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1.  Cyclosporine A as a Primary Treatment for Panniculitis-like T Cell Lymphoma: A Case with a Long-Term Remission 
Subcutaneous panniculitis-like T cell lymphoma (SPTL) is a distinctive cutaneous lymphoma characterized by an infiltration of subcutaneous tissue by neoplastic T cells, similar to panniculitis. It is well-established that patients who are diagnosed with SPTL usually respond poorly to chemotherapy, showing fatal outcome. As a first line treatment for SPTL, anthracycline-based chemotherapy was most frequently used. For the treatment of SPTL, the efficacy of cyclosporine A has been recently reported in relapsed SPTL after anthracycline-based chemotherapy. However, it is still not clear whether cyclosporine A can be used as a first-line treatment against SPTL. Here, we report a case of SPTL, which achieved complete remission for nine years after first-line cyclosporine A therapy. This study suggests that cyclosporine A can induce a complete long-term remission as a first-line treatment.
doi:10.4143/crt.2014.46.3.312
PMCID: PMC4132451  PMID: 25038767
Subcutaneous panniculitis-like T cell lymphoma; Cyclosporine A; Remission
2.  Polyphenols Isolated from Allium cepa L. Induces Apoptosis by Induction of p53 and Suppression of Bcl-2 through Inhibiting PI3K/Akt Signaling Pathway in AGS Human Cancer Cells 
Journal of Cancer Prevention  2014;19(1):14-22.
Background:
The extract of Allium cepa Linn is commonly used as adjuvant food for cancer therapy. We assumed that it includes a potential source of anti-cancer properties.
Methods:
We investigated anti-cancer effects of polyphenols extracted from lyophilized A. cepa Linn (PEAL) in AGS human cancer cells.
Results:
PEAL inhibited cell growth in a dose-dependent manner. It was related to caspase-dependent apoptosis. We confirmed this finding with annexin V staining. PEAL up-regulated p53 expression, and subsequent Bax induction, down regulated Bcl-2 protein, anti-apoptotic protein. In addition, PEAL suppressed Akt activity and PEAL-induced apoptosis were significantly accentuated with Akt inhibitor (LY294002).
Conclusions:
Our data suggested that PEAL induce caspase-dependent apoptosis through mitochondrial pathway by up-regulating p53 protein, and subsequent Bax protein as well as by modulating Bcl-2 protein, and that PEAL induces caspase-dependent apoptosis at least in part through the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. This study provides evidence that PEAL might be useful for the treatment of cancer.
PMCID: PMC4189478  PMID: 25337568
Allium cepa; polyphenols; Apoptosis; Bcl-2; Akt
3.  Anthocyanins from Vitis coignetiae Pulliat Inhibit Cancer Invasion and Epithelial-Mesenchymal Transition, but These Effects Can Be Attenuated by Tumor Necrosis Factor in Human Uterine Cervical Cancer HeLa Cells 
Recently we have demonstrated that anthocyanins from fruits of Vitis coignetiae Pulliat (AIMs) have anticancer effects. Here, we investigate the effects of AIMs on cell proliferation and invasion as well as epithelial-mesenchymal transition (EMT) which have been linked to cancer metastasis in human uterine cervical cancer HeLa cells. AIMs inhibited the invasion of HeLa cells in a dose-dependent manner. AIMs inhibited MMP-9 expression in a dose-dependent manner. AIMs inhibited the motility of HeLa cells in a wound healing test. AIMs still suppressed NF-κB activation induced by TNF. AIMs also inhibited EMT in HeLa cells. AIMs suppressed vimentin, N-cadherin, and β-catenin expression and induced E-cadherin. AIMs also suppressed expression of β-catenin and Snail, which was regulated by GSK-3. These effects of AIMs were also limited in the HeLa cells treated with TNF. In conclusion, this study indicates that AIMs have anticancer effects by suppressing NF-κB-regulated genes and EMT, which relates to suppression of IκBα phosphorylation and GSK-3 activity, respectively. However, the effects of AIMs were attenuated in the TNF-high condition.
doi:10.1155/2013/503043
PMCID: PMC3705752  PMID: 23864892
4.  Cyclosporine A treatment for relapsed subcutaneous panniculitis-like T-cell lymphoma: a case with long-term follow-up 
The Korean Journal of Hematology  2012;47(2):146-149.
Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a distinctive lymphoma characterized by an infiltration of subcutaneous tissue by neoplastic cytotoxic T cells. There was no distinction between TCR alpha/beta phenotype and TCR gamma/delta phenotype, and anthracycline-based chemotherapy was usually used for both. Here, we report a patient with recurrent SPTL who achieved a second long-term complete remission by repeated cyclosporine A (CsA) treatment. From 2000 to 2001, the patient received anthracycline-based combination chemotherapy. However, the treatment did not induce long-term remission. In 2002, he received cyclosporine treatment for about 6 months. This resulted in a 5-year remission that ended in relapse in 2008. He received CsA treatment once again and attained a second long-term remission. This case suggests that re-treatment with CsA can be a good option for relapsed SPTL cases and can result in long-term remission.
doi:10.5045/kjh.2012.47.2.146
PMCID: PMC3389065  PMID: 22783363
Subcutaneous panniculitis-like T-cell lymphoma; Cyclosporine; Treatment outcome
5.  Morin, a Flavonoid from Moraceae, Induces Apoptosis by Induction of BAD Protein in Human Leukemic Cells 
Evidence suggests that phytochemicals can safely modulate cancer cell biology and induce apoptosis. Here, we investigated the anti-cancer activity of morin, a flavone originally isolated from members of the Moraceae family in human leukemic cells, focusing on apoptosis. An anti-cancer effect of morin was screened with several human leukemic cell lines. U937 cells were most sensitive to morin, where it induced caspase-dependent apoptosis in a dose-dependent manner. It also induced loss of MMP (ΔΨm) along with cytochrome c release, down-regulated Bcl-2 protein, and up-regulated BAX proteins. The apoptotic activity of morin was significantly attenuated by Bcl-2 augmentation. In conclusion, morin induced caspase-dependent apoptosis through an intrinsic pathway by upregulating BAD proteins. In addition, Bcl-2 protein expression is also important in morin-induced apoptosis of U937 cells. This study provides evidence that morin might have anticancer properties in human leukemic cells.
doi:10.3390/ijms16010645
PMCID: PMC4307266  PMID: 25561222
morin; apoptosis; BAD; Bcl-xL; leukemia
6.  Tetraarsenic Hexoxide Induces Beclin-1-Induced Autophagic Cell Death as well as Caspase-Dependent Apoptosis in U937 Human Leukemic Cells 
Tetraarsenic hexaoxide (As4O6) has been used in Korean folk remedy for the treatment of cancer since the late 1980s, and arsenic trioxide (As2O3) is currently used as a chemotherapeutic agent. However, evidence suggests that As4O6-induced cell death pathway was different from that of As2O3. Besides, the anticancer effects and mechanisms of As4O6 are not fully understood. Therefore, we investigated the anticancer activities of As4O6 on apoptosis and autophagy in U937 human leukemic cells. The growth of U937 cells was inhibited by As4O6 treatment in a dose- and a time-dependent manner, and IC50 for As4O6 was less than 2 μM. As4O6 induced caspase-dependent apoptosis and Beclin-1-induced autophagy, both of which were significantly attenuated by Bcl-2 augmentation and N-acetylcysteine (NAC) treatment. This study suggests that As4O6 should induce Beclin-1-induced autophagic cell death as well as caspase-dependent apoptosis and that it might be a promising agent for the treatment of leukemia.
doi:10.1155/2012/201414
PMCID: PMC3170805  PMID: 21912568
7.  The Expression of Thymidine Phosphorylase in Cancer-infiltrating Inflammatory Cells in Stomach Cancer 
Journal of Korean Medical Science  2007;22(Suppl):S109-S114.
Thymidine phosphorylase (TP) has shown to be up-regulated in several cancers and to play a role in angiogenesis and invasion. Most studies regarding TP have focused on cancer cells. Recently, evidences suggest that TP in cancer-infiltrating inflammatory cells (CIICs) also affect the cancer cell behavior. To evaluate the significance of TP expression of CIICs in gastric cancer, we assessed TP expression of cancer cells and CIICs separately using immunohistochemical assay on 116 paraffin-embedded tissue samples from stomach cancer patients and investigated their clinical significance. When subjects were divided into 4 groups according to the TP expression: cancer/matrix (+/+), C/M (+/-), C/M (-/+), and C/M (-/-), intratumoral microvessel density scores were higher in the C/M (+/-) group than in the C/M (-/-) group (p=0.02). For lymph node metastasis and survival, there were no significant differences among the 4 groups. However, there were significant differences in survival (p=0.035) and LN metastasis (p=0.023) between the two groups divided by TP expression of CIICs alone irrespective of TP expression of cancer cells. Taken together, this study suggested the TP expression in CIICs could affect lymph node metastasis and patients' survival in gastric cancer.
