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.