Glycyrrhizic Acid Modulates Apoptosis through Extrinsic/Intrinsic Pathways and Inhibits Protein Kinase B- and Extracellular Signal-Regulated Kinase-Mediated Metastatic Potential in Hepatocellular Carcinoma In Vitro and In Vivo.

A previous study presented that glycyrrhizic acid as the hepatoprotective agent inhibits total parenteral nutrition-associated acute liver injury in rats. However, the anticancer effect and mechanism of glycyrrhizic acid in human hepatocellular carcinoma (HCC) is ambiguous. The purpose of the present study was to investigate the effect of glycyrrhizic acid on apoptosis dysregulation and metastatic potential in HCC in vitro and in vivo. Both SK-Hep1 and Hep3B cells were treated with different concentrations of glycyrrhizic acid for 24 or 48h. SK-Hep1/luc2 tumor-bearing mice were treated with vehicle or glycyrrhizic acid (50mg/kg/day by intraperitoneal injection) for 7 days. Tumor cells growth, apoptotic, and metastatic signaling transduction were evaluated by using MTT assay, digital caliper, bioluminescence imaging (BLI), flow cytometry, western blotting assay, and immunohistochemistry (IHC) staining. The results demonstrated glycyrrhizic acid significantly inhibits tumor cell growth, cell invasion, and expression of AKT (Ser473), extracellular-signal-regulated kinase (ERK), epidermal growth factor receptor (EGFR) phosphorylation, anti-apoptotic and metastatic proteins in HCC in vitro and in vivo. Glycyrrhizic acid also significantly triggered apoptosis and extrinsic/intrinsic apoptotic signaling transduction. In addition, PD98059 (ERK inhibitor) and LY294002 (AKT inhibitor) obviously reduced cell invasion and expression of metastasis-associated proteins. Taken together, these results indicated that glycyrrhizic acid induces apoptosis through extrinsic/intrinsic apoptotic signaling pathways and diminishes EGFR/AKT/ERK-modulated metastatic potential in HCC in vitro and in vivo.

[1]  Fei-Ting Hsu,et al.  Magnolol Induces Apoptosis and Inhibits ERK-modulated Metastatic Potential in Hepatocellular Carcinoma Cells , 2018, In Vivo.

[2]  Fei-Ting Hsu,et al.  Amentoflavone Inhibits Hepatocellular Carcinoma Progression Through Blockage of ERK/NF-ĸB Activation , 2018, In Vivo.

[3]  Ming Xu,et al.  Improvement of vascular dysfunction by argirein through inhibiting endothelial cell apoptosis associated with ET-1/Nox4 signal pathway in diabetic rats , 2018, Scientific Reports.

[4]  M. Fan,et al.  Benzyl isothiocyanate inhibits human brain glioblastoma multiforme GBM 8401 cell xenograft tumor in nude mice in vivo , 2018, Environmental toxicology.

[5]  Fei-Ting Hsu,et al.  Hyperforin Suppresses Tumor Growth and NF-κB-mediated Anti-apoptotic and Invasive Potential of Non-small Cell Lung Cancer. , 2018, Anticancer research.

[6]  Fei-Ting Hsu,et al.  Regorafenib inhibits tumor progression through suppression of ERK/NF-κB activation in hepatocellular carcinoma bearing mice , 2018, Bioscience reports.

[7]  H. Han,et al.  VEGF Overexpression Predicts Poor Survival in Hepatocellular Carcinoma , 2017, Open medicine.

[8]  Fei-Ting Hsu,et al.  Regorafenib Induces Apoptosis and Inhibits Metastatic Potential of Human Bladder Carcinoma Cells. , 2017, Anticancer research.

[9]  Fei-Ting Hsu,et al.  Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro. , 2017, Oncology letters.

[10]  P. Wee,et al.  Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways , 2017, Cancers.

[11]  Fei-Ting Hsu,et al.  Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells. , 2017, Oncology reports.

[12]  Masatoshi Kudo,et al.  Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial , 2017, The Lancet.

[13]  Meiwan Chen,et al.  Glycyrrhetinic Acid Mediated Drug Delivery Carriers for Hepatocellular Carcinoma Therapy. , 2016, Molecular pharmaceutics.

[14]  Chao‐Lin Kuo,et al.  Bufalin inhibits migration and invasion in human hepatocellular carcinoma SK‐Hep1 cells through the inhibitions of NF‐kB and matrix metalloproteinase‐2/‐9‐signaling pathways , 2015, Environmental toxicology.

