The relationship between high fish consumption and low mortality following coronary heart disease (CHD) and low incidence of breast cancer was first mentioned 3 decades ago. The fishes of interest are rich in omega-3 long-chain polyunsaturated fatty acids (omega-3 LC-PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which could be the active nutrients. The current consensus about cardioprotection is that omega-3 LC-PUFAs would mainly exert antiarrhythmic effects. One of the proposed mechanisms is that circulating non-esterified LC-PUFAs partition into cardiac cells membrane phospholipids and exert a direct effect on ionic channels and/or modify intracellular calcium homeostasis. In another hypothesis, changes in the metabolism of phosphoinositides would be involved and lead to the differential activation of PKC isoforms. As compared to the mechanisms proposed for the cardioprotective effects of omega-3 LC-PUFAs, less is known about the molecular mechanisms involved in breast cancers prevention. Some proposed mechanisms such as the modulation of phosphoinositides metabolism and/or modulation of intracellular calcium homeostasis, are common to both pathologies. Other hypotheses involve the alteration of the cellular redox status induced by highly peroxidizable polyunsaturated fatty acids (FA), or the modulation of gene expression, both phenomena being tightly linked to apoptosis. In this review, we report and compare some proposed mechanisms for the involvement of omega-3 LC-PUFAs in both cardiac and breast cancer protection. Deliberately, we chose to discuss only the mechanisms, which are less described in other reviews such as ionic channels in cancer, calcium homeostasis, PKC activation or matrix metalloproteinases in both cancer and cardiac models. The leitmotiv along this review is that cardio- and cancero-protective effects use common pathways. Comparison of the cellular effects might therefore help to highlight the "protective" pathways.

1 Exposure to docosahexaenoı¨c acid (DHA), a long-chain polyunsaturated fatty acid, is known to block several ionic currents such as the transient outward current I TO . It has also been reported to activate certain potassium channels. It has been suggested that these effects, observed in single-cell experiments, participate in the antiarrhythmic properties of these compounds in vivo. 2 DHA is highly prone to peroxidation. To investigate the influence peroxidation may have on the effects of DHA on ion channels, we studied I TO and the steady-state outward current I SS in isolated rat ventricular myocytes under ruptured whole-cell patch-clamp conditions. 3 A measure of 10 mm DHA alone reduced I TO , evoked by a pulse to þ 70 mV, by 74.8710.8% (n ¼ 7) and activated a delayed outward current with kinetic properties different from I SS . 4 When an antioxidant, alpha-tocopherol (1 mm), was added together with DHA, the blockade of I TO was reduced to 38.577.7% (n ¼ 8) and the delayed outward current was not activated. a-Tocopherol alone had no effect on these currents. 5 When an oxidant, hydrogen peroxide (1 mm), was applied together with DHA, the blockade of I TO was almost complete (98.471.0%, n ¼ 7) and a large delayed outward current was activated. A measure of 1 mm hydrogen peroxide alone had no effect on these currents. 6 Measurements of nonperoxidized DHA in experimental solutions confirmed the negative relation between DHA concentration and the effects on the currents. 7 We conclude that rather than DHA itself, it is the peroxidation products of DHA that block I TO and activate a delayed outward current in in vitro single-cell experiments. These findings have important implications for the extrapolation of in vitro experimental findings to the antiarrhythmic effects of DHA in vivo because, in vivo, peroxidation of DHA is unlikely to occur.

The effects of an n-3 PUFA-enriched diet on cardiac cell membrane phospholipid fraction compositions and associated protein kinase-C (PKC) translocation modification have never been studied in higher mammals. This is of importance since membrane fatty acid composition has been shown to influence PKC signalling pathways. In the present study, we have tested whether the incorporation of n-3 PUFA in cardiac membrane phospholipids correlated with changes in the fatty acid composition of diacylglycerols (DAG) and led to a differential translocation of PKC isoforms. Two groups of five dogs were fed the standard diet supplemented with palm oil or fish oil for 8 weeks. Dogs fed a fish oil-enriched diet showed a preferential incorporation of EPA and, to a lesser extent, of DHA, at the expense of arachidonic acid, in the circulating TAG, plasma phospholipids, erythrocyte phospholipids and cardiomyocyte phospholipid fractions. Analysis of 1,2-DAG fatty acid composition also indicated a preferential enrichment of EPA compared with DHA. Associated with these results, a reduction in the expression of PKC-δ and PKC-ε isoforms in the particulate fractions was observed whereas no effect was seen for PKC-α and PKC-ζ. We conclude that a fish oil-enriched diet induces a modification in fatty acid composition of cardiac membrane phospholipids, associated with a differential translocation of PKC isoforms. These results can be explained by the production of structurally different DAG that may participate in some of the protective effects of n-3 PUFA against various chronic diseases.