Theranostics
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2021
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IF 11.556
Yiqun Xia,Jundixia Chen,Yun Yu,Fengjiao Wu,Xin Shen,Chenyu Qiu,Tingting Zhang,Lin Hong,Peisen Zheng,Rongrong Shao,Chenxin Xu,Fang Wu,Wei Chen,Congying Xie,Ri Cui,Peng Zou
Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.
研究领域:
肿瘤学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2020
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IF 4.831
Chi Meng,Jianqiang Qian,Zhongyuan Xu,Ji Liu,Wenpei Shan,Peng Zhu,Weizhong Zhu,Jiefei Miao,Chang-Chun Ling,Yong Ling
A series of mono- and di-methylenecyclohexenone derivatives, 3a – f and 4a – f , respectively, were designed and synthesized from piperlongumine (PL) and their in vitro and in vivo pharmacological properties were evaluated. A majority of the compounds exhibited a potent antiproliferative effect on five human cancer cell lines, especially those causing breast cancer. Compound 4f showed the highest antiproliferative potency among all of the compounds, almost a 10-fold higher inhibitory potency against thioredoxin reductase (TrxR) compared with PL in cells causing breast cancer. In addition, 4f was found to increase the levels of reactive oxygen species (ROS), thus leading to more potent antiproliferative effects. More importantly, the suppression assays of migration and invasion revealed that compound 4f could reverse the epithelial–mesenchymal transition induced by the transforming growth factor β1, and exhibit prominent anti-metastasis effects. Compound 4f also showed strong inhibition potency toward solid tumors of breast cancer in vivo . Our findings show that compound 4f is a promising therapeutic candidate in the treatment of breast cancer, which, however, needs further research to be proved.
研究领域:
药理学
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肿瘤学
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药物化学
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DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
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2023
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IF 4.5
Qing Wu,Haoran Ning,Huaiji Wang,Hongfei Hua,Wa Li,Bin Xu
The efficacy of photodynamic therapy (PDT) is still limited by the inefficient utilisation of generated ROS in tumours due to cellular redox homeostasis. To improve the therapeutic efficacy for oral carcinoma, biomimetic cell membrane-coated mesoporous nanoplatform was tailored to interfere with cellular redox homeostasis for amplified PDT. In this study, CAL-27 cancer cell membrane (CM) was encapsulated onto the mesoporous silica NPs (MSN), which were preloaded with Chlorin e6 (Ce6) and Curcumin (Cur). The biomimetic nanoparticles displayed a size of around 120 nm, which had excellent cytotoxicity under a laser and increased uptake ability to tumour cell. After internalised by cancer cells, the released Cur could effectively disturb ROS-defence system by suppressing TrxR activity, and decreasing TrxR-2 expression (p < 0.05), leading to enhanced cancer cell killing ability of PDT. The biomimetic system was found to selectively accumulate in the tumour due to its homologous targeting capability and inhibit tumour growth significantly. In a word, the biomimetic nanoplatform apparently enhanced the therapeutic effect of PDT on tumours by Cur disturbing the ROS-defence system, which exhibited a new way to enhance PDT.
研究领域:
纳米技术
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癌症研究
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药学
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生物医学工程
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治疗学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2020
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IF 5.573
Jianqiang Qian,Zhongyuan Xu,Chi Meng,Ji Liu,Pei-Ling Hsu,Yangyang Li,Weizhong Zhu,Yumin Yang,Susan L. Morris-Natschke,Kuo-Hsiung Lee,Yanan Zhang,Yong Ling
Oxidative therapy, a strategy that specifically increases reactive oxygen species (ROS) levels in tumor cells by disrupting the redox homeostasis has gained increasing interest. The antitumor effects of the natural product piperlongumine (PL) appear to result from its ability to increase intracellular ROS levels via inhibition of antioxidative thioredoxin reductase (TrxR). Twenty-seven benzylidenecyclohexenone-based PL analogues ( 2a-v and 15a-e ) were designed, synthesized and evaluated for their pharmacological properties . Most of the compounds exhibited potent antiproliferative activities against five human cancer cell lines, especially against breast tumor cells. One of the most promising analogueues 2c showed 12-fold higher inhibitory activity against the thioredoxin reductase (TrxR) than PL and surpressed the expression of TrxR1 protein in breast cancer cells and inhibited TrxR enzymatic activity . In addition, 2c increased ROS levels and resulted in marked apoptosis by regulating apoptosis-related proteins expressed in the breast cancer cells. Compound 2c also triggered the formation of autophagosomes and autolysosomes by promoting the expression of LC3-II and Beclin-1 and diminishing the expression of LC3-I and p62 proteins. Finally, 2c displayed low acute toxicity and good inhibitory potency to tumors in mice. Overall, 2c is a promising anti-breast cancer candidate warranting further investigation.