doi:10.3346/jkms.2007.22.S.S109
PMCID: PMC2694385  PMID: 17923735
Thymidine Phosphorylase; Inflammatory Cell; Matrix; Stomach Cancer
8.  A Phase II Trial of Haptaplatin/5-FU and Leucovorin for Advanced Stomach Cancer 
Purpose
Heptaplatin (SKI-2053 R) is a new platinum analogue, with a better toxicity profile than cisplatin, and has antitumor activity even in cisplatin resistant cell lines. 5-fluoruracil (5-FU) has shown synergy with platinum compounds. This phase II trial was designed to determine the efficacy and toxicities of heptaplatin/ 5-FU (5-fluorouracil) for treating stomach cancer.
Materials and Methods
Thirty-two patients with advanced, measurable gastric adenocarcinomas were enrolled in this trial. The treatment consisted of heptaplatin, 400 mg/m2/day (1 hour IV infusion), on day 1 and 5-FU, 800 mg/m2/day (12 hours IV infusion), on days 1 to 5. The cycles were repeated every 3 weeks.
Results
Of the 26 evaluable patients, 9 had partial responses and 1a complete response (overall response rate, 38%; 95% confidence interval, 19~57%). The median response duration was 23 weeks (range: 4~60 weeks). The median time to progression was 26 weeks (range: 3~68 weeks). The grades III-IV toxicities were mostly hematological toxicities: leucopenia was observed in 11 patients (35%) and thrombocytopenia 4 (13%). No definite neuropathy was observed. Grade I-II nephropathy was also noted: grade I high BUN/creatinine levels occurred in 5 patients (16%), grade II proteinuria 2 (6%), grade I proteinuria 5 (16%). Neutropenic fever developed in 5 patients (16%) and 1 died of pneumonia in a neutropenic state.
Conclusion
This study suggests that the regimen of Heptaplatin/5-FU should be effective and have a favorable toxicity profile for the patients suffering with advanced stomach cancer.
doi:10.4143/crt.2005.37.4.208
PMCID: PMC2785922  PMID: 19956515
Stomach neoplasms; Heptaplatin (SKI-2053 R); 5-FU; Chemotherapy
9.  Hesperidin Induces Paraptosis Like Cell Death in Hepatoblatoma, HepG2 Cells: Involvement of ERK1/2 MAPK 
PLoS ONE  2014;9(6):e101321.
Hesperidin, a natural flavonoid abundantly present in Citrus is known for its anti-cancer, anti-oxidant and anti-inflammatory properties. In this study we examined the effect of hesperidin on HepG2 cells. HepG2 cells treated with various concentration of hesperidin undergo a distinct type of programed cell death. Cytoplasmic vacuolization, mitochondria and endoplasmic reticulum swelling and uncondensed chromatin were observed in hesperidin treated cells. DNA electrophoresis show lack of DNA fragmentation and western blot analysis demonstrates lack of caspase activation and PARP cleavage. It was observed that hesperidin induced cell death is nonautophagic and also activate mitogen activated protein kinase ERK1/2. Taken together, the data indicate that hesperidin induces paraptosis like cell death in HepG2 cells with the activation of ERK1/2. Thus our finding suggests that hesperidin inducing paraptosis may offer an alternative tool in human liver carcinoma therapy.
doi:10.1371/journal.pone.0101321
PMCID: PMC4076305  PMID: 24977707
10.  The involvement of AMPK/GSK3-beta signals in the control of metastasis and proliferation in hepato-carcinoma cells treated with anthocyanins extracted from Korea wild berry Meoru 
Background
Activation of the Wnt pathway is known to promote tumorigenesis and tumor metastasis, and targeting Wnt pathway inhibition has emerged as an attractive approach for controlling tumor invasion and metastasis. The major pathway for inhibiting Wnt is through the degradation of β-catenin by the GSK3-beta/CK1/Axin/APC complex. It was found that Hep3B hepato-carcinoma cells respond to anthocyanins through GSK3-beta-induced suppression of beta-catenin; however, they cannot dephosphorylate GSK3-beta without AMPK activation.
