[Mode of action and molecular target of ECH, a specific inhibitor of death receptor-dependent apoptosis].
ECH (epoxycyclohexenone) specifically blocks death receptor-mediated apoptosis induced by anti-Fas antibody, Fas ligand, or TNF-alpha, whereas it has no effect on death receptor independent apoptosis induced by staurosporine, MG-132, C2-ceramide, or UV irradiation. ECH blocks the activation of pro-caspase-8 in the death-inducing signaling complex (DISC), even though recruitment of FADD and pro-caspase-8 is not affected. In Fas ligand treated cells, ECH is only able to inhibit the activation of pro-caspase-8 and it has no effect on the already-activated caspase-8. ECH has a relatively higher affinity to pro-caspase-8, although it directly binds both pro- and active-form of caspase-8. In conclusion, ECH targets pro-caspase-8 and blocks the self-activation of pro-caspase-8 in the DISC, and thus selectively inhibits death receptor-mediated apoptosis. Moreover novel non-peptide inhibitors, RKTS-33 & RKTS-34 that are chemically synthesized derivatives of ECH have been developed.
Antibiotic Laboratory, Discovery Research Institute, RIKEN.
Yasunobu
Y
Miyake
Hideaki
H
Kakeya
Hiroyuki
H
Osada
D017209:Apoptosis / Q000187:drug effects*; D003512:Cyclohexanones / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods*; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D003512:Cyclohexanones; D004852:Epoxy Compounds; D014409:Tumor Necrosis Factor-alpha; C036468:cyclohexanone