Ginsenoside Rk3 is a novel PI3K/AKT-targeting therapeutics agent that regulates autophagy and apoptosis in hepatocellular carcinoma

Linlin Qu; Yannan Liu; Jianjun Deng; Xiaoxuan Ma; Daidi Fan

doi:10.1016/j.jpha.2023.03.006

Ginsenoside Rk3 is a novel PI3K/AKT-targeting therapeutics agent that regulates autophagy and apoptosis in hepatocellular carcinoma

J Pharm Anal. 2023 May;13(5):463-482. doi: 10.1016/j.jpha.2023.03.006. Epub 2023 Mar 24.

Authors

Linlin Qu^{1

2

3

4}, Yannan Liu^{1

2

3}, Jianjun Deng^{1

2

3}, Xiaoxuan Ma^{1

2

3}, Daidi Fan^{1

2

3}

Affiliations

¹ Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an, 710069, China.
² Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an, 710069, China.
³ Biotech. & Biomed. Research Institute, Northwest University, Xi'an, 710069, China.
⁴ Xi'an Giant Biotechnology Co., Ltd., Xi'an, 710076, China.

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Ginsenoside Rk3, an important and rare saponin in heat-treated ginseng, is generated from Rg1 and has a smaller molecular weight. However, the anti-HCC efficacy and mechanisms of ginsenoside Rk3 have not yet been characterized. Here, we investigated the mechanism by which ginsenoside Rk3, a tetracyclic triterpenoid rare ginsenoside, inhibits the growth of HCC. We first explored the possible potential targets of Rk3 through network pharmacology. Both in vitro (HepG2 and HCC-LM3 cells) and in vivo (primary liver cancer mice and HCC-LM3 subcutaneous tumor-bearing mice) studies revealed that Rk3 significantly inhibits the proliferation of HCC. Meanwhile, Rk3 blocked the cell cycle in HCC at the G1 phase and induced autophagy and apoptosis in HCC. Further proteomics and siRNA experiments showed that Rk3 regulates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway to inhibit HCC growth, which was validated by molecular docking and surface plasmon resonance. In conclusion, we report the discovery that ginsenoside Rk3 binds to PI3K/AKT and promotes autophagy and apoptosis in HCC. Our data strongly support the translation of ginsenoside Rk3 into novel PI3K/AKT-targeting therapeutics for HCC treatment with low toxic side effects.

Keywords: Apoptosis; Autophagy; Ginsenoside Rk3; Hepatocellular carcinoma; PI3K/AKT pathway.