Effects of fatty acid modification of ascites tumor cells on pulmonary metastasis in rat

Yoshida sarcoma cells were incubated with each of 4 different saturated and 17 different unsaturated fatty acid methyl and ethyl esters in order to modify the fatty acid composition of the cell membrane, and a possible correlation between the lipid fluidity of the cell membrane and the metastatic efficiency was studied. Almost all the unsaturated fatty acids used were incorporated into the tumor cell membrane, resulting in an increase of fluidity. In contrast, the incorporation of saturated fatty acids brought no change in fluidity. Exogenous treatment of the cells with palmitoleic acid (16:1, cis) induced a remarkable increase of membrane lipid fluidity resulting in easier passage of modified cells through capillary vessels, which was detected in an in vitro perfusion test of the lung. Intravenous injection of the modified cells resulted in fewer metastatic foci in the lung as compared with that of unmodified cells. A similar effect on lung metastasis was also observed in exogenous modification of the cells by linoleic acid (18:2, cis) or linolenic acid (18:3, n-3). On the other hand, although exogenous eicosapentaenoic acid (20:5, n-3) and docosahexaenoic acid (22:6, n-3) treatments induced a slight increase in the lipid fluidity of the cells, intravenous injection of the cells produced a significant increase in their metastatic potential in the lung. Interestingly, the treatment with 20:5 and 22:6 produced increased stickiness of the cells to a glass surface and reduced cellular passage through the vessels as detected by the lung perfusion test. Thus, the present results suggested that selective modification of membrane fatty acid may be a useful method for artificial regulation of the ability of circulating tumor cells to pass through vessels.     

Influence of lipids on gap-junction-mediated intercellular communication between Chinese hamster cells in vitro

The influence of lipids on gap-junction-mediated intercellular communication (i.e., metabolic cooperation) between Chinese hamster V79 cells was investigated. Unsaturated free fatty acids (oleate, linoleate, linolenate, palmitoleate, myristoleate, and arachidonate) inhibited metabolic cooperation between 6-thioguanine-resistant, hypoxanthine guanine phosphoribosyltransferase-deficient and 6-thioguanine-sensitive, hypoxanthine guanine phosphoribosyltransferase-proficient V79 cells. Saturated fatty acids (stearate, palmitate, myristate, and arachidate) had no effect. Further characterization of the effects of fatty acids on metabolic cooperation is summarized as follows: a relationship between the degree of unsaturation and the ability of unsaturated fatty acids to inhibit metabolic cooperation could not be established (i.e., inhibition of metabolic cooperation by 18:1 greater than 18:2 = 18:3); longer carbon chain monounsaturated fatty acids are more effective in inhibiting metabolic cooperation (i.e., inhibition of metabolic cooperation by 18:1 greater than 16:1 greater than or equal to 14:1); geometric isomerism is of some importance in determining the efficacy of monounsaturated fatty acids to inhibit metabolic cooperation (i.e., inhibition of metabolic cooperation by cis 18:1 greater than trans 18:1 and cis 16:1 greater than trans 16:1); and the position of the double bond(s) is relatively unimportant (i.e., inhibition of metabolic cooperation by 18:3 = gamma 18:3). Unsaturated diacylglycerol compounds (diolein, dilinolein, and 1-oleoyl-2-acetyl glycerol) inhibit metabolic cooperation; a saturated diacylglycerol compound (distearin) had no effect. The position of the unsaturated fatty acid groups is not of importance in the inhibition of metabolic cooperation by diacylglycerols containing unsaturated fatty acid moieties (i.e., 1,2-diolein and 1,3-diolein are equally efficacious in inhibiting metabolic cooperation; relative inhibition of metabolic cooperation by 18:1 greater than 1-oleoyl-2-acetyl glycerol greater than 1,2-diolein). Alterations of membrane biophysical properties and protein kinase C involvement are discussed as possible mechanisms involved in the inhibition of metabolic cooperation by unsaturated lipid.     

