Ginsenoside Rg3 in combination with artesunate overcomes sorafenib resistance in hepatoma cell and mouse models

Ying Jie Chen, Jia Ying Wu, Yu Yi Deng, Ying Wu, Xiao Qi Wang, Amy Sze Man Li, Lut Yi Wong, Xiu Qiong Fu*, Zhi Ling Yu*, Chun Liang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background 

Sorafenib is effective in treating hepatoma, but most patients develop resistance to it. STAT3 signaling has been implicated in sorafenib resistance. Artesunate (ART) and 20(R)-ginsenoside Rg3 (Rg3) have anti-hepatoma effects and can inhibit STAT3 signaling in cancer cells. This study aimed to evaluate the effects of Rg3 in combination with ART (Rg3-plus-ART) in overcoming sorafenib resistance, and to examine the involvement of STAT3 signaling in these effects. 

Methods

Sorafenib-resistant HepG2 cells (HepG2-SR) were used to evaluate the in vitro anti-hepatoma effects of Rg3-plus-ART. A HepG2-SR hepatoma-bearing BALB/c-nu/nu mouse model was used to assess the in vivo anti-hepatoma effects of Rg3-plus-ART. CCK-8 assays and Annexin V-FITC/PI double staining were used to examine cell proliferation and apoptosis, respectively. Immunoblotting was employed to examine protein levels. ROS generation was examined by measuring DCF-DA fluorescence. 

Results

Rg3-plus-ART synergistically reduced viability of, and evoked apoptosis in HepG2-SR cells, and suppressed HepG2-SR tumor growth in mice. Mechanistic studies revealed that Rg3-plus-ART inhibited activation/phosphorylation of Src and STAT3 in HepG2-SR cultures and tumors. The combination also decreased the STAT3 nuclear level and induced ROS production in HepG2-SR cultures. Furthermore, over-activation of STAT3 or removal of ROS diminished the anti-proliferative effects of Rg3-plus-ART, and removal of ROS diminished Rg3-plus-ART's inhibitory effects on STAT3 activation in HepG2-SR cells. 

Conclusions

Rg3-plus-ART overcomes sorafenib resistance in experimental models, and inhibition of Src/STAT3 signaling and modulation of ROS/STAT3 signaling contribute to the underlying mechanisms. This study provides a pharmacological basis for developing Rg3-plus-ART into a novel modality for treating sorafenib-resistant hepatoma.

Original languageEnglish
Pages (from-to)418-425
Number of pages8
JournalJournal of Ginseng Research
Volume46
Issue number3
Early online date14 Jul 2021
DOIs
Publication statusPublished - May 2022

Scopus Subject Areas

  • Biotechnology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Complementary and alternative medicine

User-Defined Keywords

  • Artesunate
  • Ginsenoside Rg3
  • Hepatoma
  • Sorafenib resistance
  • STAT3 signaling

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