INHIBITION OF NUCLEAR TRANSCRIPTION FACTOR NF-KB BY CAFFEIC ACID PHENETHYL ESTER (CAPE), DERIVATIVES OF CAPE, CAPSAICIN (8-METHYL-N-VANILLYL-6-NONENAMIDE) AND RESINIFERATOXIN

摘要

Nuclear Factor NF-.kappa.B is a protein specific to B cells, binds to aspecific DNA sequence within the immunoglobin light chain .kappa. locusenhancer region, and plays a central role in various responses, due to rapidinduction of gene expression. NF-.kappa.B controls the expressionof various inflammatory cytokines, the major histocompatibility complex genes,and adhesion molecules involved in tumor metastasis.The present invention is drawn to the inhibition of activation of NF-.kappa.Bby caffeic acid phenethyl ester (CAPE) and two analogues ofCAPE. Tumor necrosis factor (TNF) activation of NF-.kappa.B is completelyblocked by CAPE in a dose- and time-dependent manner, as isactivation by phorbol ester, ceramide, hydrogen peroxide, and okadaic acid.Additionally, capsaicin (8-methyl-N-vanillyl-6-nonenamide)and resiniferatoxin inhibit the activation of NF-.kappa.B induced by differentagents. Further, the present invention discloses methods for usingthese inhibitors in the treatment of pathological conditions caused by theactivation of NF-.kappa.B, such as toxic shock, acute inflammatoryconditions, acute phase response, atherosclerosis and cancer.