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) (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.
Krejsa
C M
CM
Department of Environmental Health, University of Washington, Seattle, Washington 98195 and Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
Nadler
S G
SG
Esselstyn
J M
JM
Kavanagh
T J
TJ
Ledbetter
J A
JA
Schieven
G L
GL
D000975:Antioxidants / Q000494:pharmacology; D001402:B-Lymphocytes / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins; D017493:Leukocyte Common Antigens / Q000187:drug effects; D008214:Lymphocytes / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D009942:Organometallic Compounds / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010618:Phenanthrolines / Q000494:pharmacology*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology; D014638:Vanadates / Q000494:pharmacology
D000975:Antioxidants; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D009942:Organometallic Compounds; D010618:Phenanthrolines; D011753:Pyrones; C105611:oxodiperoxo(1,10-phenanthroline)vanadate(V); D000072000:NF-KappaB Inhibitor alpha; C074212:bis(maltolato)oxovanadium(IV); D014638:Vanadates; D011505:Protein-Tyrosine Kinases; D017493:Leukocyte Common Antigens; D017027:Protein Tyrosine Phosphatases; C025205:1,10-phenanthroline