Role of oxidative stress in the action of vanadium phosphotyrosine phosphatase inhibitors. Redox independent activation of NF-kappaB

The role of intracellular oxidative stress in the mechanism of action of phosphotyrosine phosphatase (PTP) inhibitors was studied using three vanadium-based compounds. Sodium orthovanadate (Na3VO4), sodium oxodiperoxo(1,10-phenanthroline)vanadate(V) (pV(phen), and bis(maltolato)-oxovanadium(IV) (BMO...

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Bibliographic Details
Published in:The Journal of biological chemistry 1997-04, Vol.272 (17), p.11541
Main Authors: Krejsa, C M, Nadler, S G, Esselstyn, J M, Kavanagh, T J, Ledbetter, J A, Schieven, G L
Format: Article
Language:English
Subjects:
Antioxidants - pharmacology
B-Lymphocytes - physiology
Cell Line
DNA-Binding Proteins - metabolism
Enzyme Activation
Enzyme Inhibitors - pharmacology
Humans
I-kappa B Proteins
Leukocyte Common Antigens - drug effects
Lymphocytes - physiology
NF-KappaB Inhibitor alpha
Organometallic Compounds - pharmacology
Oxidation-Reduction
Oxidative Stress - physiology
Phenanthrolines - pharmacology
Phosphorylation
Protein Tyrosine Phosphatases - antagonists & inhibitors
Protein-Tyrosine Kinases - metabolism
Pyrones - pharmacology
Signal Transduction
T-Lymphocytes - physiology
Vanadates - pharmacology
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Summary:The role of intracellular oxidative stress in the mechanism of action of phosphotyrosine phosphatase (PTP) inhibitors was studied using three vanadium-based compounds. Sodium orthovanadate (Na3VO4), sodium oxodiperoxo(1,10-phenanthroline)vanadate(V) (pV(phen), and bis(maltolato)-oxovanadium(IV) (BMOV) differentially induced oxidative stress in lymphocytes. 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-kappaB. The antioxidant pyrrolidine dithiocarbamate (PDTC) greatly diminished the intracellular oxidation and protein phosphotyrosine accumulation induced by pV(phen). Pretreatment of cells with PDTC reduced and delayed the activation of Syk kinases and erk2. However, NF-kappaB activation by pV(phen) was markedly enhanced in lymphocytes pretreated with PDTC, and another antioxidant, N-acetylcysteine, did not prevent the activation of NF-kappaB by BMOV. These results indicate a role for oxidative stress in the biological effects of some PTP inhibitors, whereas NF-kappaB activation by PTP inhibitors is mediated by mechanisms independent of intracellular redox status.
ISSN:0021-9258