BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Xin Shen,Yiqun Xia,Hui Lu,Peisen Zheng,Junqi Wang,Yinghua Chen,Chenxin Xu,Chenyu Qiu,Yafei Zhang,Zhongxiang Xiao,Peng Zou,Ri Cui,Daoyong Ni
Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that they all have excellent anti-tumor activity. At the same time, we found these TrxR1 inhibitors all lead to an increase in AKT phosphorylation in cancer cells, but the detailed role of AKT phosphorylation in TrxR1 inhibitor-mediated cell death remains unclear. In this study, we identified the combination of AKT and TrxR1 inhibitor displayed a strong synergistic effect in colon cancer cells. Furthermore, we demonstrated that the synergistic effect of auranofin (TrxR1 inhibitor) and MK-2206 (AKT inhibitor) was caused by ROS accumulation. Importantly, we found that ATM inhibitor KU-55933 can block the increase of AKT phosphorylation caused by auranofin, and exhibited a synergistic effect with auranofin. Taken together, our study demonstrated that the activation of ATM/AKT pathway is a compensatory mechanism to cope with ROS accumulation induced by TrxR1 inhibitor, and synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Genes & Genomics
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2024
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IF 1.6
Lv Junqi,Ma Shengmao,Wang Xiaowen,Dang Jifang,Ma Fuchun
Background Non-small cell lung cancer (NSCLC) contributes to the vast majority of cancer-related deaths. Proteasome 26S subunit, non-ATPase 12 (PSMD12), a subunit of 26S proteasome complex, is known to play the tumor-promoting role in several types of cancer but its function in NSCLC remains elusive. Objective To explore the role and underlying mechanisms of PSMD12 in NSCLC. Methods The PSMD12 expression in human normal lung epithelial cell line (BEAS-2B) and four NSCLC cell lines (A549, NCI-H1299, NCI-H1975, Calu-1) were determined by qRT-PCR and western blot. Malignant phenotypes of NSCLC cells were detected by CCK-8, EdU staining, immunofluorescence staining for E-cadherin, flow cytometry, and Transwell assays to assess cell viability, proliferation, epithelial-mesenchymal transition (EMT), apoptosis, migration and invasion. Dual luciferase assay was used to verify the regulatory role of transcription factor on the promoter. Results We identified the upregulation of PSMD12 in NSCLC tissues based on the GEO datasets, which further verified in NSCLC and BEAS-2B cell lines. PSMD12 knockdown significantly suppressed malignant behaviors of NSCLC cells, including cell growth, invasion, and migration, while PSMD12 overexpression presented the opposite effects. Interestingly, we found that PSMD12 upregulated the tumor-promoting factor TrxR1 mRNA expression. For its potential mechanisms, we demonstrated that PSMD12 elevated transcription factor Nrf2 protein level and promoted Nrf2 nuclear translocation. And Nrf2 further increased TrxR1 promoter activity and enhanced TrxR1 transcription. Meanwhile, we proved that TrxR1 overexpression erased the inhibitory effect of PSMD12 knockdown. Conclusion PSMD12 promotes NSCLC progression by activating the Nrf2/TrxR1 pathway, providing a novel prognostic and therapeutic target for NSCLC treatment.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
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2024
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IF 8.2
Peisen Zheng,Yiqun Xia,Xin Shen,Hui Lu,Yinghua Chen,Chenxin Xu,Chenyu Qiu,Yafei Zhang,Peng Zou,Ri Cui,Xiaoying Huang
Lung cancer is one of the most lethal diseases in the world. Although there has been significant progress in the treatment of lung cancer, there is still a lack of effective strategies for advanced cases. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, has achieved much attention due to its antitumor properties. Nevertheless, the use of lenvatinib is restricted by the characteristics of poor efficacy and drug resistance. In this study, we assessed the effectiveness of lenvatinib combined with thioredoxin reductase 1 (TrxR1) inhibitors in human lung cancer cells. Our results indicate that the combination therapy involving TrxR1 inhibitors and lenvatinib exhibited significant synergistic antitumor effects in human lung cancer cells. Moreover, siTrxR1 also showed significant synergy with lenvatinib in lung cancer cells. Mechanically, we demonstrated that ROS accumulation significantly contributes to the synergism between lenvatinib and TrxR1 inhibitor auranofin. Furthermore, the combination of lenvatinib and auranofin can activate endoplasmic reticulum stress and JNK signaling pathways to achieve the goal of killing lung cancer cells. Importantly, combination therapy with lenvatinib and auranofin exerted a synergistic antitumor effect in vivo . To sum up, the combination therapy involving lenvatinib and auranofin may be a potential strategy for treating lung cancer.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2023
