• BMB Reports
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• 제39권5호
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• pp.469-478
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• 2006

Vascular endothelial growth factor (VEGF)-A, a major regulator for angiogenesis, binds and activates two tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). These receptors regulate physiological as well as pathological angiogenesis. VEGFR2 has strong tyrosine kinase activity, and transduces the major signals for angiogenesis. However, unlike other representative tyrosine kinase receptors which use the Ras pathway, VEGFR2 mostly uses the Phospholipase-$C{\gamma}$-Protein kinase-C pathway to activate MAP-kinase and DNA synthesis. VEGFR2 is a direct signal transducer for pathological angiogenesis including cancer and diabetic retinopathy, thus, VEGFR2 itself and the signaling appear to be critical targets for the suppression of these diseases. VEGFR1 plays dual role, a negative role in angiogenesis in the embryo most likely by trapping VEGF-A, and a positive role in adulthood in a tyrosine kinase-dependent manner. VEGFR1 is expressed not only in endothelial cells but also in macrophage-lineage cells, and promotes tumor growth, metastasis, and inflammation. Furthermore, a soluble form of VEGFR1 was found to be present at abnormally high levels in the serum of preeclampsia patients, and induces proteinurea and renal dysfunction. Therefore, VEGFR1 is also an important target in the treatment of human diseases. Recently, the VEGFR2-specific ligand VEGF-E (Orf-VEGF) was extensively characterized. Interestingly, the activation of VEGFR2 via VEGF-E in vivo results in a strong angiogenic response in mice with minor side effects such as inflammation compared with VEGF-A, suggesting VEGF-E to be a novel material for pro-angiogenic therapy.

• 생물정신의학
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• 제14권4호
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• pp.232-240
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• 2007

목 적: Cytokine 중의 하나인 vascular endothelial growth factor(VEGF)와 VEGF 수용체들은 다양한 생체내 조절 및 질병 상태와 연관이 있음이 알려져 있다. 본 연구는 정신분열병 환자에서 항정신병약물 치료에 따른 혈청내 자유(free) VEGF와 가용성 VEGFR-1, 가용성 VEGFR-2의 변화를 보기 위한 것이었다. 방 법: 각 환자들은 DSM-IV 진단기준에 의해 정신분열병으로 진단을 받았고, 약물투여 시작일을 기준으로 4주째 및 8주째에 추적 관찰하였다. 모두 13명이 환자군에 포함되었으며 항정신병약물 투여전과 투여후 4주째, 8주째에 각각 PANSS에 의한 상태 평가와 함께 자유 VEGF, sVEGFR-1, sVEGFR-2의 농도를 측정하였다. 13명의 정상 대조군을 환자군의 나이와 성별에 맞춰 선정하였다. 결 과: 정신분열병 환자군의 혈청 자유 VEGF($295.2{\pm}43.7$pg/ml)와 sVEGFR-2($8259{\pm}336.7$)의 농도는 정상 대조군($199.0{\pm}28.8$ 및 $8481{\pm}371.9$)과 비교하였을 때 의미있는 차이를 보이지 않았다. 그러나 sVEGFR-1의 농도($86.2{\pm}10.3$, p<0.05)는 정신분열병 환자군에서 대조군($59.0{\pm}6.4$)에 비해 의미있게 상승하였다. 정신분열병 환자군에서 항정신병약물 투여 후 자유 VEGF 농도는 4주째($338.9{\pm}56.5$)와 8주째($309.5{\pm}58.7$) 모두 투여 전과 비교하여 차이가 없었다. 그러나 sVEGFR-1 농도는 약물 치료후 8주째($57.3{\pm}6.3$, p<0.05)에 측정한 결과에서 유의하게 감소하였다. sVEGFR-2의 농도도 치료전과 비교하였을때 약물 치료후 4주째($7761{\pm}403.0$, p<0.05)와 8주째($7435{\pm}333.5$, p<0.05) 모두 유의하게 감소하였다. 결 론: sVEGFR-1과 sVEGFR-2 농도의 감소는 항정신병약물이 작용하는 도파민 신경계와 관련된 것으로 추정된다.

