TRi-1 is a potent, specific, and irreversible inhibitor of TXNRD1 and TXNRD2 with IC50 values of 18nM and 44nM [1]. TRi-1 can enhance the activation of Nrf2 by increasing the intracellular ROS level, leading to a compensatory increase in the relative mRNA expression levels of the classic activated genes downstream of Nrf2 [2]. TRi-1 has been widely used to reduce the senescence-associated secretory phenotype (SASP), inhibit the proliferation of cancer stem cells (CSCs) and impede tumor growth[3].
In vitro, TRi-1 treatment for 48 hours significantly inhibited the proliferation of B16-F10 cells and LLC cells with IC50 values of 20µM and 25µM, respectively[4]. Treatment of LN229TAZ(4SA) cells with 1.25μM TRi-1 for 48h significantly induced cell death in the absence of glucose[5].
In vivo, TRi-1 treatment via intraperitoneal injection at a dose of 10mg/kg daily for 5 consecutive days, followed by a 2-day drug-free period, and subsequently administered three times per week for two weeks, resulted in significant suppression of tumor volume in mouse MDA-MB-231 xenograft models without affecting body weight [6]. TRi-1 (10mg/kg), administered intraperitoneally every three days for 21 days, significantly reduced TXNRD1 levels and decreased the expression of IL-1β and C-X-C motif chemokine 15 (CXCL15) in ovarian tissues of 22-month-old mice[7].
References:
[1] Jović M, Gencheva R, Scholzen K C, et al. Development of novel analogs of the TRi-1 and TRi-2 selenoprotein thioredoxin reductase inhibitors with initial assessment of their cytotoxicity profiles[J]. Free Radical Biology and Medicine, 2025.
[2] Bonner M Y, Vancsik T, Oliveira-Coelho A, et al. Anti-Tumoral Treatment with Thioredoxin Reductase 1 Inhibitor Auranofin Fosters Regulatory T Cell and B16F10 Expansion in Mice[J]. Antioxidants, 2025, 14(11): 1351.
[3] Towers M, Hao X, Sriramkumar S, et al. Abstract B029: Targeting non-canonical function of TXNRD1 to overcome platinum resistance by eradicating ovarian cancer stem-like cells[J]. Cancer Research, 2024, 84(5_Supplement_2): B029-B029.
[4] Sabatier P, Beusch C M, Gencheva R, et al. Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin[J]. Redox Biology, 2021, 48: 102184.
[5] Tang M, Dirks K, Kim S Y, et al. Inhibition of thioredoxin reductase 1 sensitizes glucose-starved glioblastoma cells to disulfidptosis[J]. Cell Death & Differentiation, 2025, 32(4): 598-612.
[6] Stafford W C, Peng X, Olofsson M H, et al. Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy[J]. Science translational medicine, 2018, 10(428): eaaf7444.
[7] Hao X, Zhao B, Towers M, et al. TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation[J]. Nature aging, 2024, 4(2): 185-197.
TRi-1是一种强效、特异且不可逆的TXNRD1和TXNRD2抑制剂，IC50值分别为18nM和44nM[1]。TRi-1能通过增加细胞内活性氧（ROS）水平来增强Nrf2的激活，导致Nrf2下游经典激活基因的相对mRNA表达水平代偿性升高[2]。TRi-1已被广泛用于减少衰老相关分泌表型（SASP）、抑制癌症干细胞（CSCs）增殖和阻碍肿瘤生长[3]。
在体外，TRi-1处理48小时显著抑制了B16-F10细胞和LLC细胞的增殖，IC50值分别为20µM和25µM[4]。使用1.25µM TRi-1处理LN229TAZ(4SA)细胞48小时，在无葡萄糖条件下显著诱导了细胞死亡[5]。
在体内，每日腹腔注射10mg/kg剂量的TRi-1，连续5天，随后停药2天，接着每周三次给药，持续两周，显著抑制了小鼠MDA-MB-231异种移植模型中的肿瘤体积，且未影响体重[6]。每三天腹腔注射一次TRi-1（10mg/kg），持续21天，显著降低了22月龄小鼠卵巢组织中的TXNRD1水平，并减少了IL-1β和C-X-C motif chemokine 15 (CXCL15)的表达[7]。