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Last update 08 May 2025

TrxR1

Last update 08 May 2025

Basic Info

Synonyms

Gene associated with retinoic and IFN-induced mortality 12 protein, Gene associated with retinoic and interferon-induced mortality 12 protein, GRIM-12

+ [11]

Introduction

Reduces disulfideprotein thioredoxin (Trx) to its dithiol-containing form (PubMed:8577704). Homodimeric flavoprotein involved in the regulation of cellular redox reactions, growth and differentiation. Contains a selenocysteine residue at the C-terminal active site that is essential for catalysis (Probable). Also has reductase activity on hydrogen peroxide (H2O2) (PubMed:10849437). Enhances the transcriptional activity of estrogen receptors ESR1 and ESR2. Enhances the transcriptional activity of the estrogen receptor ESR2 only (PubMed:15199063). Mediates cell death induced by a combination of interferon-beta and retinoic acid (PubMed:9774665). Induces actin and tubulin polymerization, leading to formation of cell membrane protrusions.

Drugs associated with TrxR1

Ethaselen

Target

TrxR1

Mechanism

TrxR1 inhibitors

Active Org.

Peking University [+3]

Originator Org.

Peking University

Active Indication

Hematologic Neoplasms [+2]

Inactive Indication

Advanced Lung Non-Small Cell Carcinoma

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

6-Shogaol

Target

TrxR1

Mechanism

TrxR1 inhibitors

Active Org.

Shanghai University of Traditional Chinese Medicine

Originator Org.

Shanghai University of Traditional Chinese Medicine

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

TrxR1 inhibitors(Shenyang Pharmaceutical University)

Target

TrxR1

Mechanism

TrxR1 inhibitors

Active Org.

Shenyang Pharmaceutical University

Originator Org.

Shenyang Pharmaceutical University

Active Indication

Non-Small Cell Lung Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with TrxR1

CTR20140581

/ RecruitingPhase 1

乙烷硒啉分散片连续给药在TrxR高表达晚期恶性实体瘤病人中的安全性及药代动力学和药效学研究

[Translation] Safety, pharmacokinetics and pharmacodynamics of continuous administration of ethaselen dispersible tablets in patients with advanced malignant solid tumors with high TrxR expression

主要目的： 1.观察乙烷硒啉分散片连续给药在TrxR阳性肿瘤患者中的安全性 2. 研究乙烷硒啉分散片在肿瘤患者体内药代动力学 3. 研究乙烷硒啉在肿瘤患者中的药代/药效关系次要目的： 1. 观察乙烷硒啉在TrxR阳性肿瘤患者中的疗效。

[Translation]

Main objectives: 1. To observe the safety of continuous administration of ethaselen dispersible tablets in patients with TrxR-positive tumors 2. To study the pharmacokinetics of ethaselen dispersible tablets in tumor patients 3. To study the pharmacokinetic/pharmacodynamic relationship of ethaselen in tumor patients Secondary objectives: 1. To observe the efficacy of ethaselen in patients with TrxR-positive tumors.

Start Date29 Aug 2014

Sponsor / Collaborator

Peking University

[+1]

NCT02166242

/ CompletedPhase 1IIT

Phase 1c Single Arm Study of Thioredoxin Reductase Inhibitor Ethaselen, for the Treatment of Thioredoxin Reductase High Expressed Advanced Non-small Cell Lung Cancers Who Have Received More Than Two Lines Standard Treatment.

Thioredoxin reductase plays an critical role in lung cancer patients, in vitro study showed that, ethaselen, specific inhibitor of thioredoxin reductase, could inhibit lung cancer cell growth and induce apoptosis. In China, phase 1 clinical trials of ethaselen showed that 1200 mg dose ethaselen could be well tolerated, in pre-clinical study we found that, approximately 50% non-small cell lung cancers harbored high thioredoxin reductase expression(IHC result ++ or +++), phase 1a/b of ethaselen had finished in 2008, the result showed that 1200mg ethaselen per day was safety and tolerated by Chinese malignant tumor patients.In pre-clinical research, our group found that, elevated of thioredoxin reductase activity was associated with the expression of thioredoxin reductase tested by immunohistochemistry, which means high expression of this enzyme may be a favourite predicted factor of ethaselen, the specific inhibitor of thioredoxin reductase.

Start Date01 Jun 2014

Sponsor / Collaborator

Hunan Cancer Hospital

100 Clinical Results associated with TrxR1

100 Translational Medicine associated with TrxR1

0 Patents (Medical) associated with TrxR1

1,402

Literatures (Medical) associated with TrxR1

01 Dec 2025·Cancer Chemotherapy and Pharmacology

A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome

Article

Author: Piekarz, Richard ; Maher, Keri R ; Rudek, Michelle A ; Bandyopadhyay, Dipankar ; Harvey, R Donald ; Shafer, Danielle ; Schaar, Dale ; Wright, John ; Deng, Xiaoyan ; Grant, Steven

