Zhang Jihang, Li Changling, Li Wenyi, Shi Zhenpeng, Liu Zhenguo, Zhou Junyu, Tang Jing, Ren Zixuan, Qiao Yun, Liu Deshan
The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China.
Research Center for Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China.
Front Oncol. 2024 Nov 8;14:1471109. doi: 10.3389/fonc.2024.1471109. eCollection 2024.
Luteolin, a naturally occurring flavonoid compound, demonstrates promising anti-cancer properties. However, its mechanism against non-small-cell lung cancer (NSCLC) remains unknown. This study employed network pharmacology, molecular docking, molecular dynamics simulation (MDS), and experiments to investigate the potential mechanisms by which luteolin against NSCLC.
Initially, the potential targets of luteolin and NSCLC-related targets were identified from public databases such as TCMSP, GeneCards, OMIM, DrugBank, and TTD. Subsequently, the protein-protein interaction (PPI) network screening and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. The binding affinity and stability of luteolin with the core targets were assessed using molecular docking and MDS. Finally, the results were validated by experiments.
A total of 56 luteolin targets and 2145 NSCLC-related targets were identified. Six core targets, TP53, EGFR, AKT1, TNF, JUN, and CASP3, were screened via the PPI network. The GO and KEGG analyses indicated that luteolin's activity against NSCLC potentially involves PI3K-Akt, NF-kappa B, and other signaling pathways. Molecular docking revealed that luteolin had high binding affinity with the core targets. MDS confirmed the stable interaction between luteolin and key proteins TP53 and AKT1. , luteolin significantly inhibited the proliferation and migration of A549 cells, while also inducing apoptosis. In addition, luteolin downregulated the expression of p-Akt (Ser473), MDM2, and Bcl-2 but upregulated the expression of p53 and Bax, which was consistent with the effect of LY294002.
Luteolin had a good anti-NSCLC effect, and the apoptosis-inducing effect might be related to the Akt/MDM2/p53 signaling pathway.
木犀草素是一种天然存在的黄酮类化合物，具有良好的抗癌特性。然而，其抗非小细胞肺癌（NSCLC）的机制尚不清楚。本研究采用网络药理学、分子对接、分子动力学模拟（MDS）和实验来探究木犀草素抗NSCLC的潜在机制。
首先，从中药系统药理学数据库与分析平台（TCMSP）、基因卡片（GeneCards）、在线人类孟德尔遗传数据库（OMIM）、药物银行（DrugBank）和治疗靶点数据库（TTD）等公共数据库中确定木犀草素的潜在靶点和NSCLC相关靶点。随后，进行蛋白质-蛋白质相互作用（PPI）网络筛选以及基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。使用分子对接和MDS评估木犀草素与核心靶点的结合亲和力和稳定性。最后，通过实验验证结果。
共鉴定出56个木犀草素靶点和2145个NSCLC相关靶点。通过PPI网络筛选出6个核心靶点，即TP53、表皮生长因子受体（EGFR）、蛋白激酶B1（AKT1）、肿瘤坏死因子（TNF）、原癌基因蛋白c-Jun（JUN）和半胱天冬酶3（CASP3）。GO和KEGG分析表明，木犀草素抗NSCLC的活性可能涉及磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）、核因子κB（NF-κB）等信号通路。分子对接显示木犀草素与核心靶点具有高结合亲和力。MDS证实了木犀草素与关键蛋白TP53和AKT1之间的稳定相互作用。此外，木犀草素显著抑制A549细胞的增殖和迁移，同时诱导细胞凋亡。此外，木犀草素下调磷酸化蛋白激酶B（Ser473）（p-Akt（Ser473））、小鼠双微体2（MDM2）和Bcl-2的表达，但上调p53和Bax的表达，这与LY294002的作用一致。
木犀草素具有良好的抗NSCLC作用，其诱导细胞凋亡的作用可能与Akt/MDM2/p53信号通路有关。
