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Proc Natl Acad Sci U S A. Aug 20, 1996; 93(17): 9090–9095.
PMCID: PMC38600

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-kappa B in these responses has been documented, we examined the effect of CAPE on this transcription factor. Our results show that the activation of NF-kappa B by tumor necrosis factor (TNF) is completely blocked by CAPE in a dose- and time-dependent manner. Besides TNF, CAPE also inhibited NF-kappa B 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-kappa B activation. CAPE prevented the translocation of the p65 subunit of NF-kappa B to the nucleus and had no significant effect on TNF-induced I kappa B alpha degradation, but did delay I kappa B alpha resynthesis. The effect of CAPE on inhibition of NF-kappa B binding to the DNA was specific, in as much as binding of other transcription factors including AP-1, Oct-1, 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-kappa B activation and this may provide the molecular basis for its multiple immunomodulatory and antiinflammatory activities.

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  • Nolan GP, Baltimore D. The inhibitory ankyrin and activator Rel proteins. Curr Opin Genet Dev. 1992 Apr;2(2):211–220. [PubMed]
  • Liou HC, Baltimore D. Regulation of the NF-kappa B/rel transcription factor and I kappa B inhibitor system. Curr Opin Cell Biol. 1993 Jun;5(3):477–487. [PubMed]
  • Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. [PubMed]
  • Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405–455. [PubMed]
  • Baeuerle PA. The inducible transcription activator NF-kappa B: regulation by distinct protein subunits. Biochim Biophys Acta. 1991 Apr 16;1072(1):63–80. [PubMed]
  • Grilli M, Chiu JJ, Lenardo MJ. NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. Int Rev Cytol. 1993;143:1–62. [PubMed]
  • Grunberger D, Banerjee R, Eisinger K, Oltz EM, Efros L, Caldwell M, Estevez V, Nakanishi K. Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia. 1988 Mar 15;44(3):230–232. [PubMed]
  • Burke TR, Jr, Fesen MR, Mazumder A, Wang J, Carothers AM, Grunberger D, Driscoll J, Kohn K, Pommier Y. Hydroxylated aromatic inhibitors of HIV-1 integrase. J Med Chem. 1995 Oct 13;38(21):4171–4178. [PubMed]
  • Su ZZ, Lin J, Grunberger D, Fisher PB. Growth suppression and toxicity induced by caffeic acid phenethyl ester (CAPE) in type 5 adenovirus-transformed rat embryo cells correlate directly with transformation progression. Cancer Res. 1994 Apr 1;54(7):1865–1870. [PubMed]
  • Su ZZ, Grunberger D, Fisher PB. Suppression of adenovirus type 5 E1A-mediated transformation and expression of the transformed phenotype by caffeic acid phenethyl ester (CAPE). Mol Carcinog. 1991;4(3):231–242. [PubMed]
  • Hladoń B, Bylka W, Ellnain-Wojtaszek M, Skrzypczak L, Szafarek P, Chodera A, Kowalewski Z. In vitro studies on the cytostatic activity of propolis extracts. Arzneimittelforschung. 1980;30(11):1847–1848. [PubMed]
  • Guarini L, Su ZZ, Zucker S, Lin J, Grunberger D, Fisher PB. Growth inhibition and modulation of antigenic phenotype in human melanoma and glioblastoma multiforme cells by caffeic acid phenethyl ester (CAPE) Cell Mol Biol. 1992 Aug;38(5):513–527. [PubMed]
  • Chiao C, Carothers AM, Grunberger D, Solomon G, Preston GA, Barrett JC. Apoptosis and altered redox state induced by caffeic acid phenethyl ester (CAPE) in transformed rat fibroblast cells. Cancer Res. 1995 Aug 15;55(16):3576–3583. [PubMed]
  • Laranjinha J, Vieira O, Madeira V, Almeida L. Two related phenolic antioxidants with opposite effects on vitamin E content in low density lipoproteins oxidized by ferrylmyoglobin: consumption vs regeneration. Arch Biochem Biophys. 1995 Nov 10;323(2):373–381. [PubMed]
  • Kimura Y, Okuda H, Okuda T, Hatano T, Agata I, Arichi S. Studies on the activities of tannins and related compounds from medicinal plants and drugs. VII. Effects of extracts of leaves of Artemisia species, and caffeic acid and chlorogenic acid on lipid metabolic injury in rats fed peroxidized oil. Chem Pharm Bull (Tokyo) 1985 May;33(5):2028–2034. [PubMed]
  • Rao CV, Desai D, Kaul B, Amin S, Reddy BS. Effect of caffeic acid esters on carcinogen-induced mutagenicity and human colon adenocarcinoma cell growth. Chem Biol Interact. 1992 Nov 16;84(3):277–290. [PubMed]
  • Rao CV, Desai D, Simi B, Kulkarni N, Amin S, Reddy BS. Inhibitory effect of caffeic acid esters on azoxymethane-induced biochemical changes and aberrant crypt foci formation in rat colon. Cancer Res. 1993 Sep 15;53(18):4182–4188. [PubMed]
  • Zheng ZS, Xue GZ, Grunberger D, Prystowsky JH. Caffeic acid phenethyl ester inhibits proliferation of human keratinocytes and interferes with the EGF regulation of ornithine decarboxylase. Oncol Res. 1995;7(9):445–452. [PubMed]