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IF 7.9
Xi Chen,Ning Zhu,Yajie Wu,Ye Zhang,Yuxuan Zhang,Kaiwen Jin,Zhiyi Zhou,Guang Chen,Jiabing Wang
Background Sorafenib (Sora), a multi-target tyrosine kinase inhibitor, is widely recognized as a standard chemotherapy treatment for advanced hepatocellular carcinoma (HCC). However, drug resistance mechanisms hinder its anticancer efficacy. Derived from Withania somnifera , Withaferin A (WA) exhibits remarkable anti-tumor properties as a natural bioactive compound. This study aimed to examine the mechanisms that underlie the impacts of Sora and WA co-treatment on HCC. Methods Cell proliferation was evaluated through colony formation and MTT assays. Flow cytometry was employed to determine cellular apoptosis and reactive oxygen species (ROS) levels. The evaluation of apoptosis-related protein levels, DNA damage, and endoplasmic reticulum stress was conducte utilizing IHC staining and western blotting. Moreover, the caspase inhibitor Z-VAD-FMK, ATF4 siRNA, ROS scavenger N-acetyl cysteine (NAC), and TrxR1 shRNA were used to elucidate the underlying signaling pathways. To validate the antitumor effects of Sora/WA co-treatment, in vivo experiments were ultimately executed using Huh7 xenografts. Results Sora/WA co-treatment demonstrated significant synergistic antitumor impacts both in vivo and in vitro . Mechanistically, the enhanced antitumor impact of Sora by WA was achieved through the inhibition of TrxR1 activity, resulting in ROS accumulation. Moreover, ROS generation induced the activation of DNA damage and endoplasmic reticulum (ER) stress pathways, eventually triggering cellular apoptosis. Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment. Additionally, the inhibition of ATF4 by small interfering RNA (siRNA) attenuated Sora/WA co-treatment-induced apoptosis. In vivo , Sora/WA co-treatment significantly suppressed tumor growth in HCC xenograft models and decreased TrxR1 activity in tumor tissues. Conclusion Our study suggests that WA synergistically enhances the antitumor effect of Sora, offering promising implications for evolving treatment approaches for HCC.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2023
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IF 5.8
Lin Zhao,Bingling Zhong,Yanyan Zhu,Haoyi Zheng,Xumei Wang,Ying Hou,Jin-Jian Lu,Nana Ai,Xiuli Guo,Wei Ge,Yan-Yan Ma,Xiuping Chen
Glioblastoma multiforme (GBM) is one of the most lethal malignant tumors in the human brain, with only a few chemotherapeutic drugs available after surgery. Nitrovin (difurazone) is widely used as an antibacterial growth promoter in livestock. Here, we reported that nitrovin might be a potential anticancer lead. Nitrovin showed significant cytotoxicity to a panel of cancer cell lines. Nitrovin induced cytoplasmic vacuolation, reactive oxygen species (ROS) generation, MAPK activation, and Alix inhibition but had no effect on caspase-3 cleavage and activity, suggesting paraptosis activation. Nitrovin-induced cell death of GBM cells was significantly reversed by cycloheximide (CHX), N-acetyl-l-cysteine (NAC), glutathione (GSH), and thioredoxin reductase 1 (TrxR1) overexpression. Vitamins C and E, inhibitors of pan-caspase, MAPKs, and endoplasmic reticulum (ER) stress failed to do so. Nitrovin-triggered cytoplasmic vacuolation was reversed by CHX, NAC, GSH, and TrxR1 overexpression but not by Alix overexpression. Furthermore, nitrovin interacted with TrxR1 and significantly inhibited its activity. In addition, nitrovin showed a significant anticancer effect in a zebrafish xenograft model, which was reversed by NAC. In conclusion, our results showed that nitrovin induced non-apoptotic and paraptosis-like cell death mediated by ROS through targeting TrxR1. Nitrovin might be a promising anticancer lead for further development.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Biomed Research International
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2020
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IF 2.276
Peng Wu,Ting Yu,Jun Wu,Junfeng Chen
