Biomedical subjects

Sung-Dae Cho

Publications and source records attributed to Sung-Dae Cho.

12 recordsLinked to original sources

PubMed2006

Critical role of the c-JunNH2-terminal kinase and p38 mitogen-activated protein kinase pathways on sodium butyrate-induced apoptosis in DU145 human prostate cancer cells.

Sodium butyrate (NaBu) is known to exhibit anti-cancer effects via the differentiation and apoptosis of various carcinoma cells. However, the mechanism by which NaBu induces apoptosis and the involvement of protein kinases during apoptosis is not completely understood. To investigate the underlying pathways, we performed cell culture experiments in androgen-independent human prostate cancer (DU145 cells) focusing on various protein kinases. NaBu causes concentration-dependent cell detachment and growth inhibition. Exposure of DU145 cells to NaBu for 24 h caused a strong apoptotic effect with 26% nuclear fragmentation and condensation. In addition, NaBu induced caspase-3 and poly-ADP ribose polymerase cleavage and up-regulation of bax, suggesting that mitochondrial damage is involved in NaBu-induced caspase-dependent apoptosis. Interestingly, NaBu stimulated p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) activation, but not extracellular signal-regulated kinase 1/2 activation during apoptosis. Furthermore, NaBu up-regulated total protein levels and phospho forms of MAPK kinase 3 (MKK3) and MAPK kinase 4 (MKK4) as the upstream kinases of p38 MAPK and JNK independently of oxidative stress. Taken together, it is suggested that NaBu can be a promising chemopreventive agent for prostate cancer and the p38 MAPK and JNK pathways have critical roles in NaBu-induced apoptosis in DU145 cells.

Apoptosis↗

PubMed2006

The antitumor effect of LJ-529, a novel agonist to A3 adenosine receptor, in both estrogen receptor-positive and estrogen receptor-negative human breast cancers.

Agonists to A3 adenosine receptor (A3AR) have been reported to inhibit cell growth and/or induce apoptosis in various tumors. We tested the effect of a novel A3AR agonist generically known as LJ-529 in breast cancer cells. Anchorage-dependent cell growth and in vivo tumor growth were attenuated by LJ-529, independently of its estrogen receptor (ER) alpha status. In addition, apoptosis was induced as evidenced by the activation of caspase-3 and c-poly(ADP)ribose polymerase. Furthermore, the Wnt signaling pathway was down-regulated and p27(kip) was induced by LJ-529. In ER-positive cells, the expression of ER was down-regulated by LJ-529, which might have additionally contributed to attenuated cell proliferation. In ER-negative, c-ErbB2-overexpressing SK-BR-3 cells, the expression of c-ErbB2 and its downstream extracellular signal-regulated kinase pathway were down-regulated by LJ-529. However, such effect of LJ-529 acted independently of its receptor because no A3AR was detected by reverse transcription-PCR in all four cell lines tested. In conclusion, our novel findings open the possibility of LJ-529 as an effective therapeutic agent against both ER-positive and ER-negative breast cancers, particularly against the more aggressive ER-negative, c-ErbB2-overexpressing types.

Adenosine↗

PubMed2005

Chemopreventive properties of the ethanol extract of chinese licorice (Glycyrrhiza uralensis) root: induction of apoptosis and G1 cell cycle arrest in MCF-7 human breast cancer cells.

Much of the interest on the chemopreventive properties of licorice has been focused on the plant genius Glycyrrhiza glabra. In this study the ethanol extract of Chinese licorice root, Glycyrrhiza uralensis (G. uralensis) was investigated for its estrogenic effect and the ability to inhibit cell proliferation in the MCF-7 human breast cancer cell line. The extract of the root of G. uralensis was fractionated in EtOH:H(2)O (80:20) (80% ethanol). The extract exhibited estrogenic effects similar to 17beta- estradiol (E2) and induced apoptosis at the same dose level (100 microg/ml) in MCF-7 breast cancer cells, results were associated with up-regulation of tumor suppressor gene p53 and pro-apoptotic protein Bax. G. uralensis extract caused the up-regulation of p21(waf1/cip1) and down-regulation of cdk 2 and cyclin E and most significantly, induced G1 cell cycle arrest. This is the first study to show that the ethanolic extract of the root of G. uralensis has an estrogen-like activity and anti-cancer effects against MCF-7 human breast cancer cells. Whilst the use of phytoestrogens to protect against hormone-dependent cancers or as a 'natural' alternative to hormone replacement therapy remains controversial, the data in this paper support the suggestion that extracts of root of the Chinese licorice G. uralensis might be of importance in this debate.

