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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(L).
Cancer Res. 1997 Apr 01; 57(7):1320-8.CR

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+Show Affiliations

Instituto de Biología y Genética Molecular, Facultad de Medicina, CSIC-Universidad de Valladolid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9102220

Citation

Mollinedo, F, et al. "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)." Cancer Research, vol. 57, no. 7, 1997, pp. 1320-8.
Mollinedo F, Fernández-Luna JL, Gajate C, et al. 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). Cancer Res. 1997;57(7):1320-8.
Mollinedo, F., Fernández-Luna, J. L., Gajate, C., Martín-Martín, B., Benito, A., Martínez-Dalmau, R., & Modolell, M. (1997). 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). Cancer Research, 57(7), 1320-8.
Mollinedo F, et al. 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). Cancer Res. 1997 Apr 1;57(7):1320-8. PubMed PMID: 9102220.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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). AU - Mollinedo,F, AU - Fernández-Luna,J L, AU - Gajate,C, AU - Martín-Martín,B, AU - Benito,A, AU - Martínez-Dalmau,R, AU - Modolell,M, PY - 1997/4/1/pubmed PY - 1997/4/1/medline PY - 1997/4/1/entrez SP - 1320 EP - 8 JF - Cancer research JO - Cancer Res VL - 57 IS - 7 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/9102220/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__ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9102220 DB - PRIME DP - Unbound Medicine ER -