• Journal of Physiology & Pathology in Korean Medicine
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• v.25 no.6
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• pp.968-974
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• 2011

Saussurea lappa Clarke is a well-known transitional medicine in Asia including Korea, China and Japan. It has been reported that Clarke has diverse effects such as anti-viral, anti-inflammatory, anti-cancer in human gastric cells and human prostate cancer cells. However, the anti-cancer effects and the mechanism of actions of Saussurea lappa Clarke are still unknown in breast cancer. In this study, we observed that Saussurea lappa Clarke inhibits the cell growth in a dose- and time-dependent manner in highly-metastatic MDA-MB-231 breast cancer cells. In order to examine whether Saussurea lappa Clarke suppresses cell growth inducing apoptosis cell death or cell cycle arrest, we analyzed DNA contents and cell cycle distribution using a flow cytometer and western blotting in MDA-MB-231 cells. We suggest that Saussurea lappa Clarke dose not induced apoptosis and induced G2/M phase cell cycle arrest. Moreover, Saussurea lappa Clarke also decreased the expression level of metastasis-angiogenesis releated protein such as VEGF. However, dose not changed the expression level of metastasis related protease MMP-1 in highly-metastatic MDA-MB-231 breast cancer cells. Therefore, Saussurea lappa Clarke might be good and useful chemotherapy agent highly-metastatic breast cancer patients.

• Biomolecules & Therapeutics
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• v.17 no.4
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• pp.422-429
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• 2009

Invasion and metastasis is the main cause of cancer mortality. Angiogenesis is a prerequisite for the tumor growth and metastasis. Matrix metalloproteinases (MMPs) are the key enzymes playing in the invasive growth and metastasis of cancer as well as angiogenesis. Xanthohumol, a prenylated chalcone of the Hop plant (Humulus lupulus L), has been reported to suppress cancer invasion and angiogenesis. In the present study, we investigated the antiinvasive effects of xanthohumol (1) and its synthetic derivatives, 4'-O-methylxanthohumol SEM ether (2), xanthohumol C (3), and xanthohumol C MOM ether (4) in relation to MMP expression in HT-1080 human fibrosarcoma cells. The compound 1 and its derivative, 3 and 4, significantly inhibited serum-induced HT-1080 cell invasion, and 12-O-tetradecanoylphorbol-13-acetate (TPA)-enhanced activity and expression level of MMP-2 and MMP-9 in a concentration-dependant manner. In addition, they inhibited TPA-enhanced expression of MT1-MMP with relatively weak inhibition in tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 level. The compound 1 significantly decreased the cell viability, whereas the derivatives, 2 and 3 showed no cytotoxicity, and compound 4 showed slight cytotoxicity in the cells. Furthermore, in a chick chorioallantoic membrane (CAM) assay, the derivatives 3 and 4 dose-dependently suppressed vascular endothelial growth factor (VEGF)-induced angiogenesis, which is similar to that of compound 1. Taken together, the results indicate that compounds 3 and 4 may be valuable anti-angiogenic agents in the treatment of chronic diseases such as cancer and inflammation working through suppression of MMP-2 and MMP-9.

• Korean Journal of Pharmacognosy
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• v.45 no.1
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• pp.1-10
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• 2014

Ginsenoside Rg3 (G-Rg3) is one of protopanaxadiol ginsenosides characteristic of red ginseng, steamed and dried ginseng (Panax ginseng), which has recently attracted much attention for its antitumor properties in vitro and in vivo animal models. Experimental studies have demonstrated that it could promote cancer cell apoptosis, inhibit cancer cell growth, the apoptosis of cancer cells, adhesion, invasion and metastasis, and also prevent an angiogenetic formation in prostate, breast, ovarian, colorectal, gastric, liver and lung cancer etc. It has shown the antitumor activities by modulation of diverse signaling pathways, including regulation of cell proliferation mediators (CDKs and cyclins), growth factors (vascular endothelial growth factor), tumor suppressors (p53 and p21), cell death mediators (caspases, Bcl-2, Bax), inflammatory response molecules ($NF-{\kappa}B$ and COX-2), protein kinases (JNK, Akt, and AMP-activated protein kinase) and Wnt/${\beta}$-catenin signaling. In addition, the combination of Rg3 and chemotherapeutic agents have synergistically enhanced therapeutic efficacy and reduced antagonistically side effects. Furthermore, it can reverse the multidrug resistance of cancer cells, prolong the survival duration and improve life quality of cancer patients. Taken together, accumulating evidences could provide the potential of G-Rg3 in the treatment of cancers and the feasibility of further randomized placebo controlled clinical trials.