Anticarcinogenic Agents↗

PubMed2005

Effects of the histone deacetylases inhibitors sodium butyrate and trichostatin A on the inhibition of gap junctional intercellular communication by H2O2- and 12-O-tetradecanoylphorbol-13-acetate in rat liver epithelial cells.

The histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) and sodium butyrate (NaBu) are considered as potent therapeutic agents for cancer treatment presenting therapeutic benefits with less risk of side effects. The microbial metabolite, TSA is a potent reversible and highly specific inhibitor of mammalian histone deacetylases. NaBu causes hyperacetylation of core histones with effects similar to TSA but it is not a specific inhibitor of HDACs. The gap junction is a channel in the plasma membrane of most cell types which allows direct communication (gap junctional intercellular communication; GJIC) of small molecules and ions. Modulation of GJIC is a known cellular event associated with tumor promotion. The effects of NaBu and TSA on the H(2)O(2)- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced GJIC inhibition of WB cells and the mechanisms involved in the process were assessed. TSA and NaBu exerted differential preventive effects on the H(2)O(2) and TPA-induced inhibition of GJIC as well as hyperphosphorylation of connexin43 (Cx43) in WB-F344 rat liver epithelial cells (WB cells). NaBu prevented the TPA-induced GJIC inhibition via ERK1/2 inactivation whilst TSA restored the H(2)O(2)-induced GJIC inhibition and Cx43 hyperphosphorylation by preventing p38 MAP kinase. The inhibition of tyrosine phosphorylation and down-regulation of src protein observed may also contribute to Connexin 43 dephosphorylation and GJIC restoration by TSA and NaBu partly through depletion of src protein pool. Thus, TSA and NaBu exert differential effects on chemically induced GJIC inhibition via modulation of MAP kinases and partly, tyrosine kinases.

Animals↗

PubMed2005

The role of p38 MAP kinase and c-Jun N-terminal protein kinase signaling in the differentiation and apoptosis of immortalized neural stem cells.

The two distinct members of the mitogen-activated protein (MAP) kinase family c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase, play an important role in central nervous system (CNS) development and differentiation. However, their role and functions are not completely understood in CNS. To facilitate in vitro study, we have established an immortal stem cell line using SV40 from fetal rat embryonic day 17. In these cells, MAP kinase inhibitors (SP600125, SB202190, and PD98059) were treated for 1, 24, 48, and 72 h to examine the roles of protein kinases. Early inhibition of JNK did not alter phenotypic or morphological changes of immortalized cells, however overexpression of Bax and decrease of phosphorylated AKT was observed. The prolonged inhibition of JNK induced polyploidization of immortalized cells, and resulted in differentiation and inhibition of cell proliferation. Moreover, JNK and p38 MAP kinase but not ERK1/2 was activated, and p21, p53, and Bax were overexpressed by prolonged inhibition of JNK. These results indicate that JNK and p38 MAP kinase could play dual roles on cell survival and apoptosis. Furthermore, this established cell line could facilitate study of the role of JNK and p38 MAP kinase on CNS development or differentiation/apoptosis.

Animals↗

PubMed2005

Involvement of c-Jun N-terminal kinase in G2/M arrest and caspase-mediated apoptosis induced by sulforaphane in DU145 prostate cancer cells.

Sulforaphane (SFN) is a major isothiocyanate compound in cruciferous vegetables such as broccoli, cauliflower, and Brussels sprouts. Preclinical animal models have recently shown that SFN and other isothiocyanates may be useful for prostrate cancer (PCa) chemoprevention. In this study we used a DU145 human PCa cell culture model to investigate the role of protein kinase signaling pathway(s) in SFN-induced cell cycle arrest and apoptosis and whether another chemopreventive agent selenium enhances the apoptosis potency of SFN. The results showed that SFN exposure for 24 h or longer significantly decreased the number of viable DU145 cells in a dose-dependent manner with an IC50 of asymptotically equal to 10 microM. The decreased cell number was associated with G2/M phase arrest and apoptotic cell death, with the latter being evidenced by caspase-mediated cleavage of poly(ADP-ribose) polymerase and increased release of histone-associated DNA fragments. A peptide inhibitor of caspase-8 completely blocked SFN-induced apoptosis and that for caspase-9 exerted a major protection; however, neither inhibitor attenuated SFN-induced G2/M arrest. Regarding potential mediators, SFN treatment induced a transient rise of reactive oxygen species (ROS) peaking within (1/2) h and the activation of JNK within 1 h but did not have any detectable effect on the phosphorylation of p38MAPK or ERK1/2 from 6 h to 24 h. Pretreatment of cells with N-acetylcysteine to enrich intracellular glutathione blocked SFN-induced ROS and apoptotic cell death. Inhibiting the JNK activity with a pharmacologic inhibitor SP600125 abolished the induction of G2/M arrest and apoptosis by SFN, whereas chemical inhibitors for p38MAPK and MEK1/2 did not have any modulating effect on SFN-induced apoptosis. Taken together, the data indicate that SFN decreased viable DU145 cell number in large part through the generation of ROS and JNK-mediated signaling to G2/M arrest and caspase-dependent apoptosis. Selenium in the form of inorganic sodium selenite salt or methylseleninic acid did not enhance SFN-induced apoptosis in this cell culture model.

