Identification of 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranoside as a Glycine N-Methyltransferase Enhancer by High-Throughput Screening of Natural Products Inhibits Hepatocellular Carcinoma

Int J Mol Sci. 2016 May 4;17(5):669. doi: 10.3390/ijms17050669.


Glycine N-methyltransferase (GNMT) expression is vastly downregulated in hepatocellular carcinomas (HCC). High rates of GNMT knockout mice developed HCC, while overexpression of GNMT prevented aflatoxin-induced carcinogenicity and inhibited liver cancer cell proliferation. Therefore, in this study, we aimed for the identification of a GNMT inducer for HCC therapy. We established a GNMT promoter-driven luciferase reporter assay as a drug screening platform. Screening of 324 pure compounds and 480 crude extracts from Chinese medicinal herbs resulted in the identification of Paeonia lactiflora Pall (PL) extract and the active component 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) as a GNMT inducer. Purified PL extract and PGG induced GNMT mRNA and protein expression in Huh7 human hepatoma cells and in xenograft tumors. PGG and PL extract had potent anti-HCC effects both in vitro and in vivo. Furthermore, PGG treatment induced apoptosis in Huh7 cells. Moreover, PGG treatment sensitized Huh7 cells to sorafenib treatment. Therefore, these results indicated that identifying a GNMT enhancer using the GNMT promoter-based assay might be a useful approach to find drugs for HCC. These data also suggested that PGG has therapeutic potential for the treatment of HCC.

Keywords: ">d-glucopyranoside (PGG); 1,2,3,4,6-penta-O-galloyl-β-; glycine N-methyltransferase (GNMT); hepatocellular carcinomas (HCC); high-throughput screening (HTS); sorafenib.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / drug therapy*
  • Drug Discovery
  • Female
  • Glucosides / pharmacology*
  • Glucosides / therapeutic use
  • Glycine N-Methyltransferase / genetics
  • Glycine N-Methyltransferase / metabolism*
  • HEK293 Cells
  • Hep G2 Cells
  • High-Throughput Screening Assays
  • Humans
  • Liver Neoplasms / drug therapy*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mice, SCID
  • Paeonia / chemistry
  • Plant Extracts / pharmacology*
  • Plant Extracts / therapeutic use


  • 1,2,3,4,6-penta-O-galloylglucopyranoside
  • Antineoplastic Agents
  • Glucosides
  • Plant Extracts
  • Glycine N-Methyltransferase