Carcinogenesis Advance Access originally published online on March 6, 2009
Carcinogenesis 2009 30(5):818-823; doi:10.1093/carcin/bgp059
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Penta-O-galloyl-beta-D-glucose induces S- and G1-cell cycle arrests in prostate cancer cells targeting DNA replication and cyclin D1
1 Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA
2 College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100094, People's Republic of China
3 Cancer Preventive Material Development Research Center and Institute, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 131-701, Republic of Korea
* To whom correspondence should be addressed. Tel: +1 507 437 9680; Fax: +1 507 437 9606; Email: jlu{at}hi.umn.edu
Correspondence may also be addressed to Sung-Hoon Kim. Tel: +82 2 961 9233; Fax: +82 2 964 1074; Email: sungkim7{at}khu.ac.kr
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 G1 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 G1 arrest induced by PGG. Overexpressing this G1 cyclin abolished G1 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 G1 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.
Abbreviations: BrdU, 5-bromo-2'-deoxyuridine; BrdUTP, 5-bromo-2'-deoxyuridine 5'-triphosphate; CDK, cyclin-dependent kinase; DMSO, dimethyl sulfoxide; FBS, fetal bovine serum; IC, inhibitory concentration; PCa, prostate cancer; PBS, phosphate-buffered saline; PGG, penta-1,2,3,4,6-O-galloyl-beta-D-glucose; STAT3, signal transducer and activator of transcription 3
These authors contributed equally to this work and should be considered co-first authors. Received November 5, 2008; revised February 24, 2009; accepted February 26, 2009.
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