• Journal of Life Science
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• v.28 no.10
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• pp.1212-1219
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• 2018

The critical role of heat shock protein 90 (Hsp90) in tumorigenesis led to the development of several first- and second-generation Hsp90 inhibitors, which have demonstrated promising responses in cancers. In this study, we found second-generation Hsp90 inhibitor BIIB021-resistant multidrug-resistant (MDR) human cancer cells, although BIIB021 was shown to be active in first-generation Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-resistant MDR cells. MCF7-MDR and HeyA8- MDR cells were more resistant to BIIB021 than their parental counterparts, indicating that BIIB021 cannot be applicable to all cancer cells expressing MDR proteins. We revealed that dimethyl-celecoxib (DMC), one of the non-steroidal anti-inflammatory drugs (NSAIDs), potentiated cytotoxicity of BIIB021 against both BIIB021-resistant and BIIB021-sensitive MDR cells. The effectiveness of NSAIDs involving celecoxib and DMC in combination with BIIB021 led to the autophagic degradation/down-regulation of mutant p53 (mutp53) that overexpressed MDR cells and the suppression of Hsp70 induction. This resulted in sensitization of MDR cells to BIIB021. Moreover, autophagy induction by sulindac sulfide, another type of NSAID, and niclosamide, an FDA-approved anthelmintic drug, potentiated 17-AAG-mediated autophagic degradation/down-regulation of mutp53 and c-Myc, client proteins of Hsp90. Therefore, our results suggest that NSAIDs and niclosamide positively enhance the anticancer activity of Hsp90 inhibitors through an autophagic pathway. They may also be new candidates for sensitizing MDR cells to Hsp90 inhibitors.

• Korean Journal of Medicinal Crop Science
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• v.24 no.3
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• pp.228-236
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• 2016

Background: Sedum takesimense Nakai has been used as folk medicine in Korea. The present study aimed to determine the biological activity of S. takesimense by investigating the anti-inflammatory effects of S. takesimense water extract (SKLC) on the lipopolysaccharide-induced inflammatory response in RAW 264.7 cells. Methods and Results: Cytotoxicity of SKLC on RAW 264.7 cells was determinded by performing MTS assay was found to have no cytotoxic effect on RAW 264.7 cells at a concentration range of $62-500{\mu}g/m{\ell}$. Further, pretreatment of SKLC inhibited lipopolysaccharide-induced nitric oxide (NO) production in a dose-dependent manner. To determined the inhibitory mechanisms of SKLC on inflammatory mediators, we assessed the inducible nitric oxide synthase (iNOS) and cyclooxygnease-2 (COX-2) pathways. The activities of these pathways were decreased in a dose-dependent manner by SKLC. The production of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$), interleukin $(IL)-1{\beta}$, and IL-6 were also reduced. Conclusions: These results suggest that the down regulation of iNOS, COX-2, TNF-${\alpha}$, IL-$1{\beta}$, and IL-6 expression by SKLC are mediated by the down regulation of nuclear factor-${\kappa}B$ (NF-${\kappa}B$) activity, a transcription factor necessary for pro-inflammatory mediators. This might be the mechanism underlying the anti-inflammatory effects of SKLC.

• The Journal of Korean Medicine
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• v.29 no.5
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• pp.77-89
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• 2008

Objectives : This study evaluates the hair growth promoting effect of Yonnyuniksoogobon-dan on shaved C57BL6 mice. Methods : Yonnyuniksoogobon-dan was administered orally (Group I) and both orally and by skin application (Group II) once a day for 12 days. The experimental groups were compared to Control, which was orally administered physiological saline solution. Hair regrowth was photographically and histologically determined during the experimental period. The levels of hair growth cycle related factors (EGF, TGF-${\beta}$1) and vascular factors (VEGF, iNOS) were also determined by immunohistochemistry. On gross observation of hair growth, both Group I and Group II shaved C57BL6 mice showed accelerated hair regrowth. Results : The hair regrowth index of Group I increased significantly from 7 days (P<0.05) to 12 days (P<0.01) after shaving and that of Group II was significantly higher at 12 days (P<0.05). On histological observation, both Group I and Group II demonstrated histological improvement and increases in the number and diameter of the hair follicles. EGF expression on the root sheath of hair follicles was up-regulated in both Group I and II. TGF-${\beta}$1 expression on the root sheath of hair follicles was unchanged in both Group I and II. VEGF expression in the tissues surrounding hair follicles was up-regulated in both groups. iNOS expression in the tissues surrounding hair follicles was down-regulated in both groups. Conclusions : These results suggest that Yonnyuniksoogobon-dan promotes hair growth and this effect is related to up-regulation of EGF and VEFG expression and down-regulation of TGF-${\beta}$1 and iNOS expression on hair roots.

