3-Epipachysamine B suppresses proliferation and induces apoptosis of breast cancer cell via PI3K/AKT/mTOR signaling pathway.

Abstract

3-Epipachysamine B is a natural steroidal alkaloid isolated from Pachysandra terminalis Sieb. et Zucc. (known locally as Kunxianqi). Kunxianqi contains numerous compounds with demonstrated activity against breast cancer (BRCA). However, it is unknown whether 3-epipachysamine B also has anti-BRCA efficacy. In the present study, we employed network pharmacology technology to search and find potential molecular targets of 3-epipachysamine B. We applied cell proliferation, apoptosis, and western blotting assays to test the predicted key targets and the effects of 3-epipachysamine B against BRCA. Network pharmacology disclosed 80 potential BRCA-related targets of 3-epipachysamine B and assigned them to 75 signaling pathways. Of these, the most highly enriched was the PI3K/AKT signaling pathway. PIK3R1, AKT1, and mTOR had high degrees and betweenness centrality in protein-protein interaction network and are associated with PI3K/AKT signaling. Molecular docking and molecular dynamics simulation indicated strong binding between 3-epipachysamine B and PIK3R1, AKT1, and mTOR. 3-Epipachysamine B repressed the proliferation and induced the apoptosis of BRCA cells, as well as downregulated P-AKT/AKT, P-mTOR/mTOR, and P-PI3K/PI3K in the cells. The PI3K inhibitor LY294002 augmented these changes. Hence, 3-epipachysamine could also prove effective as an anticancer agent in future animal tumor model and human clinical breast cancer trials. Successful validation results could lead to a safe and effective new breast cancer treatment that improves patient prognosis and quality of life.