• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5663-5669
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• 2013

The histone methyltransferase EZH2 (enhancer of zeste homolog 2) plays critical roles in prostate cancer (PCa) development and is a potential target for PCa treatment. Triptolide possesses anti-tumor activity, but it is unknown whether its therapeutic effect relates with EZH2 in PCa. Here we described EZH2 as a target for Triptolide in PCa cells. Our data showed that Triptolide suppressed PCa cell growth and reduced the expression of EZH2. Overexpression of EZH2 attenuated the Triptolide induced cell growth inhibition. Moreover, Triptolide treatment of PC-3 cells resulted in elevated mRNA levels of target genes (ADRB2, CDH1, CDKN2A and DAB2IP) negatively regulated by EZH2 as well as reduced mRNA levelsan of EZH2 positively regulated gene (cyclin D1). Our findings suggest the PCa cell growth inhibition mediated by Triptolide might be associated with downregulation of EZH2 expression and the subsequent modulation of target genes.

• Journal of Physiology & Pathology in Korean Medicine
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• v.19 no.4
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• pp.1050-1054
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• 2005

Recently, arsenic compounds were considered as novel agents for treatment of acute promyelocytic leukemia and malignant tumors. However, it showed severe toxicity effect on normal tissue at the same time. In this study, to investigate the possible molecular mechanism (s) of arsenic compounds as candidate of anti-cancer drugs, we compared the abilities of two arsenic compounds, tetraarsenic oxide $(AS_4O_6)$ and arsenic trioxide (diarsenic oxide, $As_2O_3$), to induce cell growth inhibition as well as apoptosis induction in A549 human non-small cell lung cancer cells. Both $As_4O_6\;and\;As_2O_3$ treatment declined the cell growth and viability of A549 cells in a concentration-dependent manner, which was associated with induction of G1 arrest of the cell cycle and apoptotic cell death. However, $As_4O_6$ induced growth inhibition and apoptosis in A549 cells at much lower concentrations than $As_2O_3.\;As_4O_6$ down-regulated the levels of anti-apoptotic Bcl-2 protein, however, the levels of Bax, a pro-apoptotic protein, were up-regulated in a dose-dependent manner. In conclusion, $As_4O_6$ might be a new arsenic compound which may induce apoptosis in A549 cells by modulation the Bcl-2 family and deserves further evaluation.

• Biomolecules & Therapeutics
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• v.20 no.1
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• pp.81-88
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• 2012

Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anti-cancer agents. In recent years, a number of structurally diverse HDAC inhibitors have been identifi ed and these HDAC inhibitors induce growth arrest, differentiation and/or apoptosis of cancer cells in vitro and in vivo. However, the underlying molecular mechanisms remain unclear. This study aimed at investigating the anti-tumor activity of various HDAC inhibitors, IN-2001, using T47D human breast cancer cells. Moreover, the possible mechanism by which HDAC inhibitors exhibit anti-tumor activity was also explored. In estrogen receptor positive T47D cells, IN-2001, HDAC inhibitor showed anti-proliferative effects in dose-and time-dependent manner. In T47D human breast cancer cells showed anti-tumor activity of IN-2001 and the growth inhibitory effects of IN-2001 were related to the cell cycle arrest and induction of apoptosis. Flow cytometry studies revealed that IN-2001 showed accumulation of cells at $G_2$/M phase. At the same time, IN-2001 treatment time-dependently increased sub-$G_1$ population, representing apoptotic cells. IN-2001-mediated cell cycle arrest was associated with induction of cdk inhibitor expression. In T47D cells, IN-2001 as well as other HDAC inhibitors treatment significantly increased $p21^{WAF1}$ and $p27^{KIP1}$ expression. In addition, thymidylate synthase, an essential enzyme for DNA replication and repair, was down-regulated by IN-2001 and other HDAC inhibitors in the T47D human breast cancer cells. In summary, IN-2001 with a higher potency than other HDAC inhibitors induced growth inhibition, cell cycle arrest, and eventual apoptosis in human breast cancer possibly through modulation of cell cycle and apoptosis regulatory proteins, such as cdk inhibitors, cyclins, and thymidylate synthase.

• Korean Journal of Plant Resources
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• v.29 no.3
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• pp.289-296
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• 2016

This study was executed to evaluate the immune activity, nitrite scavenging activity and ABTS radical scavenging activity against extracts of various concentration of ethanol solvent from Codonopsis lanceolata cultured at 6 local regions. The immune responses from both human T and B cell line was significantly enhanced in the cell growth compared to control while the cell growth was influenced at a certain period of culture. The results revealed that the cell growth of both human T and B cell was altered in a time dependent manner. The nitrite scavenging activity of ethanol extracts from various solvent concentration of C. lanceolata were affected by pH. At a pH of 1.2, the nitrite scavenging effect of all of the extracts tested observed higher than that of the other two pH ranges. There was no distinct detection of nitrite scavenging effects of the pH range 6.0. The ABTS radical scavenging activity was progressively increased in a dose-dependent manner, and the activity was the highest in 100% ethanol extract. The result from this investigation suggests that the extract of Codonopsis lanceolata could be an addition to basic medicine for immune modulation and natural food additives.

