Increased potency of vanadium using organic ligands

McNeill, John H.; Yuen, Violet G.; Dai, Soter; Orvig, Chris

doi:10.1007/bf01075935

Cited by 82 publications

(36 citation statements)

References 41 publications

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“…The specificity of vanadium compounds for different PTPs may be amenable to modification by alteration of ligands (92,93). This study now demonstrates that the relative potency of vanadium may be regulated by intracellular redox state such that increased efficacy may be achieved in tissues under oxidative stress.…”

Section: Discussionmentioning

confidence: 91%

Enhanced Sensitivity of Insulin-resistant Adipocytes to Vanadate Is Associated with Oxidative Stress and Decreased Reduction of Vanadate (+5) to Vanadyl (+4)

Ennis²,

Lai

et al. 2001

Journal of Biological Chemistry

104

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Vanadate (sodium orthovanadate), an inhibitor of phosphotyrosine phosphatases (PTPs), mimics many of the metabolic actions of insulin in vitro and in vivo. The potential of vanadate to stimulate glucose transport independent of the early steps in insulin signaling prompted us to test its effectiveness in an in vitro model of insulin resistance. In primary rat adipocytes cultured for 18 h in the presence of high glucose (15 mM) and insulin (10 ؊7 M), sensitivity to insulin-stimulated glucose transport was decreased. In contrast, there was a paradoxical enhanced sensitivity to vanadate of the insulinresistant cells (EC 50 for control, 325 ؎ 7.5 M; EC 50 for insulin-resistant, 171 ؎ 32 M; p < 0.002). Enhanced sensitivity was also present for vanadate stimulation of insulin receptor kinase activity and autophosphorylation and Akt/protein kinase B Ser-473 phosphorylation consistent with more effective PTP inhibition in the resistant cells. Investigation of this phenomenon revealed that 1) depletion of GSH with buthionine sulfoximine reproduced the enhanced sensitivity to vanadate while preincubation of resistant cells with N-acetylcysteine (NAC) prevented it, 2) intracellular GSH was decreased in resistant cells and normalized by NAC, 3) exposure to high glucose and insulin induced an increase in reactive oxygen species, which was prevented by NAC, 4) EPR (electron paramagnetic resonance) spectroscopy showed a decreased amount of vanadyl (؉4) in resistant and buthionine sulfoximine-treated cells, which correlated with decreased GSH and increased vanadate sensitivity, while total vanadium uptake was not altered, and 5) inhibition of recombinant PTP1B in vitro was more sensitive to vanadate (؉5) than vanadyl (؉4). In conclusion, the parodoxical increased sensitivity to vanadate in hyperglycemia-induced insulin resistant adipocytes is due to oxidative stress and decreased reduction of vanadate (؉5) to vanadyl (؉4). Thus, sensitivity of PTP inhibition and glucose transport to vanadate is regulated by cellular redox state.

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Section: Discussionmentioning

confidence: 91%

Enhanced Sensitivity of Insulin-resistant Adipocytes to Vanadate Is Associated with Oxidative Stress and Decreased Reduction of Vanadate (+5) to Vanadyl (+4)

Ennis²,

Lai

et al. 2001

Journal of Biological Chemistry

104

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“…1A) provides the opportunity to more fully characterize the action of peroxovanadium within the cell. The action of vanadium can also be modified by organic ligands that facilitate cellular targeting and biochemical specificity (20,21); for example, we found that BMOV (Fig. 1B) induced apoptosis in B cell lineages but enhanced the activation of T cell lineages (15).…”

mentioning

confidence: 96%

Role of Oxidative Stress in the Action of Vanadium Phosphotyrosine Phosphatase Inhibitors

