Penta-O-galloyl-beta-D-glucose induces S- and G1-cell cycle arrests in prostate cancer cells targeting DNA replication and cyclin D1

被引:35
作者
Hu, Hongbo [1 ,2 ]
Zhang, Jinhui [1 ]
Lee, Hyo Jeong [1 ,3 ,4 ]
Kim, Sung-Hoon [1 ,3 ,4 ]
Lue, Junxuan [1 ]
机构
[1] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA
[2] China Agr Univ, Coll Food Sci & Nutr Engn, Beijing 100094, Peoples R China
[3] Kyung Hee Univ, Canc Prevent Mat Dev Res Ctr, Seoul 131701, South Korea
[4] Kyung Hee Univ, Inst Coll Oriental Med, Seoul 131701, South Korea
基金
美国国家卫生研究院;
关键词
TUMOR-GROWTH; INHIBITION; APOPTOSIS; INDUCTION; PENTAGALLOYLGLUCOSE; CARCINOGENESIS; P53;
D O I
10.1093/carcin/bgp059
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
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% similar to 6 mu M) 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.
引用
收藏
页码:818 / 823
页数:6
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