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Shin J.-S.,Reactive Oxygen Species Medical Research Center | Choi J.-H.,Kyung Hee University | Choi S.Y.,Korea Food Research Institute | Rhee Y.K.,Korea Food Research Institute | Hong H.-D.,Korea Food Research Institute
Carcinogenesis | Year: 2013

The triterpene saponin ginsenoside Rh2 has been shown to have antiproliferative effects on various cancer cells. However, the effect of Rh2 on the cell cycle and its underlying molecular mechanism in human leukemia cells are not fully understood. In this study, we found that Rh2 inhibited the proliferation of human leukemia cells concentration- and time-dependently with an IC50 of ~38 μM. DNA flow cytometric analysis indicated that Rh2 blocked cell cycle progression at the G1 phase in HL-60 and U937 cells, and this was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 4, CDK6, cyclin D1, cyclin D2, cyclin D3 and cyclin E at the protein level. However, CDK inhibitors (CDKIs), such as p21CIP1/WAF1 and p27KIP1, were gradually upregulated after Rh2 treatment at the protein and messenger RNA (mRNA) levels. In addition, Rh2 markedly enhanced the bindings of p21CIP1/WAF1 and p27KIP1 to CDK2, CDK4 and CDK6, and these bindings reduced CDK2, CDK4 and CDK6 activities. Furthermore, Rh2 induced the differentiation of HL-60 cells as demonstrated by biochemical assays and the expression levels of cell surface antigens. In addition, treatment of HL-60 cells with Rh2 significantly increased transforming growth factor-β (TGF-β) production, and cotreatment with TGF-β neutralizing antibody prevented the Rh2-induced downregulations of CDK4 and CDK6, upregulations of p21CIP1/WAF1 and p27KIP1 levels and the induction of differentiation. These results demonstrate that the Rh2-mediated G1 arrest and the differentiation are closely linked to the regulation of TGF-β production in human leukemia cells. © The Author 2012. Published by Oxford University Press. All rights reserved. Source


Kim J.-Y.,Kyung Hee University | Choi H.-E.,Kyung Hee University | Lee H.-H.,Kyung Hee University | Shin J.-S.,Kyung Hee University | And 5 more authors.
Oncology Reports | Year: 2015

Styrylquinazolines are synthetic analogues of resveratrol and have been suggested to cause anti-inflammatory activity by modulating prostaglandin E2 (PGE2) production. In the present study, we evaluated cytotoxic effects of various styrylquinazoline derivatives and found that (E)-8-acetoxy-2-[2-(3,4-diacetoxyphenyl)ethenyl]-quinazoline (8-ADEQ) most potently inhibited the proliferation of the human cervical carcinoma HeLa cells. Exploring the growth-inhibitory mechanisms of 8-ADEQ, we found that it causes a cell cycle arrest at the G2/M phase by DNA flow cytometric analysis, which was accompanied by upregulation of cyclin B1 expression and cyclin-dependent protein kinase 1 (Cdk1) phosphorylation. In addition, we observed that 8-ADEQ causes phosphorylation of the cell division cycle 25C (Cdc25C) protein through the activation of checkpoint kinases 1 (Chk1) and Chk2, which in turn were activated via ataxia telangiectasia mutated (ATM)/ataxia telangiectasia-Rad3-related (ATR) kinases in response to the DNA damage. Furthermore, ATM/ATR inhibitor caffeine, p53- or ATM/ATR-specific siRNA significantly attenuated 8-ADEQ-induced G2/M arrest. These results suggest that the 8-ADEQ inhibits the proliferation of human cervical cancer HeLa cells by DNA damage-mediated G2/M cell cycle arrest. 8-ADEQ.induced G2/M arrest is mediated by the activation of both Chk1/2-Cdc25 and p53-p21CIP1/WAF1 via ATM/ATR pathway, and indicates that 8-ADEQ appears to have potential in the treatment of cervical cancer. Source


Cho E.-J.,Kyung Hee University | Shin J.-S.,Kyung Hee University | Shin J.-S.,Reactive Oxygen Species Medical Research Center | Chung K.-S.,Kyung Hee University | And 6 more authors.
Journal of Agricultural and Food Chemistry | Year: 2012

Recently, we reported the anti-inflammatory effects of arvelexin isolated from Brassica rapa in macrophages. In the present study, the effects of arvelexin were investigated in a dextran sulfate sodium (DSS)-induced colitis mouse model and in a cellular model. In the DSS-induced colitis model, arvelexin significantly reduced the severity of colitis, as assessed by disease activity, colonic damage, neutrophil infiltration, and levels of colonic iNOS. Moreover, arvelexin inhibited the expressions of IL-8, IP-10, ICAM-1, and VCAM-1 in HT-29 colonic epithelial cells. Arvelexin also inhibited the TNF-α-induced adhesion of U937 monocytic cells to HT-29 cells. Furthermore, arvelexin reduced p65 NF-κB subunit translocation to the nucleus and IκBα degradation in the colonic tissues and in TNF-α-induced HT-29 cells. These results demonstrate that the ameliorative effects of arvelexin on colonic injury are mainly related to its ability to inhibit the inflammatory responses via NF-κB inactivation, and support its possible therapeutic role in colitis. © 2012 American Chemical Society. Source

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