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

Sung, 2021, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA-Cancer J. Clin., 71, 209, 10.3322/caac.21660 Zheng, 2022, Cancer incidence and mortality in China, 2016, J. Natl. Cancer Cent., 2, 1, 10.1016/j.jncc.2022.02.002 Dai, 2022, Induction of IL-6Rα by ATF3 enhances IL-6 mediated sorafenib and regorafenib resistance in hepatocellular carcinoma, Cancer Lett., 524, 161, 10.1016/j.canlet.2021.10.024 Xu, 2021, UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma, Signal Transduct. Target. Ther., 6, 190, 10.1038/s41392-021-00594-4 G. Tossetta, D. Marzioni, Natural and synthetic compounds in ovarian cancer: A focus on NRF2/KEAP1 pathway, Pharmacol. Res. 183 (2022), 106365. Zhong, 2022, Recent advances in the biosynthesis, structure–activity relationships, formulations, pharmacology, and clinical trials of fisetin, eFood, 3, 10.1002/efd2.3 Hai, 2020, Advance on the absorption, metabolism, and efficacy exertion of quercetin and its important derivatives, Food Front, 1, 420, 10.1002/fft2.50 Higbee, 2022, The emerging role of dark berry polyphenols in human health and nutrition, Food Front, 3, 3, 10.1002/fft2.128 Ren, 2021, Bringing to fore the role of peptides, polyphenols, and polysaccharides in health: the research profile of Jiaoyan Ren, Food Front, 2, 29, 10.1002/fft2.62 Liu, 2019, Ginsenoside Rg5 induces G2/M phase arrest, apoptosis and autophagy via regulating ROS-mediated MAPK pathways against human gastric cancer, Biochem. Pharmacol., 168, 285, 10.1016/j.bcp.2019.07.008 Zhu, 2020, 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, 10.1016/j.phrs.2020.104746 Liu, 2020, Chemical constituents of Panax ginseng and Panax notoginseng explain why they differ in therapeutic efficacy, Pharmacol. Res., 161, 10.1016/j.phrs.2020.105263 Chen, 2020, The anticancer activity and mechanisms of ginsenosides: An updated review, eFood, 1, 226, 10.2991/efood.k.200512.001 Qu, 2019, 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, 277, 10.1016/j.fct.2019.02.032 Wei, 2018, Anti-anemia effects of ginsenoside Rk3 and ginsenoside Rh4 on mice with ribavirin-induced anemia, Food Funct., 9, 2447, 10.1039/C8FO00368H Liu, 2019, Ginsenoside Rk3 ameliorates high-fat-diet/streptozocin induced type 2 diabetes mellitus in mice via the AMPK/Akt signaling pathway, Food Funct., 10, 2538, 10.1039/C9FO00095J Duan, 2017, Anticancer effects of ginsenoside Rk3 on non-small cell lung cancer cells: In vitro and in vivo, Food Funct., 8, 3723, 10.1039/C7FO00385D Noorolyai, 2019, The relation between PI3K/AKT signalling pathway and cancer, Gene, 698, 120, 10.1016/j.gene.2019.02.076 Wu, 2020, PI3K/AKT/mTOR pathway-related long non-coding RNAs: Roles and mechanisms in hepatocellular carcinoma, Pharmacol. Res., 160, 10.1016/j.phrs.2020.105195 Hennessy, 2005, Exploiting the PI3K/AKT pathway for cancer drug discovery, Nat. Rev. Drug Discov., 4, 988, 10.1038/nrd1902 Hay, 2005, The Akt-mTOR tango and its relevance to cancer, Cancer Cell, 8, 179, 10.1016/j.ccr.2005.08.008 Capodanno, 2009, Dysregulated PI3K/Akt/PTEN pathway is a marker of a short disease-free survival in node-negative breast carcinoma, Hum. Pathol., 40, 1408, 10.1016/j.humpath.2009.02.005 Vivanco, 2014, A kinase-independent function of AKT promotes cancer cell survival, eLife, 3, 10.7554/eLife.03751 Sanidas, 2014, Phosphoproteomics screen reveals Akt isoform-specific signals linking RNA processing to lung cancer, Mol. Cell, 53, 577, 10.1016/j.molcel.2013.12.018 Ye, 2014, ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer, Oncogene, 33, 1828, 10.1038/onc.2013.122 Yue, 2014, Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness, Cell Metab., 19, 393, 10.1016/j.cmet.2014.01.019 Xue, 2019, 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, 2580 Kwon, 2007, 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, 768, 10.1016/j.cellbi.2007.01.010 Hopkins, 2008, Network pharmacology: The next paradigm in drug discovery, Nat. Chem. Biol., 4, 682, 10.1038/nchembio.118 Nottingham, 2021, 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, 799, 10.1016/j.jpha.2021.06.002 Li, 2022, GB7 acetate, a galbulimima alkaloid from Galbulimima belgraveana, possesses anticancer effects in colorectal cancer cells, J. Pharm. Anal., 12, 339, 10.1016/j.jpha.2021.06.007 Rodríguez-Hernández, 2018, Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells, J. Cell Physiol., 234, 692, 10.1002/jcp.26855 Uehara, 2014, The DEN and CCl4-induced mouse model of fibrosis and inflammation-associated hepatocellular carcinoma, Curr. Protoc. Pharmacol., 