Epidemiology studies suggest that long chain polyunsaturated fatty acidscalled omega-3s lessen a number of significant human afflictionsincluding cancer. The mechanism for this benefit is unknown, butmounting evidence suggests that omega-3s accumulate inmembranephospholipids and there alter basic membrane properties. Here we proposeto 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 fattyacid will be esterified to the sn-2 position of syntheticphosphatidylcholines and phosphatidylethanolamines. Lipid vesicles willbe made from these omega-3 containing phosphatidylethanolamines. Lipidvesicles will be made from these omega-3 containing phospholipids and thevesicles fused with tumor cells. We will measure the effect of DHA onmembrane structure by determining fluidity gradient profiles and lipidmicroheterogeneities followed by several fluorescence techniques andlipid packing determined on Langmuir Film Balance. We are interested inhow 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 oftarget antigens. DHA-induced exfoliated vesicles will also be isolatedand their lipid compositions, physical parameters and immunologicalproperties compared to their parent tumor plasma membranes. Theexfoliated vesicles represent physically separated membrane domains. From these experiments we anticipate being able to describe for the firsttime one underlying fundamental mechanism of action of omega-3 fattyacids as anti-cancer agents.
My laboratory studies the effect of various important biochemicals on membrane structure and function.
Biomedical Research, Multidisciplinary, Biomedical Research Training, Breast Cancer, Cancer Biology, Cancer/Carcinogenesis, Drug Design, Membranes, Metabolism, Lipid, Methods of Drug Delivery, Nutrition/Dietetics, Rheumatic Diseases, Skin Cancer, Skin Diseases