Methods
We tested the effects of anthocyanins on proliferation and apoptosis by MTT and Annexin V-PI staining in vitro. Mouse xenograft models of hepato-carcinomas were established by inoculation with Hep3B cells, and mice were injected with 50 mg/kg/ml of anthocyanins. In addition, protein levels of p-GSK3-beta, beta-catenin, p-AMPK, MMP-9, VEGF, and Ang-1 were also analyzed using western blot.
Results
Anthocyanins decrease phospho-GSK3-beta and beta-catenin expression in an in vivo tumor xenograft model, increase AMPK activity in this model, and inhibit cell migration and invasion, possibly by inhibiting MMP-2 (in vitro) and the panendothelial marker, CD31 (in vivo). To elucidate the role of the GSK3-beta/beta-catenin pathway in cancer control, we conditionally inactivated this pathway, using activated AMPK for inhibition. Further, we showed that AMPK siRNA treatment abrogated the ability of anthocyanins to control cell proliferation and metastatic potential, and Compound C, an AMPK inhibitor, could not restore GSK3-beta regulation, as exhibited by anthocyanins in Hep3B cells.
Conclusion
These observations imply that the AMPK-mediated GSK3-beta/beta-catenin circuit plays crucial roles in inhibiting cancer cell proliferation and metastasis in anthocyanin-treated hepato-carcinoma cells of Meoru origin.
doi:10.1186/1472-6882-14-109
PMCID: PMC3974438  PMID: 24666969
AMP-activated protein kinase; Glycogen synthase kinase 3-beta; beta-catenin; Meoru origin anthocyanins; Anti-metastatic potential
11.  Determination of Polyphenol Components of Korean Prostrate Spurge (Euphorbia supina) by Using Liquid Chromatography—Tandem Mass Spectrometry: Overall Contribution to Antioxidant Activity 
The Korean prostrate spurge Euphorbia supina is a weed that has been used in folk medicine in Korea against a variety of diseases. Nine polyphenols were characterized for this plant by using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and the results were compared with the literature data. The individual components were validated using the calibration curves of structurally related external standards and quantified for the first time by using the validated method. Correlation coefficients (r2) were >0.9907. The limit of detection and limit of quantification of the method were >0.028 mg/L and 0.094 mg/L, respectively. Recoveries measured at 50 mg/L and 100 mg/L were 76.1–102.8% and 85.2–98.6%, respectively. The total amount of the identified polyphenols was 3352.9 ± 2.8 mg/kg fresh plant. Quercetin and kaempferol derivatives formed 84.8% of the total polyphenols. The antioxidant activities of the flavonoids were evaluated in terms of 1,1-diphenyl-2-picrylhydrazyl and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation-scavenging activity, and the reducing power showed a dose-dependent increase. Cell viability was effectively suppressed at polyphenol mixture concentrations >250 mg/L.
doi:10.1155/2014/418690
PMCID: PMC3958725  PMID: 24724040
12.  Antiproliferative Action of Conjugated Linoleic Acid on Human MCF-7 Breast Cancer Cells Mediated by Enhancement of Gap Junctional Intercellular Communication through Inactivation of NF-κB 
The major conjugated linoleic acid (CLA) isomers, c9,t11-CLA and t10,c12-CLA, have anticancer effects; however, the exact mechanisms underlying these effects are unknown. Evidence suggests that reversal of reduced gap junctional intercellular communication (GJIC) in cancer cells inhibits cell growth and induces cell death. Hence, we determined that CLA isomers enhance GJIC in human MCF-7 breast cancer cells and investigated the underlying molecular mechanisms. The CLA isomers significantly enhanced GJIC of MCF-7 cells at 40 μM concentration, whereas CLA inhibited cell growth and induced caspase-dependent apoptosis. CLA increased connexin43 (Cx43) expression both at the transcriptional and translational levels. CLA inhibited nuclear factor-κB (NF-κB) activity and enhanced reactive oxygen species (ROS) generation. No significant difference was observed in the efficacy of c9,t11-CLA and t10,c12-CLA. These results suggest that the anticancer effect of CLA is associated with upregulation of GJIC mediated by enhanced Cx43 expression through inactivation of NF-κB and generation of ROS in MCF-7 cells.