Krejsa

Nadler

Esselstyn

et al. 1997

Journal of Biological Chemistry

140

105

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The role of intracellular oxidative stress in the mechanism of action of phosphotyrosine phosphatase (PTP) inhibitors was studied using three vanadiumbased compounds. Sodium orthovanadate (Na 3 VO 4 ), 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 Na 3 VO 4 and BMOV. Syk family kinases and the mitogen-activated protein kinase erk2 were rapidly activated by pV(phen) but not by BMOV or Na 3 VO 4 . In contrast, both BMOV and pV(phen) strongly activated NF-B. 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-B activation by pV(phen) was markedly enhanced in lymphocytes pretreated with PDTC, and another antioxidant, N-acetylcysteine, did not prevent the activation of NF-B by BMOV. These results indicate a role for oxidative stress in the biological effects of some PTP inhibitors, whereas NF-B activation by PTP inhibitors is mediated by mechanisms independent of intracellular redox status.Lymphocyte signal transduction requires the activation of protein tyrosine kinases (PTKs), 1 with subsequent assembly of signaling complexes, generation of second messengers, activation of transcription factors, and gene expression (1, 2). The balance of protein tyrosine phosphorylation within the cell is controlled by the relative activities of the PTKs and PTPs in the signaling network (3). Besides dephosphorylating a variety of PTK substrates, PTPs have been shown to directly modulate the activities of PTKs (4, 5). Thus PTPs serve a crucial function in lymphocytes by controlling both the initiation and termination of receptor-based signals.The inhibition of PTPs reveals PTK substrates on which phosphotyrosine accumulates in the absence of receptor engagement (6). Some of these substrates are key phosphoproteins in lymphocyte signal transduction pathways, suggesting that PTKs involved in transmission of receptor signals are activated by the absence of PTP regulation (6 -9). However, many of the PTP inhibitors used thus far to explore lymphocyte signal transduction pathways are redox-active compounds. For example, phenylarsine oxide, a thiol-reactive compound, and H 2 O 2 , which generates hydroxyl radicals, both act as potent PTP inhibitors (6, 10). The role of intracellular oxidation in the mechanism of action of PTP inhibitors is unknown, a question this study addresses.Vanadium-based PTP inhibitors, which have been extensively studied as insulin mimetic agents, stimulate glucose uptake and fatty acid synthesis in adipocytes and mimic receptor-based signals in lymphocytes (11-15). The widely used PTP inhibitor pervanadate is a peroxovanadium compound generated by reaction of H 2 O 2 wi...

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“…In recent decades, some vanadyl complexes with several types of organic ligands have been proposed by many research groups for clinical use in humans. [28][29][30][31][32][33][34] To evaluate the insulin-mimetic vanadyl complexes, glucose-uptake in cells or tissues has been monitored, which requires radioisotope (RI) reagents. 5,6,27) In 1995, we proposed a new in vitro assay, based on the inhibition of FFA (free fatty acids)-release from isolated rat adipocytes treated with epinephrine (adrenalin), which is simple and convenient compared with the use of RI reagents.…”

mentioning

confidence: 99%

Insulin-Mimetic Vanadyl(IV) Complexes as Evaluated by Both Glucose-Uptake and Inhibition of Free Fatty Acids (FFA)-Release in Isolated Rat Adipocytes

Adachi

Sakurai

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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We have recently proposed the existence of some potent vanadyl complexes with blood glucose-lowering activity in experimental diabetic animals based on the results of an in vitro FFA (free fatty acids)-release assay in isolated rat adipocytes treated with epinephrine and evidence of an in vivo blood glucose lowering effect in experimental diabetic animals. However, the FFA assay depends indirectly on the glucose-uptake of vanadyl complexes in adipocytes. It is therefore necessary to develop a more reliable in vitro glucose-uptake assay, in place of the glucose uptake method using radioactive compounds such as 14 C-glucose, to identify insulin-mimetic vanadyl complexes. In the present study, we proposed a combined in vitro assay by using the conventional glucose oxidase method for glucose-uptake and FFA assay in isolated rat adipocytes. Insulin, vanadyl sulfate (VOSO 4 ), bis(picolinato)vanadyl (VO(pa) 2 ), and bis(6-methylpicolinato)vanadyl (VO(6mpa) 2 ) complexes exhibited concentration-dependent uptake of (؉)-D-glucose and inhibition of FFA release in the adipocytes treated with epinephrine. Vanadyl complexes were found to accelerate glucose-uptake at lower concentrations than VOSO 4 . In vitro high insulin-mimetic activity of VO(pa) 2 and VO(6mpa) 2 were thus indicated by both glucose-uptake and FFA-release, with the insulin-mimetic activity of VO(6mpa) 2 being higher than that of VO(pa) 2 , as suggested by the partition coefficient (0.330 for VO(pa) 2 and 0.595 for VO(6mpa) 2 ). The proposed assay provides a more reliable method than each single method for the evaluation of in vitro insulin-mimetic activity of compounds.Key words vanadyl compound; glucose-uptake assay; free fatty acids (FFA)-release assay; insulin-mimetic effect; adipocyte 428

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Increased potency of vanadium using organic ligands

Cited by 82 publications

References 41 publications

Enhanced Sensitivity of Insulin-resistant Adipocytes to Vanadate Is Associated with Oxidative Stress and Decreased Reduction of Vanadate (+5) to Vanadyl (+4)

Enhanced Sensitivity of Insulin-resistant Adipocytes to Vanadate Is Associated with Oxidative Stress and Decreased Reduction of Vanadate (+5) to Vanadyl (+4)

Role of Oxidative Stress in the Action of Vanadium Phosphotyrosine Phosphatase Inhibitors

Insulin-Mimetic Vanadyl(IV) Complexes as Evaluated by Both Glucose-Uptake and Inhibition of Free Fatty Acids (FFA)-Release in Isolated Rat Adipocytes

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