• Animal cells and systems
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• v.11 no.1
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• pp.9-15
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• 2007

The naphthoquinone analog (2,3-dichloro-6,9-dihydroxy-1,4-naphtoquinone, NA) has an inhibitory effect on cdc25A protein phosphatase in vitro, which is responsible for G1/S transition during cell cycle. However, the exact mechanism inducing the growth inhibition is not understood. In this study, we investigated the regulatory mechanisms of growth arrest induced by NA, as a new potent inhibitor of cdc25A phosphatase, in human hepatocarcinoma SK-hep-1 cells. We found that NA induced the G1 arrest by perturbation of protein tyrosine dephosphorylation of Cdk2, which may be resulting from inhibition of cdc25A phosphatase. In addition, p21 was expressed in a p53-independent manner and participated in the NA-induced G1 arrest by inhibiting Cdk2 activity. Although the exact mechanism is not known, the p21 expression might be related to MAPK activation. From these results, we suggest that NA induces G1 arrest via inhibition of cdc25A and induction of p53-independent p21 expression in SK-Hep-1 cells.

• Journal of the Korean Society of Food Science and Nutrition
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• v.41 no.7
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• pp.907-913
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• 2012

Piceatannol (trans-3,4,3',5'-tetrahydroxystilbene) is a polyphenol detected in grapes, rhubarb, and sugarcane. Although recent experimental data revealed that this compound is known to exhibit immunosuppressive and antitumorigenic activities in several cell lines, the molecular mechanisms underlying anticancer activity are poorly understood. In the present study, we investigated possible further mechanisms by which piceatannol exerts its anti-proliferative action in cultured human gastric cancer AGS cells. Piceatannol treatment resulted in the inhibition of growth and G1 arrest of the cell cycle in a concentration-dependent manner, as determined by MTT assay and flow cytometry analysis. The induction of G1 arrest by piceatannol was associated with the modulation of cyclin-dependent kinases (Cdks) and cyclins, up-regulation of the expression of Cdk inhibitor p21 (WAF1/CIP1) in both transcriptional and translational levels, and the inhibition of phosphorylation of retinoblastoma proteins and E2F1 expression. In addition, piceatannol treatment caused a progressive decrease in the expression levels of cyclooxygenase (COX)-2 without significant changes in the levels of COX-1, which was correlated with a decrease in prostaglandin $E_2$ synthesis.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.4
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• pp.457-466
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• 1997

The effects of DFMO or/and putrescine on the dexamethasone-induced apoptosis of CEM cells were studied to investigate the role of polyamines in anti-leukemic glucocorticoid action. Dexamethasone- induced apoptosis was preceded by significant decreases of cellular polyamine contents and putrescine uptake activity. But DFMO produced decreases of putrescine and spermidine contents and marked increase of putrescine uptake activity, but did not induce apoptosis. However, dexamethasone and DFMO, respectively, induced $G_1-arrest$ in cell cycle and hypophosphorylation of pRb, resulting in the increase of $G_1$ to S ratio and decrease of CEM cell count. DFMO enhanced the dexamethasone-induced apoptosis and $G_1-arrest$. On the other hand, putrescine little affected the apoptotic and $G_1-arresting$ activities of dexamethasone, but almost suppress the effects of DFMO and also the DFMO-dependent enhancement of dexamethasone effects. These results suggested that the dexamethasone-induced apoptosis to be associated with pRb hypophosphorylation and $G_1-arrest$ in CEM cells might be ascribed to the concomitant decreases of cellular polyamine contents and putrescine uptake activity.