doi:10.1155/2013/429393
PMCID: PMC3858871  PMID: 24371460
13.  Flavonoids Identified from Korean Scutellaria baicalensis Georgi Inhibit Inflammatory Signaling by Suppressing Activation of NF-κB and MAPK in RAW 264.7 Cells 
Scutellaria baicalensis Georgi has been used as traditional medicine for treating inflammatory diseases, hepatitis, tumors, and diarrhea in Asia. Hence, we investigated the anti-inflammatory effect and determined the molecular mechanism of action of flavonoids isolated from Korean S. baicalensis G. in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to examine cytotoxicity of the flavonoids at various concentrations of 10, 40, 70, and 100 µg/mL. No cytotoxicity was observed in RAW 264.7 cells at these concentrations. Furthermore, the flavonoids decreased production of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6, and tumor necrosis factor-alpha and inhibited phosphorylation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) in LPS-induced RAW 264.7 cells. Moreover, to identify the differentially expressed proteins in RAW 264.7 cells of the control, LPS-treated, and flavonoid-treated groups, two-dimensional gel electrophoresis and mass spectrometry were conducted. The identified proteins were involved in the inflammatory response and included PRKA anchor protein and heat shock protein 70 kD. These findings suggest that the flavonoids isolated from S. baicalensis G. might have anti-inflammatory effects that regulate the expression of inflammatory mediators by inhibiting the NF-κB signaling pathway via the MAPK signaling pathway in RAW 264.7 cells.
doi:10.1155/2013/912031
PMCID: PMC3857833  PMID: 24348728
14.  Proteomic analysis of differentially expressed proteins in vitamin C-treated AGS cells 
BMC Biochemistry  2013;14:24.
Background
Vitamin C (ascorbic acid) is an essential nutrient of most living tissues that readily acts as a strong reducing agent, which is abundant in fruits and vegetables. Although, it inhibits cell growth in many human cancer cells in vitro, treatment in cancer is still controversial. Hence, the purpose of this study was to investigate the molecular mechanism of the inhibitory effect of vitamin C on AGS cell growth, and protein profiles in AGS cells after exposure to vitamin C treatment, by using proteomic tools.
Results
Vitamin C showed a cytotoxic effect on AGS cells (IC50 300 μg/mL) and, 20 differentially expressed proteins (spot intensities which show ≥2 fold change and statistically significant, p<0.05 between the control and vitamin-C treated group) were successfully identified by assisted laser desorption/ ionization-time of flight/mass spectrometry (MALDI-TOF/MS). Of the 20 proteins, six were up-regulated and fourteen were down-regulated. Specifically, 14-3-3σ, 14-3-3ϵ, 14-3-3δ, tropomyosin alpha-3 chain and tropomyosin alpha-4 chain were down-regulated and peroxiredoxin-4 and thioredoxin domain-containing proteins 5 were up-regulated. The identified proteins are mainly involved in cell mobility, antioxidant and detoxification, signal transduction and protein metabolism. Further, the expressions of 14-3-3 isoforms were verified with immuno-blotting analysis.
Conclusions
Our proteome results suggest that the apoptosis related proteins were involved in promoting and regulating cell death of AGS cells, and might be helpful to understand the molecular mechanism of vitamin C on AGS cell growth inhibition.
doi:10.1186/1471-2091-14-24
PMCID: PMC3848938  PMID: 24067024
Vitamin C; Gastric cancer; AGS cells; Proteome analysis; 14-3-3 isoforms
15.  Flavonoids from Orostachys japonicus A. Berger Inhibit the Invasion of LnCaP Prostate Carcinoma Cells by Inactivating Akt and Modulating Tight Junctions 
Tight junctions (TJs) are a mode of cell-to-cell adhesion in epithelial or endothelial cells, and serve as a physical barrier to maintenance of homeostasis in body by controlling paracellular transport. Claudins are the most important molecules of the TJs, but paradoxically these proteins are frequently over-expressed in cancers and their overexpression is implicated in the invasive potential of cancer. Hence, we investigated the effects of flavonoids extracted from Orostachys japonicus A. Berger (FEOJ) on TJs and the expression of claudins as well as cancer invasion along with in LnCaP human prostate cancer. FEOJ suppressed cancer cell motility and invasiveness at the concentrations where FEOJ did not show anti-proliferative activity. FEOJ increased transepithelial electrical resistance (TER) associated with tightening TJs, and suppressed expression of claudin proteins. Furthermore, FEOJ suppressed the activities of MMP-2 and -9 in a dose-dependent manner, which came from the activation of tissue inhibitor of metalloproteinases (TIMPs) by FEOJ. FEOJ suppressed migration and invasion by suppressing PI3K/Akt signaling pathway. Taken together, this study suggest that FEOJ suppresses cancer migration and invasion by tightening TJs through the suppression of claudin expression, and by suppressing MMPs in LnCaP human prostate cancer cells, which at least in part results from the suppression of PI3K/Akt signaling pathway.
