Penta-O-galloyl-beta-D-glucose induces S- and G(1)-cell cycle arrests in prostate cancer cells targeting DNA replication and cyclin D1.

Abstract

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.

• Authors: Hongbo Hu, Jinhui Zhang, Hyo Jeong Lee, Sung-Hoon Kim, Junxuan Lü
• Journal: Carcinogenesis (Carcinogenesis) Vol. 30 Issue 5 Pg. 818-23 (May 2009) ISSN: 1460-2180 [Electronic] England
• PMID: 19269999 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Hydrolyzable Tannins
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• Cyclin D1
• pentagalloylglucose
• Poly(ADP-ribose) Polymerases

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Cell Cycle
• Cell Division (drug effects)
• Cell Line, Tumor
• Cell Nucleus (drug effects, pathology)
• Cyclin D1 (drug effects, metabolism)
• DNA Replication (drug effects)
• Humans
• Hydrolyzable Tannins (pharmacology)
• Male
• Poly(ADP-ribose) Polymerases (metabolism)
• Prostatic Neoplasms (genetics, pathology)