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Anti-cancer gallotannin penta-O-galloyl-beta-D-glucose is a nanomolar inhibitor of select mammalian DNA polymerases.
Biochem Pharmacol 2010; 80(8):1125-32BP

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.

Authors+Show Affiliations

Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Kobe, Japan. jlu@hi.umn.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

20599777

Citation

Mizushina, Yoshiyuki, et al. "Anti-cancer Gallotannin penta-O-galloyl-beta-D-glucose Is a Nanomolar Inhibitor of Select Mammalian DNA Polymerases." Biochemical Pharmacology, vol. 80, no. 8, 2010, pp. 1125-32.
Mizushina Y, Zhang J, Pugliese A, et al. Anti-cancer gallotannin penta-O-galloyl-beta-D-glucose is a nanomolar inhibitor of select mammalian DNA polymerases. Biochem Pharmacol. 2010;80(8):1125-32.
Mizushina, Y., Zhang, J., Pugliese, A., Kim, S. H., & Lü, J. (2010). Anti-cancer gallotannin penta-O-galloyl-beta-D-glucose is a nanomolar inhibitor of select mammalian DNA polymerases. Biochemical Pharmacology, 80(8), pp. 1125-32. doi:10.1016/j.bcp.2010.06.031.
Mizushina Y, et al. Anti-cancer Gallotannin penta-O-galloyl-beta-D-glucose Is a Nanomolar Inhibitor of Select Mammalian DNA Polymerases. Biochem Pharmacol. 2010 Oct 15;80(8):1125-32. PubMed PMID: 20599777.
* 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 -