• Microbiology and Biotechnology Letters
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• v.38 no.4
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• pp.442-447
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• 2010

We investigated anti-cancer and anti-proliferative activity of allicin and analyzed global gene expression changes by allicin treatment in human colorectal HCT116 cells. As a result, allicin decreased cell viabilities in a dose and time-dependent manner and induced apoptosis. Oligo DNA microarray analysis, we found that 7,840 genes were up-regulated more than 2-folds, whereas 10,010 genes were down-regulated more than 2-folds by $50\;{\mu}M$ allicin treatment. To confirm specific gene expressions, we performed RT-PCR. Consistent with the results of DNA microarray analysis, allicin dramatically induced ATF3 and NAG1 gene expression. Interestingly, NAG-1 protein expression was dependent on p53 presence. Taken together, our present results increase the knowledge of the molecular mechanism of anti-cancer and anti-proliferative activity mediated by allciin in human colorectal cancer cell.

• IMMUNE NETWORK
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• v.6 no.2
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• pp.59-66
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• 2006

Background: CM1 (Centrocyte/-blast Marker I) defined by a mAb developed against concanavalin-A activated PBMC, is expressed specifically on a subpopulation of centroblasts and centrocytes of human germinal center (GC) B cells. Burkitt lymphoma (BL) is a tumor consisting of tumor cells with the characteristics of GC B cell. Previously we reported that CM1 ligation with anti-CM1 mAb induced apoptosis in Ramos $(IgM^{high})$ and Raji $(IgM^{low})$ cells. Methods & Results: In the present study, we observed that CM1 ligation with anti-CM1 mAb induced Fas ligand and Fas expression in Ramos cells, but not in Raji cells. Furthermore, anti-Fas blocking antibody, ZB4, blocked CM1-mediated apoptosis effectively in Ramos cells, but not in Raji cells. Increased mitochondrial membrane permeabilization, which was measured by $DiOC_6$, was observed only in Raji cells. In contrast to no significant change of Bax known as pro-apoptotic protein, anti-apoptotic protein Bcl-2 was significantly decreased in Raji cells. In addition, we observed that CM1 ligation increased release of mitochondrial cytochrome c and upregulated caspase-9 activity in Raji cells. Conclusion: These results suggest that apoptosis induced by CM1-ligation is mediated by Fas-Fas ligand interaction in Ramos cells, whereas apoptosis is mediated by down-regulation of Bcl-2 and subsequent decrease of mitochondrial membrane potential in Raji cells.

• Food Science and Preservation
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• v.19 no.3
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• pp.455-461
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• 2012

Obesity, a strong risk factor for the development of chronic diseases, is characterized by an increase in the number and size of adipocytes differentiated from precursor cells, preadipocytes. Recent research suggests that increased reactive oxygen species (ROS) production in 3T3-L1 adipocyte facilitates adipocyte differentiation and fat accumulation. This study was to investigate whether reduced ROS production by Sargassum micracanthum extract (SME) could protect the development of obesity through inhibition of adipogenesis. 3T3-L1 preadipocytes were treated SME for up to 8 days following standard induction of differentiation. The extent of differentiation reflected by amount of lipid accumulation and ROS production was determined by Oil red O staining and nitroblue tetrazolium (NBT) assay. Treatment of SME significantly inhibited ROS production and adipocyte differentiation that is depend on down regulation of NADPH oxidase 4 (NOX4), a major ROS generator, and peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$) and CCAAT/enhancer-binding protein alpha ($C/EBP{\alpha}$), a key adipogenic transcription factor. These results indicate that SME can inhibit adipogenesis through a reduced ROS level that involves down-regulation of NOX4 expression or via modulation of adipogenic transcription factor.

• Journal of Life Science
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• v.21 no.1
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• pp.141-145
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• 2011

Actinomycin D is a natural antibiotic that is used in anti-cancer chemotherapy and is known as a transcription inhibitor. Interestingly, actinomycin D induces phosphorylation of signal transducers and activators of transcription 3 (STAT3) in renal cancer Caki cells. In this study, we examined the molecular mechanism of actinomycin D-induced STAT3 phosphorylation. Treatment with actinomycin D induced phosphorylation of STAT3 (Tyr705) in a dose- and time-dependent manner. However, actinomycin D did not induce phosphorylation of STAT3 (Ser727), STAT1 (Tyr701) and STAT1 (Ser727). Moreover, actinomycin D-induced STAT3 phosphorylation was caused by decreased protein and mRNA levels of SOCS3, but not by JAK2 and SHP-1. In addition, other transcription inhibitor (5,6-dichloro-1-b-D-ribofuranosyl benzimidazole; DRB) also induced phosphorylation of STAT3 (Tyr705). Taken together, the present study demonstrates that transcriptional inhibitors (actinomycin D and DRB) induce phosphorylation of STAT3 (Tyr705) in Caki cells by down-regulation of SOCS3.

