ROLE OF OXIDATIVE STRESS IN THE ACTION OF VANADIUM PHOSPHOTYROSINE PHOSPHATASE INHIBITORS - REDOX INDEPENDENT ACTIVATION OF NF-KAPPA-B

The role of intracellular oxidative stress in the mechanism of action of phosphotyrosine phosphatase (PTP) inhibitors was studied using thre e vanadium-based compounds, Sodium orthovanadate (Na3VO4), sodium oxod iperoxo(1,10-phenanthroline)vanadate(V) (pV(phen), and bis(maltolato) oxovanadium(IV) (BMOV) differentially induced oxidative stress in lymp hocytes, Treatment with pV(phen), which caused intracellular oxidation , induced strong protein tyrosine phosphorylation compared with Na3VO4 and BMOV, Syk family kinases and the mitogen-activated protein kinase erk2 were rapidly activated by pV(phen) but not by BMOV or Na3VO4. In contrast, both BMOV and pV(phen) strongly activated NF-kappa B. The a ntioxidant pyrrolidine dithiocarbamate (PDTC) greatly diminished the i ntracellular oxidation and protein phosphotyrosine accumulation induce d by pV(phen), Pretreatment of cells with PDTC reduced and delayed the activation of Syk kinases and erk2, However, NF-kappa B activation by pV(phen) was markedly enhanced in lymphocytes pretreated with PDTC, a nd another antioxidant, N-acetylcysteine, did not prevent the activati on of NF-kappa B by BMOV, These results indicate a role for oxidative stress in the biological effects of some PTP inhibitors, whereas NF-ka ppa B activation by PTP inhibitors is mediated by mechanisms independe nt of intracellular redox status.