Liposomal ET-18-OCH(3) induces cytochrome c-mediated apoptosis independently of CD95 (APO-1/Fas) signaling.
ELL-12, a liposome formulation of the ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH(3)), is a nonmyelosuppressive antiproliferative agent that is more effective and less toxic than the ether lipid itself in tumor model systems. We found that ELL-12 induced apoptosis in Jurkat, H9, and U-937 cells that was preceded by activation of executioner caspases. In addition, ELL-12 triggered release of cytochrome c from mitochondria to the cytoplasm before caspase-9 activation. Apoptosis, activation of caspases, and cytochrome c release were blocked by Bcl-x(L) overexpression in Jurkat T cells, suggesting a critical role for mitochondria in ELL-12-triggered cell death. Furthermore, ELL-12 had no effect on expression of CD95 ligand, and inhibition of the Fas signaling pathway with antagonistic anti-CD95 antibody did not affect apoptosis induced by ELL-12. Hence, ELL-12 could be a promising adjunct for the treatment of tumors in addition to myelosuppressive chemotherapeutic drugs and/or those that use the CD95-ligand/receptor system to trigger apoptosis.
Cuvillier
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Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007, USA.
Mayhew
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Janoff
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Spiegel
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001692:Biological Transport; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism* / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D034882:Lamins; D008081:Liposomes; D008928:Mitochondria / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D020298:U937 Cells; D051020:bcl-X Protein; D019014:fas Receptor / Q000378:metabolism*
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D004337:Drug Carriers; D034882:Lamins; D008081:Liposomes; D009687:Nuclear Proteins; D010742:Phospholipid Ethers; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor; C026659:edelfosine; D010447:Peptide Hydrolases; D020169:Caspases; C108711:DEVDase