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

Rajni Kant, Chia Hung Yen, Chung Kuang Lu, Ying Chi Lin, Jih Heng Li, Yi Ming Arthur Chen

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number669
JournalInternational Journal of Molecular Sciences
Volume17
Issue number5
DOIs
Publication statusPublished - May 4 2016
Externally publishedYes

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Glycine N-Methyltransferase
Rubiaceae
glycine
Biological Products
Amino acids
Hepatocellular Carcinoma
Screening
screening
cancer
Throughput
products
Assays
drugs
knockout mice
cells
Paeonia
Aflatoxins
Preclinical Drug Evaluations
Cell proliferation
apoptosis

Keywords

  • 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG)
  • Glycine N-methyltransferase (GNMT)
  • Hepatocellular carcinomas (HCC)
  • High-throughput screening (HTS)
  • Sorafenib

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

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title = "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",
abstract = "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.",
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author = "Rajni Kant and Yen, {Chia Hung} and Lu, {Chung Kuang} and Lin, {Ying Chi} and Li, {Jih Heng} and Chen, {Yi Ming Arthur}",
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AU - Kant, Rajni

AU - Yen, Chia Hung

AU - Lu, Chung Kuang

AU - Lin, Ying Chi

AU - Li, Jih Heng

AU - Chen, Yi Ming Arthur

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