NF-kappa B transcription factor activation by hydrogen peroxide can be decreased by 2,3-dihydroxybenzoic acid and its...

Reactive oxygen species like hydrogen peroxide (H2O2) have been shown to serve as messengers in the induction of NF-kappa B and, hence, in the activation and replication of human immunodeficiency virus type 1 (HIV-1) in human cells. Several antioxidant compounds and iron chelators have been shown to interfere with both NF-kappa B and HIV-1 activation under oxidative stress. Because 2,3-dihydroxybenzoic acid (DHB) and its ethyl ester derivative (DHB-EE) are potent oral iron chelators, we started to investigate their effects on monocytes treated with increasing H2O2 concentrations. These two compounds exert important protective effects against the cytotoxic effect of H2O2 as 300 microM DHB or DHB-EE increased cell survival from 30 to 85%. The treatment of monocytes with increasing amounts of H2O2 (from 0 to 3 mM) leads to the nuclear induction of NF-kappa B which is dose dependently inhibited by both DHB and DHB-EE. Addition of ferric ions to DHB only partially restores the NF-kappa B induction by H2O2, while this effect is almost completely restored by ferric ion addition to DHB-EE. Using spin trapping coupled to electron spin resonance, we have demonstrated that DHB and, to a lesser extent, DHB-EE trapped hydroxyl radicals produced by H2O2 photolysis. These data demonstrate that small aromatic molecules harboring both iron-chelating and antioxidant properties like DHB and DHB-EE can effectively interfere with the deleterious effects of H2O2 in monocytes where iron overload can be observed in HIV-1-infected patients.