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

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.