• Journal of Society of Preventive Korean Medicine
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• v.16 no.1
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• pp.57-70
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• 2012

The apoptotic process of gastric mucosa triggered by induction of proapoptotic gene expression, such as Bax. Stress-inducing factors may affect Bcl-2/Bax ratio and thus the rate of apoptosis through modulation of the expression of both proteins depending upon the experimental model. TGF-${\beta}$ is believed to be essential in wound healing for regulation of cell growth and differentiation and is known to be involved in tissue repair and remodeling. The polypeptide growth factors, such as vascular endothelial growth factor(VEGF), regulate essential cell functions involved in tissue healing including cell proliferation, migration, and differentiation. The purpose of this study was to investigate whether the oral administration of $Hwangyeon-tang$ (HYT) would have protect effects on gastric ulcer in rat. Sprague-Dawley rats (n=40) were randomly divided into 4 groups ; Normal, Saline, Cimetidine and HYT group. The saline, cimetidine and HYT extract were orally administrated to each group and gastric ulcer was induced with HCl/EtOH solution. After 1 hour, the stomachs were collected for histological observation and immunohistochemistry. In Results, the wound healing of gastric ulcer was promoted by HYT and the significant alterations of BAX/Bcl-2, TGF-${\beta}1$ and VEGF proteins in gastric mucosa were observed. These results suggest that Fritillaria ussuriensis extract promotes wound healing and has protective effects on gastric ulcer in rats.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6869-6874
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• 2013

Background: Vascular endothelial growth factor and matrix metalloproteinases are two important factors for angiogenesis associated with breast cancer growth and progression. The present study was aimed to examine the effects of tamoxifen and tranilast drugs singly or in combination on proliferation of breast cancer cells and also to evaluate VEGF and MMP-9 expression and VEGF secretion levels. Materials and Methods: Human breast cancer cell lines, MCF-7 and MDA-MB-231, were treated with tamoxifen and/or tranilast alone or in combination and percentage cell survival and proliferative activity were evaluated using LDH leakage and MTT assays. mRNA expression and protein levels were examined by real-time RT-PCR and ELISA assay, respectively. Results: LDH and MTT assays showed that the combined treatment of tamoxifen and tranilast resulted in a significant decrease in cell viability and cell proliferation compared with tamoxifen or tranilast treatment alone, with significant decrease in VEGF mRNA and protein levels. We also found that tamoxifen as a single agent rarely increased MMP-9 expression. A decrease in MMP-9 expression was seen after treatment with tranilast alone and in the combined treatment MMP-9 mRNA level was decreased. Conclusions: This combination treatment can able to inhibit growth, proliferation and angiogenesis of breast cancer cells.