doi:10.3390/ijms140918407
PMCID: PMC3794786  PMID: 24018886
Orostachys japonicus; flavonoids; LnCaP cells; tight junctions; Akt
16.  Anthocyanins Downregulate Lipopolysaccharide-Induced Inflammatory Responses in BV2 Microglial Cells by Suppressing the NF-κB and Akt/MAPKs Signaling Pathways 
Anthocyanins are naturally occurring polyphenols that impart bright color to fruits, vegetables and plants and have a variety of protective properties, which have generally been attributed to their antioxidant capacity. However, little is known about the molecular mechanisms underlying anti-inflammatory effects of anthocyanins related to neurodegenerative diseases. Therefore, we determined whether anthocyanins isolated from black soybean seed coats would inhibit pro-inflammatory mediators and cytokines in lipopolysaccharide (LPS)-stimulated murine BV2 microglial cells. Our results showed that anthocyanins significantly inhibited LPS-induced pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2, and pro-inflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β, without significant cytotoxicity. Anthocyanins also downregulated excessive expression of inducible NO synthase, cyclooxygenase-2, TNF-α, and IL-1β in LPS-stimulated BV2 cells. Moreover, anthocyanins inhibited nuclear translocation of nuclear factor-kappa B (NF-κB) by reducing inhibitor of NF-κB alpha degradation as well as phosphorylating extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and Akt. These findings suggest that anthocyanins may offer substantial therapeutic potential for treating inflammatory and neurodegenerative diseases accompanied by microglial activation.
doi:10.3390/ijms14011502
PMCID: PMC3565332  PMID: 23344054
anthocyanins; BV2; anti-inflammatory activity; NF-κB; MAPK; Akt
17.  Regulation of Proinflammatory Mediators via NF-κB and p38 MAPK-Dependent Mechanisms in RAW 264.7 Macrophages by Polyphenol Components Isolated from Korea Lonicera japonica THUNB 
Lonicera japonica THUNB., which abundantly contains polyphenols, has been used as a traditional medicine for thousands of years in East Asian countries because of the anti-inflammation properties. This study aimed to investigate the anti-inflammatory mechanism of polyphenol components isolated from Korea L. japonica T. by nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs) pathway. Polyphenols significantly decreased lipopolysaccharide- (LPS-) induced mRNA and protein expression of inducible nitric oxide synthase and cyclooxygenase-2, as well as mRNA expression of tumor necrosis factor-alpha, interleukin- (IL-) 1β, and IL-6. Moreover, polyphenols inhibited nuclear translocation of NF-κB p65, phosphorylation/degradation of the inhibitor of κB, and phosphorylation of p38 MAPK, whereas the extracellular signal-regulated kinase and Janus N-terminal kinase were not affected. These results indicate that polyphenol components isolated from Korea L. japonica T. should have anti-inflammatory effect on LPS-stimulated RAW 264.7 cells through the decrease of proinflammatory mediators expression by suppressing NF-κB and p38 MAPK activity.
doi:10.1155/2012/828521
PMCID: PMC3352662  PMID: 22611435
18.  Flavonoids Isolated from Korea Citrus aurantium L. Induce G2/M Phase Arrest and Apoptosis in Human Gastric Cancer AGS Cells 
Aim of the Study. Citrus species is used in traditional medicine as medicinal herb in several Asian countries including Korea. Flavonioids became known as various properties, such as anti-oxidants, anti-inflammation and anti-cancer, and so forth. The present study, the anti-cancer effect of flavonioids isolated from Citrus aurantium L. in human gastric cancer AGS cells has been investigated. Materials and Methods. The anti-proliferative activity was assayed using MTT assay. Cell cycle analysis was done using flow cytometry and apoptosis detection was done using by hoechst fluorescent staining and Annexin V-propidium iodide double staining. Western blot was used to detect the expression of protein related with cell cycle and apoptosis. Results. Flavonoids isolated from Citrus aurantium L. have the effect of anti proliferation on AGS cells with IC50 value of 99 μg/mL. Flavonoids inhibited cell cycle progression in the G2/M phase and decrease expression level of cyclin B1, cdc 2, cdc 25c. Flavonoids induced apoptosis through activate caspase and inactivate PARP. Conclusions. Flavonoids isolated from Citrus aurantium L. induced G2/M phase arrest through the modulation of cell cycle related proteins and apoptosis through activation caspase. These finding suggest flavonoids isolated from Citrus aurantium L. were useful agent for the chemoprevention of gastric cancer.
