transition through the cell cycle), increasing cell death (via necrosis and/or apoptosis), or both. The anticancer effects of fatty acids, shown in vivo, could also be mediated by effects on the host's immune system. Although it is widely recognized that nҀ3 fatty acids can alter immune and inflammatory responses, considerably less is known about CLA. For nҀ3 fatty acids, several candidate mechanisms have been proposed for their immune effects, including changes in 1) membrane structure and composition, 2) membrane-mediated functions and signals (eg, proteins, eicosanoids), 3) gene expression, and 4) immune development. Considerable work has been done that shows the potential importance of CLA as an anticancer treatment; however, many questions remain as to how this effect occurs. This review summarizes the CLA and cancer literature and then uses the evidence for the anticancer immune and tumor properties of the long-chain nҀ3 fatty acids docosahexaenoic and eicosapentaenoic acids to suggest future research directions for mechanistic studies on CLA and cancer.