Sesquiterpenoids from Eupatorium chinense L. induce G/G cell cycle arrest and apoptosis in AGS cell via DNA-PK/AKT/p53 pathway.

Ten undescribed sesquiterpenes, including 5 undescribed guaiane-type sesquiterpenes (1-5) and 5 undescribed gemmarane-type sesquiterpenes (6-10), along with fourteen known analogues (11-24) were isolated from the whole plants of Eupatorium chinense L. They structures were determined by interpretation of spectroscopic data (UV, NMR, ECD, HRESIMS, and DP4+). The cytotoxicity of sesquiterpene derivatives (1-24) was evaluated against five human cancer cell lines (Hep3B, A549, AGS, MCF-7, and HCT-116). Among these, compound 1 exhibited the most potent cytotoxic activity against the gastric adenocarcinoma AGS cell line, with an IC value of 4.33 μM. Mechanistic studies revealed that compound 1 suppresses the DNA-PK/AKT/p53 signaling pathway in AGS cells. Concomitantly, it upregulates p21 protein expression while downregulating CDK4 and cyclin D protein levels, inducing G/G phase cell cycle arrest. Furthermore, compound 1 promotes apoptosis by increasing Bax expression and decreasing Bcl-2 expression. Collectively, these findings establish compound 1 as a promising lead candidate for the development of novel anti-gastric cancer therapeutics.