• Title/Summary/Keyword: angiogenesis inhibition

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Inhibition of Lymphatic Endothelial Growth Factor Receptor in a Murine Model of Oral Squamous Cell Carcinoma (구강 편평상피세포암 마우스 모델에서 림프관내피 성장인자 수용체의 억제)

  • Kye, Jun-Young;Park, Young-Wook
    • Maxillofacial Plastic and Reconstructive Surgery
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    • v.33 no.1
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    • pp.1-9
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    • 2011
  • Purpose: Tumor associated angiogenesis and/or lymphangiogenesis are known to be linked by VEGFR signaling pathways. These processes are regulated by several growth factors including VEGFR-2, VEGFR-3. E7080 is an orally active inhibitor of multiple tyrosine kinases including VEGFR-2, 3. Therefore, it was proposed that E7080 may inhibit angiogenesis and lymphangiogenesis. The aim of this study was to determine the effect of E7080 in a nude mouse model of OSCC. Methods: KB cells were xenografted into the submucosal tissue of the mouth floor of athymic mice. Seven days after the xenograft, the mice were randomized into 2 groups. E7080 were administered orally to the experimental group once per day. The mice were sacrificed 3 weeks after the treatment. The tumors were examined histopathologically. Immunohistochemical assays with anti- VEGF-C, VEGFR-2, VEGFR-3, phosphorylated VEGFR-2/3 (pVEGFR-2/3), and D2-40 antibodies were then performed. Results: The transplantation of human OSCC tumor cells into the mouth floor resulted in the formation of orthotopic tumors. The experimental (E7080 treatment) group showed a slowly increased tumor volume. Moreover, immunohistochemical staining demonstrated higher levels of VEGF-C, VEGFR-2, VEGFR-3, pVEGFR-2/3 and D2-40 expression in the control group than in the experimental group. Conclusion: These results suggest that E7080 may provide therapeutic benefits in OSCC.

Targeting Renal Cell Carcinoma with Gambogic Acid in Combination with Sunitinib in Vitro and in Vivo

  • Jiang, Xiao-Liang;Zhang, Yao;Luo, Chun-Li;Wu, Xiao-Hou
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.12
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    • pp.6463-6468
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    • 2012
  • Purpose: To evaluated the effect of the gambogic acid (GA), one of the effective components of Garcinia, in combination with a new multi-targeted oral medication, sunitinib (SU) on renal cancer cell proliferation in vitro and on tumor growth in vivo. Methods: After treatment with GA or SU, either alone or in combination, MTT and FACS analysis were used to examine cell viability and cycle distribution of the renal carcinoma cell lines 786-0 and Caki-1. Western blotting was employed to examine the expression of proteins related to the cell cycle and vascular formation. Furthermore, a xenograft model was applied to study the antitumor efficacy of SU or GA alone or in combination, with immunohistochemistry to detect expression of proteins related to xenograft growth and angiogenesis. Western blotting was used to examine NF-${\kappa}B$ signaling pathway elements in xenografts. Results: Treatment of 786-0 and Caki-1 cells with GA or SU resulted in decreased tumor cell proliferation, especially with joint use. Cells accumulated more strongly in the sub-G1 phase after joint treatment with GA and SU than treatment of GA and SU alone. Western blotting arrays showed 1 protein significantly upregulated, 2 proteins downregulated, and 2 proteins unchanged. Moreover, combined use of GA and SU inhibited the growth and angiogenesis of xenografts generated from Caki-1 significantly. Immunohistochemistry arrays showed downregulation of the expression of proteins promoting xenograft growth and angiogenesis, and Western blotting showed inhibition of the NF-${\kappa}B$ signaling pathway after treatment by GA alone and in combination with SU in xenografts. Conclusions: Our results show that the joint use of GA and SU can provide greater antitumor efficacy compared to either drug alone and thus may offer a new treatment strategy for renal cell carcinoma.

