SELECTIVE INDUCTION OF APOPTOSIS IN CANCER-CELLS BY THE ETHER LIPID ET-18-OCH3 (EDELFOSINE) - MOLECULAR-STRUCTURE REQUIREMENTS, CELLULAR UPTAKE, AND PROTECTION BY BCL-2 AND BCL-X(L)

The ether lipid O-octadecyl-2-O-methyl-rac-glycero-3-phosphcholine (ET -18-OCH3; Edelfosine) has been shown to be a rapid inducer of apoptosi s in human leukemic cells and has been considered as a promising drug in cancer treatment, Here we have found that ET-18-OCH3 induced apopto sis not only in human tumor cell lines but also in primary tumor cell cultures from cancer patients. Human leukemic cells were highly sensit ive to ET-18-OCH3, whereas normal cells remained unaffected, Among the distinct modifications of the ET-18-OCH3 molecule assayed, we found t hat substitutions in positions sn-2 and sn-3 of the glycerol backbone resulted in a complete loss of its capacity to induce apoptosis, highl ighting the importance of the molecular structure of ET-18-OCH3 in its apoptotic effect, Induction of apoptosis by ET-18-OCH3 was very well correlated with the uptake of this ether lipid, ET-18-OCH3-resistant 3 T3 fibroblasts became sensitive and incorporated significant amounts o f the ether lipid following transformation with the SV40 virus, ET-18- OCH3-induced apoptosis as well as ET-18-OCH3 uptake were not mediated through binding of the ether lipid to the platelet-activating factor r eceptor, Overexpression of bcl-2 or bcl-x(L) by gene transfer in the h uman erythroleukemic HEL cells abrogated apoptosis induced by ET-18-OC H3. ET-18-OCH3 did not affect the expression of bcl-2, bcl-x(L), or ba r in HEL and HL-60 human leukemic cells but induced expression of c-my c, an important effector of apoptosis in several systems. Thus, ET-18- OCH3 behaves as a potent and highly selective antitumor drug able to i nduce an apoptotic pathway of cell death in tumor cells but not in non malignant cells.