• Journal of Society of Preventive Korean Medicine
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• v.14 no.1
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• pp.97-110
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• 2010

The wound healing process can be categorized as follows : inflammation, fibroplasia, neovascularization, collagen deposition, epithelialization, and wound contraction. During the healing process, various growth factors are secreted to accelerate wound healing. Previous studies have demonstrated that endogenous growth factors, such as vascular endothelial growth factor(VEGF) are the important regulatory polypeptides for coordinating the healing process. They are released from macrophages, fibroblasts, and keratinocytes at the site of injury and participate in the regulation of reepithelization, granulation tissue formation, collagen synthesis and neovascularization. Onchung-Um has been used clinically to treat various skin diseases. In addition, Onchung-Um has been also used for congestive inflammations. In the present study, we evaluated the effects of Onchung-Um on wound healing process and wound size reduction in rats. Full-thickness skin wounds ($15mm\;{\times}\;15mm$) were created on the back of rats. Rats were then divided into 2 groups : The Onchung-Um treated group that was orally administered with a dose of 193.9mg/100g of Onchung-Um extract per day for 15 days and Control group without Onchung-Um administration. Moreover, the histological changes and VEGF immunoexpressions of two groups were estimated. In results, wound closures were significantly accelerated by oral administration of Onchung-Um extract. Furthermore, in Onchung-Um treated group, there were significant increases in fibroblast migration, epithelialization compared with the Control group. VEGF expressions were also increased in Onchung-Um treated group. This study has therefore demonstrated the Onchung-Um can significantly improve the quality of wound healing and scar formation and the oral administration of Onchung-Um extract may increase early tissue angiogenesis in the incisional wound of an experimental animal model.

• Journal of Gastric Cancer
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• v.18 no.4
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• pp.356-367
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• 2018

Purpose: Kallikrein (KLK) proteases are hormone-like signaling molecules with critical functions in different cancers. This study investigated the expression of KLK6 in gastric cancer and its potential role in the growth, migration, and invasion of gastric cancer cells. Materials and Methods: In this study, we compared protein levels of KLK6, vascular endothelial growth factor (VEGF), and matrix metallopeptidase (MMP) 9 in normal gastric epithelial and gastric cancer cell lines by western blot. Fluorescence-activated cell sorting was employed to sort 2 clones of SGC-7901 cells with distinct KLK6 expression, namely, KLK6-high ($KLK6^{high}$) and KLK6-low ($KLK6^{low}$), which were then expanded. Lastly, immunohistochemical analysis was performed to investigate KLK6 expression in gastric cancer patients. Results: The expression levels of KLK6, VEGF, and MMP 9, were significantly higher in the gastric cancer cell lines SGC-7901, BGC-823, MKN-28, and MGC-803 than in the normal gastric epithelial cell line GES-1. Compared to $KLK6^{low}$ cells, $KLK6^{high}$ cells showed enhanced viability, colony-forming ability, migration, and invasion potential in vitro. Importantly, immunohistochemical analysis of a human gastric cancer tissue cohort revealed that the staining for KLK6, VEGF, and MMP9 was markedly stronger in the cancerous tissues than in the adjacent normal tissues. KLK6 expression also correlated with that of VEGF and MMP9 expression, as well as several key clinicopathological parameters. Conclusions: Together, these results suggest an important role for KLK6 in human gastric cancer progression.

• Journal of Korean Medicine Rehabilitation
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• v.15 no.1
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• pp.25-37
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• 2005

목적 : 진피(Citus Unshiu, CU)는 실험적으로 항산화, 항알러지, 항종양 효과 등이 있다고 보고되고 있다. 본 연구에서는 비만세포에서 PMA와 A23187에 의하여 유도된 싸이토카인의 증가에 대한 진피 추출물의 억제 효과와 그 기전을 알아보고자 한다. 방법 : PMA+A23187에 의한 싸이토카인 생성에 대한 진피 추출물의 억제효과 기전을 조사하기 위하여 진피를 처리한 후 $IL-1{\beta}$, IL-8, $TNF-{\alpha}$의 생산 및 혈관내피성장인자 (VEGF), 과립구 대식구 군집 자극 인자 (GM-CSF), 저산소 유도 인자(HIF-1)의 발현을 조사하였다. 결과 : 실험에서 PMA와 A23187을 처리한 경우 대조군에 비하여 $IL-1{\beta}$, IL-8, $TNF-{\alpha}$의 생산을 유의하게 증가시켰으나 진피 추출물을 처리한 군에서는 유의하게 억제되었다. 특히 $IL-1{\beta}$의 생성은 $103.7{\pm}5%$, IL-8 생성은 $34.6{\pm}7%$, $TNF-{\alpha}$의 생성은 $85.9{\pm}4.5%$ 억제되었다. (P<0.05). 또한 진피 추출물은 PMA와 A23187에 의하여 증가한 VEGF, GM-CSF, $HIF-1{\alpha}$의 발현 증가를 억제하였다 (약 90.9%의 VEGF, 61.6%의 GM-CSF). 결론 : 이러한 결과는 진피가 염증반응에 대한 HIF-1의 억제자로 작용할 수 있으면, 진피가 비만세포 매개성 염증 질환 치료제의 후보 물질이 될 것으로 사료된다.

