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Background and Purpose: Gastric cancer is one of the major malignancies worldwide. Epiberberine (EPI) is a major alkaloid from Coptis chinensis Franch and the antitumor property of EPI remains poorly understood.Method: The inhibition on gastric cancer cells was observed by MTT assays and colony formation experiments. The apoptosis, cell cycle, and reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) in gastric cancer cells were analyzed by Flow cytometry. The anti-tumor effect of EPI was evaluated with the MKN-45-beraring nude mice, and the potential mechanisms were explored by RNA-seq, qPCR, siRNA silencing and western blotting.Results: EPI inhibited the proliferation of human gastric cancer cell lines MKN-45 (harboring wild-type p53) and HGC-27 (harboring mutant p53) in a dose dependent manner. EPI induced the apoptosis and cell cycle arrest in these two cell lines, of which MKN-45 cells are more sensitive to EPI than HGC-27 cells. Further experiments indicated that EPI induced the accumulation of ROS and decreased of ΔΨm in MKN-45 cells. The significant differentially expressed genes obtained by RNA-seq were distinctly enriched in the p53 signaling pathway. The apoptosis induced by EPI in MKN-45 cells would be effectively inhibited with the treatment of p53 siRNA and p53 inhibitor PFT-α. Western blotting demonstrated that EPI diminished the expression of Bcl-2 and XIAP, and increased those of p53, Bax, p21, p27, Cytochrome C and Cleaved-caspase 3. Animal experiments confirmed that EPI significantly alleviated tumor growth in MKN-45 xenograft mice via p53/Bax pathway.Conclusions: These data indicated that EPI could be a novel anti-tumor candidate against MKN-45-related gastric cancer via targeting p53-dependent mitochondria-associated pathway. [ABSTRACT FROM AUTHOR]

• Cucurbitacin IIb (CuIIb) exhibited the proliferation inhibitory activity in A549 cells. • CuIIb induced apoptosis via STAT3 pathway. • CuIIb suppressed the cell cycle and resulted G2/M phase cell cycle arrest. • Leu694 and Met769 are key amino acids for EGFR-CuIIb binding. • CuIIb inhibited the kinase activity of EGFR and may serve as a potential EGFR TKI. Epidermal growth factor receptor (EGFR) is considered as a valid target in the clinical trials of anticancer therapy and tyrosine kinase inhibitors (TKIs) of EGFR are approved for cancer treatments. In present work, cucurbitacin IIb (CuIIb) was confirmed to exhibit the proliferation inhibitory activity in A549 cells. CuIIb induced apoptosis via STAT3 pathway, which was mitochondria-mediated and caspase-dependent. CuIIb also suppressed the cell cycle and induced G2/M phase cell cycle arrest. CuIIb was capable of suppressing the signal transmitting of the EGFR/mitogen-activated protein kinase (MAPK) pathway which was responsible for the apoptosis and cell cycle arrest. Homogeneous time-resolved fluorescence (HTRF) analysis demonstrated that the kinase activity of EGFR was inhibited by CuIIb. Molecular docking suggested that the CuIIb-EGFR binding fundamentally depends on the contribution of both hydrophobic and hydrogen-bonding interactions. Hence CuIIb may serve as a potential EGFR TKI. [ABSTRACT FROM AUTHOR]