Sesquiterpenoids from Eupatorium chinense L. induce G0/G1 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 IC₅₀ 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 G₀/G₁ 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.