Licochalcone A (LCA) exhibited anticancer activity through modulating reactive oxygen species (ROS) levels in some cancer cells and has been evidenced to suppress colorectal cancer (CRC) formation and progression. However, whether LCA mediates the progression of CRC by regulating ROS production remains unclear. To address this, HCT-116 cells were treated with LCA, resulting in G0/G1 phase arrest, apoptosis, and high ROS generation, which were attenuated by N-acetyl-L-cysteine, a ROS inhibitor. In addition, LCA suppressed the expression of thioredoxin reductase 1 (TrxR1) in HCT-116 cells, leading to high ROS levels and apoptosis. Moreover, LCA administration combined with TrxR1 inhibition further enhanced the production of ROS and apoptosis in HCT-116 cells compared to LCA administration or TrxR1 inhibition alone. These results demonstrated that LCA might enhance the production of ROS by targeting TrxR1, leading to apoptosis in HCT-116 cells, which provides potential insight for the interventional treatment of CRC.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2022
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IF 6.1
Yi Li,Wenyan She,Tangxi Guo,Tianhe Huang,Yixin liu,Pan Liu,Xiaoran Xu,Xinyu Wang,Miao Wang,Chaochao Yu,Yi Liu,Yongchang Wei
Developing novel drugs for gastric cancer (GC) is greatly needed, and a reactive oxygen species (ROS)-modulating strategy has been demonstrated to be useful for cancer treatment. However, no organic arsenical-derived ROS-modulating drug has been developed in GC. Here, we constructed ACZ2 and investigated its efficacy and potential mechanism for GC in vitro and in vivo. Our data showed that ACZ2 could inhibit GC proliferation and cause G2/M phase arrest. Moreover, ACZ2 induced ROS accumulation by depleting glutathione (GSH) and TrxR1, triggering a subsequent ER stress response by activating the PERK/EIF2/ATF4/CHOP signalling pathways, which is a crucial step for ACZ2-mediated apoptosis and autophagy. Vitally, ROS scavenger (NAC) and ER stress inhibitor (4PBA) reversed ACZ2/ROS/ER stress-mediated apoptosis and autophagy. Our in vivo results clearly demonstrated that ACZ2 suppressed tumour growth in a GC xenograft model. Collectively, our data indicated that ACZ2 is a potential agent against GC.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Biology Direct
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2026
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IF 5.5
Du Shengwei,Zheng Peisen,Li Wen,Chen Guorong,Chen Hanbin
Hepatocellular carcinoma (HCC) remains a highly aggressive malignancy with a dismal prognosis, largely due to the limited effectiveness of current therapeutic interventions. Although Motesanib (MOT) is a clinically studied VEGFR-centered inhibitor, VEGFR-targeted strategies remain limited by innate or acquired resistance. In this study, we explored a novel pharmacological strategy combining MOT with Auranofin (AF) to enhance therapeutic outcomes in HCC. Our data demonstrate that this dual-targeting approach yields robust synergistic anticancer activity across diverse experimental models. Mechanistically, we discovered that TrxR1 inhibition is critical for this sensitization, which is closely associated with autophagy-related reactive oxygen species (ROS) accumulation. Specifically, genetic depletion of Atg5 effectively suppressed ROS accumulation and attenuated cytotoxicity, suggesting that autophagy contributes to the synergistic oxidative damage. This orchestrated stress response subsequently led to sustained endoplasmic reticulum (ER) stress and JNK pathway activation, culminating in DNA damage, impaired proliferation, and reduced cell viability. Taken together, our results identify the combination of MOT and AF as a promising and mechanistically grounded treatment regimen for advanced HCC (Graphical ). Graphical
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Hui Ren,Yu-Jue Wang,Xin-Ye Wang,Xiangyun Li,Zheng Han,Guxue Zhang,Liwei Gu,Ming Bai,Guo-Dong Yao,Qingbo Liu,Shao-Jiang Song
Thioredoxin reductase 1 (TrxR1) is an important therapeutic target for nonsmall cell lung cancer (NSCLC) treatment due to its overexpression in NSCLC cells. In this work, to address the deficiency that sesquiterpene lactone containing α-methylene-γ-lactone moiety was rapidly metabolized by endogenous nucleophiles, series of novel thioether derivatives were designed and synthesized based on a reactive oxygen species (ROS)-triggered prodrug strategy. Among them, prodrug 5u exhibited potent cytotoxicity against NSCLC cells and better release rates in response to ROS. The active compound 6a released from 5u covalently binds to Cys475 and Sec498 sites on TrxR1, resulting in inhibition on TrxR1 activity, which led to redox homeostasis disorder, and caused apoptosis and ferroptosis. Moreover, prodrug 5u exhibited significant antitumor efficiency in nude mice and NSCLC organoids. Our results deliver ROS-triggered prodrug 5u as a novel TrxR1 inhibitor for the treatment of NSCLC and provide a promising strategy of ROS-activated prodrug for covalent compounds in cancer therapy.
