• Biomolecules & Therapeutics
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• v.22 no.1
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• pp.1-9
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• 2014

Vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) system has been shown to play central roles not only in physiological angiogenesis, but also in pathological angiogenesis in diseases such as cancer. Based on these findings, a variety of anti-angiogenic drugs, including anti-VEGF antibodies and VEGFR/multi-receptor kinase inhibitors have been developed and approved for the clinical use. While the clinical efficacy of these drugs has been clearly demonstrated in cancer patients, they have not been shown to be effective in curing cancer, suggesting that further improvement in their design is necessary. Abnormal expression of an endogenous VEGF-inhibitor sFlt-1 has been shown to be involved in a variety of diseases, such as preeclampsia and aged macular degeneration. In addition, various factors modulating angiogenic processes have been recently isolated. Given this complexity then, extensive studies on the interrelationship between VEGF signals and other angiogenesis-regulatory systems will be important for developing future strategies to suppress diseases with an angiogenic component.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4823-4826
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• 2012

Objective: To explore serum angiogenic factor expression in patients with osteosarcoma and its relationship with metastasis. Methods: Immunohistochemistry was used to test the expression of CD34 and FVIII-Rag in osteosarcoma tissues of 36 patients (osteosarcoma group) and microvessel density (MVD) was also recorded. In addition, ELISA was used to test the level of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-${\beta}1$ (TGF-${\beta}1$) and endostatin (ES) in the osteosarcoma group and in a control group. Results: VEGF and ES level were significantly higher than in the control group before operation (P<0.01), VEGF, bFGF and TGF-${\beta}1$ correlating with the ES level (P<0.01). Serum VEGF and ES levels of osteosarcoma patients before surgery were closely related to relapse and metastasis; moreover, serum VEGF increased with MVD (P<0.01). Postoperative VEGF and ES levels were lower than the preoperation values (P<0.01); ES level in relapse group was significantly higher than that of the non-relapse group (P<0.01). Conclusion: Preoperative serum VEGF and postoperative ES levels have great predictive value with regard to relapse of osteosarcoma patients.

• Journal of Acupuncture Research
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• v.22 no.2
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• pp.171-180
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• 2005

Background & Objective : Angiogenesis consists of the proliferation, migration, and differentiation of endothelial cells, and angiogenic factors and matrix protein interactions modulate this process. The aim of this study was to determine whether Puerariae radix could induce angiogenic activity in human umbilical vein endothelial cells (HUVECs). Methods: The angiogenic activity of Puerariae radix were evaluated by using BrdU assay, chemotactic migration assay, tube formation assay, measurement of bFGF in HUVECs, and Matrigel plug assay in mice. Results : Puerariae radix significantly increased HUVECs proliferation in a dose-dependent manner. In addition, Puerariae radix increased migration and tube-like formation in HUVECs. Interestingly,the expression of basic fibroblast growth factor (bFGF), an angiogenesis-stimulating growth factor, was dose-dependently increased by Puerariae radix. The angiogenic activity of Puerariae radix was confirmed using an in vivo Matrigel angiogenesis model, showing promotion of blood vessel formation. Conclusion : Puerariae radix significantly induces angiogenesis in vitro and in vivo. These results suggest that Puerariae radix is a potent angiogenic agent, and a promising drug, for the induction of neovascularization.

• Biomolecules & Therapeutics
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• v.31 no.4
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• pp.456-465
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• 2023

Cervical tumors represent a prevalent form of cancer affecting women worldwide; current treatment options involve surgery, radiotherapy, and chemotherapy. Angiogenesis, the process of new blood vessel formation, is a crucial factor in cervical tumor growth. The molecular mechanisms underlying the effects of the liver kinase B1 (LKB1/STK11) tumor suppressor protein on tumor angiogenesis have not been elucidated. Therefore, we investigated the role of LKB1 in cervical tumor angiogenesis both in vitro and in vivo in this study. Our results demonstrated that LKB1 inhibited cervical tumor angiogenesis by suppressing the expression of angiogenesis-related factors such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α. LKB1 directly affected both carcinoma and vascular endothelial cells, resulting in a significant reduction in tumor growth and angiogenesis. Furthermore, LKB1 was found to bind to VEGF receptor 2 (VEGFR-2) and target the VEGFR-2-mediated protein kinase B/mechanistic target of rapamycin signaling pathway in endothelial cells, thereby reducing cervical tumor growth and angiogenesis. Our study provides new insights into the molecular mechanisms underlying the anti-tumor and anti-angiogenic effects of LKB1 in cervical cancer. These findings will help develop new therapeutic strategies for cervical cancer.

• Biomolecules & Therapeutics
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• v.27 no.1
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• pp.117-125
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• 2019