• International Journal of Oral Biology
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• v.36 no.4
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• pp.179-185
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• 2011

MicroRNAs (miRNAs) are small non-coding RNAs that mediate gene expression at the post-transcriptional level by degrading or repressing targeted mRNAs. These molecules are about 21-25 nucleotides in length and exert their effects by binding to partially complementary sites in mRNAs, predominantly in the 3'-untranslated region (3'-UTR). Recent evidence has demonstrated that miRNAs can function as oncogenes or tumor suppressors through the modulation of multiple oncogenic cellular processes in cancer development, including initiation, cell proliferation, apoptosis, invasion and metastasis. In our present study, we examined the expression profile of miRNAs related to oral cancer cell growth inhibition using normal human oral keratinocytes (NHOK) and YD-38 human oral cancer cells. By miRNA microassay analysis, 40 and 31 miRNAs among the 1,769 examined were found to be up- and down-regulated in YD-38 cells compared with NHOK cells, respectively. Using qRT-PCR analysis, the expression levels of miR-30a and miR-1246 were found to be increased in YD-38 cells compared with NHOK cells, whereas miR-203 and miR-125a were observed to be decreased. Importantly, the overexpression of miR-203 and miR-125a significantly inhibited the growth of YD-38 cells. This finding and the microarray data indicate the involvement of specific miRNAs in the development and progression of oral cancer.

• Korean Journal of Food Science and Technology
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• v.46 no.4
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• pp.516-521
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• 2014

The mechanisms underlying the refractory effects of flutamide, a first-line oral anti-androgen drug, have not been entirely elucidated. In the present study, we investigated the mechanism of flutamide-induced hormone-refractory prostate cancer cell growth and its modulation by resveratrol, a phytoalexin present in grapes. Resveratrol significantly attenuated interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3) transcriptional activity and dihydrotestosterone (DHT) or IL-6-induced prostate-specific antigen (PSA) transcriptional activity. Furthermore, compared to treatment with DHT or IL-6 alone, combination treatment of cells significantly increased PSA transcriptional activity, and resveratrol markedly diminished DHT plus IL-6-induced STAT3 and PSA transcriptional activities. Thus, the inhibitory effects of resveratrol on IL-6-, DHT-, and flutamide-induced hormone-refractory prostate cancer cell growth are partly mediated by the suppression of STAT3 reporter gene activity, suggesting that resveratrol represents a promising therapy for prostate cancer.

• Archives of Pharmacal Research
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• v.20 no.6
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• pp.572-578
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• 1997

To gain further insight into how antiestrogens modulate cell function, the effects of antiestrogen on cell proliferation were studied in human breast cancer cells. We examined the effects of trans-tamoxifen on the proliferation of three human breast cancer cell lines that differed in their estrogen receptor contents. Trans-tamoxifen $(1{\mu}M)$ markedly inhibited the estrogen stimulated proliferation of MCF-7 human breast cancer cells that contained high levels of estrogen receptor $(1.15{\pm}0.03 pmole/mg protein)$ over that of control. In T47D cells that contained low levels of estrogen receptor $(0.23{\pm}0.05 pmole/mg protein)$, trans-tamoxifen $(1{\mu}M)$ showed minimal inhibition of estrogen stimulated cell proliferation over that of control. MDA-MB-231 cells, that contained no detectable levels of estrogen receptors, had their growth unaffected by trans-tamoxifen treatment. These results showed their sensitivity to growth inhibition by antiestrogen conrrelated well with their estrogen receptor content. Also we examined the effect of antiestrogen on cellular progestrone receptor level as well as plasminogen activator activity in MCF-7 cells. Trans-tamoxifen $(1{\mu}M)$ showed maximal inhibition of estrogen stimulated progestrone receptor level as well as plasminogen activator activity in MCF-7 cells that were stimulated by estrogen. It is not clear whether these inhibitions of progestrone receptor and plasminogen activator activity by estrogen are related to the antiestrogen inhibition of cell proliferation of MCF-7 cells. From the results of this study, it is clearly demonstrated that trans-tamoxifen is an antiestrogen in MCF-7 human breast cancer cells. Our data suggest that the biological effectiveness of trans-tamoxifen appear to result from its affinity of interaction with the estrogen receptor.