AbstractPurposeRelapsed and/or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome continue to have a poor prognosis with limited treatment options despite advancements in rational combination and targeted therapies. Belinostat (an HDAC inhibitor) and Pevonedistat (a NEDD8 inhibitor) have each been independently studied in hematologic malignancies and have tolerable safety profiles with limited single-agent activity. Preclinical studies in AML cell lines and primary AML cells show the combination to be highly synergistic, particularly in high-risk phenotypes such as p53 mutant and FLT-3-ITD positive cells. Here, we present the safety, pharmacokinetics and pharmacodynamics of belinostat and pevonedistat in a dose escalation Phase I study in AML and High-Risk MDS.MethodsEighteen patients (16 with AML, 2 with MDS) were treated at 5 dose levels (belinostat 800–1000 mg/m2, pevonedistat 20–50 mg/m2). Safety and tolerability were assessed according to protocol defined dose limiting toxicities (DLTs). Correlative pharmacokinetic and pharmacodynamic analyses were performed.ResultsNo dose limiting toxicities were noted. Most Grade 3 or 4 toxicities were hematologic in nature. The best response was stable disease in four patients, and complete remission in one patient who qualified as an exceptional responder. Pharmakokinetic studies revealed no association between drug exposure and best response. Pharmacodynamic RT-PCR studies demonstrated post-treatment increases in several proteins, including quantitative increases in the oxidative stress protein NQO1, ferroptosis protein SLC7A11, and GSR, linked to glutathione metabolism and oxidative stress, as did the anti-oxidants SRXN1 and TXNRD1.ConclusionsPatterns of post-treatment changes in correlative pharmacodynamic parameters may suggest possible mechanistic changes in the DNA damage response, oxidative damage, and ferroptosis pathways. The combination of pevonedistat plus belinosat is safe in an adult relapsed and/or refractory AML/High-Risk MDS population with modest but notable activity in this heavily treated, high risk population. Our findings also raise the possibility that certain extremely poor prognosis AML patients may respond to a regimen combining two targeted agents that have little or no activity when administered individually.Trial registrationClinicalTrials.gov ID NCT03772925, first posted 12/12/2018; CTEP Identifier 10246.

01 Jun 2025·Toxicology in Vitro

Environmentally relevant concentrations of antimony pose potential risks to human health: An evaluation on human umbilical vein endothelial cells

Article

Author: Wang, Shanshan ; Xiang, Ping ; Chen, Su-Zhu ; Han, Yong-He ; Cui, Xi-Wen ; Guo, Dongqian ; Chen, Xian

Antimony (Sb) ore exploitation and the use of Sb-containing drugs pose known health risks. This study investigated the toxicity of environmentally relevant concentrations of Sb (0.12-12 mg L^-1) on human umbilical vein endothelial cells (HUVECs). The 50 % lethal concentration (LC₅₀) of Sb to HUVECs was 11.4 mg L^-1. Exposing to high level of Sb induced cell cycle arrest by altering the expression of cell cycle regulators, inhibiting the transitions of G₀/G₁ to S and S to G₂/M. At 1.2 mg L^-1 Sb, CKD6 and p21 expressions in HUVECs changed to 0.75 and 1.32 folds that of no-Sb control, respectively (p < 0.01). At 12 mg L^-1 Sb, CDK2, CKD6, and p27 expressions decreased by 1.54, 4.41, and 1.54 folds (p < 0.001), while p21 expression increased by 3.03 folds (p < 0.001) as compared to control. Sb also led to cell apoptosis, evidenced by Annexin V-FITC/PI staining and changes in the expressions of Bax (1.21-1.30 folds, p < 0.01) and Bcl-2 (0.65-0.83 folds). Oxidative damage was a pivotal factor driving cell apoptosis, probably through down-regulating antioxidant genes (CAT, GPX1, and GSTP1) and up-regulating stress response genes (HO-1, SOD1, and TrxR1). The elevated H₂O₂ generated in mitochondria likely contributed to cell apoptosis due to the imbalance in H₂O₂ metabolism. These findings suggest that environmentally relevant concentrations of Sb can exert cytotoxicity to HUVECs, which should be of potential concern for human cardiovascular disease.

01 Jun 2025·Archives of Biochemistry and Biophysics

Role of protein disulfide isomerase in mediating sulfasalazine-induced ferroptosis in HT22 cells: The PDI−NOS–NO−ROS/lipid-ROS cascade

Article

Author: Wu, Yufei ; Zhu, Bao Ting

Ferroptosis is a form of regulated cell death resulting from excessive lipid peroxidation. Sulfasalazine (SAS), an anti-inflammatory drug, can induce ferroptosis through inhibiting the system Xc^- and triggering glutathione depletion. SAS has attracted considerable interest in recent years because of its potential for repurposing as an anticancer agent. Our recent studies have shown that protein disulfide isomerase (PDI) is an upstream mediator of chemically-induced ferroptosis through catalyzing the dimerization of nitric oxide synthase (NOS) and NO accumulation in cultured HT22 hippocampal neuronal cells. The present study aims to investigate SAS-induced ferroptotic cell death in HT22 cells with a focus on determining the role of PDI in mediating SAS-induced ferroptosis. We find that SAS induces ferroptotic cell death in HT22 cells, which is accompanied by a time-dependent sequential increase in the accumulation of cellular NO, ROS and lipid-ROS. We find that treatment of HT22 cells with SAS activates PDI-mediated iNOS activation (dimerization) and NO accumulation. In addition, SAS also strongly upregulates iNOS protein levels in HT22 cells. PDI knockdown or pharmacological inhibition of PDI's activity each suppresses SAS-induced iNOS dimerization, which is associated with abrogation of SAS-induced accumulation of NO, ROS and lipid-ROS, and a strong protection against ferroptotic cell death. On the other hand, PDI activation through the use of a TrxR1 inhibitor can strongly sensitize cells to SAS-induced ferroptosis. Together, these experimental observations demonstrate a crucial role of PDI in SAS-induced ferroptosis in a cell culture model through the activation of the PDI → NOS → NO → ROS/lipid-ROS pathway. Insights gained from this study also provide effective strategies to selectively sensitizing human cancer cells to SAS-induced ferroptosis, such as through the use of NO-releasing agents or TrxR1 inhibitors.

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TrxR1

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