Ginsenoside Rg3 in combination with artesunate overcomes sorafenib resistance in hepatoma cell and mouse models
© 2021 The Korean Society of Ginseng. Publishing services by Elsevier B.V..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:46 |
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| Enthalten in: |
Journal of ginseng research - 46(2022), 3 vom: 15. Mai, Seite 418-425 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Ying-Jie [VerfasserIn] |
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| Links: |
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| Themen: |
Artesunate |
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| Anmerkungen: |
Date Revised 16.07.2022 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.jgr.2021.07.002 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM341233447 |
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| 100 | 1 | |a Chen, Ying-Jie |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Ginsenoside Rg3 in combination with artesunate overcomes sorafenib resistance in hepatoma cell and mouse models |
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| 520 | |a © 2021 The Korean Society of Ginseng. Publishing services by Elsevier B.V. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Artesunate | |
| 650 | 4 | |a Ginsenoside Rg3 | |
| 650 | 4 | |a Hepatoma | |
| 650 | 4 | |a STAT3 signaling | |
| 650 | 4 | |a Sorafenib resistance | |
| 700 | 1 | |a Wu, Jia-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Yu-Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiao-Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Amy Sze-Man |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Lut Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Xiu-Qiong |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Zhi-Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Chun |e verfasserin |4 aut | |
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