DISSOCIATION OF THE EFFECTS OF THE ANTITUMOR ETHER LIPID ET-18-OCH3 ON CYTOSOLIC CALCIUM AND ON APOPTOSIS

1 We have compared the effects of O-octadecyl-2-O-methyl-sn-glycero-3- phosphocholine (ET-18-OCH3) on the cytosolic free calcium concentratio n ([Ca2+](i)) and on apoptosis in several normal and leukaemia cells, including human polymorphonuclear neutrophils (PMNs), U937 cells, and undifferentiated as well as dimethylsulphoxide-differentiated HL60 cel ls (uHL60 and dHL60, respectively). 2 ET-18-OCH3 produced apoptosis, a s evidenced by DNA degradation into oligonucleosome-size fragments, in U937 and uHL60 cells, but not in dHL60 cells or PMNs. 3 ET-18-OCH3 in duced an increase in [Ca2+](i) mediated through the platelet-activatin g factor (PAF) receptor in U937, dHL60 cells and PMNs, as shown by cro ss-desensitization experiments and by prevention of the [Ca2+](i) chan ges by the PAF antagonist WEB-2170. The EC50 values for the increase i n [Ca2+](i) induced by PAF and ET-18-OCH3 were 5 x 10(-11) and 2.5 x 1 0(-7) M, respectively. In uHL60 cells the effect of ET-18-OCH3 on [Ca2 +](i) was very small and was not affected by WEB-2170. 4 PAF did not p roduce apoptosis in any of the cell types tested. WEB-2170 did not pre vent the apoptosis induced by ET-18-OCH3. 5 The uptake of [H-3]-ET-18- OCH3 was much larger in U937 and uHL60 cells than in dHL60 cells and P MNs. 6 Our results indicate that the apoptotic effect of ET-18-OCH3 is not related to the changes in [Ca2+](i), effected by interaction with plasma membrane PAF receptors, but to other actions which are associa ted with the uptake of this drug into the cells.