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Penta-O-galloyl-beta-D-glucose induces G1 arrest and DNA replicative S-phase arrest independently of cyclin-dependent kinase inhibitor 1A, cyclin-dependent kinase inhibitor 1B and P53 in human breast cancer cells and is orally active against triple negative xenograft growth.
Breast Cancer Res. 2010; 12(5):R67.BC

Abstract

INTRODUCTION

Natural herbal compounds with novel actions different from existing breast cancer (BCa) treatment modalities are attractive for improving therapeutic efficacy and safety. We have recently shown that penta-1,2,3,4,6-O-galloyl-β-D-glucose (PGG) induced S-phase arrest in prostate cancer (PCa) cells through inhibiting DNA replicative synthesis and G(1) arrest, in addition to inducing cell death at higher levels of exposure. We and others have shown that PGG through intraperitoneal (i.p.) injection exerts a strong in vivo growth suppression of human PCa xenograft models in athymic nude mice. This study aims to test the hypothesis that the novel targeting actions of PGG are applicable to BCa cells, especially those lacking proven druggable targets.

METHODS

Mono-layer cell culture models of p53-wild type estrogen receptor (ER)-dependent MCF-7 BCa cells and p53-mutant ER-/progesterone receptor (PR)- and Her2-regular (triple-negative) MDA-MB-231 BCa were exposed to PGG for a comprehensive investigation of cellular consequences and molecular targets/mediators. To test the in vivo efficacy, female athymic mice inoculated with MDA-MB-231 xenograft were treated with 20mg PGG/kg body weight by daily gavage starting 4 days after cancer cell inoculation.

RESULTS

Exposure to PGG induced S-phase arrest in both cell lines as indicated by the lack of 5-bromo2'-deoxy-uridine (BrdU) incorporation into S-phase cells as well as G(1) arrest. Higher levels of PGG induced more caspase-mediated apoptosis in MCF-7, in strong association with induction of P53 Ser(15) phosphorylation, than in MDA-MB-231 cells. The cell cycle arrests were achieved without an induction of cyclin dependent kinase (CDK) inhibitory proteins P21(Cip1) and P27(Kip1). PGG treatment led to decreased cyclin D1 in both cell lines and over-expressing cyclin D1 attenuated G(1) arrest and hastened S arrest. In serum-starvation synchronized MCF-7 cells, down-regulation of cyclin D1 was associated with de-phosphorylation of retinoblastoma (Rb) protein by PGG shortly before G(1)-S transition. In vivo, oral administration of PGG led to a greater than 60% inhibition of MDA-MB231 xenograft growth without adverse effect on host body weight.

CONCLUSIONS

Our in vitro and in vivo data support PGG as a potential drug candidate for breast cancer with novel targeting actions, especially for a triple negative BCa xenograft model.