• 생명과학회지
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• 제34권2호
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• pp.128-137
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• 2024

이 리뷰 논문에서는 혈관 투과성, 내피세포 모집, 종양관련 혈관 및 림프관의 유지 등에서 핵심적인 과정인 angiogenesis와 lymphangiogenesis에 있어서 vascular endothelial growth factors (VEGF)가 이행하는 중요한 역할에 대해 재조명하고자 한다. VEGF는 tyrosine-kinase receptor인 VEGFR-1, VEGFR-2, VEGFR-3를 통해 그 역할을 이행하며, 이러한 VEGF-VEGFR 시스템은 암에서뿐만 아니라 비정상적인 혈관 및 림프관 형성으로 인해 야기되는 다른 질병들에 있어서도 핵심적인 요소로 각광받고 있다. 암의 측면에서 보았을 때, VEGF와 그 수용체는 종양관련 혈관 및 림프관을 형성하는 과정에서 필수적이라는 점에서 치료적인 타겟으로 이목을 끌고 있다. 때문에 암세포의 성장을 방해하기 위한 항VEGF 항체, 수용체 길항체, 수용체 기능 억제제 등과 같은 여러 가지 시도들이 있었지만, 아직까지 그 임상효과가 불확실하며 더 많은 연구들이 필요한 실정이다. 이 논문에서는 VEGF의 생리적 역할을 VEGF-A, VEGF-B, VEGF-C, VEGF-D, PLGF에 따라 나누어 설명하면서 VEGF/VEGFR 시스템의 중요성을 강조한다. VEGFR-1과 VEGFR-3은 각각 angiogenesis와 lymphangiogenesis에 핵심적인 인자이며, VEGFR-2의 경우 두 가지 모두를 일으킨다. 전반적으로 이 리뷰는 현재까지 밝혀진 암을 포함한 다양한 질병에서의 VEGF와 VEGFR의 역할에 대해 상세히 설명하고자 하였다. 이를 통해 치료 표적으로서 VEGF와 VEGFR의 활용이 더욱 촉진될 것으로 기대된다.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제33권1호
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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.

• Asian Pacific Journal of Cancer Prevention
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• 제17권4호
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• pp.2217-2221
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• 2016

Vascular endothelial growth factor 2 (VEGFR2) was initially identified as a receptor of VEGF on endothelial cells with a role in regulating angiogenesis during organism development and tumorigenesis. Previously, in cancer tissue, VEGFR2 has been reported to be expressed in endothelial cells. In our research, we found that VEGFR2 was expressed not only in endothelial cells but also cancer cells in head and neck squamous cell carcinomas (HNSCCs). Knockdown of VEGFR2 in Hep2 cells could arrest the cell cycle in G0/G1, leading to a decrease in proliferation. We also present evidence that MAPK/ERK signal pathways and expression of CDK1 downstream of VEGFR2 might regulate proliferation and cell cycle arrest. Furthermore, we discovered that down-regulate VEGRF2 in Hep2 cells could significantly affect the invasion ability. Taken together, our data suggest that VEGFR2 might regulate proliferation and invasion in HNSCC cancer cells in vivo.

• Journal of Microbiology and Biotechnology
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• 제25권8호
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• pp.1227-1233
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• 2015

Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis through binding to its specific receptors, which mainly occurs to VEGF receptor 2 (VEGFR-2), a kinase insert domain-containing receptor. Therefore, the disruption of VEGFR-2 signaling provides a promising therapeutic approach for the treatment of cancer by inhibiting abnormal or tumorinduced angiogenesis. To explore this potential, we expressed the catalytic domain of VEGFR-2 (VEGFR-2-CD) as a soluble active kinase in Escherichia coli. The recombinant protein was purified and the VEGFR-2-CD activity was investigated. The obtained VEGFR-2-CD showed autophosphorylation activity and phosphate transfer activity comparable to the commercial enzyme. Furthermore, the IC₅₀ value of known VEGFR-2 inhibitor was determined using the purified VEGFR-2-CD. These results indicated a possibility for functional and economical VEGFR-2-CD expression in E. coli to use for inhibitor screening.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제28권3호
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• pp.193-201
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• 2006

