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.

Abstract

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.

• Authors: Jai-Jen Tsai, Po-Jung Pan, Fei-Ting Hsu, Jing-Gung Chung, I-Tsang Chiang
• Journal: The American journal of Chinese medicine (Am J Chin Med) Vol. 48 Issue 1 Pg. 223-244 ( 2020) ISSN: 1793-6853 [Electronic] Singapore
• PMID: 32054305 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Glycyrrhizic Acid
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy)
• Cell Line, Tumor
• Disease Models, Animal
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Glycyrrhizic Acid (pharmacology)
• Humans
• Liver Neoplasms (drug therapy)
• Mice
• Proto-Oncogene Proteins c-akt (metabolism)