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

Volume 13 Issue 5

May 2023

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Linlin Qu, Yannan Liu, Jianjun Deng, Xiaoxuan Ma, Daidi Fan. Ginsenoside Rk3 is a novel PI3K/AKT-targeting therapeutics agent that regulates autophagy and apoptosis in hepatocellular carcinoma[J]. Journal of Pharmaceutical Analysis, 2023, 13(5): 463-482. doi: 10.1016/j.jpha.2023.03.006

Citation:

Linlin Qu, Yannan Liu, Jianjun Deng, Xiaoxuan Ma, Daidi Fan. Ginsenoside Rk3 is a novel PI3K/AKT-targeting therapeutics agent that regulates autophagy and apoptosis in hepatocellular carcinoma[J]. Journal of Pharmaceutical Analysis, 2023, 13(5): 463-482. doi: 10.1016/j.jpha.2023.03.006

Citation:

Linlin Qu, Yannan Liu, Jianjun Deng, Xiaoxuan Ma, Daidi Fan. Ginsenoside Rk3 is a novel PI3K/AKT-targeting therapeutics agent that regulates autophagy and apoptosis in hepatocellular carcinoma[J]. Journal of Pharmaceutical Analysis, 2023, 13(5): 463-482. doi: 10.1016/j.jpha.2023.03.006

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

doi: 10.1016/j.jpha.2023.03.006

Linlin Qu^a,b,c,d,
Yannan Liu^a,b,c,
Jianjun Deng^a,b,c,
Xiaoxuan Ma^a,b,c,
Daidi Fan^{a,b,c
,
,}

a. Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an, 710069, China;
b. Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an, 710069, China;
c. Biotech. & Biomed. Research Institute, Northwest University, Xi'an, 710069, China;
d. Xi'an Giant Biotechnology Co., Ltd., Xi'an, 710076, China

Funds:

This work was financially supported by the National Key R&D Program of China (Grant No.: 2021YFC2101500), the National Natural Science Foundation of China (Grant Nos.: 22078264, 21978235, 22108224, and 21978236), the Natural Science Basic Research Program of Shaanxi, China (Grant Nos.: 2023-JC-JQ-17 and 2023-JC-QN-0109), the Xi'an Science and Technology Project, China (Project No.: 20191422315KYPT014JC016), and Key Research and Development Program of Shaanxi, China (Grant No.: 2022ZDLSF05-12).

Received Date: Dec. 07, 2022
Accepted Date: Mar. 21, 2023
Rev Recd Date: Mar. 17, 2023
Publish Date: Mar. 24, 2023

Abstract

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.
- Hepatocellular carcinoma,
- Ginsenoside Rk3,
- Apoptosis,
- Autophagy,
- PI3K/AKT pathway

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References(65)

References

H. Sung, J. Ferlay, R. Siegel, et al., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA-Cancer J. Clin. 71 (2021) 209-249.

R. Zheng, S. Zhang, H. Zeng, et al., Cancer incidence and mortality in China, 2016, J. Natl. Cancer Cent. 2 (2022) 1-9.

Z. Dai, X. Wang, R. Peng, et al., Induction of IL-6Rα by ATF3 enhances IL-6 mediated sorafenib and regorafenib resistance in hepatocellular carcinoma, Cancer Lett. 524 (2022) 161-171.

J. Xu, L. Ji, Y. Ruan, et al., UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma, Signal Transduct. Target. Ther. 6 (2021), 190.

G. Tossetta, D. Marzioni, Natural and synthetic compounds in ovarian cancer: A focus on NRF2/KEAP1 pathway, Pharmacol. Res. 183 (2022), 106365.

R. Zhong, M. Farag, M. Chen, et al., Recent advances in the biosynthesis, structure-activity relationships, formulations, pharmacology, and clinical trials of fisetin, eFood 3 (2022) e3.

Y. Hai, Y. Zhang, Y. Liang, et al., Advance on the absorption, metabolism, and efficacy exertion of quercetin and its important derivatives, Food Front. 1 (2020) 420-434.

