Liposomal ET-18-OCH3 induces cytochrome c-mediated apoptosis independentlyof 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-OCH3), is a nonmyelosuppressive antiprolife rative agent that is more effective and less toxic than the ether lipid its elf in tumor model systems. We found that ELL-12 induced apoptosis in Jurka t, H9, and U-937 cells that was preceded by activation of executioner caspa ses. In addition, ELL-12 triggered release of cytochrome c from mitochondri a to the cytoplasm before caspase-9 activation. Apoptosis, activation of ca spases, and cytochrome c release were blocked by Bcl-x(L) overexpression in Jurkat T cells, suggesting a critical role for mitochondria in ELL-12-trig gered cell death. Furthermore, ELL-12 had no effect on expression of CD95 l igand, and inhibition of the Fas signaling pathway with antagonistic anti-C D95 antibody did not affect apoptosis induced by ELL-12. Hence, ELL-12 coul d be a promising adjunct for the treatment of tumors in addition to myelosu ppressive chemotherapeutic drugs and/or those that use the CD95-ligand/rece ptor system to trigger apoptosis. (C) 1999 by The American Society of Hemat ology.