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2020
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IF 4.831
Qing-Zhu Fan,Ji Zhou,Yi-Bao Zhu,Lian-Jun He,Dong-Dong Miao,Sheng-Peng Zhang,Xiao-Ping Liu,Chao Zhang
Targeting the Trp-Kyn pathway is an attractive approach for cancer immunotherapy. Thioredoxin reductase (TrxR) enzymes are reactive oxygen species (ROS) modulators that are involved in the tumor cell growth and survival processes. The 4-phenylimidazole scaffold is well-established as useful for indoleamine 2,3-dioxygenase 1 (IDO1) inhibition, while piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR. To take advantage of both immunotherapy and TrxR inhibition, we designed a first-generation dual IDO1 and TrxR inhibitor ( ZC0101 ) using the structural combination of 4-phenylimidazole and PL scaffolds. ZC0101 exhibited better dual inhibition against IDO1 and TrxR in vitro and in cell enzyme assays than the uncombined forms of 4-phenylimidazole and PL. It also showed antiproliferative activity in various cancer cell lines, and a selective killing effect between normal and cancer cells. Furthermore, ZC0101 effectively induced apoptosis and ROS accumulation in cancer cells. Knockdown of TrxR1 and IDO1 expression induced cellular enzyme inhibition and ROS accumulation effects during ZC0101 treatment, but only reduced TrxR1 expression was able to improve ZC0101 ′s antiproliferation effect. This proof-of-concept study provides a novel strategy for cancer treatment. ZC0101 represents a promising lead compound for the development of novel antitumor agents that can also be used as a valuable probe to clarify the relationships and mechanisms of cancer immunotherapy and ROS modulators.
研究领域:
肿瘤学
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药理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF NATURAL PRODUCTS
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2020
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IF 3.782
Peng Zhu,Jianqiang Qian,Zhongyuan Xu,Chi Meng,Ji Liu,Wenpei Shan,Weizhong Zhu,Yongjun Wang,Yumin Yang,Wei Zhang,Yanan Zhang,Yong Ling
The natural products piperlongumine and piperine have been shown to inhibit cancer cell proliferation through elevation of reactive oxidative species (ROS) and eventually cell death, but only have modest cytotoxic potencies. A series of 14 novel phenylallylidenecyclohexenone analogues based on piperlongumine and piperine therefore were designed and synthesized, and their pharmacological properties were evaluated. Most of the compounds produced antiproliferative activities against five human cancer cells with IC50 values lower than those of piperlongumine and piperine. Among these, compound 9m exerted the most potent antiproliferative activity against drug-resistant Bel-7402/5-FU human liver cancer 5-FU resistant cells (IC50 = 0.8 μM), which was approximately 10-fold lower than piperlongumine (IC50 = 8.4 μM). Further, 9m showed considerably lower cytotoxicity against LO2 human normal liver epithelial cells compared to Bel-7402/5-FU. Mechanistically, compound 9m inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, reduced mitochondrial transmembrane potential (MTP), and induced autophagy in Bel-7402/5-FU cells via regulation of autophagy-related proteins LC3, p62, and beclin-1. Finally, 9m activated significantly the p38 signaling pathways and suppressed the Akt/mTOR signaling pathways. In conclusion, 9m could be a promising candidate for the treatment of drug-resistant cancer cells and, as such, warrants further investigation.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2025
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IF 7.7
Ya-Xue Jia,Na Wang,Juan Zhang,Cheng-Peng Sun
Thioredoxin reductase (TrxR) is a pivotal biomarker and therapeutic target, monitoring its expression levels with good accuracy and sensitivity in cells or tissues is of great significance for clinical disease diagnosis and prognosis studies. Herin, we first develop a novel TrxR fluorescence sensing strategy based on the nucleic acid site-specific cleavage (NASC) mechanism, which highlights the benefits of prominent selectivity and high sensitivity. Notably, our NASC-based sensing strategy shows the limit of detection (LOD) is over two orders of magnitude lower than other site-specific cleavage-based approaches. Our proposed method has demonstrated the successful application in determining the TrxR level of in living cell and tissue, highlighting its potential for analyzing TrxR in clinical samples. The results convincingly illustrated that the NASC strategy stands as a highly promising molecular instrument for unraveling the physiological roles of TrxR within living organisms.
研究领域:
生物化学
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分子生物学
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细胞生物学
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分析化学
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生物医学工程
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产品关联
DOI
高影响因子
BIOMATERIALS
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2020
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IF 10.317
Jichun Yang,Shuojiong Pan,Shiqian Gao,Yiheng Dai,Huaping Xu
Thioredoxin reductase (TrxR) is an essential mammalian enzyme that possesses a selenocysteine active site. TrxR is overexpressed in many malignant tumors and has a close relationship with apoptosis, drug resistance, recurrence and metastasis of tumors. Recently, TrxR has emerged as a promising target for anticancer therapy. Herein, we developed a TrxR-interfering drug delivery system (DDS) based on RGD-PEG-PUSeSe-PEG-RGD self-assembling micelles for imaging-guided gemcitabine (GEM) chemosensitization and anti-recurrence/metastasis therapy. The diselenide-containing micelles were degraded in response to TrxR stimuli for GEM releasing. In the meantime, the dissociated polymers’ chain segments targeted the active site of TrxR via Se–Se/Se–S dynamic reactions for activity inhibition. This inhibition by the micelles not only provided chemosensitization, but reduced tumor recurrence/metastasis risk via the induction of residual tumor cell apoptosis by triggering ROS production post-chemotherapy. In this work, we took the transformation between Se-containing dynamic covalent bonds developed by our group from in vitro to in vivo , which furthered the knowledge on the biochemistry of selenium and provided aspects to develop new TrxR inhibitors. Overall, the TrxR-interfering DDS combined excellent antitumor effects for primary solid tumors with the inhibition of tumor recurrence/metastasis during post-treatment care, providing new perspectives for efficient cancer therapy.
研究领域:
癌症治疗
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药学
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生物化学
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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