Penta-O-galloyl-beta-D-glucose induces S- and G1-cell cycle arrests in prostate cancer cells targeting DNA replication and cyclin D1
Open Access
- 6 March 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Carcinogenesis: Integrative Cancer Research
- Vol. 30 (5), 818-823
- https://doi.org/10.1093/carcin/bgp059
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% ∼6 μM) 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.Keywords
This publication has 18 references indexed in Scilit:
- Penta-1,2,3,4,6-O-galloyl-β-d-glucose induces p53 and inhibits STAT3 in prostate cancer cellsin vitroand suppresses prostate xenograft tumor growthin vivoMolecular Cancer Therapeutics, 2008
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- Mechanisms of action of novel agents for prostate cancer chemopreventionEndocrine-Related Cancer, 2006
- Pentagalloylglucose inhibits estrogen receptor α by lysosome‐dependent depletion and modulates ErbB/PI3K/Akt pathway in human breast cancer MCF‐7 cellsMolecular Carcinogenesis, 2006
- Chemoprevention of Prostate CancerAnnual Review of Medicine, 2006
- Penta- O -galloyl-beta- d -glucose suppresses tumor growth via inhibition of angiogenesis and stimulation of apoptosis: roles of cyclooxygenase-2 and mitogen-activated protein kinase pathwaysCarcinogenesis: Integrative Cancer Research, 2005
- Induction of G1 Arrest and Apoptosis in Human Jurkat T Cells by Pentagalloylglucose through Inhibiting Proteasome Activity and Elevating p27Kip1, p21Cip1/WAF1, and Bax ProteinsPublished by Elsevier BV ,2004
- p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrestCell, 1994
- p53 Mutations in Human CancersScience, 1991
- Aphidicolin prevents mitotic cell division by interfering with the activity of DNA polymerase-αNature, 1978