Fangchinoline derivatives inhibits PI3K signaling in vitro and in vivo in non-small cell lung cancer

文献类型： 外文期刊

第一作者： Chen, Jia-shu

作者： Chen, Jia-shu;Guo, Xu;Sun, Jin-yue;Wang, Mu-xuan;Gao, Xiu-zheng;Han, Jin-long;Sun, Hui;Liu, Chao;Wang, Zhen;Zhang, Kai

作者机构：

关键词： Fangchinoline; Anticancer; In vitro and in vivo; Molecular mechanism

期刊名称：BIOORGANIC CHEMISTRY （ 影响因子：5.1； 五年影响因子：5.3 ）

ISSN： 0045-2068

年卷期： 2023 年 138 卷

页码：

收录情况： SCI

摘要： Fangchinoline (Fan) are extracted from the traditional Chinese medicine Stephania tetrandra S., which is a bis -benzyl isoquinoline alkaloids with anti-tumor activity. Therefore, 25 novel Fan derivatives have been synthe-sized and evaluated for their anti-cancer activity. In CCK-8 assay, these fangchinoline derivatives displayed higher proliferation inhibitory activity on six tumor cell lines than the parental compound. Compared to the parent Fan, compound 2h presented the anticancer activity against most cancer cells, especially A549 cells, with an IC50 value of 0.26 & mu;M, which was 36.38-fold, and 10.61-fold more active than Fan and HCPT, respectively. Encouragingly, compound 2h showed low biotoxicity to the human normal epithelial cell BEAS-2b with an IC50 value of 27.05 & mu;M. The results indicated compound 2h remarkably inhibited the cell migration by decreasing MMP-2 and MMP-9 expression and inhibited the proliferation of A549 cells by arresting the G2/M cell cycle. Meanwhile, compound 2h could also induce A549 cell apoptosis by promoting endogenous pathways of mito-chondrial regulation. In nude mice presented that the growth of tumor tissues was markedly inhibited by the consumption of compound 2h in a dose-dependent manner, and it was found that compound 2h could inhibit the mTOR/PI3K/AKT pathway in vivo. In docking analysis, high affinity interaction between 2h and PI3K was responsible for drastic kinase inhibition by the compound. To conclude, this derivative compound may be useful as a potent anti-cancer agent for treatment of NSCLC.

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