Role of endocytosis in the action of ether lipids on WEHI-3B, HL60, and FDCP-mix A4 cells.

We investigated the effect of a number of platelet activating factor antagonists on cell killing by 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphoryl choline (ET-18-OCH3). Of six platelet activating factor antagonists tested, four were found to protect WEHI-3B leukemic cells against cell death induced by ET-18-OCH3. Certain other compounds, not platelet activating factor antagonists, had similar protective effects. The protective compounds were all lipophilic weak bases. We describe experiments that indicate that these compounds protect by inhibition of endocytic uptake of ET-18-OCH3. Sensitive cells showed rapid endocytic uptake, whereas in resistant cells, uptake was slow. Uptake of ET-18-OCH3 could be suppressed by inhibitors of endocytosis such as chloroquine, monensin, and vinblastine. We conclude that one of the principal determinants of sensitivity or resistance to ether lipids may be the rate at which cells take them up by endocytosis.