title: 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).
abstract: 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-xL 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-xL, 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.
authors.affiliation: Instituto de Biología y Genética Molecular, Facultad de Medicina, CSIC-Universidad de Valladolid, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Mollinedo
authors.forename: J L
authors.initials: JL
authors.lastname: Fernández-Luna
authors.forename: C
authors.initials: C
authors.lastname: Gajate
authors.forename: B
authors.initials: B
authors.lastname: Martín-Martín
authors.forename: A
authors.initials: A
authors.lastname: Benito
authors.forename: R
authors.initials: R
authors.lastname: Martínez-Dalmau
authors.forename: M
authors.initials: M
authors.lastname: Modolell
mesh_terms: D000418:Albumins / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015870:Gene Expression; D019254:Genes, bcl-2 / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010742:Phospholipid Ethers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
chemical_list: D000418:Albumins; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D051020:bcl-X Protein; C026659:edelfosine; D013498:Suramin