Docosahexaenoic acid increases permeability of lipid vesicles and tumor cells

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Abstract
Docosahexaenoic acid (DHA), a long‐chain polyunsaturated ω3 fatty acid, is tested to determine its mode of action as an anti‐cancer agent. We demonstrate that DHA can increase the permeability of phospholipid vesicles, as monitored by vesicle swelling in isomolar erythritol and leakage of sequestered carboxylfluorescein, and T27A tumor cells, as monitored by swelling in isomolar erythritol and release of sequestered51Cr. DHA was incorporated into lipid vesicles as either the free fatty acid or as 1‐stearoyl‐2‐docosahexaenoyl‐sn‐glycero‐3‐phosphocholine. DHA was incorporated into the tumor cells by fusion with vesicles made from the mixed‐chain phosphatidylcholines. DHA is demonstrated here to be much more effective in increasing permeability than is oleic acid, the major unsaturated fatty acid normally found in tumor plasma membranes. It is proposed that incorporation of DHA makes tumor plasma membranes substantially more permeable, which may explain, in part, its anti‐tumor properties.