• Tuberculosis and Respiratory Diseases
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• v.68 no.1
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• pp.22-28
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• 2010

Background: Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis. VEGF production is regulated by HIF-$1{\alpha}$ and EGFR. This study examined the relationship between the clinicopathological factors and VEGF, HIF-$1{\alpha}$ and EGFR protein overexpression, and evaluated their prognostic value in patients with a surgically resected non-small cell lung cancer (NSCLC). Methods: Patients who underwent a surgical resection at Kangnam St. Mary's hospital were reviewed retrospectively. The core biopsy samples from 54 patients with NSCLC were assembled on a tissue microarray (TMA), and immunohistochemical staining for the VEGF, HIF-$1{\alpha}$ and EGFR proteins was performed. The overexpression of these proteins was evaluated in relation to age, gender, histology and staging by univariate analysis. The clinicopathological prognostic factors were analyzed. Results: Multivariate analysis performed by Cox regression (odds ratio 2.8, 95% CI 1.0~8.2, p=0.046) revealed HIF-$1{\alpha}$ overexpression to be an unfavorable factor. There was no correlation between the overexpression of these proteins and the clinicopathological factors. VEGF showed a positive relationship with EGFR, but there was no statistical significance [$p(x^2)=0.06$]. Conclusion: HIF-$1{\alpha}$ overexpression predicts shorter survival in patients with a surgically resected NSCLC. Therefore, HIF-$1{\alpha}$ may be a poor prognostic factor in NSCLC.

• Journal of Physiology & Pathology in Korean Medicine
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• v.27 no.6
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• pp.738-744
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• 2013

The purpose of this study is to investigate effects of White Ginseng-Ejung-tang water extract (EJ) on production of various cytokines such as interleukin (IL)-2, IL-5, IL-6, IL-10, IL-12p70, macrophage inflammatory protein (MIP)-2, vascular endothelial growth factor (VEGF), keratinocyte-derived chemokine(KC), tumor necrosis factor (TNF)-${\alpha}$, and granulocyte macrophage colony-stimulating factor (GM-CSF) in RAW 264.7 mouse macrophages stimulated by lipopolysaccharide (LPS). Levels of cytokines were measured by High-throughput multiplex bead array cytokine assay based on xMAP (multi-analyte profiling beads) technology. EJ significantly decreased levels of IL-2, IL-12p70, IL-5, MIP-2 for 24 h incubation at the concentrations of 25, 50, and 100 ${\mu}g/mL$ in LPS-induced RAW 264.7 (P < 0.05). EJ significantly decreased levels of IL-6 at the concentrations of 50 and 100 ${\mu}g/mL$ (P < 0.05). EJ significantly decreased levels of IL-10 and VEGF at the concentrations of 25 and 100 ${\mu}g/mL$ (P < 0.05). EJ significantly decreased levels of KC at the concentrations of 100 ${\mu}g/mL$ (P < 0.05). EJ did not show any significant effect on TNF-${\alpha}$ and GM-CSF production. These results suggest that EJ has anti-inflammtory property related with its inhibition of IL-2, IL-5, IL-6, IL-10, IL-12p70, MIP-2, VEGF, and KC production in LPS-induced macrophages.