Fatty acid composition of phospholipids and neutral lipids and lipid peroxidation in human breast cancer and lipoma tissue

Since unsaturated fatty acids have been shown to control celldivision experimentally the fatty acid composition in humanmammary cancers as compared with the healthy surrounding tissuewas studied. Both phospholipid and neutral lipid fractions wereextracted for study and further lipid per-oxidation expressedas thiobarbituric add reactive substances was measured. Fora comparison a benign adipose tissue tumor, lipoma, was studied.There was a 3.6-fold increase in phospholipid contents of canceras compared with a reference tissue. No such differences wereobserved between lipoma and surrounding adipose tissue. In thephospholipid fatty acids of mammary cancers there was a markedincrease in the relative amounts of unsaturated fatty acids,especially arachidonic acid, while saturated fatty acids weredecreased, as compared with a healthy reference breast tissueor lipomas. The data suggest that the fatty acids might havea role in the development of breast cancer, possibly relatedto the formation of reactive metabolites of unsaturated fattyacids in the initiation of cancer or to their promotional effects.     

Promotion of 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis by high dietary fat in the rat: possible role of intercellular communication

The effect of high levels of dietary fat on the promotion phase of rat mammary tumorigenesis and the effect of unsaturated and saturated fatty acids on metabolic cooperation in hamster cells were examined. Female Sprague-Dawley rats were given iv injections of 5 mg 7,12-dimethylbenz[a]anthracene (DMBA) and subsequently placed on 20% high-fat (HF) and 4.5% corn oil control (CF) diets. Rats treated with DMBA and fed HF diet for the entire duration of the experiment developed more tumors with shorter latency than rats fed CF diet for the entire experiment. Rats fed HF diet for 3 weeks at different times after DMBA treatment showed similar, enhanced mammary tumor development. Lengthening the duration of HF diet treatment (0, 3, 6, 16 wk) increased mammary tumor development, suggesting a time dose-response relationship. Removal of the HF diet treatment partially reversed its stimulatory effects on tumor development. These results indicate that dietary fat acts as a classical tumor promoter to enhance mammary tumorigenesis. The influence of unsaturated and saturated fatty acids on metabolic cooperation between 6-thioguanine-sensitive (6-TGS) and 6-thioguanine-resistant (6-TGr) Chinese hamster V79 cells was examined. Linoleic acid, palmitoleic acid, and arachidonic acid significantly increased the recovery of 6-TGr cells at noncytotoxic concentrations. Stearic acid, palmitic acid, and arachadic acid had no effect on the recovery of 6-TGr cells at either cytotoxic or noncytotoxic concentrations. These results demonstrate that unsaturated fatty acids but not saturated fatty acids can inhibit metabolic cooperation between Chinese hamster V79 cells, and suggest, mechanistically, that high dietary levels of polyunsaturated fat could promote tumorigenesis by inhibition of intercellular communication.     

Susceptibility of mammary tumor cells to complement-mediated cytolysis after in vitro or in vivo fatty acid manipulation

The susceptibility of line 168 murine mammary tumor cells to complement (C)-mediated lysis was tested after in vitro treatment with several saturated or unsaturated fatty acids dissolved in different solvents or presented in the form of micelles to the cells. The lytic susceptibility of these cultured cells was compared with similar tumor cells obtained either from mice maintained on diets containing different concentrations and saturations of fatty acids or from cultures supplemented with serum from tumor-free control mice fed pair-matched diets. Although changes in dietary fat concentration and saturation resulted in alterations of the tumor cell fatty acid composition, those alterations did not influence the susceptibility of tumor cells to C-mediated lysis. However, single, or combinations of, unsaturated fatty acids dissolved in ethanol, unlike saturated fatty acids, reduced the lytic susceptibility of tumor cells in vitro. Hexane added to culture medium significantly suppressed the lytic susceptibility; however, when used as a carrier no significant differences were observed among treatments with the individual fatty acids at several concentrations. This result may be due to the effect of hexane on the cell membrane because this treatment also affected the osmotic fragility of the cells. Fatty acids as micelles did not influence the susceptibility of tumor cells to lysis. We concluded that only in vitro manipulation of fatty acids in some vehicles influenced the susceptibility of target tumor cells to C-mediated lysis; this finding did not parallel the situation that occurred in vivo. Moreover, the use of different vehicles to present fatty acids to tumor cells may further alter the susceptibility to C-mediated lysis.     

