Lycorine Exerts Antitumor Effects on the Osimertinib-Resistant Non-Small Cell Lung Cancer by Inhibiting NOTCH3/HES1 Signaling

IF 2.8 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biochemical and Molecular Toxicology Pub Date : 2025-09-15 DOI:10.1002/jbt.70501

Chen Wang, Chaoyang Zeng, Aimin Wang, Yue Shang, Jun Ni, Gaojie Li, Liping Li, Shuohan Xi, Wendie Wang, Shuzhen Chen

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Abstract

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.

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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

非小细胞肺癌（NSCLC）对奥希替尼的耐药在临床应用中不可避免地发生。石蒜碱是从amaryllidiaceae属中分离出来的，具有多种药理作用，包括抗癌作用。在这里，我们研究了石蒜碱对奥希替尼耐药细胞的影响及其潜在机制。CCK8实验、伤口愈合和迁移实验的数据显示，石蒜碱对奥希替尼耐药的NSCLC细胞有抑制作用。在体内，石蒜碱降低了耐奥西替尼的非小细胞肺癌异种移植物的生长。转录组学分析结果显示，石蒜碱显著降低了奥西莫替尼耐药PC9 （PC9/OR）细胞中Notch3 mRNA的水平。证实了石蒜碱确实降低了奥希替尼耐药细胞中Notch3 mRNA/蛋白及其下游Hes1蛋白的水平。耐药细胞中MMP9和MMP2蛋白水平也在石蒜碱处理后降低。此外，奥希替尼耐药细胞的Notch3/Hes1蛋白水平高于奥希替尼敏感细胞。Notch3和Hes1敲低可促进奥西替尼在耐药细胞中的抗增殖和抗迁移作用。值得注意的是，在体内和体外，石蒜碱都增强了奥希替尼对其耐药细胞的抗肿瘤活性。总的来说，我们的数据显示，石蒜碱通过Notch3/Hes1途径抑制奥西替尼耐药NSCLC细胞的增殖和转移。

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来源期刊

Journal of Biochemical and Molecular Toxicology 生物-毒理学

CiteScore

5.80

自引率

2.80%

发文量

277

审稿时长

6-12 weeks

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.