Ginsenoside Rg3 and sorafenib combination therapy relieves the hepatocellular carcinomaprogression through regulating the HK2-mediated glycolysis and PI3K/Akt signaling pathway

References

• Ranganathan S, Lopez-Terrada D, Alaggio R. Hepato blastoma and pediatric hepatocellular carcinoma: an update. Pediatr Dev Pathol. 2020;23(2):79–95.
   PubMed Web of Science ®Google Scholar
• Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249.
   PubMed Web of Science ®Google Scholar
• Ikeda M, Morizane C, Ueno M, et al. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Jpn J Clin Oncol. 2018;48(2):103–114.
   PubMed Web of Science ®Google Scholar
• Rimassa L, Santoro A. Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial. Expert Rev Anticancer Ther. 2009;9(6):739–745.
   PubMed Web of Science ®Google Scholar
• Cheng AD, Kang Y-K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.
   PubMed Web of Science ®Google Scholar
• Xia S, Pan Y, Liang Y, et al. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine. 2020;51:102610.
   PubMed Web of Science ®Google Scholar
• He M, Li Q, Zou R, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol. 2019;5(7):953–960.
   PubMed Web of Science ®Google Scholar
• Li Z, Jiao D, Han X, et al. Transcatheter arterial chemoembolization combined with simultaneous DynaCT-guided microwave ablation in the treatment of small hepatocellular carcinoma. Cancer Imaging. 2020;20(1):13.
   PubMed Web of Science ®Google Scholar
• Feng J, Yang, JH, Li, JH, et al. Transcatheter arterial chemoembolisation combined with radiofrequency ablation on hepatocellular carcinoma and levels of relevant markers. J Coll Physicians Surg Pak. 2020;30(3):259–262.
   PubMed Web of Science ®Google Scholar
• Wang Y, Zhang Q, Chen Y, et al. Antitumor effects of immunity-enhancing traditional Chinese medicine. Biomed Pharmacother. 2020;121:109570.
   PubMed Web of Science ®Google Scholar
• Sun M, Ye Y, Xiao L, et al. Anticancer effects of ginsenoside Rg3 (Review). Int J Mol Med. 2017;39(3):507–518.
   PubMed Web of Science ®Google Scholar
• Li L, Wang Y, Guo R, et al. Ginsenoside Rg3-loaded, reactive oxygen species-responsive polymeric nanoparticles for alleviating myocardial ischemia-reperfusion injury. J Control Release. 2020;317:259–272.
   PubMed Web of Science ®Google Scholar
• Lee H, Kong G, Tran Q, et al. Relationship between ginsenoside rg3 and metabolic syndrome. Front Pharmacol. 2020;11:130.
   PubMed Web of Science ®Google Scholar
• Ren Z, Chen X, Hong L, et al. Nanoparticle conjugation of ginsenoside Rg3 inhibits hepatocellular carcinoma development and metastasis. Small. 2020;16(2):e1905233.
   PubMed Web of Science ®Google Scholar
• Hu S, Zhu Y, Xia X, et al. Ginsenoside Rg3 prolongs survival of the orthotopic hepatocellular carcinoma model by inducing apoptosis and inhibiting angiogenesis. Anal Cell Pathol (Amst). 2019;2019:3815786.
   PubMedGoogle Scholar
• Wu CX, Wang XQ, Chok SH, et al. Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma. Theranostics. 2018;8(14):3737–3750.
   PubMed Web of Science ®Google Scholar
• Zhao L, Shou H, Chen L, et al. Effects of ginsenoside Rg3 on epigenetic modification in ovarian cancer cells. Oncol Rep. 2019;41(6):3209–3218.
   PubMed Web of Science ®Google Scholar
• Lu X, Gao H, Zhu B, et al. Circular RNA circ_RANBP9 exacerbates polycystic ovary syndrome via microRNA -136-5p/XIAP axis. Bioengineered. 2021;12(1):6748–6758.
   PubMed Web of Science ®Google Scholar
• Perez-Rodriguez S, Ramírez-Lira MDJ, Trujillo-Roldán MA, et al. Nutrient supplementation strategy improves cell concentration and longevity, monoclonal antibody production and lactate metabolism of Chinese hamster ovary cells. Bioengineered. 2020;11(1):463–471.
   PubMed Web of Science ®Google Scholar
• Li H, Xuan J, Zhang W, et al. Long non-coding RNA SNHG5 regulates ulcerative colitis via microRNA-375/Janus kinase-2 axis. Bioengineered. 2021;12(1):4150–4158.
   PubMed Web of Science ®Google Scholar
• Han D, Yu Z, Zhang H, et al. Microenvironment-associated gene HSD11B1 may serve as a prognostic biomarker in clear cell renal cell carcinoma: a study based on TCGA, RTqPCR, Western blotting, and immunohistochemistry. Bioengineered. 2021;12(2):10891–10904.
   PubMed Web of Science ®Google Scholar
• Clark T, Maximin S, Meier J, et al. Hepatocellular carcinoma: review of epidemiology, screening, imaging diagnosis, response assessment, and treatment. Curr Probl Diagn Radiol. 2015;44(6):479–486.
