Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside Rg3 in combination with artesunate overcomes sorafenib resistance in hepatoma cell and mouse models

  • Chen, Ying-Jie (School of Chinese Medicine, Hong Kong Baptist University) ;
  • Wu, Jia-Ying (School of Chinese Medicine, Hong Kong Baptist University) ;
  • Deng, Yu-Yi (School of Chinese Medicine, Hong Kong Baptist University) ;
  • Wu, Ying (School of Chinese Medicine, Hong Kong Baptist University) ;
  • Wang, Xiao-Qi (School of Chinese Medicine, Hong Kong Baptist University) ;
  • Li, Amy Sze-man (School of Chinese Medicine, Hong Kong Baptist University) ;
  • Wong, Lut Yi (School of Chinese Medicine, Hong Kong Baptist University) ;
  • Fu, Xiu-Qiong (School of Chinese Medicine, Hong Kong Baptist University) ;
  • Yu, Zhi-Ling (School of Chinese Medicine, Hong Kong Baptist University) ;
  • Liang, Chun (Division of Life Science, Hong Kong University of Science and Technology)
  • Received : 2021.04.20
  • Accepted : 2021.07.07
  • Published : 2022.05.01
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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, overactivation 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.

Keywords

Acknowledgement

This study was supported by Jilin Yatai (Group) Co., Ltd., Guangzhou MSTB (grant No.: 202009020005), Hong Kong ITC (Grant No.: ITS/092/20), Shenzhen STIC (grant No.: JCYJ20200109150719846) and STIB of Guangzhou Development District (grant No.: CY2019-005).

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