Liposomal ET-18-OCH3 induces cytochrome c-mediated apoptosis independently of CD95 (APO-1/Fas) signaling
Liposomal ET-18-OCH3 induces cytochrome c-mediated apoptosis independently of CD95 (APO-1/Fas) signaling
复制标题
DOI：
10.1182/blood.v94.10.3583.422k31_3583_3592
复制
发表时间：
1999-11-15
期刊：
影响因子：
20.3
通讯作者：
Spiegel, S
中科院分区：
文献类型：
--
作者：
Cuvillier, O;Mayhew, E;Spiegel, S
EIL-12是乙醚-脂质1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine(ET-OCH_3)的脂质体制剂，在肿瘤模型系统中是一种非骨髓抑制抗增殖剂，比乙醚脂质本身更有效，毒性更低。我们发现ELL-12诱导Jurkat、H9和U-937细胞凋亡，在此之前激活执行半胱氨酸天冬氨酸酶。此外，ELL-12在caspase-9激活之前触发了细胞色素c从线粒体释放到细胞质。Bclx(L)过表达可抑制Jurkat T细胞的凋亡、caspase激活和细胞色素c的释放，提示线粒体在ELL-12诱导的细胞死亡中起关键作用。此外，ELL-12对CD95配体的表达没有影响，拮抗CD95抗体抑制Fas信号通路不影响ELL-12诱导的细胞凋亡。因此，除了骨髓抑制化疗药物和/或那些使用CD95配体/受体系统触发细胞凋亡的药物外，ELL-12可能是一种很有前途的肿瘤辅助治疗药物。(C)1999年由美国血液病学会主办。
ELL-12, a liposome formulation of the ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-OCH3), 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. (C) 1999 by The American Society of Hematology.