Mebendazole (MBZ), a microtubule depolymerizing drug commonly used for the treatment of helminthic infections, has recently been noted as a repositioning candidate for angiogenesis inhibition and cancer therapy. However, the definite anti-angiogenic mechanism of MBZ remains unclear. In this study, we explored the inhibitory mechanism of MBZ in endothelial cells (ECs) and developed a novel strategy to improve its anti-angiogenic therapy. Treatment of ECs with MBZ led to inhibition of EC proliferation in a dose-dependent manner in several culture conditions in the presence of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) or FBS, without selectivity of growth factors, although MBZ is known to inhibit VEGF receptor 2 kinase. Furthermore, MBZ inhibited EC migration and tube formation induced by either VEGF or bFGF. However, unexpectedly, treatment of MBZ did not affect FAK and ERK1/2 phosphorylation induced by these factors. Treatment with MBZ induced shrinking of ECs and caused G2-M arrest and apoptosis with an increased Sub-G1 fraction. In addition, increased levels of nuclear fragmentation, p53 expression, and active form of caspase 3 were observed. The marked induction of autophagy by MBZ was also noted. Interestingly, inhibition of autophagy through knocking down of Beclin1 or ATG5/7, or treatment with autophagy inhibitors such as 3-methyladenine and chloroquine resulted in marked enhancement of anti-proliferative and pro-apoptotic effects of MBZ in ECs. Consequently, we suggest that MBZ induces autophagy in ECs and that protective autophagy can be a novel target for enhancing the anti-angiogenic efficacy of MBZ in cancer treatment.

• BMB Reports
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• v.41 no.4
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• pp.278-286
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• 2008

Angiogenesis, the formation of blood vessels, is essential for preparing a closed circulatory system in the body, and for supplying oxygen and nutrition to tissues. Major diseases such as cancer, rheumatoid arthritis, and atherosclerosis include pathological angiogenesis in their malignant processes, suggesting anti-angiogenic therapy to be a new strategy for suppression of diseases. However, until the 1970s, the molecular basis of angiogenesis was largely unknown. In recent decades, extensive studies have revealed a variety of angiogenic factors and their receptors, including vascular endothelial growth factor (VEGF)-VEGFRs, Angiopoietin-Tie, Ephrin-EphRs and Delta-Notch to be the major regulators of angiogenesis in vertebrates. VEGF and its receptors play a central role in physiological as well as pathological angiogenesis, and functional inhibitors of VEGF and VEGFRs such as anti-VEGF neutralizing antibody and small molecules that block the tyrosine kinase activity of VEGFRs have recently been approved for use to treat patients with colorectal, lung, renal and liver cancers. These drugs have opened a novel field of cancer therapy, i.e. anti-angiogenesis therapy. However, as yet they cannot completely cure patients, and cancer cells could become resistant to these drugs. Thus, it is important to understand further the molecular mechanisms underlying not only VEGF-VEGFR signaling but also the VEGF-independent regulation of angiogenesis, and to learn how to improve anti-angiogenesis therapy.

• BMB Reports
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• v.40 no.3
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• pp.439-443
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• 2007

Tumor growth and metastasis are dependent on angiogenesis, and endothelial cell invasion and migration are apparent means of regulating tumor progression. We report here that saxatilin, a snake venom-derived disintegrin, suppresses the angiogenesis-inducing properties of NCI-H460 human lung cancer cells. Culture supernatants of NCI-H460 cells are able to induce human umbilical vascular endothelial cell (HUVEC) invasion and tube formation. However, treatment of the cancer cells with saxatilin resulted in reduced angiogenic activity of the culture supernatant. This suppressed angiogenic property was found to be associated with the level of vascular endothelial growth factor (VEGF) in the culture supernatant. Further experimental evidence indicated that saxatilin inhibits VEGF production in NCI-H460 cells by affecting hypoxia induced factor-1$\alpha$ (HIF-1$\alpha$) expression via the Akt pathway.

• Journal of Physiology & Pathology in Korean Medicine
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• v.26 no.4
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• pp.437-440
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• 2012

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that Cryptotanshione(CT), a tanshinone from oriental traditional medicinal herb Danshen (Salvia miltiorrhiza Bunge), had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells. CT inhibited the protein expression of hypoxia-inducible factor-1alpha (HIF-$1{\alpha}$) under hypoxic condition. Consistently, CT blocked hypoxia-induced phosphorylation and nuclear accumulation of STAT3. In addition, CT reduced cellular of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Of note, chromatin immunoprecipitation (ChiP) assay revealed that CT inhibited binding of STAT3 to VEGF promoter. Taken together, our results suggest that CT has anti-angiogenic activity by disturbing the binding STAT3 to the VEGF promoter in PC-3 cells.

• Korean Journal of Microbiology
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• v.44 no.4
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• pp.282-288
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• 2008

Tissue ischemia resulting from the constriction or obstruction of blood vessels leads to an illness that may affect many organs including the heart, brain, and legs. In recent years, considerable progress has been made in the field of therapeutic angiogenesis and the new approaches are expected to cure those "no-option patients" who are unsuited to conventional therapies. Although single angiogenic growth factor may be successful in inducing angiogenesis, combination of multiple growth factors is increasingly sought these days to augment the therapeutic responses. This trend is proper in light of the fact that blood vessel formation is a complex and multi-step process that requires the actions of many different factors. To meet the growing need for functionally significant blood flow recovery in the ischemic tissues, a novel strategy that can provide concerted actions of multiple factors is required. One way to achieve such a goal is to use a transcription factor that can orchestrate the expression of multiple target genes in the ischemic region and thus induce significant level of angiogenesis. Here, a putative transcription factor, cardiac ankyrin repeat protein (CARP), was evaluated in adenoviral vector context for angiogenic activity in human umbilical vein endothelial cells. The results indicated significant increase in proliferation, capillary-like structure formation, and induction of vascular endothelial growth factor, a typical angiogenic gene. Taken together, these results suggest that CARP represents itself as a novel target for therapeutic angiogenesis and warrants further investigation.

• 대한임상약리학회:학술대회논문집
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• 1994.12a
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• pp.31-31
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• 1994