Oleate activates phosphatidylinositol 3-kinase and promotes proliferation and reduces apoptosis of MDA-MB-231 breast cancer cells, whereas palmitate has opposite effects

Epidemiological studies and experiments using animal models and cultured breast cancer cells have suggested that a high intake of dietary fat could increase breast cancer risk. Little is known about the biochemical pathways by which various free fatty acids (FFAs) influence breast cancer cell proliferation and apoptosis. The present study was designed to investigate the effects of the two most abundant circulating FFAs, oleate and palmitate, on established human breast cancer cell lines after a short period of serum starvation. The unsaturated FFA oleate (C:18:1) stimulated cell proliferation, whereas the saturated FFA palmitate (C:16) dose dependently inhibited it. The half maximal effective concentrations of oleate and palmitate in the presence of albumin were 5 and 25 microM, respectively. The growth-inhibitory effect of palmitate in MDA-MB-231 cells was related to the induction of apoptosis as indicated by morphological and biochemical criteria. Moreover, oleate protected cells against the proapoptotic action of palmitate. Oleate and palmitate increased and decreased phophatidylinositol 3-kinase (PI3-K) activity, respectively, and the actions of the two FFAs on the enzyme were antagonistic. The PI3-K inhibitors wortmannin and LY294002 completely blocked the proliferative action of oleate. 2-Bromopalmitate, a nonmetabolizable analogue, did not affect MDA-MB-231 cell proliferation, suggesting that palmitate must be metabolized to exert its effect. Thus, various types of fatty acids are not equivalent with respect to their actions on breast cancer cell proliferation and apoptosis. The results support the concept that PI3-K is implicated in the control of breast cancer cell growth by FFAs and that PI3-K may provide a link between fat and cancer. The data are also consistent with the view that the type of FFA and their ratios in the diet in addition to the total amount of fat influence mammary carcinogenesis.     

The effect of C18 fatty acids on cancer cells in culture

The influence of the 18 carbon chain length series of fatty acids on the growth of an SP210 mouse myeloma cell line were tested. The saturated fatty acid (C18:0, stearic acid) exhibited no cytotoxic or cytostatic effects, while the unsaturated fatty acids of the omega 9, omega 6, and omega 3 series proved effective in limiting cell growth. Although an overall concentration dependent cytotoxic effect was demonstrated with cis- and trans-mono- and dienoic fatty acids, within a narrow range of concentrations cell growth was stimulated. cis - C18:3 omega 6 and cis-C18:3 omega 3 showed the most dramatic effects, with ID50 values of 15 mg/ml for both, compared to ID50 values of 35 and 40 micrograms/ml with cis- and trans- C18:2 moeities, and ID50 values of 35 and 25 micrograms/ml with cis- and trans - C18:1 compounds, respectively.     

Correlation between the ability of tumor cells to incorporate specific fatty acids and their sensitivity to killing by a specific antibody plus guinea pig complement.

Line-1 diethylnitrosamine-induced guinea pig tumor cells can be rendered sensitive to killing by rabbit anti-Forssman IgM antibody plus guinea pig complement (GPC) or antitumor antibody plus GPC following prolonged incubation (17 hr ) of the cells with one of several metabolic inhibitors. Compared to control cells, these cells have been shown to be inhibited in their ability to incorporate fatty acids into complex cellular lipids, which suggested that lipid synthesis is of fundamental importance for the ability of the tumor cells to resist humoral immune killing. In this study, drug-treated cells that were rendered sensitive to killing by anti-Forssman antibody plus GPC, but not antitumor antibody plus GPC, were inhibited in their incorporation of saturated (palmitic or stearic acid), but not an unsaturated, fatty acid (linoleic acid). These data suggested that the fatty acid composition of specific lipids may also be important for the resistance of these tumor cells to killing by antibody and complement.     