J. Higbee, P. Solverson, M. Zhu, et al., The emerging role of dark berry polyphenols in human health and nutrition, Food Front. 3 (2022) 3-27.

J. Ren, Bringing to fore the role of peptides, polyphenols, and polysaccharides in health: the research profile of Jiaoyan Ren, Food Front. 2 (2021) 29-31.

Y. Liu, D. Fan, Ginsenoside Rg5 induces G2/M phase arrest, apoptosis and autophagy via regulating ROS-mediated MAPK pathways against human gastric cancer, Biochem. Pharmacol. 168 (2019) 285-304.

Y. Zhu, C. Zhu, H. Yang, et al., Protective effect of ginsenoside Rg5 against kidney injury via inhibition of NLRP3 inflammasome activation and the MAPK signaling pathway in high-fat diet/streptozotocin-induced diabetic mice, Pharmacol. Res. 155 (2020), 104746.

H. Liu, X. Lu, Y. Hu, et al., Chemical constituents of Panax ginseng and Panax notoginseng explain why they differ in therapeutic efficacy, Pharmacol. Res. 161 (2020), 105263.

H. Chen, H. Yang, D. Fan, et al., The anticancer activity and mechanisms of ginsenosides: An updated review, eFood 1 (2020) 226-241.

L. Qu, Y. Zhu, Y. Liu, et al., Protective effects of ginsenoside Rk3 against chronic alcohol-induced liver injury in mice through inhibition of inflammation, oxidative stress, and apoptosis, Food Chem. Toxicol. 126 (2019) 277-284.

B. Wei, Z. Duan, C. Zhu, et al., Anti-anemia effects of ginsenoside Rk3 and ginsenoside Rh4 on mice with ribavirin-induced anemia, Food Funct. 9 (2018) 2447-2455.

Y. Liu, J. Deng, D. Fan, Ginsenoside Rk3 ameliorates high-fat-diet/streptozocin induced type 2 diabetes mellitus in mice via the AMPK/Akt signaling pathway, Food Funct. 10 (2019) 2538-2551.

Z. Duan, J. Deng, Y. Dong, et al., Anticancer effects of ginsenoside Rk3 on non-small cell lung cancer cells: In vitro and in vivo, Food Funct. 8 (2017) 3723-3736.

S. Noorolyai, N. Shajari, E. Baghbani, et al., The relation between PI3K/AKT signalling pathway and cancer, Gene 698 (2019) 120-128.

Y. Wu, Y. Zhang, X. Qin, et al., PI3K/AKT/mTOR pathway-related long non-coding RNAs: Roles and mechanisms in hepatocellular carcinoma, Pharmacol. Res. 160 (2020), 105195.

B. Hennessy, D. Smith, P. Ram, et al., Exploiting the PI3K/AKT pathway for cancer drug discovery, Nat. Rev. Drug Discov. 4 (2005) 988-1004.

N. Hay, The Akt-mTOR tango and its relevance to cancer, Cancer Cell 8 (2005) 179-183.

A. Capodanno, A. Camerini, C. Orlandini, et al., Dysregulated PI3K/Akt/PTEN pathway is a marker of a short disease-free survival in node-negative breast carcinoma, Hum. Pathol. 40 (2009) 1408-1417.

I. Vivanco, Z.C. Chen, B. Tanos, et al., A kinase-independent function of AKT promotes cancer cell survival, eLife 3 (2014), e03751.

I. Sanidas, C. Polytarchou, M. Hatziapostolou, et al., Phosphoproteomics screen reveals Akt isoform-specific signals linking RNA processing to lung cancer, Mol. Cell 53 (2014) 577-590.

Q. Ye, W. Cai, Y. Zheng, et al., ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer, Oncogene 33 (2014) 1828-1839.

S. Yue, J. Li, S. Lee, et al., Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness, Cell Metab. 19 (2014) 393-406.

S. Xue, Y. Zhou, J. Zhang, et al., Anemoside B4 exerts anti-cancer effect by inducing apoptosis and autophagy through inhibiton of PI3K/Akt/mTOR pathway in hepatocellular carcinoma, Am. J. Transl. Res. 11 (2019) 2580-2589.

