Small molecule inhibitors of mammalian thioredoxin reductase

Cai, Wenqing; Zhang, Liangwei; Song, Yanlin; Wang, Baolin; Zhang, Baoxin; Cui, Xuemei; Hu, Guanming; Liu, Yaping; Wu, Jincai; Fang, Jianguo

doi:10.1016/j.freeradbiomed.2011.10.447

Cited by 164 publications

(133 citation statements)

References 95 publications

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“…This molecular link between HDAC3 and TrxR1 led us to speculate that pharmacological tools inhibiting HDAC might have a synergistic effect with drugs acting on TrxR1. Since both TrxR1 (6,60) and HDAC inhibitors (15) are a part of the therapeutic agents used in cancer treatment, our data reinforce the importance of evaluating cardiac function during such treatments.…”

Section: The Pleiotropic Roles Of Cardiac Hdac3supporting

confidence: 69%

“…TrxR exists as a homodimer, with a head to tail orientation with each monomer consisting of an FAD prosthetic group, an NADPH binding site, and a catalytic site with a redox-active disulfide bond. Due to the significant involvement of TrxR in cell survival and proliferation, numerous investigations have focused on a better understanding of the TrxR structure-function relationship to design efficient inhibitory drugs that could be of benefit to treat diseases such as cancer (6,60).…”

Section: Introductionmentioning

confidence: 99%

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Aggregate-Prone R120GCRYAB Triggers Multifaceted Modifications of the Thioredoxin System

Mustafi

Grose

Zhang

et al. 2014

Antioxidants & Redox Signaling

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Aims: The human mutation R120G in the aB-crystallin (CRYAB) causes a multisystemic disease that is characterized by hypertrophic cardiomyopathy and cytoplasmic protein aggregates. In transgenic mice, human R120GCRYAB (hR120GTg) expression in heart sequentially modifies the REDOX status, in part by the activation of the nuclear factor, erythroid derived 2, like 2 (Nrf2). Thioredoxin system (TS) components are NRF2 target genes, so it could be hypothesized that TS was affected in hR120GTg mice. Results: Transgenic hearts overexpressed thioredoxin 1 (Trx1), which was identified by isotope coded affinity tag-mass spectrometry, among hundreds of peptides displaying an increased reduced/oxidized ratio. Coupled to this higher level of reduced cysteines, the activity of thioredoxin reductase 1 (TrxR1) was augmented by 2.5-fold. Combining mutiple experimental approaches, the enzymatic regulation of TrxR1 by a histone deacetylase 3 (HDAC3)-dependent level of acetylation was confirmed. In vitro and in vivo functional tests established that TrxR1 activity is required to mitigate aggregate development, and this could be mediated by Bcl-2-associated athanogene 3 (BAG3) as a potential TS substrate. Innovation and Conclusions: This study uncovers the compartmentalized changes and the involvement of TS in the cardiac stress response elicited by misfolded proteins such as R120GCRYAB. Our work suggests that R120GCRYAB triggers a defensive pathway acting through the newly identified interacting partners HDAC3, TrxR1, and BAG3 to counter aggregate growth. Therefore, those interactors may function as modifier genes contributing to the variable onset and expressivity of such human diseases. Furthermore, our work underscores the potential organismal effects of pharmacological interventions targeting TS and HDAC.

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Section: The Pleiotropic Roles Of Cardiac Hdac3supporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Aggregate-Prone R120GCRYAB Triggers Multifaceted Modifications of the Thioredoxin System

Mustafi

Grose

Zhang

et al. 2014

Antioxidants & Redox Signaling

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“…Selectivity of an inhibitor is one of the major hurdles in the development of a successful TrxR inhibitor. Most existing TrxR inhibitors inhibit the enzyme through the Sec/Cys residues 25 . Some of the inhibitors including ethaselen and curcumin 5,11 form covalent bonds with both selenothiol and thiol groups at the active site of TrxR1.…”

Section: Discussionmentioning

confidence: 99%

Evaluation ofN-acetyl-S-(p-chlorophenylcarbamoyl)cysteine as an irreversible inhibitor of mammalian thioredoxin reductase1

Chen

Jiang

Lin

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Context: Thioredoxin reductase (TrxR) is up-regulated in a number of human malignant cells and becomes a promising target for anticancer drug development. Objective: To evaluate N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine (NACC), a potent anticancer agent against melanoma, as an inhibitor of mammalian TrxR1. Material and methods: The mechanism of inhibition against TrxR1 was investigated using substrate protection, dialysis and liquid chromatography-tandem mass spectrometry. Results: NACC inhibits TrxR1 in a time and concentration dependent manner. The K i and k inact of NACC against TrxR1 were determined to be 80 mM and 0.178 min À1, respectively. The inhibition occurred only in the presence of NADPH and persisted after extensive dialysis. The tandem mass spectrometric analysis demonstrated that the selenocysteine rather than cysteine residue at the active site was p-chlorophenyl carbamoylated by NACC. Inhibition of intracellular TrxR by NACC in cultured melanoma cells was observed. Discussion and conclusion: NACC which irreversibly inhibits TrxR1 by forming a covalent bond with selenocysteine can be an effective tool in the study of TrxR1.

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“…TrxR overactivation and dysfunction are closely related to tumor development, TrxR inhibitors have been considered as promising cancer chemotherapy agents (Cai et al, 2012).…”

Section: Larva Of the Aquatic Midge Chironomus Riparius Is Widelymentioning

confidence: 99%

A unique thioredoxin reductase plays defensive roles against oxidative, nitrosative and nutritional stresses in Schizosaccharomyces pombe

Ji¹,

Lim²,

Kim³

2016

The Korean Journal of Microbiology

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A unique Schizosaccharomyces pombe TrxR + gene encoding thioredoxin reductase (TrxR) was found to be positively regulated by stress-inducing agents through the stress-responsive transcription factor Pap1. In the present study, the protective roles of S. pombe TrxR were evaluated using the TrxR-overexpressing recombinant plasmid pHSM10. In the presence of hydrogen peroxide (H2O2) and superoxide anion-generating menadione (MD), S. pombe TrxR increased cellular growth and the total glutathione (GSH) level, while it reduced levels of intracellular reactive oxygen species (ROS). The nitric oxide (NO) levels of the TrxR-overexpressing cells, in the presence of H2O2 and MD, were maintained to be similar to those of the corresponding non-treated cells. Although S. pombe TrxR was able to scavenge NO generated by sodium nitroprusside (SNP), it had no significant modulating effects on cellular growth, ROS levels, or the total GSH level of SNP-exposed yeast cells, compared with the differences in those of the two non-treated cell cultures. TrxR increased the cellular growth and total GSH level, which were diminished by nitrogen starvation. It also scavenged ROS and NO produced during nitrogen starvation. Taken together, the S. pombe TrxR protects against oxidative, nitrosative, and nutritional stresses.

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Small molecule inhibitors of mammalian thioredoxin reductase

Cited by 164 publications

References 95 publications

Aggregate-Prone R120GCRYAB Triggers Multifaceted Modifications of the Thioredoxin System

Aggregate-Prone R120GCRYAB Triggers Multifaceted Modifications of the Thioredoxin System

Evaluation ofN-acetyl-S-(p-chlorophenylcarbamoyl)cysteine as an irreversible inhibitor of mammalian thioredoxin reductase1

A unique thioredoxin reductase plays defensive roles against oxidative, nitrosative and nutritional stresses in Schizosaccharomyces pombe

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