Cimigenoside functions as a novel γ-secretase inhibitor and inhibits the proliferation or metastasis of human breast cancer cells by γ-secretase/Notch axis

• Published in: Pharmacological research Vol. 169; p. 105686
• Main Authors: Jia, Hui, Liu, Mingyue, Wang, Xinying, Jiang, Qiyu, Wang, Shu, Santhanam, Ramesh Kumar, Lv, Chongning, Zhao, Qingchun, Lu, Jincai
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.07.2021
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Breast cancer; Breast Neoplasms - drug therapy; Cell Line, Tumor - drug effects; Cell Proliferation - drug effects; EMT; Female; Humans; MCF-7 Cells - drug effects; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Neoplasm Transplantation; Notch; PSEN-1; Receptors, Notch - metabolism; Triterpenes - pharmacology; Triterpenes - therapeutic use; γ-secretase; Breast cancer; γ-secretase; PSEN-1; EMT; Notch; Apoptosis
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2021.105686

Breast cancer (BC) occurrence and development tremendously affect female health. Currently breast cancer targeted drugs are still scarce. Natural products have become the main source of targeted drug for breast cancer due to low toxicity and high efficiency. Cimigenoside, natural compound isolated and purified from Cimicifuga dahurica (Turcz.) Maxim has been suggested to utilize for breast cancer treatment, however the mechanism of action has not been elucidated yet. In this article, the antitumor potential of Cimigenoside against breast cancer in vitro and in vivo study. Moreover, we further predicted the possible binding mode of Cimigenoside with γ-secretase through molecular docking studies. The results show that Cimigenoside has a significant inhibitory effect towards the proliferation or metastasis of breast cancer cells via suppressing the Notch signaling pathway-mediated mitochondrial apoptosis and EMT (epithelial mesenchymal transition). In terms of mechanism, Cimigenoside could inhibit the activation of PSEN-1, the catalytic subunit of γ-secretase, and also by cleaving the Notch protein mediated by PSEN-1. Overall, our findings provide scientific support to utilize Cimigenoside as an effective targeted drug for clinical treatment of BC. [Display omitted] ●Cimigenoside inhibits the growth of human breast cancer in vivo and in vitro.●Cimigenoside exerts anti-tumor activity by blocking Notch signaling pathway.●Cimigenoside inhibits the activation of the catalytic subunit PSEN-1 of γ-secretase.●Cimigenoside is expected to become a potential therapeutic drug for breast cancer.