Targeting EGFL7 Expression through RNA Interference Suppresses Renal Cell Carcinoma Growth by Inhibiting Angiogenesis

  • Xu, Han-Feng;Chen, Lei;Liu, Xian-Dong;Zhan, Yun-Hong;Zhang, Hui-Hui;Li, Qing;Wu, Bin
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.7
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    • pp.3045-3050
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    • 2014
  • Renal cell carcinoma (RCC) is the most lethal of all urological cancers and tumor angiogenesis is closely related with its growth, invasion, and metastasis. Recent studies have suggested that epidermal growth factor-like domain multiple 7 (EGFL7) is overexpressed by many tumors, such as colorectal cancer and hepatocellular carcinoma; it is also correlated with progression, metastasis, and a poor prognosis. However, the role of EGFL7 in RCC is not clear. In this study, we examined how EGFL7 contributes to the growth of RCC using a co-culture system in vitro and a xenograft model in vivo. Downregulated EGFL7 expression in RCC cells affected the migration and tubule formation of HMEC-1 cells, but not their growth and apoptosis in vitro. The level of focal adhesion kinase (FAK) phosphorylation in HMEC-1 cells decreased significantly when co-cultured with 786-0/iEGFL7 cells compared with 786-0 cells. After adding rhEGFL7, the level of FAK phosphorylation in HMEC-1 cells was significantly elevated compared with phosphate-buffered saline (PBS) control. However, FAK phosphorylation was abrogated by EGFR inhibition. The average size of RCC local tumors in the 786-0/iEGFL7 group was noticeably smaller than those in the 786-0 cell group and their vascular density was also significantly decreased. These data suggest that EGFL7 has an important function in the growth of RCC by facilitating angiogenesis.

Inhibitory Effects of Rehmannia glutinosa Liboschitz on Endothelial Cell Proliferation

  • Lee, Sung-Jin;Lee, Hak-Kyo
    • Korean Journal of Medicinal Crop Science
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    • v.15 no.5
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    • pp.311-314
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    • 2007
  • Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are the most important angiogenic molecules associated with tumor-induced neovascularization. This study was carried out to investigate inhibitory effect of extracts from root of Rehmannia glutinosa LIBOSCHITZ (Rehmannia Radix and Rehmannia Radix Preparata) on endothelial cell proliferation. The methanol extracts from the medicinal herb were fractionated into n-hexane, ethyl acetate, n-butanol and aqueous fractions. Among the four fractions, the n-butanol fraction from R. Radix on exhibited highly effective inhibition (${\approx}79%$ inhibition) on the binding of KDR/Flk-1-Fc to immobilized $VEGF_{165}$ and then ethyl acetate fraction from R. Radix (${\approx}45%$ inhibition) at the concentration of $100\;{\mu}g/ml$. The n-butanol fraction efficiently blocked the VEGF- and bFGF-induced HUVEC proliferation in a dose-dependent manner, but did not affect the growth of HT1080 human fibrosarcoma cells. The n-butanol fraction more efficiently blocked the binding of KDR/Flk-1-Fc to immobilized $VEGF_{165}$ and VEGF- and bFGF-induced human umbilical vein endothelial cell proliferation than the fraction from R. Radix Preparata. Our results suggest that Rehmannia Radix may be used as a candidate for developing anti-angiogenic agent.

Effect of Whalakyuoleyng-dan plus Yinsamyangwui-tang on Anti-angionesis (활락효영단합인삼양위탕(活絡效靈丹合人蔘養胃湯)이 혈관신생(血管新生) 억제(抑制)에 미치는 영향(影響))