Reversible proliferation arrest of rat 3y1 fibroblasts and selective killing of simian-virus transformed derivation of 3y1 by short-chain Fatty-acids

We examined the effect of saturated fatty acids with carbon number from 2 to 10 on proliferation and survival of rat untransformed fibroblast 3Y1 cells and its transformed derivation induced by Simian virus 40 (SV-3Y1). Acetic acid (C2) had no effect on proliferation of these cells. Among medium-chain fatty acids (C6-C10), caproic acid (C6) showed the lowest proliferation inhibitory effect. Caprylic (C8), pelargonic (C9), and capric acid (C10) exerted killing activity to both 3Y1 cells and SV-3Y1 cells, and the toxicity increased with the elongation of their alkyl chains. The toxicity was a little greater to 3Y1 cells than to SV-3Y1 cells. In contrast, short-chain fatty acids caused reversible proliferation arrest in 3Y1 cells at 25 mM in propionic (C3), 5 mM in butyric (C4) and 10 mM in valeric (C5) acids. These short-chain fatty acids arrested 3Y1 cells not only in the GI phase but also in the G2 phase of the cell cycle. To SV-3Y1 cells, however, these short-chain fatty acids were cytotoxic. The cytotoxicity to SV-3Y1 cells was the greatest in butyric acid among short-chain fatty acid tested. These results suggest that short-chain fatty acids exert ploliferation-arresting activity against normal cells while exerting killing activity to the transformed cells.     

Relationship of the uptake and beta-oxidation of 18-carbon fatty acids with stimulation of murine mammary tumor cell growth

The effects of stearic (18:0), oleic (18:1) and linoleic (18:2) acid on the in vitro growth of murine mammary tumor cell line 4526 were compared to 4526 uptake and beta-oxidation of those fatty acids. Both 18:1 and 18:2 stimulated, while 18:0 inhibited growth. Likewise, uptake and oxidation rates were much lower for 18:0 than for 18:1 and 18:2. The influence of glucose, insulin and fatty acid-depletion on 4526 fatty acid incorporation and oxidation was also determined. The correlation between effects on in vitro growth and ability to assimilate 18:0, 18:1 and 18:2 may partially explain the stimulation by unsaturated and inhibition by saturated fatty acids of in vivo 4526 tumorigenesis.     

Effect of eicosapentaenoic acid and other fatty acids on the growth in vitro of human pancreatic cancer cell lines.

A number of polyunsaturated fatty acids have been shown to inhibit the growth of malignant cells in vitro. To investigate whether fatty acids modify the growth of human pancreatic cancer, lauric, stearic, palmitic, oleic, linoleic, alpha-linolenic, gamma-linolenic, arachidonic, docosahexaenoic and eicosapentaenoic (EPA) acids were each incubated with the cells lines MIA PaCa-2, PANC-1 and CFPAC at concentrations ranging from 1.25 microM to 50 microM and the effect of each fatty acid on cell growth was examined. All the polyunsaturated fatty acids tested had an inhibitory effect, with EPA being the most potent (ID50 2.5-5 microM). Monounsaturated or saturated fatty acids were not inhibitory. The action of EPA could be reversed with the anti-oxidant vitamin E acetate or with oleic acid. The cyclo-oxygenase inhibitors indomethacin and piroxicam had no effect on the action of EPA. The action of EPA appeared to be associated with the generation of lipid peroxides, although the level of lipid peroxidation did not always appear to correlate directly with the extent of cell death. The ability of certain fatty acids to inhibit significantly the growth of three human pancreatic cancer cell lines in vitro at concentrations which could be achieved in vivo suggests that administration of such fatty acids may be of therapeutic benefit in patients with pancreatic cancer.     

Correlation of DNA synthesis-inhibiting activity and the extent of transmembrane permeation into tumor cells by unsaturated or saturated fatty alcohols of graded chain-length upon hyperthermia

The carcinostatic activity has been studied for fatty acids of diverse species but scarcely for fatty alcohols. Three unsaturated fatty alcohols at 35-50 microM inhibited DNA synthesis and the proliferation of tumor cells by a combination with hyperthermia to greater extents in the order: oleyl (C18:1)-> linoleyl (C18:2)-> alpha-linolenyl (C18:3) alcohol, which is an order inverse to that known for the corresponding fatty acids (4). In contrast, two saturated fatty alcohols, palmityl (C16:0)- and stearyl (C18:0) alcohols, did not inhibit at the same concentrations. At 100 microM, palmityl alcohol inhibited, whereas stearyl alcohol did not. The effective fatty alcohols appreciably permeated the cells. The inhibition of the unsaturated fatty alcohols on DNA synthesis and proliferation was nearly proportional to the amount of their intercellular accumulation at 37 degrees C or 42 degrees C; the most inhibitory, oleyl alcohol, was the most membrane-permeable, whilst inversely the least inhibitory, alpha-linolenyl alcohol, was the least permeable. A proportional correlation was not observed for saturated fatty alcohols; palmityl alcohol underwent an approximate 2-fold more abundant accumulation than other fatty alcohols, but was weakly inhibitory. Thus, oleyl alcohol may exert an antitumor action via appropriately efficient transmembrane permeation and a combination with hyperthermia.     

