Baicalein inhibits the invasion and metastatic capabilities of hepatocellular carcinoma cells via down-regulation of the ERK pathway

• Published in: PloS one 2013-09, Vol.8 (9), p.e72927
• Main Authors: Chen, Kunlun, Zhang, Shu, Ji, Yuanyuan, Li, Jun, An, Peng, Ren, Hongtao, Liang, Rongrui, Yang, Jun, Li, Zongfang
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antioxidants - administration & dosage; Antioxidants - chemistry; Antioxidants - pharmacology; Cancer metastasis; Cancer treatment; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemical compounds; Combined treatment; Disease Models, Animal; Dose-Response Relationship, Drug; Engineering research; Enzyme Activation - drug effects; Extracellular signal-regulated kinase; Flavanones - administration & dosage; Flavanones - chemistry; Flavanones - pharmacology; Gelatinase A; Gelatinase B; Gene Expression Regulation, Neoplastic - drug effects; Health aspects; Hepatocellular carcinoma; Herbal medicine; Historical account; Hospitals; Humans; Inflammation; Inhibition; Inhibitors; Invasiveness; Kinases; Laboratory animals; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; MAP Kinase Signaling System - drug effects; Matrix metalloproteinase; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Medical prognosis; Medicine; Metabolic pathways; Metalloproteinase; Metastases; Metastasis; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Penicillin; Pharmacology; Plasmids; Proteinase; Signal transduction; Tissue inhibitor of metalloproteinase 1; Tissue inhibitor of metalloproteinase 2; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tissue Inhibitor of Metalloproteinase-2 - genetics; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Transcription, Genetic; U-Plasminogen activator; Uranium; Urokinase; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072927

Baicalein, a widely used Chinese herbal medicine, has historically been used in anti-inflammatory and anti-cancer therapies. However, the anti-metastatic effect and molecular mechanism(s) of baicalein on hepatocellular carcinoma (HCC) remain poorly understood. Therefore, the purpose of this study was to assess the anti-metastatic effects of baicalein and related mechanism(s) on HCC. Based on assays utilized in both HCC cell lines and in an animal model, we found that baicalein inhibited tumor cell metastasis in vivo and in vitro. Furthermore, after treatment with baicalein for 24 hours, there was a decrease in the levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (u-PA) expression as well as proteinase activity in hepatocellular carcinoma MHCC97H cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 were increased in a dose-dependent fashion. Moreover, baicalein treatment dramatically decreased the levels of the phosphorylated forms of MEK1 and ERK1/2. MEK1 overexpression partially blocked the anti-metastatic effects of baicalein. Combined treatment with an ERK inhibitor (U0126) and baicalein resulted in a synergistic reduction in MMP-2, MMP-9 and u-PA expression and an increase in TIMP-1 and TIMP-2 expression; the invasive capabilities of MHCC97H cells were also inhibited. In conclusion, baicalein inhibits tumor cell invasion and metastasis by reducing cell motility and migration via the suppression of the ERK pathway, suggesting that baicalein is a potential therapeutic agent for HCC.