研究领域:
肿瘤学
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药物化学
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生物化学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2025
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IF 12.9
Xinrong Zou,Xinyao Fan,Ping Xu,Xiufeng Yu,Chan Luo,Zhuxi Kang,Xin Shen,Jiaoni Zheng,Jisheng Wang,Baicheng He,Zeng Tu,Xiaoming Fu,Yongbo Peng
Diabetes mellitus (DM) aggravates periodontitis due to disordered glucose metabolism, leading to accelerated bone destruction and increasing dental plaque reproduction to induce local inflammation. The hyperglycemic state of DM leads to reactive oxygen species (ROS) overproduction that inhibits osteogenic differentiation in periodontal. These make a great challenge for the treatment of diabetic periodontitis. ROS-scavenging materials with additional anti-inflammation and anti-bacterial properties are highly sought after for the treatment of diabetic periodontitis. Herein, we have prepared the selenium-albumin corona rinse (H@Se NPs) through the albumin/nano-Se assembly strategy. H@Se NPs have better anti-inflammation via promoting the polarization of macrophages from the M1 to M2 phenotype and anti-bacterial effects than the commercially available selenium nanoparticles (Se NPs). Additionally, H@Se NPs can scavenge ROS to modulate the periodontal osteogenic microenvironment, a mechanism that involves regulating thioredoxin reductase 1 (TrxR1) synthesis and activating the TrxR1/ROS/β-catenin cascade. Furthermore, studies conducted in vivo have verified that H@Se NPs can suppress the formation of subgingival microbial colonies while enhancing osteogenic differentiation in diabetic pathological environments and improving periodontal bone regeneration via ROS scavenging. Collectively, these findings unveil new therapeutic paradigms for the clinical management of diabetic periodontitis.
研究领域:
牙科医学
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纳米医学
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糖尿病研究
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炎症生物学
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氧化应激与抗氧化剂
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骨组织再生
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2021
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IF 7.376
Yue Zhang,Shibo Sun,Weiping Xu,Rui Yang,Yijia Yang,Jianli Guo,Kun Ma,Jianqiang Xu
Shikonin , a naturally occurring naphthoquinone with potent anti-tumor activity, has been reported to induce cancer cell death via targeting selenoenzyme thioredoxin reductase 1 (TrxR1; TXNRD1). However, the interaction between shikonin and TrxR1 remains unclear, and the roles of the cellular antioxidant system in shikonin induced cell death are obscure. Here, we found that shikonin modified the Sec 498 residue of TrxR1 to fully inhibit its antioxidant activity , however, the shikonin-modified TrxR1 still remained intrinsic NADPH oxidase activity, which promotes superoxide anions production. Besides, TrxR1 efficiently reduced shikonin in both selenocysteine dependent and selenocysteine independent manners, and the oxygen-coupled redox cycling of shikonin also generates excessive superoxide anions. The inhibitory effects and the redox cycling of shikonin towards TrxR1 caused cancer cell ROS-dependent necroptosis. Interestingly, as we evaluated, some cancer cell lines were insensitive to shikonin, especially kelch-like ECH associated protein 1 (KEAP1)-mutant non-small cell lung cancer (NSCLC) cells, which harbor constitutive activation of the nuclear factor-erythroid 2-related factor 2 (NRF2). NADPH bankruptcy caused by glucose starvation or glucose limitation (inhibiting glucose transporter 1 by BAY-876) could efficiently overcome the resistance of KEAP1-mutant NSCLC cells to shikonin. Glucose-6-phosphate dehydrogenase (G6PD), was known as a rate-limiting enzyme in the pentose phosphate pathway , however, the pharmacological inhibition of G6PD by 6-aminonicotinamide (6-AN), enhanced the shikonin-induced cytotoxicity but has no selectivity on KEAP1-mutant NSCLC cells. This study will be helpful in applying shikonin for potential chemotherapy, and in combinational treatment of KEAP1-mutant NSCLC.
研究领域:
肿瘤学
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药理学
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细胞生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
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