Kidney total fatty acids in renal cell carcinoma and infection

Lipids extracted from the kidneys of adults with renal cell carcinoma or infection after careful dissection of lesions and from organs showing minimal alterations were saponified and the fatty acids converted to the methyl esters. Gas chromatographic criteria were applied to the esters as such and to hydrogenated aliquots, and the relative percentages of the component acids were ascertained. The various lipid classes were well represented in the total fatty acid mixtures. The unsaturated acids ranged higher than the saturated homologs. Comparisons of the fatty acids were carried out on the basis of age, sex, kidney position, mode of acquisition (surgery and autopsy), and pathology. Several small but statistically significant differences were discerned according to the categories but with few exceptions, these involved acids occurring at low levels and with wide variance.     

Fish oil constituent docosahexa-enoic acid selectively inhibits growth of human papillomavirus immortalized keratinocytes

The omega-3-fatty acids inhibit proliferation of breast cancer cells whereas omega-6-fatty acids stimulate growth. In this study, we examined effects of these fatty acids on human pre-cancerous cells. Cervical keratinocytes, immortalized with the oncogenic human papillomavirus (HPV) type 16, were treated with linoleic acid, an omega-6-fatty acid, and the omega-3-fatty acids, eicosapentaenoic and docosahexaenoic acids. Using both cell counts and bromodeoxyuridine incorporation, docosahexaenoic acid inhibited growth of these cells to a greater extent than eicosapenta-enoic acid. Linoleic acid had no effect. The effect of docosahexaenoic acid was dose dependent and caused growth arrest. Docosahexaenoic acid inhibited growth of HPV16 immortalized foreskin keratinocytes and laryngeal keratinocytes grown from explants of benign tumors caused by papillomavirus, but had no effect on normal foreskin and laryngeal keratinocytes. Docosahexaenoic acid inhibited growth in the presence of estradiol, a growth stimulator for these cells. Indomethacin, a cyclooxygenase inhibitor like docosahexaenoic acid, had only minimal effect on growth. Alpha-tocopherol, a peroxidation inhibitor, abrogated effects of docosahexaenoic acid implying that inhibitory effects were via lipid peroxidation.     

Polyunsaturated fatty acid-induced cytotoxicity against tumor cells and its relationship to lipid peroxidation

The contribution of lipid peroxidation to the killing of human breast cancer cells by gamma-linolenate (GLA) was examined. Other fatty acids of different cytotoxic potential containing 2, 4, 5, and 6 double bonds were also tested for comparison. It was found that the cytotoxic potential varied with the ability of the fatty acids to stimulate the production of superoxide radicals. Neither hydrogen peroxide nor hydroxy radicals are significantly involved in cell killing. As nonspecific indicators of lipid peroxidation, measurements of the loss of unsaturated fatty acid in the phospholipids together with the generation of hydroperoxide breakdown products were done with the use of the thiobarbituric acid test. The results of these experiments showed that the effectiveness of a given fatty acid in killing cancer cells correlated with the intracellular thiobarbituric acid-reactive material (TBARM) content: GLA and arachidonate with 3 and 4 double bonds generated the most TBARM and were the most cytotoxic fatty acids, whereas docosahexaenoate with 6 double bonds was the least effective either in raising TBARM or in killing the malignant cells. Iron and copper accelerated the rate of cell death, whereas antioxidants such as vitamin E and butylated hydroxyanisole inhibited the effect of GLA dose dependently. Indomethacin, an inhibitor of endoperoxide formation, did not reduce either cell kill or TBARM amounts. In contrast, the addition of vitamin E acetate to the cancer cell cultures challenged with eicosapentaenoate reduced both cell killing and TBARM content. These results suggest that the effectiveness of a given fatty acid in killing cancer cells correlated with the extent of lipid peroxidation of the added fatty acid in the cells.     

