Caffeic Acid Phenethyl Ester and Curcumin: A Novel Class of Heme Oxygenase-1 Inducers

Abstract

Heme oxygenase-1 (HO-1) is a redox-sensitive inducible protein that provides efficient cytoprotection against oxidative stress. Curcumin, a polyphenolic natural compound that possesses anti-tumor and anti-inflammatory properties, has been reported recently to induce potently HO-1 expression in vascular endothelial cells (Free Rad Biol Med 28:1303-1312. Here, we extend our previous findings by showing that caffeic acid phenethyl ester (CAPE), another plant-derived phenolic agent, markedly increases heme oxygenase activity and HO-1 protein in astrocytes. The effect seems to be related to the peculiar chemical structures of curcumin and CAPE, because analogous antioxidants containing only portions of these two molecules were totally ineffective. At a final concentration of 30 M, both curcumin and CAPE maximally up-regulated heme oxygenase activity while promoting marked cytotoxicity at higher concentrations (50 -100 M). Similar results were obtained with Curcumin-95, a mixture of curcuminoids commonly used as a dietary supplement. Incubation of astrocytes with curcumin or CAPE at concentrations that promoted maximal heme oxygenase activity resulted in an early increase in reduced glutathione followed by a significant elevation in oxidized glutathione contents. A curcumin-mediated increase in heme oxygenase activity was not affected by the glutathione precursor and thiol donor N-acetyl-L-cysteine. These data suggest that regulation of HO-1 expression by polyphenolic compounds is evoked by a distinctive mechanism which is not necessarily linked to changes in glutathione but might depend on redox signals sustained by specific and targeted sulfydryl groups. This study identifies a novel class of natural substances that could be used for therapeutic purposes as potent inducers of HO-1 in the protection of tissues against inflammatory and neurodegenerative conditions. Heme oxygenase-1 (HO-1) is a ubiquitous and redox-sensitive inducible stress protein (Motterlini et al., 2002). In mammals, the crucial participation of HO-1 gene expression in alleviating organ dysfunction and counteracting metabolic disorders is supported by consistent reports showing a protective role for the products of the enzymatic activity of HO-1. Heme serves as a substrate for HO-1 in the formation of carbon monoxide, free ferrous iron, and biliverdin; the latter is rapidly converted to bilirubin by biliverdin reductase (Choi and Alam, 1996;. A substantial body of evidence demonstrates that increased carbon monoxide and bilirubin effectively contribute to modulate important physiological processes within the cardiovascular, immune, and nervous systems. These include the regulation of vessel tone (Motterlini et al., 1998), inhibition of platelet aggregation (Durante and Schafer, 1998), and prevention of cell death and tissue injury (Clark et al., 2000b). The overall concept emerging from these and other studies is that the induction of HO-1 is an essential step in the cellular adaptation to stress inflicted by pathological events.Apart from ...

Phenolic acids from malt are efficient acetylcholinesterase and butyrylcholinesterase inhibitors

“…Rosmarinic acid, resveratrol and o-and p-coumaric acids (5-100 mM L À1 ) were not able to activate the HO-1 enzyme; on the contrary, some of the mentioned compounds decreased HO-1 activity at the concentrations tested. Unlike them, ethyl ferulate, when applied at low (15 and 5 mM L À1 ), but not high, concentrations effectively induced HO-1 activity and mRNA expression in astrocytes as well as protein expression in astrocytes (in cell cultures) after 6 h of incubation (70).…”

“…Scapagnini et al (70), for instance, showed that caffeic acid phenethyl ester significantly increased the expression of heme oxygenase-1 (HO-1) in astrocytes in cell cultures at low (15-50 mM L À1 ) but not at high concentrations (up to 100 mM L À1 ). The induction of the enzyme was accompanied by an early increase in the levels of reduced gluthatione followed by an elevation in the content of the oxidized form of gluthatione.…”

Comparative effects of curcuminoids on endothelial heme oxygenase-1 expression: ortho-methoxy groups are essential to enhance heme oxygenase activity and protection

“…It has been reported that curcumin protects endothelial cells against oxidative injury (Motterlini et al, 2000;Scapagnini et al, 2002;Foresti et al, 2005). We therefore examined whether DMC and BDMC could also be cytoprotective against oxidative injury in endothelial cells.…”

“…Previous studies have shown that endothelial HO-1 provides cytoprotection against oxidative injury (Motterlini et al, 2000;Scapagnini et al, 2002;Foresti et al, 2005). Thus, we tested whether curcuminoid-induced HO-1 expression could facilitate cytoprotective effect.…”

“…Their chemical structures are illustrated in Figure 1. Ongoing experimental and clinical studies suggest that curcumin and its curcuminoids exhibit unique cytoprotective (Scapagnini et al, 2002), antiinflammatory (Selvam et al, 2005) and anticancer properties . In recent years, it has also been reported that curcumin acts as a non-stressful and non-cytotoxic inducer of the cytoprotective heme oxygenase (HO)-1 and can maximize the intrinsic antioxidant potential of cells (Motterlini et al, 2000).…”