DU145型
PI3K/AKT/mTOR通路
化学
药理学
蛋白激酶B
活力测定
细胞生长
癌症研究
MCF-7型
细胞凋亡
癌细胞
癌症
生物化学
生物
内科学
医学
LNCaP公司
人体乳房
作者
Hongyan Lin,Dashan Ai,Qingqing Liu,Wang Xl,Qingqing Chen,Zongchao Hong,Yuheng Tao,Jian Gao,Hongyan Lin
标识
DOI:10.1016/j.jsbmb.2023.106426
摘要
Glabridin is a natural isoflavone with estrogen receptor agonism and significant anti-tumor activity. Additionally, glabridin has a regulation effect on PI3K/AKT/mTOR pathway, but its exact target remains unclear. In this study, we evaluated the antitumor activity of glabridin against breast cancer and prostate cancer cells, and further clarified its targeting to PI3K. We found that glabridin could significantly inhibit the cell viability of human breast cancer and prostate cancer cell lines. It induced caspase activation cascade and cell apoptosis through decreasing the mitochondrial transmembrane potential and increasing the intracellular reactive oxygen species (ROS). Moreover, glabridin could attenuate epithelial-mesenchymal transition (EMT) progression by inhibiting cell migration. PharmMapper calculation showed that PI3Kγ might be the most potential target protein because of the highest Normal Fit score (0.9735) and z'-score (0.9797). Molecular docking and bio-layer interferometry (BLI) analysis further demonstrated the PI3Kγ targeting of glabridin. In vivo experiments showed that glabridin can effectively inhibit the tumor growth of breast cancer xenograft model, and does not show obvious hepatorenal toxicity. Moreover, glabridin could effectively promote the anti-proliferation and pro-apoptotic effects of tamoxifen on MDA-MB-231 cell and taxol on DU145 cell. Elucidating the targeting of glabridin to PI3K may lay a theoretical foundation for the structural derivatization of glabridin, which is expected to greatly promote the application and development of glabridin in the field of cancer therapy.
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