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.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 11221, Taiwan. rajnihpmicro@gmail.com.|Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung 80708, Taiwan. rajnihpmicro@gmail.com.
authors.forename: Rajni
authors.initials: R
authors.lastname: Kant
authors.affiliation: Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung 80708, Taiwan. chyen@kmu.edu.tw.|Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. chyen@kmu.edu.tw.|Lipid Science and Aging Research Center (CHY), Kaohsiung Medical University, Kaohsiung 80708, Taiwan. chyen@kmu.edu.tw.|Research Center for natural products and Drug Development (CHY), Kaohsiung Medical University, Kaohsiung 80708, Taiwan. chyen@kmu.edu.tw.
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Yen
authors.affiliation: National Research Institute of Chinese Medicine, Taipei 11221, Taiwan. cklu@nricm.edu.tw.|Department of Life Sciences and Institute of Genome Sciences, College of Life Science, National Yang-Ming University, Taipei 11221, Taiwan. cklu@nricm.edu.tw.
authors.forename: Chung-Kuang
authors.initials: CK
authors.lastname: Lu
authors.affiliation: School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. yclin@kmu.edu.tw.|Ph.D. Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. yclin@kmu.edu.tw.
authors.forename: Ying-Chi
authors.initials: YC
authors.lastname: Lin
authors.affiliation: School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. jhlitox@kmu.edu.tw.|Ph.D. Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. jhlitox@kmu.edu.tw.
authors.forename: Jih-Heng
authors.initials: JH
authors.lastname: Li
authors.affiliation: Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung 80708, Taiwan. arthur@kmu.edu.tw.|Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80708, Taiwan. arthur@kmu.edu.tw.|Department of Microbiology and Immunology, Institute of Medical Research and Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. arthur@kmu.edu.tw.
authors.forename: Yi-Ming Arthur
authors.initials: YM
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D055808:Drug Discovery; D005260:Female; D005960:Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D050938:Glycine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D029596:Paeonia / Q000737:chemistry; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C000615595:1,2,3,4,6-penta-O-galloylglucopyranoside; D000970:Antineoplastic Agents; D005960:Glucosides; D010936:Plant Extracts; D050938:Glycine N-Methyltransferase
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