  • Sud'ina GF, Mirzoeva OK, Pushkareva MA, Korshunova GA, Sumbatyan NV, Varfolomeev SD. Caffeic acid phenethyl ester as a lipoxygenase inhibitor with antioxidant properties. FEBS Lett. 1993 Aug 23;329(1-2):21–24. [PubMed]
  • Bhimani RS, Troll W, Grunberger D, Frenkel K. Inhibition of oxidative stress in HeLa cells by chemopreventive agents. Cancer Res. 1993 Oct 1;53(19):4528–4533. [PubMed]
  • Frenkel K, Wei H, Bhimani R, Ye J, Zadunaisky JA, Huang MT, Ferraro T, Conney AH, Grunberger D. Inhibition of tumor promoter-mediated processes in mouse skin and bovine lens by caffeic acid phenethyl ester. Cancer Res. 1993 Mar 15;53(6):1255–1261. [PubMed]
  • Chaturvedi MM, LaPushin R, Aggarwal BB. Tumor necrosis factor and lymphotoxin. Qualitative and quantitative differences in the mediation of early and late cellular response. J Biol Chem. 1994 May 20;269(20):14575–14583. [PubMed]
  • Schreiber E, Matthias P, Müller MM, Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. [PMC free article] [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Nabel G, Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. [PubMed]
  • Collart MA, Baeuerle P, Vassalli P. Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B. Mol Cell Biol. 1990 Apr;10(4):1498–1506. [PMC free article] [PubMed]
  • Hassanain HH, Dai W, Gupta SL. Enhanced gel mobility shift assay for DNA-binding factors. Anal Biochem. 1993 Aug 15;213(1):162–167. [PubMed]
  • Singh H, LeBowitz JH, Baldwin AS, Jr, Sharp PA. Molecular cloning of an enhancer binding protein: isolation by screening of an expression library with a recognition site DNA. Cell. 1988 Feb 12;52(3):415–423. [PubMed]
  • Singh S, Aggarwal BB. Protein-tyrosine phosphatase inhibitors block tumor necrosis factor-dependent activation of the nuclear transcription factor NF-kappa B. J Biol Chem. 1995 May 5;270(18):10631–10639. [PubMed]
  • Reddy SA, Chaturvedi MM, Darnay BG, Chan H, Higuchi M, Aggarwal BB. Reconstitution of nuclear factor kappa B activation induced by tumor necrosis factor requires membrane-associated components. Comparison with pathway activated by ceramide. J Biol Chem. 1994 Oct 14;269(41):25369–25372. [PubMed]
  • Meyer M, Schreck R, Baeuerle PA. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J. 1993 May;12(5):2005–2015. [PMC free article] [PubMed]
  • Finco TS, Beg AA, Baldwin AS., Jr Inducible phosphorylation of I kappa B alpha is not sufficient for its dissociation from NF-kappa B and is inhibited by protease inhibitors. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11884–11888. [PMC free article] [PubMed]
  • Mahon TM, O'Neill LA. Studies into the effect of the tyrosine kinase inhibitor herbimycin A on NF-kappa B activation in T lymphocytes. Evidence for covalent modification of the p50 subunit. J Biol Chem. 1995 Dec 1;270(48):28557–28564. [PubMed]
  • Thanos D, Maniatis T. NF-kappa B: a lesson in family values. Cell. 1995 Feb 24;80(4):529–532. [PubMed]
  • Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev. 1995 Nov 15;9(22):2723–2735. [PubMed]
  • Eicher DM, Tan TH, Rice NR, O'Shea JJ, Kennedy IC. Expression of v-src in T cells correlates with nuclear expression of NF-kappa B. J Immunol. 1994 Mar 15;152(6):2710–2719. [PubMed]
  • Schreck R, Meier B, Männel DN, Dröge W, Baeuerle PA. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med. 1992 May 1;175(5):1181–1194. [PMC free article] [PubMed]
  • Schulze-Osthoff K, Beyaert R, Vandevoorde V, Haegeman G, Fiers W. Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF. EMBO J. 1993 Aug;12(8):3095–3104. [PMC free article] [PubMed]
  • Staal FJ, Roederer M, Herzenberg LA, Herzenberg LA. Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9943–9947. [PMC free article] [PubMed]
  • Schütze S, Potthoff K, Machleidt T, Berkovic D, Wiegmann K, Krönke M. TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced "acidic" sphingomyelin breakdown. Cell. 1992 Nov 27;71(5):765–776. [PubMed]
  • Mathias S, Dressler KA, Kolesnick RN. Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10009–10013. [PMC free article] [PubMed]
  • Yang Z, Costanzo M, Golde DW, Kolesnick RN. Tumor necrosis factor activation of the sphingomyelin pathway signals nuclear factor kappa B translocation in intact HL-60 cells. J Biol Chem. 1993 Sep 25;268(27):20520–20523. [PubMed]
  • Meichle A, Schütze S, Hensel G, Brunsing D, Krönke M. Protein kinase C-independent activation of nuclear factor kappa B by tumor necrosis factor. J Biol Chem. 1990 May 15;265(14):8339–8343. [PubMed]
  • Fesen MR, Kohn KW, Leteurtre F, Pommier Y. Inhibitors of human immunodeficiency virus integrase. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2399–2403. [PMC free article] [PubMed]

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