Wang Chen, Zeng Chaoyang, Wang Aimin, Shang Yue, Ni Jun, Li Gaojie, Li Liping, Xi Shuohan, Wang Wendie, Chen Shuzhen
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
J Biochem Mol Toxicol. 2025 Sep;39(9):e70501. doi: 10.1002/jbt.70501.
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.
在临床应用中，非小细胞肺癌（NSCLC）对奥希替尼不可避免地会产生耐药性。石蒜碱是从石蒜科植物中分离得到的，具有多种药理作用，包括抗癌作用。在此，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检测、伤口愈合实验和迁移实验的数据表明，石蒜碱对奥希替尼耐药的NSCLC细胞具有抑制作用。在体内，石蒜碱可抑制奥希替尼耐药的NSCLC异种移植瘤的生长。转录组分析结果显示，石蒜碱可显著降低奥希替尼耐药的PC9（PC9/OR）细胞中Notch3 mRNA的水平。经证实，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。石蒜碱处理后，耐药细胞中MMP9和MMP2蛋白水平也有所降低。此外，奥希替尼耐药细胞中Notch3/Hes1蛋白水平高于奥希替尼敏感细胞。Notch3和Hes1基因敲低可促进奥希替尼对耐药细胞的抗增殖和抗迁移作用。值得注意的是，石蒜碱在体外和体内均增强了奥希替尼对其耐药细胞的抗肿瘤活性。总体而言，我们的数据表明，石蒜碱通过Notch3/Hes1途径抑制奥希替尼耐药的NSCLC细胞的增殖和转移。