Squamous cell carcinoma(SCC) of head and neck(SCCHN) is the sixth most common human malignant tumor. However, despite advances in prevention and treatment of SCC, the five-year survival rates for patients remain still low. To improve the outcome for patients with SCCHN, novel treatment strategies are needed. Overexpression of the epidermal growth factor(EGF) and activation of its receptor(EGFR) are associated with progressive growth of SCCHN. Vascular endothelial growth factor(VEGF) signaling molecules are related with neoangiogenesis and vascular metastasis of SCC. In this study, we determined the therapeutic effect of AEE788(Novartis Pharma AG, Basel, Switzerland), which is a dual inhibitor of EGFR/ErbB2 and VEGFR tyrosine kinases, on human oral SCC. At first, we screened the expression of EGFR, c-ErbB2(HER-2) and VEGFR-2 in a series of human oral SCC cell lines. And then we evaluated the effects of AEE788 on the phosphorylation of EGFR and VEGFR-2 in a oral SCC cell line expressing EGFR/HER-2 and VEGFR-2. We also evaluated the effects of AEE788 alone, or with paclitaxel(Taxol) on the oral SCC cell growth and apoptosis. As a result, all oral SCC cells expressed EGFR and VEGFR-2. Treatment of oral SCC cells with AEE788 led to dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation, growth inhibition, and induction of apoptosis. Moreover, AEE788 sensitizes the cells to paclitaxel-mediated toxicity and apoptosis. These data mean EGFR and VEGFR-2 can be reliable targets for molecular therapy of oral SCC, and therefore warrant clinical use of EGFR/VEGFR inhibition in the treatment of patients with recurrent or metastatic oral SCC.

• Bulletin of the Korean Chemical Society
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• 제30권9호
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• pp.2083-2086
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• 2009

Human vascular endothelial growth factor receptor 2 (hVEGFR2) is an important signaling protein involved in angiogenesis and attractive drug target in cancer therapy. It has been reported that flavonols, a class of flavonoids, have anti-angiogenic activity in various cancer cell lines. We performed receptor-oriented pharmacophore based in silico screening for identification of hVEGFR2 inhibitors from flavonol database. By comparing with three X-ray complex structures of hVEGFR2 and its inhibitors, we evaluated the specific interactions between inhibitors and receptors and determined a single pharmacophore map. This map consisted of four features, a hydrogen bonding acceptor (HBA) on Cys917, two hydrogen bonding donors on Glu917 (HBD1) and Glu883 (HBD2), and one hydrophobic interaction (Lipo) with Val846, Ala864, Val897, Val914 and Phe1045 of hVEGFR2. Using this map, we searched a flavonol database including 9 typical flavonols and proposed that five flavonols, kaempferol, quercetin, fisetin, morin, and rhamnetin can be potent inhibitors of hVEGFR2. 3-OH of C-ring and 4’-OH of B-ring of flavonols are the essential features for hVEGFR2 inhibition. This study will be helpful for understanding the mechanism of inhibition of hVEGFR2 by natural products.

• Bulletin of the Korean Chemical Society
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• 제33권6호
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• pp.1890-1894
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• 2012

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been implicated in the pathogenesis of rheumatoid arthritis, which is angiogenesis dependent. Antibody-based molecular imaging improves targeting, and antibody radiolabeling is useful for monitoring biological events $in$ $vivo$ $via$ PET or SPECT. We investigated the potential of molecular imaging to diagnose arthritis with VEGFR-2 $in$ $vivo$. The $^{123}I$-VEGFR-2 antibody was prepared by the iodogen tube method. The radioligand was injected into arthritic mice, and micro SPECT/CT was performed. The arthritic mice were examined by 4.7-T MRI and immunohistochemistry. The $^{123}I$-VEGFR-2 antibody showed high uptake in the arthritic region at 1 h postinjection on SPECT/CT but no uptake in the control animals after radioligand injection. In MR images, the arthritic tissue of the mice was correlated with regions labeled by the $^{123}I$-VEGFR-2 antibody. Immunohistochemical localization showed markedly increased expression of VEGFR-2 in the endothelial cells, fibroblasts, and macrophages of the arthritic mice.

• Asian Pacific Journal of Cancer Prevention
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• 제16권16호
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• pp.7089-7095
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• 2015

Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic option in the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately. Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has been associated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity. Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins. AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGNPC- 0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC.