Evodiamine inhibits growth of vemurafenib drug-resistant melanoma via suppressing IRS4/PI3K/AKT signaling pathway

作者全名："Guo, Xingxian; Huang, Shiying; Zhang, Yonghong; Wang, Hong; Li, Lisha; Ran, Jianhua; Chen, Dilong; Li, Xiaopeng; Li, Jing"

作者地址："[Guo, Xingxian] Chongqing Med Univ, Ctr Lipid Res, Minist Educ, Chongqing, Peoples R China; [Guo, Xingxian] Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Minist Educ, Chongqing, Peoples R China; [Huang, Shiying] Zigong First Peoples Hosp, Dept Clin Lab, Zigong, Peoples R China; [Li, Lisha; Li, Jing] Chongqing Med Univ, Dept Histol & Embryol, Lab Stem Cell & Tissue Engn, Chongqing 400010, Peoples R China; [Wang, Hong] Chongqing Med Univ, Chongqing Hlth Ctr Women & Children, Dept Pharm, Women & Childrens Hosp, Chongqing, Peoples R China; [Zhang, Yonghong] Chongqing Med Univ, Clin Big Data & Drug Evaluat Med Data Sci Acad, Chongqing Engn Res Ctr, Chongqing, Peoples R China; [Ran, Jianhua] Chongqing Med Univ, Coll Basic Med, Neurosci Res Ctr, Chongqing, Peoples R China; [Chen, Dilong; Li, Xiaopeng] Chongqing Three Gorges Med Coll, Fac Basic Med Sci, Chongqing Key Lab Dev & Utilizat Genuine Med Mat T, Wanzhou 404100, Peoples R China; [Chen, Dilong] Chongqing Inst Food & Drug Control, NMPA Key Lab Qual Monitoring Narcot Drugs & Psycho, Chongqing, Peoples R China"

通信作者："Li, J (通讯作者)，Chongqing Med Univ, Dept Histol & Embryol, Lab Stem Cell & Tissue Engn, Chongqing 400010, Peoples R China.; Li, XP (通讯作者)，Chongqing Three Gorges Med Coll, Fac Basic Med Sci, Chongqing Key Lab Dev & Utilizat Genuine Med Mat T, Wanzhou 404100, Peoples R China."

来源：JOURNAL OF NATURAL MEDICINES

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001156938100001

JCR分区：Q3

影响因子：2.5

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Evodiamine IRS4 vemurafenib-resistant melanoma growth

摘要："Evodiamine, a novel alkaloid, was isolated from the fruit of tetradium. It exerts a diversity of pharmacological effects and has been used to treat gastropathy, hypertension, and eczema. Several studies reported that evodiamine has various biological effects, including anti-nociceptive, anti-bacterial, anti-obesity, and anti-cancer activities. However, there is no research regarding its effects on drug-resistant cancer. This study aimed to investigate the effect of evodiamine on human vemurafenib-resistant melanoma cells (A375/R cells) proliferation ability and its mechanism. Cell activity was assessed using the cell counting kit-8 (CCK-8) method. Flow cytometry assay was used to assess cell apoptosis and cell cycle. A xenograft model was used to analyze the inhibitory effects of evodiamine on tumor growth. Bioinformatics analyses, network pharmacology, and molecular docking were used to explore the potential mechanism of evodiamine in vemurafenib-resistant melanoma. RT-qPCR and Western blotting were performed to reveal the molecular mechanism. The alkaloid extract of the fruit of tetradium, evodiamine showed the strongest tumor inhibitory effect on vemurafenib-resistant melanoma cells compared to treatment with vemurafenib alone. Evodiamine inhibited vemurafenib-resistant melanoma cell growth, proliferation, and induced apoptosis, conforming to a dose-effect relationship and time-effect relationship. Results from network pharmacology and molecular docking suggested that evodiamine might interact with IRS4 to suppress growth of human vemurafenib-resistant melanoma cells. Interestingly, evodiamine suppressed IRS4 expression and then inhibited PI3K/AKT signaling pathway, and thus had the therapeutic action on vemurafenib-resistant melanoma."

基金机构：Chongqing Municipal Education Commission; Chongqing Medical University

基金资助正文："We appreciate the great assistance of Lab of Stem Cell and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University."