M. Kwon, T. Nam, A polysaccharide of the marine Alga Capsosiphon fulvescens induces apoptosis in AGS gastric cancer cells via an IGF-IR-mediated PI3K/Akt pathway, Cell Biol. Int. 31 (2007) 768-775.

A. Hopkins, Network pharmacology: The next paradigm in drug discovery, Nat. Chem. Biol. 4 (2008) 682-690.

E. Nottingham, E. Mazzio, S. Surapaneni, et al., Synergistic effects of methyl 2-cyano-3, 11-dioxo-18beta-olean-1,-12-dien-30-oate and erlotinib on erlotinib-resistant non-small cell lung cancer cells, J. Pharm. Anal. 11 (2021) 799-807.

Z. Li, L. Mao, B. Yu, et al., GB7 acetate, a galbulimima alkaloid from Galbulimima belgraveana, possesses anticancer effects in colorectal cancer cells, J. Pharm. Anal. 12 (2022) 339-349.

M. Rodriguez-Hernandez, R. Gonzalez, A. de la Rosa, et al., Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells, J. Cell Physiol. 234 (2018) 692-708.

T. Uehara, I. Pogribny, I. Rusyn, The DEN and CCl4-induced mouse model of fibrosis and inflammation-associated hepatocellular carcinoma, Curr. Protoc. Pharmacol. 66 (2014), 1430.

J. Ye, L. Li, J. Yin, et al., Tumor-targeting intravenous lipid emulsion of paclitaxel: Characteristics, stability, toxicity, and toxicokinetics, J. Pharm. Anal. 12 (2022) 901-912.

X. Jiang, Y. Lin, Y. Wu, et al., Identification of potential anti-pneumonia pharmacological components of Glycyrrhizae Radix et Rhizoma after the treatment with Gan An He Ji oral liquid, J. Pharm. Anal. 12 (2022) 839-851.

Y. Zhao, Y. Wang, Y. Wu, et al., PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson’s disease in diabetic rats, J. Pharm. Anal. 13 (2023) 187-200.

W. Ye, L. Li, Z. Feng, et al., Sensitive detection of alkaline phosphatase based on terminal deoxynucleotidyl transferase and endonuclease IV-assisted exponential signal amplification, J. Pharm. Anal. 12 (2022) 692-697.

X. Wang, Y. Shen, S. Wang, et al., PharmMapper 2017 update: A web server for potential drug target identification with a comprehensive target pharmacophore database, Nucleic Acids Res. 45 (2017) W356-W360.

D. Szklarczyk, J. Morris, H. Cook, et al., The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible, Nucleic Acids Res. 45 (2017) D362-D368.

P. Shannon, A. Markiel, O. Ozier, et al., Cytoscape: A software environment for integrated models of biomolecular interaction networks, Genome Res. 13 (2003) 2498-2504.

D. Huang, B. Sherman, R. Lempicki, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources, Nat. Protoc. 4 (2009) 44-57.

Y. Meng, J. Chen, Y. Liu, et al., A highly efficient protein corona-based proteomic analysis strategy for the discovery of pharmacodynamic biomarkers, J. Pharm. Anal. 12 (2022) 879-888.

D. Chandrashekar, B. Bashel, S. Balasubramanya, et al., UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses, Neoplasia 19 (2017) 649-658.

R. Kerbel, Antiangiogenic therapy: A universal chemosensitization strategy for cancer?, Science 312 (2006) 1171-1175.

U. Harkus, M. Wankell, P. Palamuthusingam, et al., Immune checkpoint inhibitors in HCC: Cellular, molecular and systemic data, Semin. Cancer Biol. 86 (2022) 799-815.

