{"title":"石蒜碱通过抑制NOTCH3/HES1信号通路对奥西替尼耐药非小细胞肺癌的抗肿瘤作用","authors":"Chen Wang, Chaoyang Zeng, Aimin Wang, Yue Shang, Jun Ni, Gaojie Li, Liping Li, Shuohan Xi, Wendie Wang, Shuzhen Chen","doi":"10.1002/jbt.70501","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>The resistance of non-small cell lung cancer (NSCLC) to osimertinib unavoidably occurs in clinical use. Lycorine is isolated from <i>Amaryllidaceae genera</i> and possesses a variety of pharmacological effects including anticancer. Here, we investigated the influences of lycorine on osimertinib-resistant cells and its underlying mechanisms. The data from CCK8 assay, wound healing, and migration assay revealed the inhibitory effect of lycorine in the NSCLC cells resistant to osimertinib. In vivo, lycorine reduced the growth of osimertinib-resistant NSCLC xenografts. The results from transcriptomic analysis showed that lycorine significantly decreased the level of Notch3 mRNA in osimertinib-resistant PC9 (PC9/OR) cells. It was verified that lycorine indeed lowered the level of Notch3 mRNA/protein and its downstream Hes1 protein in osimertinib-resistant cells. The MMP9 and MMP2 protein levels were also lessened in the resistant cells after lycorine treatment. Moreover, Notch3/Hes1 protein levels were higher in osimertinib-resistant cells than those in osimertinib-sensitive cells. Notch3 and Hes1 knockdown promoted the antiproliferation and anti-migration effects of osimertinib in the resistant cells. Notably, lycorine enhanced the antitumor activity of osimertinib against its resistant cells both in vitro and in vivo. Overall, our data reveal that lycorine inhibits the proliferation and metastasis of osimertinib-resistant NSCLC cells via Notch3/Hes1 pathway.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 9","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Lycorine Exerts Antitumor Effects on the Osimertinib-Resistant Non-Small Cell Lung Cancer by Inhibiting NOTCH3/HES1 Signaling\",\"authors\":\"Chen Wang, Chaoyang Zeng, Aimin Wang, Yue Shang, Jun Ni, Gaojie Li, Liping Li, Shuohan Xi, Wendie Wang, Shuzhen Chen\",\"doi\":\"10.1002/jbt.70501\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>The resistance of non-small cell lung cancer (NSCLC) to osimertinib unavoidably occurs in clinical use. Lycorine is isolated from <i>Amaryllidaceae genera</i> and possesses a variety of pharmacological effects including anticancer. Here, we investigated the influences of lycorine on osimertinib-resistant cells and its underlying mechanisms. The data from CCK8 assay, wound healing, and migration assay revealed the inhibitory effect of lycorine in the NSCLC cells resistant to osimertinib. In vivo, lycorine reduced the growth of osimertinib-resistant NSCLC xenografts. The results from transcriptomic analysis showed that lycorine significantly decreased the level of Notch3 mRNA in osimertinib-resistant PC9 (PC9/OR) cells. It was verified that lycorine indeed lowered the level of Notch3 mRNA/protein and its downstream Hes1 protein in osimertinib-resistant cells. The MMP9 and MMP2 protein levels were also lessened in the resistant cells after lycorine treatment. Moreover, Notch3/Hes1 protein levels were higher in osimertinib-resistant cells than those in osimertinib-sensitive cells. Notch3 and Hes1 knockdown promoted the antiproliferation and anti-migration effects of osimertinib in the resistant cells. Notably, lycorine enhanced the antitumor activity of osimertinib against its resistant cells both in vitro and in vivo. Overall, our data reveal that lycorine inhibits the proliferation and metastasis of osimertinib-resistant NSCLC cells via Notch3/Hes1 pathway.</p></div>\",\"PeriodicalId\":15151,\"journal\":{\"name\":\"Journal of Biochemical and Molecular Toxicology\",\"volume\":\"39 9\",\"pages\":\"\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2025-09-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Biochemical and Molecular Toxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jbt.70501\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biochemical and Molecular Toxicology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jbt.70501","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Lycorine Exerts Antitumor Effects on the Osimertinib-Resistant Non-Small Cell Lung Cancer by Inhibiting NOTCH3/HES1 Signaling
The resistance of non-small cell lung cancer (NSCLC) to osimertinib unavoidably occurs in clinical use. Lycorine is isolated from Amaryllidaceae genera and possesses a variety of pharmacological effects including anticancer. Here, we investigated the influences of lycorine on osimertinib-resistant cells and its underlying mechanisms. The data from CCK8 assay, wound healing, and migration assay revealed the inhibitory effect of lycorine in the NSCLC cells resistant to osimertinib. In vivo, lycorine reduced the growth of osimertinib-resistant NSCLC xenografts. The results from transcriptomic analysis showed that lycorine significantly decreased the level of Notch3 mRNA in osimertinib-resistant PC9 (PC9/OR) cells. It was verified that lycorine indeed lowered the level of Notch3 mRNA/protein and its downstream Hes1 protein in osimertinib-resistant cells. The MMP9 and MMP2 protein levels were also lessened in the resistant cells after lycorine treatment. Moreover, Notch3/Hes1 protein levels were higher in osimertinib-resistant cells than those in osimertinib-sensitive cells. Notch3 and Hes1 knockdown promoted the antiproliferation and anti-migration effects of osimertinib in the resistant cells. Notably, lycorine enhanced the antitumor activity of osimertinib against its resistant cells both in vitro and in vivo. Overall, our data reveal that lycorine inhibits the proliferation and metastasis of osimertinib-resistant NSCLC cells via Notch3/Hes1 pathway.
期刊介绍：
The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.
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