• Proceedings of the Korean Society of Toxicology Conference
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• 2002.11b
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• pp.138-138
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• 2002

8-hydroxydeoxyguanosine (oh8dG) potently inhibits proliferation of KG-1, a human leukemia cell line in vitro, but little is known regarding to molecular mechanisms mediating this effect. Here we demonstrate that treatment of KG-1, deficient in 8-oxoguanine glycosylase (OGG1) activity, with oh8dG lead to G1 arrest associated with a dramatic decrease in the levels of cyclin D3 and cyclin-dependent kinase 4 (cdk4) and accompanied by an increase in the expression of p21.(omitted)

• Journal of Life Science
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• v.16 no.4
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• pp.589-597
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• 2006

Genistein, a natural isoflavonoid phytoestrogen, is a strong inhibitor of protein tyrosine kinase and DNA topoisomerase activities. There are several studies documenting molecular alterations leading to cell cycle arrest and induction of apoptosis by genistein as a chemopreventive agent in a variety of cancer cell lines; however, its mechanism of action and its molecular targets on human bladder carcinoma and leukemic cells remain unclear. In the present study, we have addressed the mechanism of action by which genistein suppressed the proliferation of T24 bladder carcinoma and U937 leukemic cells. Genistein significantly inhibited the cell growth and induced morphological changes, and induced the G2/M arrest of the cell cycle in both T24 and U937 cells with a relatively stronger cytotoxicity in U937. The G2/M arrest in T24 cells was associated with the inhibition of cyclin A, cyclin B1 and Cdc25C protein expression without alteration of tumor suppressor p53 and cyclin-dependent kinase (Cdk) inhibitor p21(WAF1/CIP1). However, the inhibitory effects of genistein on the cell growth of U937 cells were connected with a marked inhibition of cyclin B1 and an induction of Cdk inhibitor p21 proteins by p53-independent manner. These data suggest that genistein may exert a strong anticancer effect and additional studies will be needed to evaluate the different mechanisms between T24 and U937 cells.

• Journal of Life Science
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• v.23 no.9
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• pp.1109-1117
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• 2013

Induction of G1 Arrest by Methanol Extract of Lycopus lucidus in Human Lung Adenocarcinoma A549 Cells Lycopus lucidus, a herbaceous perennial, is used as a traditional remedy in East Asia, including China and Korea. It has been reported that L. lucidus has anti-allergic effects, inhibitory effects on cholesterol acyltransferase in high glucose-induced vascular inflammation, and anti-proliferative effects in human breast cancer cells. However, the molecular mechanisms of the anti-cancer effects of L. lucidus have not yet been fully determined. In this study, we evaluated the anti-cancer effect and the mechanism of action of L. lucidus in human lung adenocarcinoma A549 cells using methanol extracts of L. lucidus (MELL). MELL treatment showed cytotoxic activity in a dose-dependent manner and induced G1 arrest in A549 cells. The induction of G1 arrest by MELL was associated with the up-regulation of phospho-CHK2 and the down-regulation of Cdc25A phosphatase. In addition, MELL treatment induced decreased expression of G1/S transition-related proteins, including CDK2, CDK4, CDK6, cyclin D1 and cyclin E. MELL also regulated the mRNA expression of CDK2 and cyclin E. On the other hand, the expression of p53 and the cyclin-dependent kinase inhibitor p21 was not induced by MELL. Collectively, these results suggest that MELL may exert an anti-cancer effect by cell cycle arrest at G1 phase through the ATM/CHK2/Cdc25A/CDK2 pathway in A549 cells.

• Journal of Life Science
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• v.19 no.7
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• pp.871-877
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• 2009

We investigated the effects of sodium butyrate, a histone deacetylase inhibitor, on the cell cycle progression in human monocytic leukemia U937 cells. Exposure of U937 cells to sodium butyrate resulted in growth inhibition, G1 arrest of the cell cycle and induction of apoptosis in a dose-dependent manner as measured by MTT assay and flow cytometry analysis. The increase in G1 arrest was associated with the down-regulation in cyclin D1, E, A, cyclin-dependent kinase (Cdk) 4 and 6 expression, and up-regulation of Cdk inhibitors such as p21 and p27. Sodium butyrate treatment also inhibited the phosphorylation of retinoblastoma protein (pRB) and p130, however, the levels of transcription factors E2F-1 and E2F-4 were not markedly modulated. Furthermore, the down-regulation of phosphorylation of pRB and p130 by this compound was associated with enhanced binding of pRB and E2F-1, as well as p130 and E2F-4, respectively. Overall, the present results demonstrate a combined mechanism involving the inhibition of pRBjp130 phosphorylation and induction of Cdk inhibitors as targets for sodium butyrate that may explain some of its anti-cancer effects in U937 cells.

