Ebselen-binding equilibria between plasma and target proteins

Ullrich, Volker; Weber, Peter; Meisch, F.; Appen, F. Von

doi:10.1016/0006-2952(96)00109-8

Cited by 45 publications

(34 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Considering the role of ebselen on A431 cell cycle, we observed that apoptosis was increased for both populations and this result is in agreement with ebselen-induced apoptosis in HepG2 cells. 48 Nevertheless, in response to ebselen treatment, differences were observed for G2-S and mitosis phases; in fact, for 2D cell population G2-S phase decreased and mitosis remained unchanged, while for 3D cells G2-S phase remained unchanged and mitosis increased. It is noteworthy from results obtained with DPI or ebselen that cellular organization may dramatically modulate cell response to effectors since in some case opposite results were obtained depending on the cellular model analyzed, monolayer (2D) or aggregate (3D).…”

Section: Inhibitors Of Ros-p38 Mapk Induced a Shift Toward 2d Structurementioning

confidence: 96%

“…The glutathione peroxidase mimic, ebselen, at concentrations about twice the therapeutic plasma levels, 48,49 which was shown to offer protective effect against H 2 O 2 -induced DNA damage, 50,51 resulted in a similar shift of 3D toward 2D populations. Considering the role of ebselen on A431 cell cycle, we observed that apoptosis was increased for both populations and this result is in agreement with ebselen-induced apoptosis in HepG2 cells.…”

Section: Inhibitors Of Ros-p38 Mapk Induced a Shift Toward 2d Structurementioning

confidence: 99%

See 1 more Smart Citation

Monolayer versus aggregate balance in survival process for EGF‐induced apoptosis in A431 carcinoma cells: Implication of ROS‐P38 MAPK‐integrin α2β1 pathway

Morazzani

Carvalho

Kovacic

et al. 2004

Intl Journal of Cancer

View full text Add to dashboard Cite

A431 cells escape EGF-induced apoptosis by forming cell aggregates. We show that these clusters migrate and merge with neighboring ones, resulting in larger structures composed of a multilayer central (3D) population surrounded by a cell monolayer (2D). We found that after 48 hr of 10 nM EGF treatment, 3D structure formation correlates with ␣2␤1 integrin upregulation. Blockade of ␣2 integrin impairs 3D structure formation. We studied the involvement of reactive oxygen species (ROS) in this process. We show that A431 cells express the NADPH oxidase catalytic subunits Nox1. EGF-induced dose-dependant ROS production was inhibited by the NADPH oxidase inhibitor, diphenylene iodonium (DPI), in these cells while rotenone was ineffective. Inhibition of ROS level in A431 cells with DPI or ebselen (glutathione peroxydase mimic) as well as P38 MAP kinase inhibition by SB203580 decreases ␣2 integrin subunit expression and induces a shift to 3D versus 2D populations. Cell cycle analysis of 2D cells shows that DPI, ebselen and SB203580 decrease the number of cells in S/G2 phase without affecting the cell number in mitosis phase. On the contrary, for 3D cells, these treatments increased the proportion of cells in mitosis without modification of the cell number in S/G2 phase. For both populations, apoptosis was increased by DPI and ebselen. Resistance of cell aggregates by paclitaxel to cell death is usually described. We show that DPI abolishes paclitaxel resistance of 3D cell aggregates. We observed a greater than additive effect between paclitaxel and DPI resulting in an increased proportion of cells in S/G2 phase for 3D populations. These results suggested that the ROS-P38 MAP kinase-␣2␤1 integrin pathway was implicated in the A431 survival process by modulating the balance between 2D/3D cells. © 2004 Wiley-Liss, Inc. Key words: reactive oxygen species; ␣2␤1 integrin; P38 MAP kinase; EGF receptor; adenocarcinoma A431 cell; apoptosis resistance; paclitaxel Epidermal growth factor (EGF) stimulates growth of a great variety of normal and tumoral cells. 1 Nevertheless, a number of tumor cells that overexpress EGF receptors (EGFR) are growthinhibited upon EGF treatment. 2,3 This paradoxical phenomenon has been best characterized in human squamous carcinoma A431 cells, which express a high number of EGFR. 4 These cells have thus been shown to exhibit a biphasic response to EGF in that they are weakly stimulated by picomolar concentrations of EGF but exhibit marked inhibition of proliferation in the presence of nanomolar EGF. 3,5 The growth-inhibitory action of EGF can lead to cell cycle block due to elevation of cyclin-dependent kinase inhibitor p21/CIP1 protein level correlated to G1/S arrest 6 -8 and/or to apoptosis. 9 -11 In A431 cells and in MDA-MB-468, another human cancer cell line overexpressing EGFR, the p21/CIP1-dependent STAT signaling pathway was shown to be required for apoptosis. 12,13 Nevertheless, a proportion of A431 cells escape the EGF-induced apoptosis process and these survival cells were characteriz...

show abstract

Section: Inhibitors Of Ros-p38 Mapk Induced a Shift Toward 2d Structurementioning

confidence: 96%

Section: Inhibitors Of Ros-p38 Mapk Induced a Shift Toward 2d Structurementioning

confidence: 99%

Monolayer versus aggregate balance in survival process for EGF‐induced apoptosis in A431 carcinoma cells: Implication of ROS‐P38 MAPK‐integrin α2β1 pathway

Morazzani

Carvalho

Kovacic

et al. 2004

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Experimental animal studies show that brain levels of ebselen were about 20% of the plasma level (12,30). Formation of ebselen diselenide was found to be a common feature when ebselen concentrations are high and enzyme concentrations are low.…”

mentioning

confidence: 99%

Ebselen: A substrate for human thioredoxin reductase strongly stimulating its hydroperoxide reductase activity and a superfast thioredoxin oxidant

Zhao

Masayasu

Holmgren

2002

Proc. Natl. Acad. Sci. U.S.A.