   PubMed Web of Science ®Google Scholar
• Jianhuang, Huang J, Deng Q, et al. Exome sequencing of hepatitis B virus―associated hepatocellular carcinoma. Nat Genet. 2012;44(10):1117–1121.
   PubMed Web of Science ®Google Scholar
• Tang W, Chen Z, Zhang W, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020;5(1):87.
   PubMed Web of Science ®Google Scholar
• Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66.
   PubMed Web of Science ®Google Scholar
• Zheng Q, Bao X-Y, Zhu P-C, et al. Ginsenoside Rb1 for myocardial ischemia/reperfusion injury: preclinical evidence and possible mechanisms. Oxid Med Cell Longev. 2017;2017:6313625.
   PubMed Web of Science ®Google Scholar
• Liu T, Duo L, Duan P. Ginsenoside Rg3 sensitizes colorectal cancer to radiotherapy through downregulation of proliferative and angiogenic biomarkers. Evid Based Complement Alternat Med. 2018;2018:1580427.
   PubMed Web of Science ®Google Scholar
• Nakhjavani M, Hardingham, JE, Palethorpe, HM, et al. Ginsenoside Rg3: potential molecular targets and therapeutic indication in metastatic Breast cancer. Medicines (Basel). 2019;6(1):17.
   PubMedGoogle Scholar
• Dai Y, Wang W, Sun Q, et al. Ginsenoside Rg3 promotes the antitumor activity of gefitinib in lung cancer cell lines. Exp Ther Med. 2019;17(1):953–959.
   PubMed Web of Science ®Google Scholar
• Qi F, Zhao L, Zhou A, et al. The advantages of using traditional Chinese medicine as an adjunctive therapy in the whole course of cancer treatment instead of only terminal stage of cancer. Biosci Trends. 2015;9(1):16–34.
   PubMed Web of Science ®Google Scholar
• Xue JX, Zhu Z-Y, Bian W-H, et al. The traditional Chinese medicine kangai injection as an adjuvant method in combination with chemotherapy for the treatment of breast cancer in Chinese patients: a meta-analysis. Evid Based Complement Alternat Med. 2018;2018:6305645.
   PubMed Web of Science ®Google Scholar
• Lu M, Fei Z, Zhang G. Synergistic anticancer activity of 20(S)-Ginsenoside Rg3 and sorafenib in hepatocellular carcinoma by modulating PTEN/Akt signaling pathway. Biomed Pharmacother. 2018;97:1282–1288.
   PubMed Web of Science ®Google Scholar
• Kim DG, Jung KH, Lee D-G, et al. 20(S)-ginsenoside Rg3 is a novel inhibitor of autophagy and sensitizes hepatocellular carcinoma to doxorubicin. Oncotarget. 2014;5(12):4438–4451.
   PubMedGoogle Scholar
• Yang J, Ren B, Yang G, et al. The enhancement of glycolysis regulates pancreatic cancer metastasis. Cell Mol Life Sci. 2019;77(2):305–321.
   PubMed Web of Science ®Google Scholar
• Vaupel P, Multhoff G. Revisiting the Warburg effect: historical dogma versus current understanding. J Physiol. 2021;599(6):1745–1757.
   PubMed Web of Science ®Google Scholar
• Lu J, Tan M, Cai Q. The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett. 2015;356(2 Pt A):156–164.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Tan X, Luo J, et al. The miR-30a-5p/CLCF1 axis regulates sorafenib resistance and aerobic glycolysis in hepatocellular carcinoma. Cell Death Dis. 2020;11(10):902.
   PubMed Web of Science ®Google Scholar
• Wang Q, Guo X, Li L, et al. N(6)-methyladenosine METTL3 promotes cervical cancer tumorigenesis and Warburg effect through YTHDF1/HK2 modification. Cell Death Dis. 2020;11(10):911.
   PubMed Web of Science ®Google Scholar
• Garcia SN, Guedes RC, Marques MM. Unlocking the potential of HK2 in cancer metabolism and therapeutics. Curr Med Chem. 2019;26(41):7285–7322.
   PubMed Web of Science ®Google Scholar
• Shi T, Ma Y, Cao L, et al. B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by regulating HK2. Cell Death Dis. 2019;10(4):308.
   PubMed Web of Science ®Google Scholar
• Liu R, Chen Y, Liu G, et al. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. 2020;11(9):797.
   PubMed Web of Science ®Google Scholar
• Ediriweera MK, Tennekoon KH, Samarakoon SR. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: biological and therapeutic significance. Semin Cancer Biol. 2019;59:147–160.
   PubMed Web of Science ®Google Scholar
• Bamodu OA, Chang H-L, Ong J-R, et al. Elevated PDK1 expression drives PI3K/AKT/MTOR signaling promotes radiation-resistant and dedifferentiated phenotype of hepatocellular carcinoma. Cells. 2020;9(3):746.
   PubMed Web of Science ®Google Scholar
• Sun F, Wang, J, Sun Q, Q, et al. Interleukin-8 promotes integrin beta3 upregulation and cell invasion through PI3K/Akt pathway in hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):449.
   PubMed Web of Science ®Google Scholar
• Jafari M, Ghadami, E, Dadkhah, T, et al. PI3k/AKT signaling pathway: erythropoiesis and beyond. J Cell Physiol. 2019;234(3):2373–2385.
   PubMed Web of Science ®Google Scholar