• Journal of Life Science
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• v.19 no.7
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• pp.892-898
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• 2009

MIF is a progesterone analogue and is known as a potent progesterone antagonist. Although MIF has been known to inhibit prostate cancer cell growth, its molecular mechanisms are not yet clear. In the present study, when the cells were treated for 2-4 days with 5-40 $\mu$M of MIF, the growth and viability of LNCaP cells were significantly decreased in a dose- and time-dependent manner. When the cells, cultivated in a normal 2 mM calcium concentration medium, were treated with 15 $\mu$M MIF for 1 day, the intracellular calcium level increased by 26% compared to the control. Similar results were also found in cells located in the calcium-free reaction buffer, indicating that MIF induced the increase of intracellular Ca$^{2+}$ levels, regardless of the presence of calcium in the surrounding medium. In the cells treated with various concentrations of MIF, the intracellular calcium levels increased in a dose dependent manner. Cells treated with MIF revealed typical early apoptotic signs, i.e., chromosome condensation and nuclei fragmentation. In cells treated with 40 11M MIF, Bcl-2 decreased to 19% of the control. The expression of Bax increased to almost 2 fold of the control. These results demonstrated very clearly that MIF treatment blocks the expression of Bcl-2 but stimulates the expression of Bax. According to the results of the present investigation, the apoptotic mechanism of MIF is triggered by intracellular modulation.

• Asian-Australasian Journal of Animal Sciences
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• v.28 no.12
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• pp.1742-1750
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• 2015

As a novel approach for disease control and prevention, nutritional modulation of the intestinal health has been proved. However, It is still unknown whether branched-chain amino acid (BCAA) is needed to maintain intestinal immune-related function. The objective of this study was to determine whether BCAA supplementation in protein restricted diet affects growth performance, intestinal barrier function and modulates post-weaning gut disorders. One hundred and eight weaned piglets ($7.96{\pm}0.26kg$) were randomly fed one of the three diets including a control diet (21% crude protein [CP], CON), a protein restricted diet (17% CP, PR) and a BCAA diet (BCAA supplementation in the PR diet) for 14 d. The growth performance, plasma amino acid concentrations, small intestinal morphology and intestinal immunoglobulins were tested. First, average daily gain (ADG) (p<0.05) and average daily feed intake (ADFI) (p<0.05) of weaned pigs in PR group were lower, while gain:feed ratio was lower than the CON group (p<0.05). Compared with PR group, BCAA group improved ADG (p<0.05), ADFI (p<0.05) and feed:gain ratio (p<0.05) of piglets. The growth performance data between CON and BCAA groups was not different (p>0.05). The PR and BCAA treatments had a higher (p<0.05) plasma concentration of methionine and threonine than the CON treatment. The level of some essential and functional amino acids (such as arginine, phenylalanine, histidine, glutamine etc.) in plasma of the PR group was lower (p<0.05) than that of the CON group. Compared with CON group, BCAA supplementation significantly increased BCAA concentrations (p<0.01) and decreased urea concentration (p<0.01) in pig plasma indicating that the efficiency of dietary nitrogen utilization was increased. Compared with CON group, the small intestine of piglets fed PR diet showed villous atrophy, increasing of intra-epithelial lymphocytes (IELs) number (p<0.05) and declining of the immunoglobulin concentration, including jejunal immunoglobulin A (IgA) (p = 0.04), secreted IgA (sIgA) (p = 0.03) and immunoglobulin M (p = 0.08), and ileal IgA (p = 0.01) and immunoglobulin G (p = 0.08). The BCAA supplementation increased villous height in the duodenum (p<0.01), reversed the trend of an increasing IELs number. Notably, BCAA supplementation increased levels of jejunal and ileal immunoglobulin mentioned above. In conclusion, BCAA supplementation to protein restricted diet improved intestinal immune defense function by protecting villous morphology and by increasing levels of intestinal immunoglobulins in weaned piglets. Our finding has the important implication that BCAA may be used to reduce the negative effects of a protein restricted diet on growth performance and intestinal immunity in weaned piglets.

• Biomolecules & Therapeutics
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• v.16 no.2
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• pp.87-94
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• 2008

In view of obtaining potential anticancer compounds, we studied the inhibitory activity and the cytotoxic effects of a candidate compound in cancer cells. The cytotoxic effects of cannabidiol (CBD) in vitro were evaluated in NIH3T3 fibroblasts, B16 melanoma cells, A549 lung cancer cells, MDA-MB-231 breast cancer cells, Lenca kidney cells and SNU-C4 colon cancer cells. The cells were cultured in various concentrations of CBD for 48 h and 25 ${\mu}$M of CBD for 6-36 h. The cells were observed to exhibit inhibitory effects of the cell viability in their growth, and then cytotoxicity was estimated. The inhibitory activity of CBD was increased in all cancer cells and showed especially strong increment in breast cancer cells. The cytotoxicity of CBD increased in a dose- and time-dependent manner with growth inhibition in all cancer cell lines. Also, to assess the membrane toxicity induced by CBD, we investigated lactate dehydrogenase (LDH) release. After treatment with various concentrations of CBD, LDH release rate of cancer cells was accelerated. On the other hand, in the induction of cell death, caspase-3, -8 and -9 activations were detected in cancer cells after treatment with various concentrations of CBD, and CBD effectively induced activity of caspase-3, -8 and -9 in A549 lung cancer cells, MDAMB-231 breast cancer cells and Renca kidney cells. Therefore these results suggest that CBD has a possibility of anticancer agents and anticancer effects against cancer cells by modulation of apoptotic pathway in the range of 5-80 ${\mu}$M concentration.