Modulation of protein kinase C activity and [3H]phorbol 12,13-dibutyrate binding by various tumor promoters in mouse brain cytosol

Using protein kinase C partially purified from mouse brain cytosol, we examined the effect of a number of phorbol ester and nonphorbol tumor promoters on protein kinase C enzymatic activity and [3H]phorbol 12,13-dibutyrate binding. Mezerein and phorbol 12-retinoate 13-acetate, second stage tumor promoters, as well as the weak tumor promoter 4-O-methylphorbol 12-myristate 13-acetate stimulated kinase activity to the same extent as did the complete tumor promoter phorbol 12-myristate 13-acetate. In contrast, the nonphorbol ester tumor promoters anthralin, cantharidin, benzoyl peroxide, and 7-bromomethyl-benz(a)anthracene did not affect kinase activity. The unsaturated fatty acids palmitoleic, oleic, linoleic, linolenic, and arachidonic acids, some of which have been reported to be weak tumor promoters, stimulated protein kinase C activity in the presence of phospholipids, as well as causing some activation in the absence of phospholipids. The saturated fatty acids butyric, lauric, myristic, and palmitic acids had relatively little effect. The fatty acids showed generally similar structure-activity relationships for inhibition of [20-3H]phorbol 12,13-dibutyrate binding as for stimulation of kinase activity. The unsaturated fatty acids typically decreased binding levels for the reconstituted aporeceptor, while the saturated fatty acids did not. The nature of this inhibition was explored in the case of arachidonic acid. Scatchard analysis demonstrated decreases in both the maximum number of binding sites as well as the apparent binding affinity, indicative of a complex mechanism. As expected for a lipophilic ligand, the effect of the arachidonic acid was reduced in the presence of elevated levels of phospholipid. Our results suggest that fatty acids are capable of modulating the phorbol 12,13-dibutyrate receptor:protein kinase C.     

Enhancement of carcinostatic activity of omega-hydroxy fatty acids by their esterification through increased uptake into tumor cells

Diverse omega-hydroxy fatty acids (omegaHFAs) and their derivatives were examined for their ability to diminish the cell viability of Ehrlich ascites tumor cells by the mitochondrial dehydrogenase-based WST-1 assay and trypan blue dye exclusion assay. Of the diverse omegaHFAs, hydroxyhexadecanoic acid (omegaH16:0) was appreciably carcinostatic, and hydroxypentadecanoic acid (omegaH15:0) or hydroxypentadecenoic acid (omegaH15:1) was weakly carcinostatic at a dose of 100 micro M, whereas hydroxydodecanoic acid (omegaH12:0) and hydroxyhexadecenoic acid (omegaH16:1) acid were scarcely carcinostatic at the same dose. In contrast their sodium salt derivatives except omegaH16:0 were not carcinostatic. Enhancement of the carcinostatic activity was markedly exerted by ethylesterization of omegaHFAs with the saturated fatty moiety such as omegaH16:0 and omegaH15:0, whereas ethylesters of the unsaturated omegaHFAs such as omegaH15:1 and omegaH16:1 were weakly carcinostatic. Thus intramolecular introduction of a double bond was shown to weaken the carcinostatic activity in case of either omegaHFAs or their ethylester, being in contrast to the conventional knowledge concerning the enhancement of carcinostatic activities of non-hydroxy fatty acids appendant with more double bonds. The intracellular uptake amount of each omegaHFA as quantified by gas chromatography was the following order: omegaH16:0 ethylester (10.1 pg/cell) > omegaH15:0 ethylester (6.4 pg/cell) > omegaH16:0 (3.4 pg/cell) > omegaH15:0 (2.8 pg/cell), which accords with the order of carcinostatic activities of four saturated omegaHFAs in contrast to discord between both the orders for unsaturated omegaHFAs which could be scarcely detected as the intact form within cells. The results indicate that enhancement of carcinostatic activity of omegaH16:0 by ethylesterization was attributed to an appreciable correlation between intracellular uptake amounts and carcinostatic activities for diverse omegaHFAs with saturated fatty moiety, being not true for unsaturated omegaHFAs.     