• The Journal of Internal Korean Medicine
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• v.36 no.1
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• pp.13-21
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• 2015

Objectives : In Korea, Rhus verniciflua Stokes (RVS) has been used in traditional medicine for various diseases such as back pain, syndromes of the blood system in women, gastrointestinal disease, and cancer. However, the molecular mechanisms of its anti-cancer activity have not been clearly elucidated yet. Methods : This study investigated the possible mechanisms by which RVS extract (RVE) exerts its anti-proliferative action in cultured human breast carcinoma MCF-7 cells. Results : Treatment with RVE in MCF-7 cells resulted in inhibition of cell viability through G1 arrest of the cell cycle and induction of apoptosis in a time- and concentration-dependent manner, as determined by MTT assay and flow cytometry analysis. The induction of G1 arrest by RVE treatment was associated with the inhibition of cyclin D1, cyclin-dependent kinase (Cdk) 2, retinoblastoma protein (pRB), and mouse double minute 2 (MDM2) expression. Moreover, RVE treatment concentration dependently increased the levels of tumor suppressor p53, which was associated with the marked induction of Cdk inhibitors such as p21 (Waf1/Cip1) and p27 (Kip1). However, the inhibition of p53 function by the wild-type p53-specific inhibitor, pifithrin-α, abolished the above-mentioned effects of RVE, showing that p53 was responsible for the cytotoxicity of RVE Conclusions : These data indicate that a molecular pathway involving p53-dependent G1 cell cycle arrest plays a pivotal role in the cellular response to RVE, and demonstrate the potential applications of RVE as an anti-cancer drug for breast cancer treatment.

• Journal of Life Science
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• v.23 no.5
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• pp.622-628
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• 2013

Diallyl trisulfide (DATS), one of the major organosulfur components of garlic (Allium sativum), has various biological effects such as anti-microbial and anti-cancer activities. However, the molecular mechanisms of growth inhibition related to cell cycle arrest are poorly understood. In this study, we investigated the effects of DATS on cell cycle progression in U937 human leukemia cells. Treatment with DATS in U937 cells resulted in inhibition of cell viability through G2/M arrest and apoptosis. DATS-induced G2/M arrest was associated with up-regulation of cyclin B1 and cyclin-dependent kinase 1 (CDK1). DATS also significantly increased levels of phospho-histone H3, which is a mitosis-specific marker, indicating that DATS induced mitotic arrest but not G2 arrest in U937 cells. DATS treatment also generated the reactive oxygen species (ROS) in U937 cells; however, pretreatment with N-acetyl-l-cysteine (NAC), a ROS scavenger, significantly attenuated DATS-induced mitotic arrest and apoptosis. Taken together, our data indicate that DATS exhibits anti-cancer effects through mitotic arrest and apoptosis in a ROS-dependent manner.

• YAKHAK HOEJI
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• v.58 no.1
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• pp.33-39
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• 2014

The objective of this study is to evaluate the anticancer effects of the isoflavone extract from Chungkukjang in human breast cancer, MDA-MB-453 cells. For this study, MDA-MB-453 cells were treated with 12.5, 25, and $50{\mu}g$ isoflavone extract for 24, 48, and 72 hr. Cell proliferations were decreased in a time- and dose-dependent manner. Reduced cell proliferation was suspected by apoptosis or cell cycle arrest. Therefore, after treatment of $50{\mu}g$ isoflavone extract, apoptotic cells were investigated by annexin V staining. The results indicated that isoflavone extract increased the number of early apoptotic cells compared with control. Cleaved PARP was also increased. Next, we investigated the cell cycle and related proteins. The isoflavone extract leads to cell cycle arrest at the G2/M phase. Moreover isoflavone extract had influenced cell cycle relate proteins such as cyclin B1, cyclin A, and p21. These results suggest that isoflavone extract from Chungkukjang induce apoptosis and cell cycle arrest at G2/M phase via regulation of cell cycle-related proteins in MDA-MB-453 cells.