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Silibinin inhibits ethanol metabolism and ethanol-dependent cell proliferation in an in vitro model of hepatocellular carcinoma.

ABSTRACT: Chronic ethanol consumption is a known risk factor for developing hepatocellular carcinoma (HCC). The use of plant-derived antioxidants is gaining increasing clinical prominence as a potential therapy to ameliorate the effects of ethanol on hepatic disease development and progression. This study demonstrates silibinin, a biologically active flavanoid derived from milk thistle, inhibits cytochrome p4502E1 induction, ethanol metabolism and reactive oxygen species generation in HCC cells in vitro. These silibinin-mediated effects also inhibit ethanol-dependent increases in HCC cell proliferation in culture.

SUBMITTER: Brandon-Warner E

PROVIDER: S-EPMC3099213 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Silibinin inhibits ethanol metabolism and ethanol-dependent cell proliferation in an in vitro model of hepatocellular carcinoma.

Brandon-Warner Elizabeth E Sugg James A JA Schrum Laura W LW McKillop Iain H IH

Cancer letters 20091108 1

Chronic ethanol consumption is a known risk factor for developing hepatocellular carcinoma (HCC). The use of plant-derived antioxidants is gaining increasing clinical prominence as a potential therapy to ameliorate the effects of ethanol on hepatic disease development and progression. This study demonstrates silibinin, a biologically active flavanoid derived from milk thistle, inhibits cytochrome p4502E1 induction, ethanol metabolism and reactive oxygen species generation in HCC cells in vitro. ...[more]

PMID: 19900758

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Project description:BACKGROUND: We have previously demonstrated that peroxisome proliferator-activated receptor (PPARγ) activation inhibits hepatocarcinogenesis. We aim to investigate the effect of PPARγ on hepatocellular carcinoma (HCC) metastatic potential and explore its underlying mechanisms. METHODS: Human HCC cells (MHCC97L, BEL-7404) were infected with adenovirus-expressing PPARγ (Ad-PPARγ) or Ad-lacZ and treated with or without PPARγ agonist (rosiglitazone). The effects of PPARγ on cell migration and invasive activity were determined by wound healing assay and Matrigel invasive model in vitro, and in an orthotopic liver tumour metastatic model in mice. RESULTS: Pronounced expression of PPARγ was demonstrated in HCC cells (MHCC97L, BEL-7404) treated with Ad-PPARγ, rosiglitazone or Ad-PPARγ plus rosiglitazone, compared with control (Ad-LacZ). Such induction markedly suppressed HCC cell migration. Moreover, the invasiveness of MHCC97L and BEL-7404 cells infected with Ad-PPARγ, or treated with rosiglitazone was significantly diminished up to 60%. Combination of Ad-PPARγ and rosiglitazone showed an additive effect. Activation of PPARγ by rosiglitazone significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. Key mechanisms underlying the effect of PPARγ in HCC include upregulation of cell adhesion genes, E-cadherin and SYK (spleen tyrosine kinase), extracellular matrix regulator tissue inhibitors of metalloproteinase (TIMP) 3, tumour suppressor gene retinoblastoma 1, and downregulation of pro-metastatic genes MMP9 (matrix metallopeptidase 9), MMP13, HPSE (heparanase), and Hepatocyte growth factor (HGF). Direct transcriptional regulation of TIMP3, MMP9, MMP13, and HPSE by PPARγ was shown by ChIP-PCR. CONCLUSION: Peroxisome proliferator-activated receptor-gamma exerts an inhibitory effect on the invasive and metastatic potential of HCC in vitro and in vivo, and is thus, a target for the prevention and treatment of HCC metastases.

Dataset Information

Silibinin inhibits ethanol metabolism and ethanol-dependent cell proliferation in an in vitro model of hepatocellular carcinoma.

Publications

Silibinin inhibits ethanol metabolism and ethanol-dependent cell proliferation in an in vitro model of hepatocellular carcinoma.

Similar Datasets

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