  • Ko, Ki-Wan;Park, Joon-Hyuk;Kang, Hee;Kim, Sung-Hoon;Yu, Young-Beob;Shim, Bum-Sang;Choi, Seung-Hoon;Ahn, Koo-Seok
    • THE JOURNAL OF KOREAN ORIENTAL ONCOLOGY
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    • v.7 no.1
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    • pp.77-97
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    • 2001
  • Anti-angiogenesis is one of therapies which have been high-lightened on the research of cancer treatment. Anti-angiogenesis means that new blood vessels are created from a existing capillary tube and it is a important process on metastasis and permeation when cancer is created or formed. Since angiogenesis have been under research, a complete recovery oriented treatment against cancer have been suggested blocking metastasis, delaying the growth of cancer cell, and blocking the supply of oxygen and nutritive substance through the web of blood vessels. Until now, there are several anti-angiogenesis, which have been known to the public, such as thalidomide, angiostatin, endostatin, 2-methoxyestradiol, TNP-470, and marimastat, etc. Additionally, 17 clinical testing projects about anti-angiogenesis are on the process in NCI(National Cancer Institute). Especially, TNP-470 showed effectiveness against cancer on clinical testing after finishing animal testing. Based on existing researches showing that Yinsamyangwui-tang is effective to strengthening body resistance and Whallakhyolenyng-dan effects cells on the inside of blood vessel because Whallakhyolenyng- dan restrains cell adhesion during the restraining period of a blood vessel, I tried to research the effect of Whalakhyolenyng-dan plus Yinsamyangwui-tang on angiogenesis. I made a conclusion putting into operation through using SK-Hep-1 (KCLB 30052), A549(KCLB 10185), AGS(KCLB 21739), and BCE(Bovine Capillary Endothelial Cell). Followings are the results of my experimental research: 1. According to the researching results of anti-cancer activation against cancer cell, Whallkhyoleyng dan plus Yinsamyangwui-tang decreased the number of cancer cells -- While injecting $600{\mu}g/ml$, injected groups decreased 3.1% more comparing with the contrastive group of SK-Hep-1, 49.7% more comparing with the contrastive group of A549, and 31.0% more comparing with the contrastive group of AGS. 2. According to the researching results of DNA composition effect between BCE and cancer cell, Whallakhyoleyng-dan plus Yinsamyangwui-tang reduced the rate of SK-Hep-1 synthesis inhibition by 59.1% at $600{\mu}g/ml$ intensity comparing with contrastive group; for A549, 72.6%; for AGS, 6.1%, for BCE, 28.9%. 3. According to the researching results about the effect of BCE cell to angiogenesis, angiogenesis was restrained at $400{\mu}g/ml$ intensity during 18 hours observation. 4. In the case of aortic ring assay, the half level of angiogenesis was reduced comparing with the contrastive group while injecting with $400{\mu}g/ml$ intensity; with $800{\mu}g/ml$, under 10% comparing with contrastive group; and with $1600{\mu}g/ml$, complete restrain. According to the above results, Whallakhyoleyng-dan plus Yinsamyangwui-tang was proved to have an anti-angiogenetic effects.

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Anti-cancer effect of glabridin by reduction of extracellular vesicles secretion in MDA-MB-231 human breast cancer cells (유방암세포에서 세포외 소포체 분비 감소를 통한 glabridin의 항암효과)

  • Choi, Sang-Hun;Hwang, Jin-Hyeon;Baek, Moon-Chang;Cho, Young-Eun
    • Journal of Nutrition and Health
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    • v.55 no.2
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    • pp.240-249
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    • 2022
  • Purpose: Glabridin (GD) is a bio-available isoflavane isolated from the root extract of licorice (Glycyrrhiza glabra L.). It exhibits a variety of pharmacological activities such as anti-inflammatory and anti-oxidant activities. However, extracellular vesicles (EVs) secretion and the anti-cancer mechanism of action remains largely unknown. The present study investigates the anticancer effects of GD by determining the inhibition of EVs secretion in the human breast cancer cell line, MDA-MB-231. Methods: Cell viability, reactive oxygen species (ROS) production, migration, invasion rate, and vascular endothelial growth factor (VEGF) concentration were assessed in MDA-MB-231 cells treated with increasing concentrations of GD (0.1, 1, 5, 10, 20 µM). Subsequently, EV secretion and exosomal DEL-1 protein expression were evaluated to determine the anticancer effects of GD. Results: The results showed that GD significantly inhibited the cell proliferation of MDA-MB-231 cells in a dose- or time-dependent manner. Also, ROS production and apoptosis marker protein cleaved caspase-3 were significantly increased in GD-treated MDA-MB-231, compared to control. Furthermore, GD exposure resulted in significantly decreased not only migration and invasion rates but also the VEGF concentration, thereby contributing to a reduction in angiogenesis. Interestingly, the concentration and number of EVs as well as EV marker proteins, such as CD63 and TSG101, were decreased in GD-treated MDA-MB-231 cells. Markedly, extracellular matrix protein DEL-1 as angiogenesis factor was decreased in EVs from GD-treated MDA-MB-231 cells. Conclusion: This study identifies that the anti-cancer molecular mechanism of GD is exerted via inhibition of angiogenesis and EVs secretion, indicating the potential of GD as a chemotherapeutic agent for breast cancer.

