Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B.

Abstract

Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have antimitogenic, anticarcinogenic, antiinflammatory, and immunomodulatory properties. The molecular basis for these diverse properties is not known. Since the role of the nuclear factor NF-cB in these responses has been documented, we examined the effect of CAPE on this transcription factor. Our results show that the activation of NF-KcB by tumor necrosis factor (TNF) is completely blocked by CAPE in a dose-and time-dependent manner. Besides TNF, CAPE also inhibited NF-cB activation induced by other inflammatory agents including phorbol ester, ceramide, hydrogen peroxide, and okadaic acid. Since the reducing agents reversed the inhibitory effect of CAPE, it suggests the role of critical sulfhydryl groups in NF-KcB activation. CAPE prevented the translocation of the p65 subunit of NF-cB to the nucleus and had no significant effect on TNF-induced IKcBa degradation, but did delay IucBa resynthesis. The effect of CAPE on inhibition of NF-cB binding to the DNA was specific, in as much as binding of other transcription factors including AP-1, Oct-i, and TFIID to their DNA were not affected. When various synthetic structural analogues of CAPE were examined, it was found that a bicyclic, rotationally constrained, 5,6-dihydroxy form was superactive, whereas 6,7-dihydroxy variant was least active. Thus, overall our results demonstrate that CAPE is a potent and a specific inhibitor of NF-KcB activation and this may provide the molecular basis for its multiple immunomodulatory and antiinflammatory activities.

Differential susceptibility to TRAIL of normal versus malignant human urothelial cells

“…Caffeic acid phenethyl ester (CAPE) has been shown to inhibit translocation of NF-kB. 31 To confirm the efficacy of CAPE in our system, we showed that pre-treatment of 253J cells with CAPE alone or with a combination of CAPE and TRAIL abrogated translocation of the p50 and p65 nuclear factor (NF)-kB subunits to the nucleus (Supplementary Figure 2). SB202190 specifically inhibits the activity of p38 MAPK by competing for the ATP-binding sites of the a and b isoforms.…”

Caesalpinia sappan extract inhibits IL1β-mediated overexpression of matrix metalloproteinases in human chondrocytes

“…We show here that, indeed, NF-kB p65/p50 overexpression leads to MMP-13 promoter transactivation and that CSE suppresses the p65/p50-driven MMP-13 promoter activation, thereby suggesting that CSE's MMP-inhibitory actions are related to its blockade of the NF-kB signaling. Furthermore, the comparison to CAPE, a chemically defined specific inhibitor of NF-kB (Natarajan et al 1996), revealed that CSE was only about 4 times less active in our assay. Our results go along with previous reports demonstrating that CSE and its constituents interfere with NF-kB signaling in different cell types.…”

Inhibitors of NF-κB signaling: 785 and counting

“…In addition, inhibitors of mitochondrial electron transport that suppress ROI production (like rotenone) or overexpression of antioxidizing enzymes, such as MnSOD and catalase, can block TNFa-induced activation of NF-kB (Schulze-Osthoff et al, 1993;Manna et al, 1998Manna et al, , 1999. Caffeic acid phenethyl ester, a phenolic antioxidant and a structural relative of flavonoids, may directly interfere with DNA binding by NF-kB (Natarajan et al, 1996), and this effect on DNA binding can be reversed by reducing agents like dithiothreitol . Therefore, all antioxidants probably do not act at the same level to inhibit NF-kB.…”