Abstract
BackgroundThe present study sought to further investigate the in vitro and in vivo anticancer effects of a representative omega-3 fatty acid, docosahexaenoic acid (DHA), with a focus on assessing the induction of oxidative stress and apoptosis as an important mechanism for its anticancer actions.Methodology/Principal Findings In vitro studies showed that DHA strongly reduces the viability and DNA synthesis of MCF-7 human breast cancer cells in culture, and also promotes cell death via apoptosis. Mechanistically, accumulation of reactive oxygen species and activation of caspase 8 contribute critically to the induction of apoptotic cell death. Co-presence of antioxidants or selective inhibition or knockdown of caspase 8 each effectively abrogates the cytotoxic effect of DHA. Using athymic nude mice as an in vivo model, we found that feeding animals the 5% fish oil-supplemented diet for 6 weeks significantly reduces the growth of MCF-7 human breast cancer cells in vivo through inhibition of cancer cell proliferation as well as promotion of cell death. Using 3-nitrotyrosine as a parameter, we confirmed that the fish oil-supplemented diet significantly increases oxidative stress in tumor cells in vivo. Analysis of fatty acid content in plasma and tissues showed that feeding animals a 5% fish oil diet increases the levels of DHA and eicosapentaenoic acid in both normal and tumorous mammary tissues by 329% and 300%, respectively.Conclusions/SignificanceDHA can strongly induce apoptosis in human MCF-7 breast cancer cells both in vitro and in vivo. The induction of apoptosis in these cells is selectively mediated via caspase 8 activation. These observations call for further studies to assess the effectiveness of fish oil as a dietary supplement in the prevention and treatment of human breast cancer.
Highlights
Omega-3 fatty acids (FAs") are long-chain polyunsaturated FAs
We first determined the effect of docosahexaenoic acid (DHA) and EPA on the viability (MTT assay) of cultured MCF-7, MDA-MB-231 and MDA-MB435s cells
The results of our present study showed that DHA, an omega-3 FA, has a strong anticancer activity in cultured MCF-7 human breast cancer cells through a combination of multiple actions, including inhibition of DNA synthesis, suppression of cell viability, and induction of apoptotic cell death
Summary
Omega-3 fatty acids (FAs") are long-chain polyunsaturated FAs. The principal dietary source of eicosapentaenoic acid (EPA, 20:5n3) and docosahexaenoic acid (DHA, 22:6n-3) is from oily coldwater fish [1,2]. Epidemiological studies have suggested that an increased fish oil intake is associated with a reduced breast cancer incidence in humans [3,4] Consistent with this epidemiological observation, laboratory studies have shown that omega-3 FAs can suppress the formation and growth of breast cancer in animal models [5,6,7,8]. A number of mechanisms have been proposed for the anticancer actions of omega-3 FAs, including suppression of neoplastic transformation, inhibition of cell proliferation, enhancement of apoptosis, and antiangiogenicity [1,9]. The present study sought to further investigate the in vitro and in vivo anticancer effects of a representative omega-3 fatty acid, docosahexaenoic acid (DHA), with a focus on assessing the induction of oxidative stress and apoptosis as an important mechanism for its anticancer actions
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