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Anti-cancer gallotannin penta-O-galloyl-beta-D-glucose is a nanomolar inhibitor of select mammalian DNA polymerases.

Abstract

Penta-1,2,3,4,6-O-galloyl-beta-D-glucose (PGG) has been shown by us and others to inhibit the in vivo growth of human prostate cancer (PCa) xenografts in athymic nude mice and mouse lung cancer allograft in syngenic mice without evident adverse effect on their body weight. We observed a rapid inhibition of DNA synthesis in S-phase cells in PGG-exposed cancer cells and in PGG-treated isolated nuclei. The purpose of the present study was to test the hypothesis that PGG inhibits DNA replicative synthesis through a direct inhibition of one or more DNA polymerases (pols). Using purified pols, we show that PGG exhibited a selective inhibition against the activities of B-family replicative pols (alpha, delta and epsilon) and Y-family (eta, iota and kappa) of bypass synthesis pols, and the inhibitory effect of PGG on pol alpha was the strongest with IC(50) value of 13 nM. PGG also inhibited pol beta, but the potency was an order of magnitude less than against pol alpha. PGG inhibition of pol alpha and kappa activity was non-competitive with respect to the DNA template-primer and the dNTP substrate; whereas it inhibited pol beta competitively. Docking simulation on pol beta, which is the only mammalian pol with solved crystal structure, suggests several favorable interactions with the catalytic pocket/binding site for the incoming dNTP. These results support PGG as a novel inhibitor of select families of mammalian pols by distinct mechanisms, and suggest that the potent pol inhibition may contribute to its anti-cancer efficacy.

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    ,

    Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Kobe, Japan. jlu@hi.umn.edu

    , , ,

    Source

    Biochemical pharmacology 80:8 2010 Oct 15 pg 1125-32

    MeSH

    Animals
    Antineoplastic Agents
    Cattle
    Computer Simulation
    DNA
    DNA Damage
    DNA-Directed DNA Polymerase
    Humans
    Hydrolyzable Tannins
    Mice
    Models, Molecular
    Molecular Structure
    Nucleic Acid Synthesis Inhibitors
    Plants
    Protein Binding
    Protein Conformation
    Rats

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    20599777

    Citation

    * When formatting your citation, note that all book, journal, and database titles should be italicized* Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Anti-cancer gallotannin penta-O-galloyl-beta-D-glucose is a nanomolar inhibitor of select mammalian DNA polymerases. AU - Mizushina,Yoshiyuki, AU - Zhang,Jinhui, AU - Pugliese,Angelo, AU - Kim,Sung-Hoon, AU - Lü,Junxuan, Y1 - 2010/06/26/ PY - 2010/04/05/received PY - 2010/06/18/revised PY - 2010/06/21/accepted PY - 2010/7/6/entrez PY - 2010/7/6/pubmed PY - 2010/10/12/medline SP - 1125 EP - 32 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 80 IS - 8 N2 - Penta-1,2,3,4,6-O-galloyl-beta-D-glucose (PGG) has been shown by us and others to inhibit the in vivo growth of human prostate cancer (PCa) xenografts in athymic nude mice and mouse lung cancer allograft in syngenic mice without evident adverse effect on their body weight. We observed a rapid inhibition of DNA synthesis in S-phase cells in PGG-exposed cancer cells and in PGG-treated isolated nuclei. The purpose of the present study was to test the hypothesis that PGG inhibits DNA replicative synthesis through a direct inhibition of one or more DNA polymerases (pols). Using purified pols, we show that PGG exhibited a selective inhibition against the activities of B-family replicative pols (alpha, delta and epsilon) and Y-family (eta, iota and kappa) of bypass synthesis pols, and the inhibitory effect of PGG on pol alpha was the strongest with IC(50) value of 13 nM. PGG also inhibited pol beta, but the potency was an order of magnitude less than against pol alpha. PGG inhibition of pol alpha and kappa activity was non-competitive with respect to the DNA template-primer and the dNTP substrate; whereas it inhibited pol beta competitively. Docking simulation on pol beta, which is the only mammalian pol with solved crystal structure, suggests several favorable interactions with the catalytic pocket/binding site for the incoming dNTP. These results support PGG as a novel inhibitor of select families of mammalian pols by distinct mechanisms, and suggest that the potent pol inhibition may contribute to its anti-cancer efficacy. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/20599777/Anti_cancer_gallotannin_penta_O_galloyl_beta_D_glucose_is_a_nanomolar_inhibitor_of_select_mammalian_DNA_polymerases_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(10)00465-X DB - PRIME DP - Unbound Medicine ER -