Effect of epiberberine from Coptis chinensis Franch on inhibition of tumor growth in MKN-45 xenograft mice

Min Yu; Li Ren; Fan Liang; Yaru Zhang; Lingmin Jiang; Wenyu Ma; Chunming Li; Xuegang Li; Xiaoli Ye

doi:10.1016/j.phymed.2020.153216

Effect of epiberberine from Coptis chinensis Franch on inhibition of tumor growth in MKN-45 xenograft mice

Phytomedicine. 2020 May 17:76:153216. doi: 10.1016/j.phymed.2020.153216. Online ahead of print.

Authors

Min Yu¹, Li Ren¹, Fan Liang¹, Yaru Zhang¹, Lingmin Jiang², Wenyu Ma¹, Chunming Li², Xuegang Li³, Xiaoli Ye⁴

Affiliations

¹ Chongqing Key Laboratory of Plant Resource Conservation and Germplasm Innovation, School of Life Sciences, Southwest University, Chongqing 400715, China.
² Chongqing Productivity Promotion Center of Chinese Traditional Medicine Mod-ernization, School of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China.
³ Chongqing Productivity Promotion Center of Chinese Traditional Medicine Mod-ernization, School of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China. Electronic address: Xuegangli@swu.edu.cn.
⁴ Chongqing Key Laboratory of Plant Resource Conservation and Germplasm Innovation, School of Life Sciences, Southwest University, Chongqing 400715, China. Electronic address: yexiaoli@swu.edu.cn.

PMID: 32534357
DOI: 10.1016/j.phymed.2020.153216

Abstract

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.

Keywords: Apoptosis; Cell cycle arrest; Epiberberine; Gastric cancer; p53.