Docosahexaenoic acid increases permeability of lipid vesicles and tumor cells

Abstract

Docosahexaenoic acid (DHA), a long-chain polyunsaturated omega 3 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 isosmolar erythritol and leakage of sequestered carboxyfluorescein, and T27A tumor cells, as monitored by swelling in isosmolar erythritol and release of sequestered 51Cr. 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.

Docosahexaenoic acid affects cell signaling by altering lipid rafts

“…Demel et al [78] demonstrated that DHA incorporated into the sn-2 position of PC enhanced permeability to glucose, erythritol and glycerol. Measuring bilayer permeability to erythritol and carboxyfluorescein, Stillwell et al [79] established that DHA enhanced bilayer permeability 2 to 3 fold more than oleic acid in identical phospholipids. Huster et al [80] used 17 O NMR to follow water permeability across lipid bilayers.…”

“…DHA as either the free fatty acid or as part of a mixed chain PC (18:0-22:6PC) enhanced SUV fusion to a much larger extent than did PCs with other, less unsaturated fatty acids [85]. When T27A tumor cells were fused with vesicles containing 18:0-22:6PC, the tumor plasma membrane became leakier [79], had altered expression of surface proteins [89], altered domain structure [90], decreased cell deformability [91], increased cytolysis by cytotoxic T-lymphocytes [86] and decreased cell longevity [3,89]. Upon fusion with SUVs made from 18:0-XPC, where X is stearic, oleic, α-linolenic, arachidonic, eicosapentaenoic or DHA, only DHA was cytotoxic [88].…”

Essential fatty acids and the brain: possible health implications

“…This important ®nding raised many questions, but in particular the issue about the biochemical and biophysical mechanisms that lead to their essentiality. To date, a multitude of mechanisms have been explored, for example, their eects on; the structural integrity and¯uidity of membranes [33,130]; enzyme activities [80,120,125]; lipid-protein interactions [117]; and their role as precursors for eicosanoids, such as prostaglandins, leukotrienes and thromboxanes.…”

Synergistic Effects of Highly Unsaturated Fatty Acid‐containing Phosphatidyl‐ethanolamine on Differentiation of Human Leukemia HL‐60 Cells by Dibutyryl Cyclic Adenosine Monophosphate

“…11) An exogenous supplement of HUFAcontaining PL also affects the membrane environment and influences various cellular functions. [12][13][14] We previously reported that the enhancing effect of DHA-PL on RAinducing differentiation was stronger than that of DHA. 15) Since signal transduction enzymes such as protein kinase C (PKC) 16,17) and adenylate cyclase 18) are affected by specific molecular species of PLs, the membrane modification by HUFA-PL may be effective to enhance the sensitivity of leukemia cells to differentiation-inducing drugs.…”