Fatty acid composition of phospholipids of erythrocyte membranes and risk of breast cancer

Five fatty acids, two saturated--palmitic (C16:0), stearic (C18:0), and three unsaturated--oleic (C18:1), linoleic (C18:2) and arachidonic (C20:4) were assayed in red cell membranes of breast cancer patients and healthy controls. No significant difference in the levels of saturated fatty acids was established between the two groups, although mean values were somewhat lower in cancer patients. Mean levels of unsaturated fatty acids were also lower in breast cancer patients, with the difference being significant for arachidonic acid in postmenopausal women. There was no significant difference in polyunsaturated/saturated acid ratio between patients and controls in either cycling or postmenopausal group. In controls, the levels of the fatty acids checked, particularly, those of arachidonic acid were higher in menopause than in premenopause. However, no difference in the fatty acid levels was observed between pre- and postmenopausal cancer patients.     

Eicosapentaenoic acid and sulphur substituted fatty acid analogues inhibit the proliferation of human breast cancer cells in culture

Numerous studies have shown dietary fatty acids toinfluence the progression of several types of cancers.The purpose of the present investigation was toexamine the influence of various types of fattyacids, including -3 fatty acids and a newclass of hypolipidemic peroxisome proliferating fatty acid analogues,namely the 3-thia fatty acids, on MCF-7 humanbreast cancer cell growth. 3-thia fatty acids representnon--oxidizable fatty acid analogues in which a sulphuratom substitutes for the -methylene group (3-position) inthe saturated and unsaturated fatty acids.The effects of increasing concentrations of palmitic acid,tetradecylthioacetic acid (a 3-thia fatty acid), eicosapentaenoic acid,docosahexaenoic acid, and two 3-thia polyunsaturated fatty acidson the proliferation of MCF-7 cells, maintained inserum-free culture, were studied. At the highest concentrationof fatty acid used (64 µM) tetradecylthioacetic acidwas found to be the most effective ofall fatty acids tested in inhibiting cell growth,whilst palmitic acid and docosahexaenoic acid had nosignificant effect on cell growth. Thus, of thetwo dietary polyunsaturated -3 fatty acids eicosapentaenoic acidand docosahexaenoic acid, only eicosapentaenoic acid possesses aninhibitory effect on the proliferation of MCF-7 cells.In all cases the inhibitory effect of thefatty acid was found to be reversible.Tetradecylthioacetic acid has been shown to be apotent peroxisome proliferator. It was, therefore, hypothesized thattetradecylthioacetic acid may inhibit the human MCF-7 cellgrowth by increasing the level of oxidative stresswithin the cell. However, use of agents whichmodify the cell's protective apparatus against oxidative stresshad no influence on the inhibitory effect oftetradecylthioacetic acid.These experiments indicate that tetradecylthioacetic acid inhibits cellgrowth by mechanisms which may be independent ofoxidative status.     

Increased cytotoxicity of polyunsaturated fatty acids on human tumoral B and T-cell lines compared with normal lymphocytes.

Epidemiological and experimental data suggest that fatty acids may modulate the growth of tumor cells. We have analyzed the effect of different types of fatty acids, bound to serum proteins in physiological conditions, on the lipid composition and growth of human neoplastic B and T-cell lines and compared their effect on normal lymphocyte proliferation. Fatty acids with 0 to 2 unsaturations (stearic, oleic, and linoleic), at concentrations up to 50 or 100 microM did not significantly affect the proliferation of leukemic cells. However, long-chain polyunsaturated fatty acids (PUFA), and mainly docosahexaenoic (22:6, n-3), were cytotoxic at concentrations greater than or equal to 20 microM after 48-72 h in culture. Simultaneous supplementation with vitamin E restored normal cell growth. The amount of end-products of lipid peroxidation in cells correlated with the observed toxicity but the amount of superoxides did not. Fatty acid supplementations increased cell triacylglycerol content but did not affect the degree of unsaturation of phospholipids, cholesterol/phospholipids molar ratio, or membrane fluidity. Glutathione-S-transferase activity was low in Raji and CEM cells, moderate in lymphocytes and high in Ramos cells and did not increase with supplementations. The proliferation of normal lymphocytes, which produced lower amounts of end-products of lipid perodixation, was not inhibited, but in some cases stimulated, by PUFA (with the exception of 30 microM 22:6). The extension of these results to situations in vivo could lead to use of PUFA for delaying leukemia progression or in adjuvant chemotherapy.