NF-KAPPA-B TRANSCRIPTION FACTOR ACTIVATION BY HYDROGEN-PEROXIDE CAN BE DECREASED BY 2,3-DIHYDROXYBENZOIC ACID AND ITS ETHYL-ESTER DERIVATIVE

Reactive oxygen species like hydrogen peroxide (H2O2) have been shown to serve as messengers in the induction of NF-kappa B and, hence, in t he activation and replication of human immunodeficiency virus type 1 ( HIV-1) in human cells, Several antioxidant compounds and iron chelator s have been shown to interfere with both NF-kappa B and HIV-1 activati on under oxidative stress, Because 2,3-dihydroxybenzoic acid (DHB) and its ethyl ester derivative (DHB-EE) are potent oral iron chelators, w e started to investigate their effects on monocytes treated with incre asing H2O2 concentrations, These two compounds exert important protect ive effects against the cytotoxic effect of H2O2 as 300 mu M DHB or DH B-EE increased cell survival from 30 to 85%, The treatment of monocyte s with increasing amounts of H2O2 (from 0 to 3 mM) leads to the nuclea r 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 complet ely restored by ferric ion addition to DHE-EE, Using spin trapping cou pled to electron spin resonance, we have demonstrated that DHB and, to a lesser extent, DHB-EE trapped hydroxyl radicals produced by H2O2 ph otolysis, These data demonstrate that small aromatic molecules harbori ng both iron-chelating and antioxidant properties like DHB and DHB-EE can effectively interfere with the deleterious effects of H2O2 in mono cytes where iron overload can be observed in HIV-1-infected patients. (C) 1995 Academic Press, Inc.