Docosahexaenoic acid in phosphatidylcholine mediates cytotoxicity more effectively than other ω-3 and ω-6 fatty acids

We reported previously that docosahexaenoic acid (22:6)-containing phosphatidylcholine (PC), but not oleic acid-containing PC nor 22:6-containing phosphatidylethanolamine, is toxic to tumor cells in vitro. To test whether other polyunsaturated fatty acids share 22:6ʹs cytotoxic activity, we treated cultured T27A murine leukemia cells with PC liposomes composed of stearic acid in the sn-1 position and α-linolenic acid (α-18:3), arachidonic acid (20:4), or eicosapentaenoic acid (20:5) in the sn-2 position. PC containing 22:6 in both positions was also tested. Following treatment, the cells were monitored for fatty acid composition, liposome uptake and viability. Here we demonstrate that cytotoxicity is unique to 22:6-containing PCs and is not shared by PCs with other polyunsaturated ω-3 and ω-6 fatty acids. Because PCs with fatty acids other than 22:6 were taken up by cells but did not kill the cells, we propose that 22:6-containing PCs incorporated into cellular membranes produce unique changes in the membrane structure incompatible with cell survival. PC liposomes containing 22:6 are potential drug delivery vehicles that may, by virtue of their cytotoxicity, serve concomitantly as adjunct cancer therapy.