Penta-O-galloyl-β-D-glucose induces G1arrest and DNA replicative S-phase arrest independently of P21 cyclin-dependent kinase inhibitor 1A, P27 cyclin-dependent kinase inhibitor 1B and P53 in human breast cancer cells and is orally active against triple-negative xenograft growth

Abstract

IntroductionNatural 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 G1 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 drugable targets.MethodsMono-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 20 mg PGG/kg body weight by daily gavage starting 4 days after cancer cell inoculation.ResultsExposure 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 G1 arrest. Higher levels of PGG induced more caspase-mediated apoptosis in MCF-7, in strong association with induction of P53 Ser15 phosphorylation, than in MDA-MB-231 cells. The cell cycle arrests were achieved without an induction of cyclin dependent kinase (CDK) inhibitory proteins P21Cip1 and P27Kip1. PGG treatment led to decreased cyclin D1 in both cell lines and over-expressing cyclin D1 attenuated G1 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 G1-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.ConclusionsOur 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.

Vitamin B2 Sensitizes Cancer Cells to Vitamin-C-Induced Cell Death via Modulation of Akt and Bad Phosphorylation

“…MDA-MB-231 is a representative of triple-negative breast cancer that lacks effective targeted therapy. 28 The present study demonstrated that combining serum achievable level of vitamins C and B 2 can achieve a synergistic cytotoxic effect on multiple types of cancer cells, including a cell line of triple-negative breast cancer, providing an additional support for combination as a practical approach for improving the chemotherapeutic outcome. Findings of the present study may have important clinical implications for vitamin-C-based combinatorial therapy, especially for the management of triple-negative breast cancer.…”

Differential Cytotoxicity of Penta-O-galloyl-β-D-glucose in Human Cancer and Normal Cell Lines of Various Origins

“…Several previous studies have demonstrated that PGG treatment is often used for cancer chemotherapy owing to its anti-tumor effects [5,8,16]. The cells treated with PGG were induced to apoptotic cell death through the mediation of caspase activity in several human cell lines [14,29].…”

“…In the others studies, PGG treatment induced G0/G1 arrest and DNA replicative S-phase arrest of the cell cycles in human breast cancer cells, MDA-MB-231 and MCF-7 cells. Furthermore, in vivo growth of MDA-MB231 xenograft orally ingested was highly inhibited without any adverse effect on the host body weight in a dose-dependent manner and growth of DU145 xenograft was also inhibited by activating p53 tumor suppressor pathway and decreasing STAT3 oncogenic signaling [5,14]. Otherwise, PGG combined to VEGF receptor, and blocked the angiogenesis by inhibiting endothelial cell growth and The cause of differential cytotoxic effect by PGG treatment in human cell lines of various origins is still unclear.…”

“…Recently, 1, 2, 3, 4, 6-Penta-Ogalloyl-β-D-glucose (PGG) found in many plant species, a simple hydrolysable tannin, has been considered as a candidate anti-cancer drug. It has been previously demonstrated that PGG treatment induces cellular cytotoxic effects, including the induction of cellular apoptotic cell death, elevated expression of activating p53 tumor suppressor, arrest of cell cycle and blocking angiogenesis by inhibiting VEGF expression in several types of human cancer cells [5,8,12,21]. Moreover, different studies have reported a wide variety of biological activities, such as anti-microbial, anti-platelet-coagulation functions as well as anti-tumor effects in human cancer cells by PGG treatment [4].…”

Penta-O-galloyl-beta-D-glucose enhances antitumor activity of imatinib and suppresses the growth of K562 cells in mice

“…PGG was isolated from the gallnut of Rhus chinensis Mill as previously described (Chai et al, 2010). The yellowish active compound was identified as PGG by nuclear magnetic resonance (NMR) and fast atom bombardment mass spectrometry (FAB-MS) analyses.…”