Thioredoxin regenerates proteins inactivated by oxidative stress in endothelial cells

Fernando, M. Rohan; Nanri, Hiroki; Yoshitake, Shinichirou; Nagata-Kuno, Kazue; Minakami, Shigeki

doi:10.1111/j.1432-1033.1992.tb17363.x

Cited by 195 publications

(114 citation statements)

References 40 publications

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“…Thioredoxin/thioredoxin reductase signalling therefore may be a novel pathway to target in this malignancy. Thioredoxin and thioredoxin reductase are also important proteins present in endothelial cells to tackle oxidative stress (Fernando et al, 1992;Anema et al, 1999). So a putative thioredoxin inhibitor may have potential antiangiogenic activity.…”

Section: Discussionmentioning

confidence: 99%

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Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study

et al. 2005

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AW464 (NSC 706704) is a novel benzothiazole substituted quinol compound active against colon, renal and certain breast cancer cell lines. NCI COMPARE analysis indicates possible interaction with thioredoxin/thioredoxin reductase, which is upregulated under hypoxia. Through activity on HIF1a, VEGF levels are regulated and angiogenesis controlled. A thioredoxin inhibitor could therefore exhibit enhanced hypoxic toxicity and indirect antiangiogenic effects. In vitro experiments were performed on colorectal and breast cancer cell lines under both normoxic and hypoxic conditions and results compared against those obtained with normal cell lines, fibroblasts and keratinocytes. Antiangiogenic effects were studied using both large and microvessel cells. Indirect antiangiogenic effects (production of angiogenic growth factors) were studied via ELISA. We show that AW464 exerts antiproliferative effects on tumour cell lines as well as endothelial cells with an IC 50 of B0.5 mM. Fibroblasts are however resistant. Proliferating, rather than quiescent, endothelial cells are sensitive to the drug indicating potential antiangiogenic rather than antivascular action. Endothelial differentiation is also inhibited in vitro. Hypoxia (1% O 2 for 48 h) sensitises colorectal cells to lower drug concentrations, and in HT29s greater inhibition of VEGF is observed under such conditions. In contrast, bFGF levels are unaffected, suggesting possible involvement of HIF1a. Thus, AW464 is a promising chemotherapeutic drug that may have enhanced potency under hypoxic conditions and also additional antiangiogenic activity.

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Section: Discussionmentioning

confidence: 99%

“…Thioredoxin and thioredoxin reductase have been identified as major redox proteins in HUVEC (Fernando et al, 1992;Anema et al, 1999) and therefore inhibition of thioredoxin should have direct antiproliferative effects. This was corroborated by this study.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study

et al. 2005

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“…Two half-reactions occur in the reduction of Trx by TR, in which the reduction of the FAD prosthetic group of TR by NADPH and electron transfer to the active site cysteines in TR occurs f&t. The second halfreaction is the reduction of bound oxidized Trx [2]. Trx functions in vitro as a co-factor for reduction of proteins [3,4], as a protective system against oxidizing species [5,6], and can catalyze the in vitro folding of proteins [7j. Trx has also been shown to modulate the activity of transcription factors such as AP-1 [8,9], TFIIIC [lo], BZLFl [ 111, and NF-KB [ 121 and steroid receptors [13,14], suggesting a role for Trx in the redox-regulation of gene expression.…”

Section: Iutroductionmentioning

confidence: 99%

Biochemical, structural, and biological properties of human thioredoxin active site peptides

1994

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The human rcdox protein thioredoxin is an autocrine growth factor for some cancer cells. Redox activity is essential for this function but other required structural features of thioredoxin are not known. Two I-mer peptides (I and II) and one 1Cmer pcptide (III) were designed based on the amino acid sequence of the redox active site of thioredoxin. Peptide I and peptide III contained the wild-type sequence of thioredoxin while peptide II contained serine residues in place of the catalytically active cysteines. Circular dichroism spectroscopy indicated that all three peptides were comprised mainly of random coil, with peptide III containing slightly more ordered secondary structure. Peptides I and III were substrates for thioredoxin rcductase with KM values of 890 and 265 ,uM, respectively. The redox inactive peptide II could not compete with thioredoxin for reduction by thioredoxin reductase in a coupled insulin reduction assay. However, peptide II was a competitive inhibitor for the reduction of $5'~dithiobis-(2nitrobenzoic acid) by thioredoxin reductase. All three peptides gave only background levels of stimulation of the proliferation of Swiss 3T3 murine fibroblasts when compared to the stimulation caused by thioredoxin. These results suggest that while the ability of thioredoxin to stimulate cellular proliferation is redox-dependent, more information than that contained in the redox active site domain alone defined by 14 amino acids is required.

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“…However, in this situation, some cell components (lipids, proteins, DNA) are steadily altered: there is also a mild oxidative stress. But, over a large range of rates of ROS production, the attack of the organism is fairly efficiently counteracted and DNA and membranes are repaired before consistent damages are inflicted to the cells [19][20][21].…”

Section: Overview Of Radical Phenomenamentioning

confidence: 99%

“…An extracellular SOD (EC-SOD) [93], a ubiquitous thioredoxin [12,20] and peroxiredoxin, an enzyme controlling ROS concentration at the level of the nuclear membrane [49], are also important in the same respect. The seven enzymes, the activities of which are dependent on mineral trace elements, are essential for the positive outcome of the reproduction both in monogastrics and in ruminants [29,49,50,71,[94][95][96].…”

Section: Defense Against Ros and The Outcome Of Gestationmentioning

confidence: 99%

Gestation linked radical oxygen species fluxes and vitamins and trace mineral deficiencies in the ruminant

2006

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-In mammals, radical oxygen species (ROS) are essential factors of cell replication, differentiation and growth (oxidative signal), notably during gestation, but are also potentially damaging agents. In Women, ROS play a role in remodeling of uterine tissues, implantation of the embryo, settlement of the villi and development of blood vessels characteristic of gestation. The body stores of vitamins and minerals of gestating females are used to keep ROS fluxes at a level corresponding to oxidative signals and to prevent an imbalance between their production and scavenging (oxidative stress), which would be detrimental to the mother and fetus. There is some evidence that, although based on different regulatory mechanisms, most of the effects of ROS reported in humans also occur in pregnant ruminant females, some of which have been actually reported. Many vitamins and trace elements have dual effects in the organism of mammals: (a) they are involved in the control of metabolic pathways or/and gene expression, (b) but most of the time they also display ROS trapping activity or their deficiencies induce high rates of ROS production. Deficiencies induce different disorders of gestation and can be induced by different kinds of stress. An example is given, corresponding to the decreased contents of cobalt of forages, when exposed to sustained heavy rains, so that the supply of vitamins B12 to the organism of the ruminant that grazes them is reduced and failure of gestation is induced. Outdoor exposure of ruminants to adverse climatic conditions by itself can increase the vitamin and trace element requirements. Adaptation of production systems taking into account these interactions between gestation and sources of stress or change of the quality of feeding stuffs as well as further developments of knowledge in that field is necessary to promote sustainable agricultural practices.gestation / ovine / bovine / vitamins / trace elements / antioxidant enzymes / radical oxygen species / radical phenomena

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Thioredoxin regenerates proteins inactivated by oxidative stress in endothelial cells

Cited by 195 publications

References 40 publications

Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study

Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study

Biochemical, structural, and biological properties of human thioredoxin active site peptides

Gestation linked radical oxygen species fluxes and vitamins and trace mineral deficiencies in the ruminant

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