doi:10.1155/2012/515901
PMCID: PMC3238396  PMID: 22194772
19.  Agaricus blazei Extract Induces Apoptosis through ROS-Dependent JNK Activation Involving the Mitochondrial Pathway and Suppression of Constitutive NF-κB in THP-1 Cells 
Agaricus blazei is widely accepted as a traditional medicinal mushroom, and it has been known to exhibit immunostimulatory and anti-cancer activity. However, the apoptotic mechanism in cancer cells is poorly understood. In this study, we have investigated whether A. blazei extract (ABE) exerts antiproliferative and apoptotic effects in human leukemic THP-1 cells. We observed that ABE-induced apoptosis is associated with the mitochondrial pathway, which is mediated by reactive oxygen species (ROS) generation and prolonged c-Jun N-terminal kinase (JNK) activation. In addition, the ABE treatment resulted in the accumulation of cytochrome c in the cytoplasm, an increase in caspase activity, and an upregulation of Bax and Bad. With those results in mind, we found that ABE decreases constitutive NF-κB activation and NF-κB-regulated gene products such as IAP-1 and -2. We concluded that ABE induces apoptosis with ROS-dependent JNK activation and constitutive activated NF-κB inhibition in THP-1 cells.
doi:10.1093/ecam/nep176
PMCID: PMC3137680  PMID: 19861509
20.  Suppressive Effect on Lipopolysaccharide-Induced Proinflammatory Mediators by Citrus aurantium L. in Macrophage RAW 264.7 Cells via NF-κB Signal Pathway 
Citrus fruits have been used as an edible fruit and a traditional medicine since ancient times. In particular, the peels of immature citrus fruits are used widely in traditional herbal medicine in Korea, as they are believed to contain bioactive components exerting anti-inflammatory activity. This study examined whether the crude methanol extract of Citrus aurantium L. (CME) has a suppressive effect on inducible enzymes and proinflammatory cytokines by inhibiting the NF-κB pathway in LPS-stimulated macrophage RAW 264.7 cells. The cells were pretreated with the indicated concentrations of CME (5, 10, 20, and 50 μg/mL) and then treated with LPS (1 μg/mL). The results showed that CME (10, 20, and 50 μg/mL) inhibited the LPS- (1 μg/mL) induced mRNA and protein expression of iNOS in macrophage Raw 264.7 cells. In addition, the expression of COX-2 was inhibited at the mRNA and protein levels by CME in a dose-dependent manner. The mRNA expression of proinflammatory cytokines, such as TNF-α and IL-6, were markedly reduced by CME (10, 20, and 50 μg/mL). Moreover, CME clearly suppressed the nuclear translocation of the NF-κB p65 subunits, which was correlated with its inhibitory effect on I-κB phosphorylation. These results suggest that CME has anti-inflammatory properties by modulating the expression of COX-2, iNOS, and proinflammatory cytokines, such as TNF-α and IL-6, in macrophage RAW 264.7 cells via the NF-κB pathway.
doi:10.1155/2011/248592
PMCID: PMC2952293  PMID: 20953420
21.  AMP kinase/cyclooxygenase-2 pathway regulates proliferation and apoptosis of cancer cells treated with quercetin 
Experimental & Molecular Medicine  2009;41(3):201-207.