66, 10.1002/0471141755.ph1430s66 Ye, 2022, Tumor-targeting intravenous lipid emulsion of paclitaxel: Characteristics, stability, toxicity, and toxicokinetics, J. Pharm. Anal., 12, 901, 10.1016/j.jpha.2022.08.002 Jiang, 2022, 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, 839, 10.1016/j.jpha.2022.07.004 Zhao, 2023, PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson’s disease in diabetic rats, J. Pharm. Anal., 13, 187, 10.1016/j.jpha.2022.11.006 Ye, 2022, Sensitive detection of alkaline phosphatase based on terminal deoxynucleotidyl transferase and endonuclease IV-assisted exponential signal amplification, J. Pharm. Anal., 12, 692, 10.1016/j.jpha.2021.09.012 Wang, 2017, PharmMapper 2017 update: A web server for potential drug target identification with a comprehensive target pharmacophore database, Nucleic Acids Res., 45, W356, 10.1093/nar/gkx374 Szklarczyk, 2017, The STRING database in 2017: Quality-controlled protein–protein association networks, made broadly accessible, Nucleic Acids Res., 45, D362, 10.1093/nar/gkw937 Shannon, 2003, Cytoscape: A software environment for integrated models of biomolecular interaction networks, Genome Res., 13, 2498, 10.1101/gr.1239303 Huang, 2009, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources, Nat. Protoc., 4, 44, 10.1038/nprot.2008.211 Meng, 2022, A highly efficient protein corona-based proteomic analysis strategy for the discovery of pharmacodynamic biomarkers, J. Pharm. Anal., 12, 879, 10.1016/j.jpha.2022.07.002 Chandrashekar, 2017, UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses, Neoplasia, 19, 649, 10.1016/j.neo.2017.05.002 Kerbel, 2006, Antiangiogenic therapy: A universal chemosensitization strategy for cancer?, Science, 312, 1171, 10.1126/science.1125950 Harkus, 2022, Immune checkpoint inhibitors in HCC: Cellular, molecular and systemic data, Semin. Cancer Biol., 86, 799, 10.1016/j.semcancer.2022.01.005 Singal, 2022, HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis, J. Hepatol., 77, 128, 10.1016/j.jhep.2022.01.023 Bai, 2017, Cell cycle regulation and anticancer drug discovery, Cancer Biol. Med., 14, 348, 10.20892/j.issn.2095-3941.2017.0033 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. Ingham, 2017, Cell-cycle therapeutics come of age, J. Clin. Oncol., 35, 2949, 10.1200/JCO.2016.69.0032 Ko, 2020, Hepatocellular carcinoma: Recent advances and emerging medical therapies, F1000Res., 9, 10.12688/f1000research.24543.1 Offermanns, 2008 Wan, 2021, Panax ginseng and its ginsenosides: Potential candidates for the prevention and treatment of chemotherapy-induced side effects, J. Ginseng Res., 45, 617, 10.1016/j.jgr.2021.03.001 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. Varghese, 2021, Therapeutic effects of vitamin D and cancer: An overview, Food Front., 2, 417, 10.1002/fft2.97 Yao, 2021, Warangalone induces apoptosis in HeLa cells via mitochondria-mediated endogenous pathway, eFood, 2, 259, 10.53365/efood.k/145663 Zhang, 2022, 18beta-glycyrrhetinic acid induces ROS-mediated apoptosis to ameliorate hepatic fibrosis by targeting PRDX1/2 in activated HSCs, J. Pharm. Anal., 12, 570, 10.1016/j.jpha.2022.06.001 Zhao, 2020, The algal polysaccharide ulvan suppresses growth of hepatoma cells, Food Front., 1, 83, 10.1002/fft2.13 Cheng, 2018, Prodigiosin stimulates endoplasmic reticulum stress and induces autophagic cell death in glioblastoma cells, Apoptosis, 23, 314, 10.1007/s10495-018-1456-9 Zhang, 2021, A multifaceted review on dihydromyricetin resources, extraction, bioavailability, biotransformation, bioactivities, and food applications with future perspectives to maximize its value, eFood, 2, 164, 10.53365/efood.k/143518 Yonekawa, 2013, Autophagy and cell death, Essays Biochem., 55, 105, 10.1042/bse0550105 Zhang, 2020, A discovery of clinically approved formula FBRP for repositioning to treat HCC by inhibiting PI3K/AKT/NF-κB activation, Mol. Ther. Nucleic Acids, 19, 890, 10.1016/j.omtn.2019.12.023 Yang, 2015, Twist promotes reprogramming of glucose metabolism in breast cancer cells through PI3K/AKT and p53 signaling pathways, Oncotarget, 6, 25755, 10.18632/oncotarget.4697 Fu, 2015, 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, 10.1186/s13045-015-0117-5 Sophia, 2018, 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, 10.1038/s41419-018-1126-4 Braicu, 2022, Natural compounds modulate the crosstalk between apoptosis-and autophagy-regulated signaling pathways: Controlling the uncontrolled expansion of tumor cells, Semin. Cancer Biol., 80, 218, 10.1016/j.semcancer.2020.05.015