• Microbiology and Biotechnology Letters
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• v.43 no.4
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• pp.357-366
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• 2015

Quorum sensing (QS) is involved in the process of cell-to-cell communication and as a gene regulatory mechanism, which has been implicated in bacterial pathogenicity. Bacteria use this QS system to control a variety of physiological processes. In this study, pomegranate (Punica granatum L.) peel extract (PPE) was first screened for its ability to inhibit QS in bio-reporter strains (Chromobacterium violaceum and C. violaceum CV026). Next, the ability of PPE to inhibit swimming motility and biofilm formation was examined in Y. enterocolitica. Additionally, changes in the expression of specific genes involved in the synthesis of the N-acylhomoserine lactones (AHLs; yenI and yenR) and in the flagellar regulon (fliA, fleB and flhDC) were evaluated by reverse transcription (RT)-PCR. The results show that PPE specifically inhibited and reduced QS-controlled violacein production by 78.5% in C. violaceum CV026, and decreased QS-associated biofilm formation and swimming motility in Y. enterocolitica without significantly affecting bacterial growth. These inhibitory effects were also associated with the down-regulation of gene expression involved in the synthesis of AHLs and in motility. Our results suggest that PPE could be a potential therapeutic agent to prevent enteropathogens in humans, as well as highlight the need to further investigate the in vivo properties of PPE for clinical applications.

• Korean Journal of Bronchoesophagology
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• v.3 no.1
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• pp.70-78
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• 1997

The development of preneoplastic and neoplastic squamous cell proliferations of body sites such as the skin, female lower genital tract, and larynx is strongly associated with specific types of human papillomaviruses (HPV). Antitumor $CD^{8+}$ cells recognize peptide antigens presented on the surface of tumor cells by major histocompatibility complex (MHC) class I molecules. The MHC class I molecule is a heterodimer composed of an integral membrane glycoprotein designated the alpha chain and a noncovalently associated, soluble protein called beta-2-microglobulin( $\beta$ -2-m). Loss of $\beta$-2-m generally eliminates antigen recognition by antitumor $CD^{8+}$ T cells. We evaluated the expression of $\beta$-2-m as a potential means of tumor escape from immune recognition and the presence of HPV DNA as a cause of laryngeal squamous cell carcinomas (SCCs). Laryngeal SCCs (n=39) were analyzed for MHC class I expression by immunohistochemistry and for presence of HPV by in situ hybridization technique. The results were as follows : 1) HPV DNA was detected in 10 (25.64%) out of 39 cases in laryngeal squamous cell carcinomas. 2) MHC class I down-regulation (heterogenous and negative expression) in HPV positive lesions was higher than HPV negative lesions. 3) The expression of MHC class I was related to cellular differentiation regardless of T-stage and nodal involvement. In conclusion, HPV was thought to be the etiological factor of SCC of larynx, and we found that the down-regulation of MHC class I was a common phenomenon In laryngeal SCC and may provide a way for tumor cells to escape from immune surveillance.

• BMB Reports
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• v.55 no.4
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• pp.198-203
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• 2022

As negative regulators of cytokine signaling pathways, suppressors of cytokine signaling (SOCS) proteins have been reported to possess both pro-tumor and anti-tumor functions. Our recent studies have demonstrated suppressive effects of SOCS1 on epithelial to mesenchymal signaling in colorectal cancer cells in response to fractionated ionizing radiation or oxidative stress. The objective of the present study was to determine the radiosensitizing action of SOCS1 as an anti-tumor mechanism in colorectal cancer cell model. In HCT116 cells exposed to ionizing radiation, SOCS1 over-expression shifted cell cycle arrest from G2/M to G1 and promoted radiation-induced apoptosis in a p53-dependent manner with down-regulation of cyclin B and up-regulation of p21. On the other hand, SOCS1 knock-down resulted in a reduced apoptosis with a decrease in G1 arrest. The regulatory action of SOCS1 on the radiation response was mediated by inhibition of radiation-induced Jak3/STAT3 and Erk activities, thereby blocking G1 to S transition. Radiation-induced early ROS signal was responsible for the activation of Jak3/Erk/STAT3 that led to cell survival response. Our data collectively indicate that SOCS1 can promote radiosensitivity of colorectal cancer cells by counteracting ROS-mediated survival signal, thereby blocking cell cycle progression from G1 to S. The resulting increase in G1 arrest with p53 activation then contributes to the promotion of apoptotic response upon radiation. Thus, induction of SOCS1 expression may increase therapeutic efficacy of radiation in tumors with low SOCS1 levels.