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Vol. 61, Issue 3, 554-561, March 2002
Department of Biochemistry (G.S., V.C., A.M.G.S.) and Department of
Experimental and Clinical Pharmacology (G.S.), Faculty of Medicine,
University of Catania, Catania, Italy; and Vascular Biology Unit,
Department of Surgical Research, Northwick Park Institute for Medical
Research, Harrow, Middlesex, United Kingdom (R.F., C.J.G., R.M.)
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, 2000). 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 µM, both
curcumin and CAPE maximally up-regulated heme oxygenase activity while
promoting marked cytotoxicity at higher concentrations (50-100 µM).
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.
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