227

182

View full text Add to dashboard Cite

Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], a selenoorganic compound with glutathione peroxidase-like activity is used in clinical trials against stroke. Human and bovine TrxR catalyzed the reduction of ebselen to ebselen selenol by NADPH with an apparent K M-value of 2.5 M and a kcat of 588 min ؊1 . The addition of thioredoxin (Trx) stimulated the TrxR-catalyzed reduction of ebselen several-fold. This result was caused by a very fast oxidation of reduced Trx by ebselen with a rate constant in excess of 2 ؋ 10 7 M ؊1 s ؊1 . This rate is orders of magnitude faster than the reaction of dithiol Trx with insulin disulfides. Ebselen competed with disulfide substrates for reduction by Trx and, therefore, acted as an inhibitor of protein disulfide reduction by the Trx system. The inherent H2O2 reductase activity of mammalian TrxR dependent on its active-site selenocysteine residue was stimulated 10-fold by 2 M ebselen and 25-fold in the additional presence of 5 M Trx. Furthermore, the apparent KM-value of TrxR for H2O2 was lowered 25-fold to about 100 M. Our results demonstrate that ebselen is a TrxR peroxidase which, in the presence of Trx, acted as a mimic of a peroxiredoxin. The activity with TrxR and oxidation of reduced Trx offer mechanistic explanations for the in vivo effects of ebselen as an antioxidant and anti-inflammatory agent. Our results demonstrate that the mechanism of action of ebselen may be predominantly via the Trx system rather than via glutathione.selenol ͉ inflammation ͉ signal transduction ͉ oxidative stress ͉ redox regulation E bselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] is a lipidsoluble seleno-organic compound that exhibits a weak glutathione peroxidase (GPx)-like activity in vitro (1-6). The specificity for substrates ranges from H 2 O 2 to smaller organic hydroperoxides and includes membrane-bound phospholipid and cholesterylester hydroperoxides. Because ebselen is effective against membrane hydroperoxides, it inhibits both nonenzymatic and enzymatic lipid peroxidation in cells and has anti-inflammatory activity in various animal models (5, 6). Ebselen also will directly inhibit inflammation-related enzymes such as 5-lipoxygenase, nitric oxide synthases, NADPH oxidase, protein kinase C, and ATPase by chemically modifying an SH-group forming a selenosulfide complex (5, 6).Because of its anti-inflammatory properties, ebselen has been used in the treatment of patients with acute ischemic stroke (7,8) or delayed neurological deficits after aneurysmal subarachnoid hemorrhage (9). The results of these clinical trials indicate the benefit of ebselen as a neuroprotective agent. Also, recent animal studies show neuroprotective, antioxidant, and antiinflammatory actions of ebselen in a rodent model of permanent middle as well as transient cerebral artery occlusion (10-13).Thioredoxin (Trx) reductase (TrxR) is a dimeric FADcontaining enzyme that catalyzes the NADPH-dependent reduction of the active-site disulfide in oxidized Trx (Trx-S 2 ) to give a dithiol in reduced Trx [Trx-(SH) 2 ] (14...

show abstract

“…These ligands probably become disulfide bonded in the plasma, because the albumin that is formed and secreted from the liver is in the free thiol form (17). Certain drugs containing thiol groups also bind to Cys 34 of albumin (19,21,22 to be the most probable binding site for low molecular weight thiols including homocysteine. In an earlier study where plasma proteins were resolved by gel filtration chromatography, it appeared that homocysteine was associated with albumin; however, the mechanism of homocysteinylation was not addressed (23).…”

mentioning

confidence: 99%

Albumin Thiolate Anion Is an Intermediate in the Formation of Albumin-S–S-Homocysteine

Sengupta¹,

Chen²,

Togawa³

et al. 2001

Journal of Biological Chemistry

158

173

View full text Add to dashboard Cite

show abstract

Ebselen-binding equilibria between plasma and target proteins

Cited by 45 publications

References 11 publications

Monolayer versus aggregate balance in survival process for EGF‐induced apoptosis in A431 carcinoma cells: Implication of ROS‐P38 MAPK‐integrin α2β1 pathway

Monolayer versus aggregate balance in survival process for EGF‐induced apoptosis in A431 carcinoma cells: Implication of ROS‐P38 MAPK‐integrin α2β1 pathway

Ebselen: A substrate for human thioredoxin reductase strongly stimulating its hydroperoxide reductase activity and a superfast thioredoxin oxidant

Albumin Thiolate Anion Is an Intermediate in the Formation of Albumin-S–S-Homocysteine

Contact Info

Product

Resources

About