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
N1 - Funding Information:
This work was supported in part by the “Academic Frontier” Project for Private Universities: matching fund subsidy from the Ministry of Education, Science, Sports, and Culture of Japan (MEXT), 2006–2010 (YM). YM acknowledges a Grant-in-Aid for Young Scientists (A) (No. 19680031 ) from MEXT, and The Salt Science Research Foundation , No. 09S3 (Japan). Support for this work also came from the US National Institutes of Health grant CA136953 (JL).
PY - 2010/10
Y1 - 2010/10
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 (α, δ and e{open}) and Y-family (η, ι and κ) of bypass synthesis pols, and the inhibitory effect of PGG on pol α was the strongest with IC50 value of 13nM. PGG also inhibited pol β, but the potency was an order of magnitude less than against pol α PGG inhibition of pol α and κ activity was non-competitive with respect to the DNA template-primer and the dNTP substrate; whereas it inhibited pol β competitively. Docking simulation on pol β, 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.
AB - 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 (α, δ and e{open}) and Y-family (η, ι and κ) of bypass synthesis pols, and the inhibitory effect of PGG on pol α was the strongest with IC50 value of 13nM. PGG also inhibited pol β, but the potency was an order of magnitude less than against pol α PGG inhibition of pol α and κ activity was non-competitive with respect to the DNA template-primer and the dNTP substrate; whereas it inhibited pol β competitively. Docking simulation on pol β, 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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U2 - 10.1016/j.bcp.2010.06.031
DO - 10.1016/j.bcp.2010.06.031
M3 - Article
C2 - 20599777
AN - SCOPUS:77956224958
SN - 0006-2952
VL - 80
SP - 1125
EP - 1132
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 8
ER -