A. Singal, E. Zhang, M. Narasimman, et al., HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis, J. Hepatol. 77 (2022) 128-139.

J. Bai, Y. Li, G. Zhang, Cell cycle regulation and anticancer drug discovery, Cancer Biol. Med. 14 (2017) 348-362.

M. Hong, M. Almutairi, S. Li, et al., Wogonin inhibits cell cycle progression by activating the glycogen synthase kinase-3 beta in hepatocellular carcinoma, Phytomedicine 68 (2020), 153174.

M. Ingham, G. Schwartz, Cell-cycle therapeutics come of age, J. Clin. Oncol. 35 (2017) 2949-2959.

K. Ko, L. Mak, K. Cheung, et al., Hepatocellular carcinoma: Recent advances and emerging medical therapies, F1000Res. 9 (2020), F1000 Faculty Rev-620.

S. Offermanns, W. Rosenthal, Encyclopedia of molecular pharmacology, Springer Science and Business Media, Berlin, 2008.

Y. Wan, J. Wang, J. Xu, et al., Panax ginseng and its ginsenosides: Potential candidates for the prevention and treatment of chemotherapy-induced side effects, J. Ginseng Res. 45 (2021) 617-630.

Y. Liu, X. Wang, D. He, et al., Protection against chemotherapy-and radiotherapy-induced side effects: A review based on the mechanisms and therapeutic opportunities of phytochemicals, Phytomedicine 80 (2021), 153402.

J. Varghese, B. Balasubramanian, S. Velayuthaprabhu, et al., Therapeutic effects of vitamin D and cancer: An overview, Food Front. 2 (2021) 417-425.

Z. Yao, L. Wang, D. Cai, et al., Warangalone induces apoptosis in HeLa cells via mitochondria-mediated endogenous pathway, eFood 2 (2021) 259-270.

Q. Zhang, P. Luo, L. Zheng, et al., 18beta-glycyrrhetinic acid induces ROS-mediated apoptosis to ameliorate hepatic fibrosis by targeting PRDX1/2 in activated HSCs, J. Pharm. Anal. 12 (2022) 570-582.

C. Zhao, G. Lin, D. Wu, et al., The algal polysaccharide ulvan suppresses growth of hepatoma cells, Food Front. 1 (2020) 83-101.

S. Cheng, N. Chen, H. Kuo, et al., Prodigiosin stimulates endoplasmic reticulum stress and induces autophagic cell death in glioblastoma cells, Apoptosis 23 (2018) 314-328.

H. Zhang, G. Caprioli, H. Hussain, et al., A multifaceted review on dihydromyricetin resources, extraction, bioavailability, biotransformation, bioactivities, and food applications with future perspectives to maximize its value, eFood 2 (2021) 164-184.

T. Yonekawa and A. Thorburn, Autophagy and cell death, Essays Biochem., 55 (2013) 105-117.

Y. Zhang, X. Mao, W. Chen, et al., A discovery of clinically approved formula FBRP for repositioning to treat HCC by inhibiting PI3K/AKT/NF-κB activation, Mol. Ther. Nucleic Acids 19 (2020) 890-904.

L. Yang, Y. Hou, J. Yuan, et al., Twist promotes reprogramming of glucose metabolism in breast cancer cells through PI3K/AKT and p53 signaling pathways, Oncotarget 6 (2015) 25755-25769.

Q. Fu, Y. Liu, Y. Fan, et al., Alpha-enolase promotes cell glycolysis, growth, migration, and invasion in non-small cell lung cancer through FAK-mediated PI3K/AKT pathway, J. Hematol. Oncol. 8 (2015), 22.

J. Sophia, J. Kowshik, A. Dwivedi, et al., Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer, Cell Death Dis. 9 (2018), 1087.

C. Braicu, O. Zanoaga, A. Zimta, et al., Natural compounds modulate the crosstalk between apoptosis-and autophagy-regulated signaling pathways: Controlling the uncontrolled expansion of tumor cells, Semin. Cancer Biol. 80 (2022) 218-236.

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