Carcinogenesis Advance Access published online on March 6, 2009
Carcinogenesis, 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 The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA
2 Cancer Preventive Material Development Research Center and Institute, College of Oriental Medicine, Kyunghee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 131-701, Republic of Korea
3 College of Food Science and Nutritional Engineering, China Agricultural University. Beijing, The People's Republic of China
Corresponding authors: Junxuan Lü, Ph.D., Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, Phone: 507-437-9680, Fax: 507-437-9606, E-mail: jlu{at}hi.umn.edu
Sung-Hoon Kim, OMD, Ph.D., College of Oriental Medicine, Kyunghee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 131-701, Republic of Korea. Phone: 82-2-961-9233; Fax: 82-2-964-1074; E-mail: 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 hydrolysable 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 sub-apoptotic 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 (IC50 
6 µM) of BrdU 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 down regulation of cyclin D1 with G1 arrest induced by PGG. Over-expressing 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 down regulation to contribute to anti-cancer activity. Our data raise the hypothesis that PGG may be a novel inhibitor of DNA polymerases.
Key Words: Prostate cancer • S- and G1 arrest • DNA replicative synthesis • cyclin D1
* These two authors contributed equally and should be considered co-first authors.
Received November 5, 2008; revised February 24, 2009; accepted February 26, 2009.
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