ω-3 Polyunsaturated fatty acid (PUFA), docosahexaenoic acid (DHA; 22:6n-3) and other ω-3 and ω-6 PUFAs have raised interest as novel anticancer agents by exerting selective cytotoxic effects on human cancer cells without affecting normal tissues. Here, we examined the in vitro relationship between exogenous supplementation with DHA and breast cancer chemosensitivity to taxanes. We measured cell viability in the highly metastatic human breast cancer cell line MDA-MB-231 exposed sequentially to DHA followed by paclitaxel (Taxol) or docetaxel (Taxotere). As DHA by itself showed cytotoxic effects, possible synergistic interactions between DHA and taxanes were assessed, employing the combination index (CI) method and the isobologram analysis. Both methods showed a strong synergism (CI ∼0.5; P<0.005) between DHA and taxanes in MDA-MB-231 cells. When the increase in taxanes efficacy was measured by dividing the IC50 values (50% inhibitory concentrations) obtained when the cells were exposed to taxanes alone by those after DHA pre-exposure, we found that DHA enhanced the cytotoxic activity of taxanes against MDA-MB-231 cells in a dose-dependent manner (up to 13- and 5-fold increase in Taxol and Taxotere efficacy, respectively). Importantly, sequential exposure to DHA followed by taxanes also yielded strong synergism in Her-2/neu (c-erbB-2)-overexpressing and taxanes-resistant SK-Br3 and BT-474 breast cancer cells. Moreover, exogenous supplementation with DHA significantly decreased the expression of Her-2/neu-codified p185Her-2/neu oncoprotein (up to 78% reduction in BT-474 cells). Our results provide experimental support to the hypothesis that ω-3 PUFAs can be used as modulators of tumor cell chemosensitivity and provide the rationale for in vivo preclinical investigation. In addition, this is the first study demonstrating that ω-3 PUFA DHA downregulates Her-2/neu oncogene expression in human breast cancer cells.
1Department of Medicine, Breast Cancer Translational Research Laboratory, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois (USA)
2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
3Medical Oncology, Institut Catala d'Oncologia, Hospital Universitari de Girona Dr Josep Trueta, Girona, Catalonia, Spain
Correspondence to: J A Menendez, Evanston Northwestern Healthcare Research Institute, 1001 University Pl., Evanston, Illinois 60201, USA
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Received 21 January 2004 Accepted 16 June 2004