Wei Jiang, Zhiwei Yang, Pu Chen, Man Zhao, Yubo Wang, Jingyuan Wang, Xinru Li, Meichen Wang, Peng Hou
{"title":"Tolperisone诱导UPR介导的肿瘤抑制,并通过靶向LSD1与蛋白酶体抑制剂和免疫疗法协同作用。","authors":"Wei Jiang, Zhiwei Yang, Pu Chen, Man Zhao, Yubo Wang, Jingyuan Wang, Xinru Li, Meichen Wang, Peng Hou","doi":"10.1080/14728222.2023.2259097","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Drug repurposing is an attractive strategy for extending the arsenal of oncology therapies. Tolperisone is an old centrally acting muscle relaxant used for treatment of chronic pain conditions. In this study, we investigated the therapeutic effect and mechanism of tolperisone in human cancers and explored the combination strategy with proteasome inhibitor and immunotherapy.</p><p><strong>Research design and methods: </strong>The antitumor effect of tolperisone was evaluated by measuring half maximal inhibitory concentration, cell death, and cell growth. RNA sequencing, western blotting, molecular docking, enzyme activity assay, and ChIP-qPCR were performed to reveal the underlying mechanism. Xenograft models were used to evaluate the efficacy of tolperisone alone or in combination with proteasome inhibitor or immunotherapy.</p><p><strong>Results: </strong>Tolperisone inhibited cell growth and induced cell death in human cancer cell lines. Unfolded protein responses (UPR) pathway was hyperactivated in tolperisone-treated cells. We further identified histone lysine-specific demethylase 1 (LSD1) as a potential target of tolperisone, which directly demethylates UPR-related genes in H3K4me2. Tolperisone synergistically improved the efficacy of MG132 by enhancing UPR and sensitized tumors to immunotherapy by reprogramming M2 macrophages into M1 phenotype.</p><p><strong>Conclusions: </strong></p><p><p>Tolperisone inhibits human cancer by targeting LSD1. Repurposing tolperisone in cancer therapy by a combination strategy implies clinical potential.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tolperisone induces UPR-mediated tumor inhibition and synergizes with proteasome inhibitor and immunotherapy by targeting LSD1.\",\"authors\":\"Wei Jiang, Zhiwei Yang, Pu Chen, Man Zhao, Yubo Wang, Jingyuan Wang, Xinru Li, Meichen Wang, Peng Hou\",\"doi\":\"10.1080/14728222.2023.2259097\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Drug repurposing is an attractive strategy for extending the arsenal of oncology therapies. Tolperisone is an old centrally acting muscle relaxant used for treatment of chronic pain conditions. In this study, we investigated the therapeutic effect and mechanism of tolperisone in human cancers and explored the combination strategy with proteasome inhibitor and immunotherapy.</p><p><strong>Research design and methods: </strong>The antitumor effect of tolperisone was evaluated by measuring half maximal inhibitory concentration, cell death, and cell growth. RNA sequencing, western blotting, molecular docking, enzyme activity assay, and ChIP-qPCR were performed to reveal the underlying mechanism. Xenograft models were used to evaluate the efficacy of tolperisone alone or in combination with proteasome inhibitor or immunotherapy.</p><p><strong>Results: </strong>Tolperisone inhibited cell growth and induced cell death in human cancer cell lines. Unfolded protein responses (UPR) pathway was hyperactivated in tolperisone-treated cells. We further identified histone lysine-specific demethylase 1 (LSD1) as a potential target of tolperisone, which directly demethylates UPR-related genes in H3K4me2. Tolperisone synergistically improved the efficacy of MG132 by enhancing UPR and sensitized tumors to immunotherapy by reprogramming M2 macrophages into M1 phenotype.</p><p><strong>Conclusions: </strong></p><p><p>Tolperisone inhibits human cancer by targeting LSD1. Repurposing tolperisone in cancer therapy by a combination strategy implies clinical potential.</p>\",\"PeriodicalId\":12185,\"journal\":{\"name\":\"Expert Opinion on Therapeutic Targets\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2023-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Expert Opinion on Therapeutic Targets\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14728222.2023.2259097\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/9/13 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Expert Opinion on Therapeutic Targets","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14728222.2023.2259097","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/9/13 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Tolperisone induces UPR-mediated tumor inhibition and synergizes with proteasome inhibitor and immunotherapy by targeting LSD1.
Background: Drug repurposing is an attractive strategy for extending the arsenal of oncology therapies. Tolperisone is an old centrally acting muscle relaxant used for treatment of chronic pain conditions. In this study, we investigated the therapeutic effect and mechanism of tolperisone in human cancers and explored the combination strategy with proteasome inhibitor and immunotherapy.
Research design and methods: The antitumor effect of tolperisone was evaluated by measuring half maximal inhibitory concentration, cell death, and cell growth. RNA sequencing, western blotting, molecular docking, enzyme activity assay, and ChIP-qPCR were performed to reveal the underlying mechanism. Xenograft models were used to evaluate the efficacy of tolperisone alone or in combination with proteasome inhibitor or immunotherapy.
Results: Tolperisone inhibited cell growth and induced cell death in human cancer cell lines. Unfolded protein responses (UPR) pathway was hyperactivated in tolperisone-treated cells. We further identified histone lysine-specific demethylase 1 (LSD1) as a potential target of tolperisone, which directly demethylates UPR-related genes in H3K4me2. Tolperisone synergistically improved the efficacy of MG132 by enhancing UPR and sensitized tumors to immunotherapy by reprogramming M2 macrophages into M1 phenotype.
Conclusions:
Tolperisone inhibits human cancer by targeting LSD1. Repurposing tolperisone in cancer therapy by a combination strategy implies clinical potential.
期刊介绍:
The journal evaluates molecules, signalling pathways, receptors and other therapeutic targets and their potential as candidates for drug development. Articles in this journal focus on the molecular level and early preclinical studies. Articles should not include clinical information including specific drugs and clinical trials.
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