AMPK (AMP-activated protein kinase) is highly conserved in eukaryotes, where it functions primarily as a sensor of cellular energy status. Recent studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumor cells. In this study, quercetin activated AMPK in MCF breast cancer cell lines and HT-29 colon cancer cells, and this activation of AMPK seemed to be closely related to a decrease in COX-2 expression. The application of a COX-2 inhibitor or cox-2-/- cells supported the idea that AMPK is an upstream signal of COX-2, and is required for the anti-proliferatory and pro-apoptotic effects of quercetin. The suppressive or growth inhibitory effects of quercetin on COX-2 were abolished by treating cancer cells with an AMPK inhibitor Compound C. These results suggest that AMPK is crucial to the anti-cancer effect of quercetin and that the AMPK-COX-2 signaling pathway is important in quercetin-mediated cancer control.
doi:10.3858/emm.2009.41.3.023
PMCID: PMC2679247  PMID: 19293639
AMP-activated protein kinases; apoptosis; cyclooxygenase-2; growth inhibitors; HT-29 cells; quercetin
22.  A Phase II Trial of Docetaxel and Ifosfamide for Patients with Platinum-Resistant or Refractory Non-Small Cell Lung Cancer in a Salvage Setting 
Purpose
We conducted a phase II study of docetaxel and ifosfamide chemotherapy for patients with platinum-resistant or refractory non-small-cell lung cancer (NSCLC) to evaluate the response and toxicity profiles as a salvage treatment.
Materials and Methods
Between July 2000 and July 2004, 40 patients who had previously received platinum-based regimen as the first-line or second-line therapy were enrolled in this study. The treatment consisted of a docetaxel 75 mg/m2 intravenous infusion on day 1 and intravenous ifosfamide 3 g/m2 with Mesna® uroprotectione on day 1 through 3. This regimen was repeated every 3 weeks.
Results
One hundred thirty cycles of treatment were given, with a median of 3 cycles (range: 2~6 cycles). All the patients were evaluable for the response rate and toxicity profile. The major toxicity was myelosuppression. Grade 3~4 neutropenia occurred in 30 patients (75%) during treatment. Febrile neutropenia occurred in 16 patients (40%). Five of 40 patients (12.5%) had a partial response (95% confidence interval, 3.3~21.7%). The median time to disease progression was 2.65 months (range: 2.02~3.20 months), and the median survival was 5.24 months (range: 2.99~7.49 months).
Conclusion
Salvage chemotherapy with docetaxel and ifosfamide showed a low efficacy and a high proportion of severe neutropenia in patients with platinum-resistant or refractory advanced NSCLC.
doi:10.4143/crt.2004.36.5.287
PMCID: PMC2843870  PMID: 20368817
Non-small cell lung cancer; Chemotherapy; Docetaxel; Ifosfamide; Salvage therapy
23.  Chylothorax in Gorham's disease. 
Journal of Korean Medical Science  2002;17(6):826-829.
A 25-yr-old woman presented with a right pleural effusion. Destruction of 9th through 12th ribs, adjacent vertebral bodies, and transverse processes was noted on plain radiograph and a large low-attenuated, irregular shaped mass lesion with peripheral rim enhancement, destroying vertebral body and transverse process, was revealed on the computed tomographic scan. Magnetic resonance imaging showed high signal on T1- weighted image and iso- and low signal on T2-weighted image for the mass lesion replacing the vertebral bony cortex and marrow space. An open rib biopsy revealed the histopathological changes of Gorham's disease (essential osteolysis), even though only bloody fluid filling the empty space and rib and vertebral transverse process destruction were grossly observed on operation. Even though there was no definite response to radiotherapy and pleurodesis, the patient showed stable condition up to 20 months after diagnosis.
PMCID: PMC3054959  PMID: 12483010
24.  Reactive cutaneous cytophagocytosis in nocardiosis. 
Journal of Korean Medical Science  2002;17(2):279-282.
Cutaneous nocardiosis, which usually manifests in the form of pustules, abscesses, or subcutaneous nodules, is occasionally found in immunocompromised patients. A 59-yr-old Korean man with myasthenia gravis and thymoma developed nodular skin lesions on his trunk. Histopathologically, abscess formation with a dense infiltrate of neutrophils and many cytophagic histiocytes were observed. Numerous filamentous organisms, which turned out to be Nocardia asteroides by culture, were also found. After sulfamethoxazole-trimethoprim therapy, all of the skin lesions rapidly decreased in size, with a marked diminution of the number of cytophagic histiocytes, and cleared up within four months. On reporting a case of cutaneous nocardiosis showing unusual histopathologic findings, we considered that reactive conditions should be included in the differential diagnosis of the cutaneous cytophagocytosis, and that nocardiosis could be one of the diseases showing reactive cytophagocytosis.
PMCID: PMC3054841  PMID: 11961320

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