Ankaflavin and Monascin Induce Apoptosis in Activated Hepatic Stellate Cells through Suppression of the Akt/NF-κB/p38 Signaling Pathway

J Agric Food Chem. 2016 Dec 14;64(49):9326-9334. doi: 10.1021/acs.jafc.6b03700. Epub 2016 Dec 2.

Abstract

The increased proliferation of activated hepatic stellate cells (HSCs) is associated with hepatic fibrosis and excessive extracellular matrix (ECM)-protein production. We examined the inhibitory effects of the Monascus purpureus-fermented metabolites, ankaflavin and monascin (15 and 30 μM), on the Akt/nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK) signaling pathways in HSC-T6 (activated hepatic stellate cell line). Ankaflavin and monascin (30 μM) induced apoptosis and significantly inhibited cell growth (cell viabilities: 80.2 ± 5.43% and 62.8 ± 8.20%, respectively, versus control cells; P < 0.05). Apoptosis and G1 phase arrest (G1 phase percentages: 76.1 ± 2.85% and 79.9 ± 1.80%, respectively, versus control cells 65.9 ± 4.94%; P < 0.05) correlated with increased p53 and p21 levels and caspase 3 activity and decreased cyclin D1 and Bcl-2-family protein levels (P < 0.05, all cases). The apoptotic effects of ankaflavin and monascin were HSC-T6-specific, suggesting their potential in treating liver fibrosis.

Keywords: Monascus purpureus; ankaflavin; apoptosis; liver fibrosis; monascin.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Flavins / pharmacology*
  • Hepatic Stellate Cells / cytology*
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / metabolism
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / physiopathology*
  • Male
  • Monascus / chemistry*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Plant Extracts / pharmacology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Signal Transduction / drug effects*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Flavins
  • Heterocyclic Compounds, 3-Ring
  • NF-kappa B
  • Plant Extracts
  • ankaflavin
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • monascin