[15]  Fei-Ting Hsu,et al.  Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-κB signaling. , 2014, International journal of oncology.

[16]  Ping Liu,et al.  Glycyrrhizic Acid in the Treatment of Liver Diseases: Literature Review , 2014, BioMed research international.

[17]  T. Tsai,et al.  Glycyrrhizin Represses Total Parenteral Nutrition-Associated Acute Liver Injury in Rats by Suppressing Endoplasmic Reticulum Stress , 2013, International journal of molecular sciences.

[18]  Fei-Ting Hsu,et al.  Sorafenib inhibits TPA-induced MMP-9 and VEGF expression via suppression of ERK/NF-κB pathway in hepatocellular carcinoma cells. , 2012, In vivo.

[19]  Jing-Gung Chung,et al.  Curcumin-Induced Apoptosis in Human Hepatocellular Carcinoma J5 Cells: Critical Role of Ca+2-Dependent Pathway , 2012, Evidence-based complementary and alternative medicine : eCAM.

[20]  T. Goto,et al.  Hepatocellular carcinoma with extrahepatic metastasis , 2011, Cancer.

[21]  Z. Nawaz,et al.  Glycyrrhizin as antiviral agent against Hepatitis C Virus , 2011, Journal of Translational Medicine.

[22]  F. Chiodi,et al.  Role of Fas/FasL in regulation of inflammation in vaginal tissue during HSV-2 infection , 2011, Cell Death and Disease.

[23]  Jin Chung,et al.  Induction of apoptosis by HAC-Y6, a novel microtubule inhibitor, through activation of the death receptor 4 signaling pathway in human hepatocellular carcinoma cells. , 2010, Oncology reports.

[24]  M. Zeytunlu,et al.  Expression of matrix metalloproteinase‐9 in predicting prognosis of hepatocellular carcinoma after liver transplantation , 2010, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[25]  G. Bao,et al.  Expression and biological significance of c-FLIP in human hepatocellular carcinomas , 2009, Journal of experimental & clinical cancer research : CR.

[26]  I. Fabregat.  Dysregulation of apoptosis in hepatocellular carcinoma cells. , 2009, World journal of gastroenterology.

[27]  Q. Wang,et al.  Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP‐9 , 2009, Hepatology research : the official journal of the Japan Society of Hepatology.

[28]  I. Rusyn,et al.  Protective effect of Juzen‐taiho‐to on hepatocarcinogenesis is mediated through the inhibition of Kupffer cell‐induced oxidative stress , 2008, International journal of cancer.

[29]  X. Sun,et al.  Glycyrrhizin attenuates endotoxin- induced acute liver injury after partial hepatectomy in rats. , 2007, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[30]  C. Der,et al.  Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer , 2007, Oncogene.

[31]  C. Harris,et al.  TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer , 2007, Oncogene.

[32]  D. Schuppan,et al.  Herbal medicine in the treatment of liver diseases. , 2007, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[33]  M. Kuwano,et al.  PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib. , 2006, Cancer research.

[34]  S. Osada,et al.  Evaluation of extracellular signal regulated kinase expression and its relation to treatment of hepatocellular carcinoma. , 2005, Journal of the American College of Surgeons.

[35]  D. Hovsepian,et al.  Elevated plasma levels of matrix metalloproteinase-9 in patients with abdominal aortic aneurysms: a circulating marker of degenerative aneurysm disease. , 2000, Journal of vascular and interventional radiology : JVIR.

[36]  M. Monden,et al.  The status of Fas and Fas ligand expression can predict recurrence of hepatocellular carcinoma , 2000, British Journal of Cancer.

[37]  K. Chayama,et al.  The long term efficacy of glycyrrhizin in chronic hepatitis C patients , 1997, Cancer.

[38]  H. Kotaki,et al.  Administration-route dependency of absorption of glycyrrhizin in rats: intraperitoneal administration dramatically enhanced bioavailability. , 1995, Biological & pharmaceutical bulletin.

[39]  Yen-Chung Chen,et al.  Hyperforin Inhibits Cell Growth by Inducing Intrinsic and Extrinsic Apoptotic Pathways in Hepatocellular Carcinoma Cells. , 2017, Anticancer research.

[40]  L. Shang,et al.  Clinicopathologic characteristics and prognoses for multicentric occurrence and intrahepatic metastasis in synchronous multinodular hepatocellular carcinoma patients. , 2013, Asian Pacific journal of cancer prevention : APJCP.

[41]  M. Peck-Radosavljevic,et al.  Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy. , 2006, Journal of hepatology.