Anticarcinogenic Agents↗

PubMed2005

Role of gap junctional intercellular communication (GJIC) through p38 and ERK1/2 pathway in the differentiation of rat neuronal stem cells.

Gap junctional intercellular communications (GJIC) contributes to neural function in development and differentiation of CNS. In this study, we have investigated the expression of GJIC during the differentiation of neuronal stem cells and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neuronal stem cell-derived cells from rat brain. During neuronal stem cell differentiation, expressions of Cx43 and 32 were increased for the duration of 72 hr, however the effect were decreased on the 7d. In the neuronal stem cell-derived cells, pretreatments with p38 MAP kinase inhibitor, SB203580, and MEK inhibitor, PD98059, could protect GJIC against TPA-induced inhibition of GJIC. Our data suggest that GJIC plays an important role during neuronal stem cell differentiation, and ERK1/2 and p38 MAP kinase signaling pathway may be closely related functionally to regulate gap junction in rat neuronal stem cell-derived cells.

Animals↗

PubMed2004

Ras/MAP kinase pathways are involved in Ras specific apoptosis induced by sodium butyrate.

Histone deacetylase inhibitors such as TSA, SAHA, and NaBu etc. are prospective cancer therapeutics of growing interest. Here, we demonstrated that oncogenic ras-transformed rat liver epithelial (WB-ras) cells were specifically undergone apoptosis by 48 h treatment of NaBu. During this, inhibition of ras proteins, especially farnesylated form of ras, and down-regulation of ERK1/2 were observed, which suggest ras/raf/MEK/ERK down-regulation, while p38 MAP kinase was maintained up-regulated. In addition, up-regulation of pro-apoptotic proteins such as p53 and p21CIP1/WAF1, and down-regulation of cell cycle regulator/anti-apoptotic proteins such as cdk2, -4 and phosphorylated Akt were observed concurrently with an increase in apoptotic cell portion. A phosphatase inhibitor, sodium orthovanadate (SOV), efficiently blocked apoptosis and restored responsible proteins for each phenomenon including ERK1/2 while SB203580, a specific p38 MAP kinase inhibitor, showed minor effect on them. Thus, ras/ERK signaling pathway can be considered in chemotherapeutic strategies of NaBu regardless of its inhibitory action on histone deacetylase.

Animals↗

PubMed2003

Pre-validation study for OECD enhanced test guideline 407 protocol by gavage for 4 weeks using propylthiouracil and tamoxifen.

To develop and pre-validate an enhanced protocol for OECD Test Guideline 407, we performed a 28-day repeated-dose toxicity study using the administration of propylthiouracil (PTU) and tamoxifen (TAM) in Sprague-Dawley (SD) rats. Six male and female SD rats were treated orally with PTU in corn oil at the dose of 0, 0.1, 1, or 10 mg/kg per day and TAM at dose of 0, 5, 30 or 200 microg/kg per day for 4 weeks. In the study using PTU, the body weights were reduced from the third week of the study in 10 mg/kg per day group. In clinical biochemistry, the levels of 3,5,3'-triiodothyronine (T3) and thyroxine (T4, 3,5,3',5'-tetraiodothyrosine) were also significantly decreased in 10 mg/kg per day group. Also, thyroid glands in 10 mg/kg per day group were bigger than those in the control group. In the histopathological examination, diffuse hyperplasia and hypertrophy of thyroid follicular cells were observed in all treatment groups, leading to the reduction of lumen size and papillary enfolding of lining epithelium. In the study using TAM, the body weights were reduced from the first week of the study in 200 microg/kg per day group. Relative testes and epididymes weights were increased and relative right ovary and uterus weights were reduced in 200 microg/kg per day group. Also, in the histopathological finding severe endometrial squamous metaplasia and endometrial gland atrophy and severe follicular cystic change were observed in TAM 200 microg/kg per day-treated group. On the basis of the results, the thyroid hormone levels, gross findings, and histopathological findings may be useful parameters for the detection of the endocrine-related effect of PTU and also reproductive organ weight and histopathological findings may be good parameters to detect the effect of TAM. Therefore, it is concluded that enhanced OECD TG407 might be useful for screening and detecting endocrine disrupters.

