Influence of n-3 fatty acids on the growth of human breast cancer cellsin vitro: Relationship to peroxides and Vitamin-E

Abstract

Epidemiological studies suggest a causal relationship of dietary polyunsaturated fatty acids (PUFA's) with the morbidity and mortality from breast cancer. In order to reveal possible underlying mechanisms of these findings, we studied the influence of n-3 and n-6 PUFA's in comparison to oleic acid on the proliferation of well characterized estrogen dependent (MCF-7, ZR-75, T-47-D) and estrogen independent (MDA-MB-231, HBL-100) breast cancer cells in culture. The cell growth inhibitory effect was related to the formation of lipid peroxidation products. Normal human skin fibroblasts served as a control. In fibroblasts, the addition of 20 micrograms/ml of exogenous fatty acids either had no effect or caused an insignificant increase of proliferation. Similar results were obtained with MCF-7 cells. In all other breast cancer cell types, n-3 long-chain PUFA's, eicosapentaenoic and docosahexaenoic acids, were the most effective fatty acids in arresting the cell growth. Alpha-linolenic and gamma-linolenic acid exerted a variable effect on cell proliferation depending on the cell line investigated. Oleic acid significantly stimulated the proliferation of hormone-independent breast cancer cells while it had no effect on the proliferation of hormone-dependent cells. Viability studies by trypan blue excretion indicated that the arrest in cell growth was not due to major cytotoxic effects. The addition of PUFA's to breast cancer cells caused a significant increase in the formation of conjugated dienes and lipid hydroperoxides in the cellular lipids; their content was significantly correlated with the capacity of arresting cell growth. In contrast, the addition of PUFA's to fibroblasts did not increase lipid hydroperoxide formation. The addition of Vitamin E to cancer cells at a concentration of 10 microM to the PUFA-supplemented medium almost completely restored cell growth. Our data indicate that PUFA's significantly interfere with cell proliferation of breast cancer cells in vitro due to the formation of oxidation products. In addition to that, there must be other factors involved, most probably related to the differential metabolism of PUFA's in tumor cells. Our findings may have some impact on treatment and prevention of breast cancer.

Multiplication and death-type of leukemia cell lines exposed to very long-chain polyunsaturated fatty acids

“…[7][8][9] Several authors have reported reduced multiplication of malignant cultured cells incubated with n-3 fatty acids. 10,11 This effect has also been reported in leukemia cell lines. 12,13 Moreover, n-3 fatty acids and some other polyunsaturated fatty acids (PUFA) may decrease DNA synthesis and viability of cultured human lymphocytes.…”

“…However, the apoptosis induced by EPA in Ramos cells, was not affected by vitamin E. It has been demonstrated that the reduced cell multiplication induced by PUFA in human breast carcinoma cells and human T cells, is reversed by vitamin E and related to formation of free radicals. 11,15 However, in two very similar reports, the addition of antioxidants together with PUFA had no reversible effect. 14,16 As none of these studies investigated if the reduced cell multiplication with PUFA was caused by apoptosis or necrosis, the discrepancies in these reports may be explained by our present findings.…”

“…11 To address this issue, concentrations of 5 and 50 mol/l of the antioxidant vitamin E was added to Raji and Ramos cells prior to the addition of 60 mol/l EPA. After 2 days, the cells were counted and stained with PI/HO342.…”

Acide alpha-linolénique, anti-oxydants et croissance tumorale mammaire

“…Les données récentes produites en culture cellulaire indiquent que les AGPI n-3, incluant l'acide alpha-linolénique, inhibent la prolifération de cellules tumorales mammaires par l'intermédiaire d'une production accrue de lipoperoxydes, et qu'une supplémentation en vitamine E, principale vitamine anti-oxydante, supprime ces effets [25]. De façon similaire, une étude utilisant un modèle animal de carcinogenèse mammaire a indiqué que l'effet inhibiteur d'apports alimentaires riches en huiles de poissons (contenant des AGPI n-3 à longue chaîne) au niveau de la croissance tumorale mammaire est aboli par une supplémentation en agents anti-oxydants [26].…”

Enhancement of doxorubicin cytotoxicity by polyunsaturated fatty acids in the human breast tumor cell line MBA-MB-231: Relationship to lipid peroxidation

“…In response to oxidative stress, PUFAs undergo free-radical chain reaction breakdown, which results in the formation of fatty acid hydroperoxides and hydroxides as immediate products and aldehydes, among other endproducts. Either in cultured tumor cells (Chajès et al, 1996) or in tumor-bearing animals (Gonzalez et al, 1993), PUFA supplementation caused a decrease in cell proliferation or in tumor growth correlated with a concomitant increase in the level of cellular lipid peroxidation. These observations suggest that PUFAs interfere with tumor cell proliferation in vitro and in vivo due to the formation of oxidation products.…”