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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 |
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글쓴이 : 최고관리자
날짜 : 09-03-16 11:27
조회 : 1887
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Hu H, Zhang J, Lee HJ, Kim SH, Lu J.
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 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 (IC(50) approximately 6 muM) 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 G(1) arrest induced by PGG. Over-expressing 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 down regulation to contribute to anti-cancer activity. Our data raise the hypothesis that PGG may be a novel inhibitor of DNA polymerases.
Carcinogenesis
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