Caffeic Acid Phenethyl Ester Induces Leukocyte Apoptosis, Modulates Nuclear Factor-Kappa B and Suppresses Acute Inflammation

Abstract

Nuclear factor kappa-B (NF-κB) is a heterodimeric transcription factor with a pivotal role in orchestrating immune and inflammatory processes. Inflammatory cytokines and prostanoids activate NF-κB, which, in turn, stimulates expression of cytokines, proteases, adhesion molecules and other inflammatory mediators. Caffeic acid phenethyl ester (CAPE) is a compound that modulates nuclear binding of the NF-κB p65 subunit (RelA). To determine whether CAPE decreases the viability of cells participating in host defense, we first tested its in vitro effect on a glucocorticoid-sensitive and -resistant cell line of lymphoid origin. CAPE induced apoptotic cell death in a dose-dependent fashion and to a similar extent in both cell lines. Furthermore, a low concentration of CAPE decreased the LD₅₀ of dexamethasone by 3- to 5-fold. Since therapeutic induction of apoptosis of activated inflammatory cells holds the attraction of destroying effector cells safely without secondary tissue damage, we examined the effects of CAPE in a rat model of carrageenin-induced subcutaneous inflammation. Local administration of CAPE resulted in increased leukocyte apoptosis and marked reduction in exudate leukocyte, neutrophil and monocyte concentrations at the inflammatory site. CAPE decreased expression of cytosolic IκBα and increased nuclear translocation of p65. These findings may suggest that novel anti-inflammatory therapies can be based upon activation of NF-κB-mediated transcription of genes curbing the inflammatory response and that CAPE or its analogs hold therapeutic promise.

Rosmarinic Acid Induces p56lck-Dependent Apoptosis in Jurkat and Peripheral T Cells via Mitochondrial Pathway Independent from Fas/Fas Ligand Interaction

“…An Lck-dependent apoptosis was not observed in other polyphenolic compounds, such as curcumin, resveratrol, and CAPE (17,18,33), at the range of 12.5-30 M (Fig. 2D; data not shown).…”

Natural products as targeted modulators of the nuclear factor-κB pathway

“…Quercetin, also a protein tyrosine kinase inhibitor, and genistein inhibit TNF-a -induced NF-j B activation by halting the degradation of Ij B but not DNA binding of NF-j B (Natarajan et al 1998). Finally, caOE eic acid phenyl ester (CAPE) also inhibited NF-j B in U937 cells (87.5 l m ) induced with TNF-a , PMA, ceramide, okadaic acid or H 2 O 2 (Natarajan et al 1996), indicating that CAPE may be acting on a point where all these stimulation pathways merge in their activation of NF-j B. CAPE was also speci® c to NF-j B because the activation of transcription factors Ap-1, TFIID and Oct-1 were unaOE ected (see also Orban et al (2000) for a modulatory eOE ect of CAPE on apoptosis and NF-j B).…”

Caffeic acid phenethyl ester triggers apoptosis through induction of loss of mitochondrial membrane potential in CCRF-CEM cells

“…Statistical significance was determined using Student's t test, and P \ 0.05 was considered significant effects on normal healthy cells (Cassileth et al 2008;Engdal et al 2009). Recently, caffeic acid phenethyl ester (CAPE), obtained from honeybee propolis (Grunberger et al 1998), has attracted notice in that it represented antitumoral (Chiao et al 1995), anti-inflammatory (Michaluart et al 1999;Orban et al 2000), antiviral (Fesen et al 1994), antioxidant (Bhimani et al 1993), and anti-angiogenic (Liao et al 1999) effects. Although the ability of CAPE to induce apoptosis has been reported for various types of cancer, very little is known about the effects of CAPE on human CCRF-CEM cells (Michaluart et al 1999;Fesen et al 1994;Chiao et al 1995;Grunberger et al 1998;Orban et al 2000;Bhimani et al 1993;Liao et al 1999).…”