Gelastatins, New Inhibitors of Matrix Metalloproteinases from Westerdykella multispora F50733

  • Lee, Ho-Jae;Chung, Myung-Chul;Lee, Choong-Hwan;Chun, Hyo-Kon;Rhee, Joon-Shick;Kho, Yung-Hee
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 1998.11a
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    • pp.128-128
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    • 1998
  • Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases that degrade extracellular matrix and basement membrane. These enzymes are play important roles in tumor cell invasion and metastasis, as well as angiogenesis and other connective tissue diseases. In our screening program for inhibitors of MMP-2 from fungal metabolites, we have isolated novel non-peptidic inhibitors of MMPs, designated gelastatin A and B from the culture broth of Westerdykella multispora F50733. The structures of gelastatin A and B were determined to be 3-(5E-hexa-2E,4E-dienylidene-2-oxo-5,6-dihydro-2H-pyran-3yl)-propanoic acid and 3-(5Z-hexa-2E,4E-dienylidene-2-oxo-5,6-dihydro-2H-pyran-3yl)-propanoic acid, respectively. Gelastatin A and B exist as a mixture of two stereoisomers in a ratio of 2: 1. The 2: 1 mixture of gelastatin A and B inhibited activated MMP-2 and MMP-9 with an IC$\sub$50/ value of 0.63, 5.29 ${\mu}$M, respectively. They inhibited the invasion of B16F10 melanoma cells through basement membrane Matrigel with dose dependent.

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Antitumor Effect of Schizandrin by Inhibiting Angiogenesis (Schizandrin의 신혈관형성억제에 의한 항암효과)

  • Yoon, Mi So;Kim, Do Yoon;Yu, Ho Jin;Park, Joo-Hoon;Jang, Sang Hee;Won, Kyung-Jong;Kim, Bokyung;Lee, Hwan Myung
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.26 no.5
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    • pp.687-692
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    • 2012
  • Schizandra chinensis extract has been known to possess a variety of efficacy including antitumor. However, it remains unclear how schizandrin, which is a major biological active ingredient of Schizandra chinensis, exerts antitumor effect. This study was designed to investigate the mechanism by which schizandrin inhibits tumor growth and metastasis. In in vivo test using tumor model mice injected with B16BL6 cell line, mice treated with 10 and 100 ${\mu}g/ml$ schizandrin showed a significant inhibition by $73.79{\pm}6.43%$ and $90.46{\pm}1.72%$, respectively, compared with positive tumor controls. Schizandrin did not exert a significant toxicity for the normal cells (HUVECs) and tumor cell lines (A549, B16BL6, Du145, Huh7). Treatment with schizandrin at 10 and 100 ${\mu}g$/head significantly inhibited the tumor-induced angiogenesis by $68.04{\pm}32.21%$ and $103.8{\pm}34.99%$ compared with the positive control group, respectively. Using in vivo lung metastasis model, tumor metastasis assay revealed that 10 and 100 ${\mu}g$/head schizandrin significantly decreased the metastatic lung tumor by $37.51{\pm}8.15%$ and $75.53{\pm}4.38%$ compared with positive controls, respectively. On the other hand, schizandrin did not affect the adherence of B16BL6 cell line to extracellular matrix protein. These results demonstrate that schizandrin exerts inhibitory effect on tumor growth and metastasis by inhibiting angiogenesis. This study thus suggest that schizandrin may be a candidate molecule target for cancer drug development.