Authors+Show Affiliations

The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20809980

Citation

Chai, Yubo, et al. "Penta-O-galloyl-beta-D-glucose Induces G1 Arrest and DNA Replicative S-phase Arrest Independently of Cyclin-dependent Kinase Inhibitor 1A, Cyclin-dependent Kinase Inhibitor 1B and P53 in Human Breast Cancer Cells and Is Orally Active Against Triple Negative Xenograft Growth." Breast Cancer Research : BCR, vol. 12, no. 5, 2010, pp. R67.
Chai Y, Lee HJ, Shaik AA, et al. Penta-O-galloyl-beta-D-glucose induces G1 arrest and DNA replicative S-phase arrest independently of cyclin-dependent kinase inhibitor 1A, cyclin-dependent kinase inhibitor 1B and P53 in human breast cancer cells and is orally active against triple negative xenograft growth. Breast Cancer Res. 2010;12(5):R67.
Chai, Y., Lee, H. J., Shaik, A. A., Nkhata, K., Xing, C., Zhang, J., Jeong, S. J., Kim, S. H., & Lu, J. (2010). Penta-O-galloyl-beta-D-glucose induces G1 arrest and DNA replicative S-phase arrest independently of cyclin-dependent kinase inhibitor 1A, cyclin-dependent kinase inhibitor 1B and P53 in human breast cancer cells and is orally active against triple negative xenograft growth. Breast Cancer Research : BCR, 12(5), R67. https://doi.org/10.1186/bcr2634
Chai Y, et al. Penta-O-galloyl-beta-D-glucose Induces G1 Arrest and DNA Replicative S-phase Arrest Independently of Cyclin-dependent Kinase Inhibitor 1A, Cyclin-dependent Kinase Inhibitor 1B and P53 in Human Breast Cancer Cells and Is Orally Active Against Triple Negative Xenograft Growth. Breast Cancer Res. 2010;12(5):R67. PubMed PMID: 20809980.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Penta-O-galloyl-beta-D-glucose induces G1 arrest and DNA replicative S-phase arrest independently of cyclin-dependent kinase inhibitor 1A, cyclin-dependent kinase inhibitor 1B and P53 in human breast cancer cells and is orally active against triple negative xenograft growth. AU - Chai,Yubo, AU - Lee,Hyo-Jeong, AU - Shaik,Ahmad Ali, AU - Nkhata,Katai, AU - Xing,Chengguo, AU - Zhang,Jinhui, AU - Jeong,Soo-Jin, AU - Kim,Sung-Hoon, AU - Lu,Junxuan, Y1 - 2010/09/01/ PY - 2010/04/22/received PY - 2010/09/01/accepted PY - 2010/9/3/entrez PY - 2010/9/3/pubmed PY - 2013/2/13/medline SP - R67 EP - R67 JF - Breast cancer research : BCR JO - Breast Cancer Res VL - 12 IS - 5 N2 - INTRODUCTION: Natural herbal compounds with novel actions different from existing breast cancer (BCa) treatment modalities are attractive for improving therapeutic efficacy and safety. We have recently shown that penta-1,2,3,4,6-O-galloyl-β-D-glucose (PGG) induced S-phase arrest in prostate cancer (PCa) cells through inhibiting DNA replicative synthesis and G(1) arrest, in addition to inducing cell death at higher levels of exposure. We and others have shown that PGG through intraperitoneal (i.p.) injection exerts a strong in vivo growth suppression of human PCa xenograft models in athymic nude mice. This study aims to test the hypothesis that the novel targeting actions of PGG are applicable to BCa cells, especially those lacking proven druggable targets. METHODS: Mono-layer cell culture models of p53-wild type estrogen receptor (ER)-dependent MCF-7 BCa cells and p53-mutant ER-/progesterone receptor (PR)- and Her2-regular (triple-negative) MDA-MB-231 BCa were exposed to PGG for a comprehensive investigation of cellular consequences and molecular targets/mediators. To test the in vivo efficacy, female athymic mice inoculated with MDA-MB-231 xenograft were treated with 20mg PGG/kg body weight by daily gavage starting 4 days after cancer cell inoculation. RESULTS: Exposure to PGG induced S-phase arrest in both cell lines as indicated by the lack of 5-bromo2'-deoxy-uridine (BrdU) incorporation into S-phase cells as well as G(1) arrest. Higher levels of PGG induced more caspase-mediated apoptosis in MCF-7, in strong association with induction of P53 Ser(15) phosphorylation, than in MDA-MB-231 cells. The cell cycle arrests were achieved without an induction of cyclin dependent kinase (CDK) inhibitory proteins P21(Cip1) and P27(Kip1). PGG treatment led to decreased cyclin D1 in both cell lines and over-expressing cyclin D1 attenuated G(1) arrest and hastened S arrest. In serum-starvation synchronized MCF-7 cells, down-regulation of cyclin D1 was associated with de-phosphorylation of retinoblastoma (Rb) protein by PGG shortly before G(1)-S transition. In vivo, oral administration of PGG led to a greater than 60% inhibition of MDA-MB231 xenograft growth without adverse effect on host body weight. CONCLUSIONS: Our in vitro and in vivo data support PGG as a potential drug candidate for breast cancer with novel targeting actions, especially for a triple negative BCa xenograft model. SN - 1465-542X UR - https://www.unboundmedicine.com/medline/citation/20809980/Penta_O_galloyl_beta_D_glucose_induces_G1_arrest_and_DNA_replicative_S_phase_arrest_independently_of_cyclin_dependent_kinase_inhibitor_1A_cyclin_dependent_kinase_inhibitor_1B_and_P53_in_human_breast_cancer_cells_and_is_orally_active_against_triple_negative_xenograft_growth_ L2 - https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr2634 DB - PRIME DP - Unbound Medicine ER -