Epidemiology studies suggest that long chain polyunsaturated fatty acids called omega-3s lessen a number of significant human afflictions including cancer. The mechanism for this benefit is unknown, but mounting evidence suggests that omega-3s accumulate in membrane phospholipids and there alter basic membrane properties. Here we propose to investigate how incorporation of one omega-3 fatty acid, docosahexaenoic acid (DHA), affects membrane structure and function, leading to enhanced immunological eradication of tumor cells. The fatty acid will be esterified to the sn-2 position of synthetic phosphatidylcholines and phosphatidylethanolamines. Lipid vesicles will be made from these omega-3 containing phosphatidylethanolamines. Lipid vesicles will be made from these omega-3 containing phospholipids and the vesicles fused with tumor cells. We will measure the effect of DHA on membrane structure by determining fluidity gradient profiles and lipid microheterogeneities followed by several fluorescence techniques and lipid packing determined on Langmuir Film Balance. We are interested in how these physical properties affect membrane permeability to the anti- cancer drug doxorubicin as well as the tumor cell's sensitivity to cell- mediated and antibody plus complement-mediated lysis and expression of target antigens. DHA-induced exfoliated vesicles will also be isolated and their lipid compositions, physical parameters and immunological properties compared to their parent (tumor) plasma membranes. The exfoliated vesicles represent physically separated membrane domains. From these experiments we anticipate being able to describe for the first time one underlying fundamental mechanism of action of omega-3 fatty acids as anti-cancer agents.
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