• Molecules and Cells
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• v.38 no.6
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• pp.528-534
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• 2015

Hypoxia-inducible factor (HIF) is a key regulator of tumor growth and angiogenesis. Recent studies have shown that, BIX01294, a G9a histone methyltransferase (HMT)-specific inhibitor, induces apoptosis and inhibits the proliferation, migration, and invasion of cancer cells. However, not many studies have investigated whether inhibition of G9a HMT can modulate HIF-$1{\alpha}$ stability and angiogenesis. Here, we show that BIX01294 dose-dependently decreases levels of HIF-$1{\alpha}$ in HepG2 human hepatocellular carcinoma cells. The half-life of HIF-$1{\alpha}$, expression of proline hydroxylase 2 (PHD2), hydroxylated HIF-$1{\alpha}$ and von Hippel-Lindau protein (pVHL) under hypoxic conditions were decreased by BIX01294. The mRNA expression and secretion of vascular endothelial growth factor (VEGF) were also significantly reduced by BIX01294 under hypoxic conditions in HepG2 cells. BIX01294 remarkably decreased angiogenic activity induced by VEGF in vitro, ex vivo, and in vivo, as demonstrated by assays using human umbilical vein endothelial cells (HUVECs), mouse aortic rings, and chick chorioallantoic membranes (CAMs), respectively. Furthermore, BIX01294 suppressed VEGF-induced matrix metalloproteinase 2 (MMP2) activity and inhibited VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR-2), focal adhesion kinase (FAK), and paxillin in HUVECs. In addition, BIX01294 inhibited VEGF-induced formation of actin cytoskeletal stress fibers. In conclusion, we demonstrated that BIX01294 inhibits HIF-$1{\alpha}$ stability and VEGF-induced angiogenesis through the VEGFR-2 signaling pathway and actin cytoskeletal remodeling, indicating a promising approach for developing novel therapeutics to stop tumor progression.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.30 no.5
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• pp.400-405
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• 2004

Angiogenesis inhibition is major concern to cancer chemotherapy and many studies about compound inhibiting angiogenesis is in progression. The long-known preventive effect of plant-based diet on tumorigenesis and other chronic diseases is well documented. Especially soy extract, genistein, is known to be potent angiogenesis inhibitor and prevent development and progression of tumor. In the present study, the effect of angiogenesis on tumorigenesis and chemopreventive effect of genistein by angiogenesis inhibition in hamster buccal pouch oral carcinigenesis model induced by 7.12-dimethylbenza(a)nthracene (DMBA) was studied. Forty eight Syrian Golden young adult hamsters (150-200 gm) were divided into two groups. In control group, 0.5% DMBA in heavy mineral oil was applied to hamster buccal pouch three times a week and in experimental group, 0.1 mg of genistein is administered orally everyday in addition to DMBA application. The animals were euthanized from 2 weeks to 16 weeks with interval of 2 week. H&E staining and immunohistochemistry was performed to evaluate microvessel density by using factor VIII-related antigen and avidin-biotin technique. Microvessels per area was quantified and compared between control and experimental group statistically. The results were as follows. 1. Microvessel density was increased time dependently in both groups and especially the increase was significant from 12 weeks to 16 weeks. 2. When comparing both group, the experimental group showed significantly low microvessel density than control group in 12 weeks (p=0.043), 14 weeks (p=0.050), 16 weeks (p=0.037). Based on these results, it was concluded that genistein influenced oral carcinogenesis by angiogenesis inhibition.

• Journal of Korean Ophthalmic Optics Society
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• v.7 no.1
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• pp.39-43
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• 2002

This study was investigated the anti-angiogenic activities of Cnidium officinale Makino and Tabanus bovinus by using Chorioallantoic membrane (CAM) and rat cornea. First experiment, the fertilized chicken eggs were kept in a humidified egg incubator at $37^{\circ}C$. After 4 days incubation, about 3 ml of albumin was aspirated from eggs with an hypodermic needles through a small hole drilled at the narrow end of the eggs, and the shell membrane on the floor of the air sac was peeled away. Embryos with chorioallantois of 3~5 mm in diameter were employed for the assay of antiangiogenic activity. Retinoic acid was used as a positive control for this experiment. After 48 h of treatment. branching pattern of blood vessels below coverslip containing retinoic acid ($10{\mu}g/egg$) was dramatically decreased. A simiar angiogenic inhibition was observed in the CAM treated with $50{\mu}g/egg$ of Cnidium omcinale Makino and Tabanus bovinus extracts. Second experiment, rat corneal neovascularization was induced by suturing (one stitch) the cornea with 10-0 nylon, and terramycin was applied on the cornea for I week to prevent corneal inflammation. In the cornea of rats untreated with herbal extracts, numerous vessels were usually seen invading the cornea by day 2 or 3 after suture, and reaching the lesion area within 5~6 days. Corneal neovascularization was gradually increased and peaked at 3 weeks. In contrast to this, herbal extracts conspicuously inhibited the angiogenesis, Oral administration of herbal extracts (20 mg/kg body weight/day) for 4 weeks significantly inhibited the rat corneal angiogenesis induced by suture, and the length of blood vessels in herbal medicine-treated rat cornea was conspicuously lower than that in control animals. A similar phenomenon was also observed in the rat cornea treated with thalidomide (200 mg/kg body weight/day). These findings indicate the anti-angiogenic properties of Cnidium officinale Makino and Tabanus bovinus, suggesting that these properties may be one of the pharmacological mechanisms underlying the anti-tumor and anti-metastatic activities of herbal extracts tested in this study.

• ALGAE
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• v.29 no.4
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• pp.355-366
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• 2014

Fucoxanthin is known to be an effective cell proliferation inhibitor with anti-tumor and anti-angiogenic activities. However, there is a lack of data regarding the biological effects of cis isomers of fucoxanthin. To assess the potential therapeutic properties of 9'-cis-(6'R) fucoxanthin (FcA), and 13-cis and 13'-cis-(6'R) fucoxanthin complex (FcB) isolated from Sarggassum siliquastrum, we investigated their inhibitory effects on matrix metalloproteinases (MMPs) in phorbol 12-myristate 13-acetate (PMA)-induced human fibrosarcoma (HT1080) cells. FcA and FcB reduced MMP-2 and MMP-9 protein and mRNA levels, as well as the migration of these cells, in a dose-dependent manner. Additionally, FcA and FcB increased levels of MMPs inhibition factors such as tissue inhibitor of metalloproteinase-1. FcA and FcB significantly inhibited the transcriptional activity of nuclear factor ${\kappa}B$ (NF-${\kappa}B$) and by inhibiting c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases. Our results demonstrate that suppression of the NF-${\kappa}B$, JNK, and p38 signaling pathways may inhibit PMA-induced MMP-2 and MMP-9 activity. Therefore, FcA and FcB may be useful in noninvasive therapeutic strategies against fibrosarcoma metastasis.