Animals↗

PubMed2002

The roles of ERK1/2 and p38 MAP kinases in the preventive mechanisms of mushroom Phellinus linteus against the inhibition of gap junctional intercellular communication by hydrogen peroxide.

Modulation of gap junctional intercellular communication (GJIC) is a known cellular event associated with tumor promotion. The present study was undertaken to test the potential preventive effect of mushroom Phellinus linteus extract (PL) on the inhibition of GJIC, induced by hydrogen peroxide (H(2)O(2)), in WB-F344 rat liver epithelial cells (WB cells). Cells were pre-incubated with PL (5 and 25 microg/ml) for 24 h and this was followed by co-treatment with PL and H(2)O(2) (500 microM) for 1 h. PL (at 5 and 25 microg/ml) prevented the inhibition of GJIC and blocked the hyper-phosphorylation of connexin 43 by H(2)O(2). Moreover, H(2)O(2) activated p38 kinase, extracellular signal-regulated protein kinases (ERK)1/2 and c-Jun N-terminal kinase (JNK) in WB cells. The present study indicates that PL is able to inactivate both ERK1/2 and p38 MAP kinases. However, PL did not affect the JNK pathway. For this reason, to elucidate the relation between MAP kinases and GJIC, we treated cells with PD98059 (an MEK inhibitor) and SB202190 (a p38 kinase inhibitor). These inhibitors were also found to prevent the inhibition of GJIC induced by H(2)O(2), which suggests that PL may act as a natural anticancer product by preventing the inhibition of GJIC through the inactivation of ERK1/2 and p38 MAP kinases. In addition, our results indicate that the p38 kinase signaling pathway may be closely related functionally to the gap junction in rat liver epithelial cells.

Agaricales↗

PubMed2002

Additive estrogenic activities of the binary mixtures of four estrogenic chemicals in recombinant yeast expressing human estrogen receptor.

To evaluate the estrogenic activities of several chemicals such as 17beta-estradiol (E2), rho-nonylphenol, bisphenol A, butylparaben, and combinations of these chemicals, we used recombinant yeasts containing the human estrogen receptor [Saccharomyces cerevisiae ER + LYS 8127]. We evaluated E2 was most active in the recombinant yeast assay, followed by rho-nonylphenol, bisphenol A, butylparaben. The combinations of some concentrations of 17-estradiol as a strong estrogen and bisphenol A or butylparaben as a weak estrogen showed additive estrogenic effects. Also, the combinations of some concentrations of nonlyphenol and butylparaben and combination of butylparaben and bisphenol A showed additive effects in the estrogenic activity. Therefore, the estrogenic activities of the combinations of two chemicals were additive, not synergistic.

Benzhydryl Compounds↗

PubMedDate not supplied

Augmentation of sodium butyrate-induced apoptosis by p38 MAP kinase inhibition in rat liver epithelial cells.

Sodium butyrate (NaBu) has an inhibitory effect on histone deacetylases (HDACs). The mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAP, kinase are known to be modulated during NaBu-induced apoptosis. In the present study, we showed that low concentrations of NaBu could induce apoptosis synergistically with the inhibition of p38 MAP kinase as proven by using specific p38 MAP kinase inhibitor and dominant negative p38 transfection in a ras-transformed rat liver epithelial cell line (WB-ras). There were no changes in HDAC1, suggesting that NaBu might be able to kill transformed cells bypassing the HDAC inhibitory effect. We further demonstrated that inhibition of p38 MAP kinase potentiated apoptotic cascades, including cleavage of poly(ADP-ribose) polymerase, caspase-3, and decrease in Bcl-2/Bax ratio even at a lower concentration of NaBu. Thus, p38 MAP kinase played inhibitory roles in NaBu-induced apoptosis, and simultaneous modulation of MAP kinases in NaBu treatment could increase the efficiency of the chemotherapeutic effect of NaBu.

Animals↗