Study on Antiangiogenic and Antitumor Activities of Processed Rhus verniciflua Stokes extract (법제 옻나무 추출물의 혈관형성저해 및 항암효과에 관한 연구)

  • Choi, Won-Cheol;Lee, Jae-Ho;Lee, Eun-Ok;Lee, Hyo-Jung;Yoon, Sung-Woo;Ahn, Kyoo-Seok;Kim, Sung-Hoon
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.20 no.4
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    • pp.825-829
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    • 2006
  • Rhus verniciflua Stokes has been used for treatment of blood stasis and abdominal mass in Oriental medicine. Rhus verniciflua Stokes has been experimentally reported to exert antioxidant, antiproliferative, antithrombotic and apoptotic activities. In the present study, the antiangiogenic and in vivo antitumor activities of aqueous extract of processed Rhus verniciflua Stokes (Nexia) by heat were examined to elucidate its anticancer mechanism. Nexia showed weak cytotoxiicty against human umbilical vein endothelial cells (HUVEC) and Lewis lung carcinoma cells (LLC) with IC50 of${\sim}200\;{\mu}g/ml\;and\;>200\;{\mu}g/ml$, respectively. Nexia significantly inhibited the proliferation and migratory activity in vascular endothelial growth factor(VEGF) treated HUVEC. Furthermore, Nexia effectively suppressed the tumor volume in A549 nonsmall lung cancer bearing athymic nude mice, CanN. Cg-Foxn 1nu/CrljBgi up to 40.7% as well as tumor weight incised from LLC cells innoculated into the flank of C57BL/6 mice up to -50% compared with untreated control at a dose of 300 mg/kg. Taken together, these results suggest that processed Rhus verniciflua Stokes may inhibit the growth of Lewis lung carcinoma cells partly via inhibition of angiogenesis and can be potently applied to angiogenesis dependent cancers. However, it still needs a further research on molecular mechanism, angiogenesis animal study and clinical trial in future.

Delphinidin Suppresses Angiogenesis via the Inhibition of HIF-1α and STAT3 Expressions in PC3M Cells (전립선 암세포에서 delphinidin에 의한 HIF-1α와 STAT3 억제를 통한 혈관내피 성장 인자 발현 저해 효과)

  • Kim, Mun-Hyeon;Kim, Mi-Hyun;Park, Young-Ja;Chang, Young-Chae;Park, Yoon-Yub;Song, Hyun-Ouk
    • Korean Journal of Food Science and Technology
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    • v.48 no.1
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    • pp.66-71
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    • 2016
  • Delphinidin is a blue-red pigment and one of the major anthocyanins in plants. It plays an important role in anti-oxidant, anti-inflammatory, anti-mutagenic and anti-cancer properties. In this study, we investigated the inhibitory effects of delphinidin on vascular endothelial growth factor (VEGF) gene expression, an important factor involved in angiogenesis and tumor progression in human prostate cancer. Delphinidin decreased levels of epidermal growth factor (EGF)-induced VEGF mRNA expression in PC-3M cells. The expression of the EGF-induced hypoxia inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) and signaling transducer and activator of transcription 3 (STAT3) proteins, which are the major transcription factors for VEGF, were inhibited by delphinidin. In addition, delphinidin decreases HRE-promoter reporter gene activity, suggesting that delphinidin can suppress the transcription of HIF-$1{\alpha}$ under EGF induction, leading to a decrease in the expression of VEGF. Delphinidin specifically suppressed the phosphorylation of Akt, p70S6K, and 4EBP1, but not the phosphorylation of EGFR. Therefore, our results suggest that delphinidin may inhibit human prostate cancer progression and angiogenesis by inhibiting HIF-$1{\alpha}$, STAT3 and VEGF gene expression.