Docosahexanoic Acid Improves Chemotherapy Efficacy by Inducing CD95 Translocation to Lipid Rafts in ER⁻ Breast Cancer Cells

Abstract

Docosahexanoic acid (DHA) and eicosapentanoic acid (EPA) have been shown to possess anti-carcinogenic properties in mammary cancers, both in vitro and in vivo. The objective of this study was to investigate the effect of treating three different breast cancer cell lines with DHA or EPA on cellular growth, chemotherapy efficacy, and CD95 expression and localization in the cell. MDA-MB-231, MCF-7 and SKBr-3 cells were incubated with EPA or DHA with or without chemotherapy agents [doxorubicin (dox), Herceptin]. Cell growth was assessed by WST-1 assay and CD95 expression was investigated using flow cytometry, Western blotting and confocal microscopy. DHA and EPA inhibited the growth of all three breast cancer cell lines in a dose-dependent fashion (P < 0.05). DHA, and to a lesser extent EPA, induced the movement and raft clustering of CD95 in the cell membrane (via confocal microscopy) and the surface expression (via flow cytometry) in MDA-MB-231 cells. Neither fatty acid altered the growth/metabolic activity of the non-transformed MCF-12A breast cell line. Pre-treatment with DHA, but not EPA, improved the efficacy of dox in estrogen receptor negative MDA-MB-231 cells (P < 0.05), but not in the other two cell lines. Pre-treating cells with DHA increased CD95 surface expression (threefold) and the plasma membrane raft content of CD95 (2fold) and FADD (>4-fold) after dox treatment, compared to dox treatment alone (P < 0.05). This study demonstrated that pre-treatment of estrogen receptor negative MDA-MB-231 cells with DHA increased the anti-cancer effects of dox and presents evidence to suggest that this may be mediated in part by CD95-induced apoptosis.

Stearidonic acid-enriched flax oil reduces the growth of human breast cancer in vitro and in vivo

“…Palmitic acid (PA; C16:0), stearic acid (SA; C18:0), c-linolenic acid (GLA; C18:3n-6), ALA, and eicosadienoic acid (EDA; C20:2n-6) from NuChek Prep Inc (Elysian, MN, USA), and oleic acid (OA; C18:1n-9), linoleic acid (LA; C18:2n-6), and SDA from Matreya (Pleasant Gap, PA, USA) were conjugated to bovine serum albumin (Fisher Scientific, Edmonton, AB, Canada) as previously described [2]. Cells were plated in triplicate at a density of 2.…”

“…There are promising results showing that long-chain n3 polyunsaturated fatty acids (LCPUFA), primarily eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3), can reduce the growth of human breast tumor cells in vitro [1][2][3][4] and in experimental models of breast cancer [5][6][7][8][9]. A key mechanism for anti-cancer effects of n-3 LCPUFA is via incorporation into membrane phospholipid (PL) and their subsequent effect on membrane-mediated functions and signals (reviewed by [10]).…”

“…A key mechanism for anti-cancer effects of n-3 LCPUFA is via incorporation into membrane phospholipid (PL) and their subsequent effect on membrane-mediated functions and signals (reviewed by [10]). Changes in n-3 LCPUFA content in membrane lipids have been associated with changes in membrane content of the CD95 death receptor [2], raft-associated epidermal growth factor receptor and phosphorylation [2,4,11], and changes in caspases, proapoptotic proteins, and NF-kB, all which ultimately reduce cell survival [10,[12][13][14]. N-3 LCPUFA are preferentially enriched in the membrane PL, primarily phosphatidylethanolamine (PE), phosphatidylcholine (PC), and phosphatidylinositol (PI) [15].…”

Isolation and Identification of an Antimutagenic Phthalate Derivative Compound from Octopus (<i>Paraoctopus limaculatus</i>)

“…Marine fauna and flora usually produce secondary metabolites with structural features distinct from other natural sources, which are of interest for potential industrial and medical applications [1,2]. One of the components of interest is the lipid fraction of marine organisms that have been associated with the prevention of chronic degenerative diseases such as cardiovascular diseases and cancer [3][4][5][6][7]. Unsaturated fatty acids ω-3 and ω-6 isolated from different marine sources have been shown to be anti-mutagenic and anticarcinogenic [8].…”

Bioactive fractions from cantabrian anchovy (Engraulis encrarischolus) viscera

“…Much of the research in this area has been focused on marine lipidic compounds found in seafood such as unsaturated fatty acids ω-3 and ω-6, to which prevention of chronico-degenerative illnesses have been attributed (Burgos-Hernández et al, 2001;Farzaneh-Far et al, 2010;Shahidi & Miraliakbari, 2004;Ewaschuk et al, 2012;Chen et al, 2015;Darghosian et al, 2015;Leslie et al, 2015;Eide et al, 2016). However, little attention has been given to the chemical composition of seafood wastes (skin, viscera, and fish heads) as a source of biologically active molecules.…”