Penta-O-galloyl-beta-D-glucose induces S- and G(1)-cell cycle arrests in prostate cancer cells targeting DNA replication and cyclin D1.
We have recently shown that penta-1,2,3,4,6-O-galloyl-beta-D-glucose (PGG), a naturally occurring hydrolyzable gallotannin, inhibited the in vivo growth of human androgen-independent p53-mutant DU145 prostate cancer (PCa) xenograft in athymic nude mice without adverse effect on their body weight. We have also shown that PGG induced caspase-mediated apoptosis in the DU145 cells and the androgen-dependent human p53-wild-type LNCaP cells. Here, we investigated the cell cycle effects of PGG in these and other PCa cells. Our data show that treatment with subapoptotic doses of PGG induced S-arrest, whereas higher doses of PGG induced not only S-arrest but also G(1) arrest. We show, for the first time, that irrespective of the p53 functional status of the PCa cell lines, PGG exerted a rapid (within 2 h) and potent inhibition (inhibitory concentration by 50% approximately 6 microM) of 5-bromo-2'-deoxyuridine incorporation into S phase cells. In isolated nuclei, PGG inhibited DNA replicative synthesis with superior efficacy than a known DNA polymerase alpha inhibitor, aphidocolin. In addition to the S-arrest action, we have found a close association of downregulation of cyclin D1 with G(1) arrest induced by PGG. Overexpressing this G(1) cyclin abolished G(1) arrest, but hastened the S-arrest induction by PGG. Together, our data indicate that PGG induced PCa S-arrest probably through DNA replicative blockage and induced G(1) arrest via cyclin D1 downregulation to contribute to anticancer activity. Our data raise the hypothesis that PGG may be a novel inhibitor of DNA polymerases.
Hu
Hongbo
H
Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
Zhang
Jinhui
J
Lee
Hyo Jeong
HJ
Kim
Sung-Hoon
SH
Lü
Junxuan
J
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects*; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*
D000590:Amino Acid Chloromethyl Ketones; D047348:Hydrolyzable Tannins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019938:Cyclin D1; C435084:pentagalloylglucose; D011065:Poly(ADP-ribose) Polymerases