Increased Generation of Lipid-derived and Ascorbate Free Radicals by LI210 Cells Exposed to the Ether Lipid Edelfosine1

Using the spin trap a-(4-pyridyl-l-oxide)-A'-fert-butylnitrone, we have detected a lipid-derived carbon-centered free radical generated from in tact 1,1210 lymphoblastic leukemia cells that were exposed to 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (edelfosine or I IIK-()( II,) and oxidative stress. The spectral characteristics, including hyperfine splitting constants of ¡IN= 15.61G and a" = 2.65G, were consistent with the spin trapping of an alkyl radical. Radical detection required iron and prior enrichment of cellular components with the polyunsaturated fatty acid docosahexaenoic acid; unmodified cells failed to generate detectable free radical. Ascorbate further enhanced radical generation. The detection of lipid-derived free radicals when intact cells are exposed to edelfosine provides further evidence that oxidative stress may play an important role in the cytotoxic mechanism of this class of anticancer drug.