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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_L¹

Laboratory of Leukocyte Biology, Instituto de Biología y Genética Molecular, Facultad de Medicina, CSIC-Universidad de Valladolid, C/Ramón y Cajal 7, E-47005 Valladolid, Spain [F. M., C. G., B. M-M., R. M-D.]; Servicio de Inmunología, Hospital Universitario Marques de Valdecilla, INSALUD, E-39008 Santander, Spain [J. L. F-L., A. B.]; and Max-Planck-Institut für Immunbiologie, D-79108 Freiburg, Germany [M. M.]

The ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH₃; Edelfosine) has been shown to be a rapid inducer of apoptosis in human leukemic cells and has been considered as a promising drug in cancer treatment. Here we have found that Et-18-OCH₃ induced apoptosis not only in human tumor cell lines but also in primary tumor cell cultures from cancer patients. Human leukemic cells were highly sensitive to ET-18-OCH₃, whereas normal cells remained unaffected. Among the distinct modifications of the ET-18-OCH₃ molecule assayed, we found that substitutions in positions sn-2 and sn-3 of the glycerol backbone resulted in a complete loss of its capacity to induce apoptosis, highlighting 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 3T3 fibroblasts became sensitive and incorporated significant amounts of 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 receptor. Overexpression of bcl-2 or bcl-x_L by gene transfer in the human erythroleukemic HEL cells abrogated apoptosis induced by ET-18-OCH₃. ET-18-OCH₃ did not affect the expression of bcl-2, bcl-x_L, or bax in HEL and HL-60 human leukemic cells but induced expression of c-myc, an important effector of apoptosis in several systems. Thus, ET-18-OCH₃ behaves as a potent and highly selective antitumor drug able to induce an apoptotic pathway of cell death in tumor cells but not in nonmalignant cells.

¹ This work was supported in part by Grant FIS96/1434 from Fondo de Investigación Sanitaria, Grant VA71/96 from Junta de Castilla y León, Grant SAF96/0274 from Comision Interministerial de Ciencia y Tecnología, Grant PB95/0713 from Dirección General de Ciencia y Tecnología, and Grants 168A and AI-40/96 from Acciones Integradas Hispano-Alemanas. C. G. is a recipient of a fellowship from "Fondo de Investigación Sanitaria."

² To whom requests for reprints should be addressed. Phone: 34-83-423062; Fax: 34-83-423588.

Received 10/ 9/96. Accepted 2/ 2/97.

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