• Journal of Microbiology and Biotechnology
• /
• v.16 no.12
• /
• pp.1904-1911
• /
• 2006

The cell-free extracts of 250 yeasts were screened for their in vitro anti-angiogenic activity, to develop a new cancer metastasis inhibitor. Saccharomyces cerevisiae K-7 was selected as the producer of the anti-angiogenic agent, because it had the highest anti-angiogenic activity. The anti-angiogenic agent was produced maximally from hydrolysates of Saccharomyces cerevisiae K-7, when the yeast was cultured in yeast extract-peptone-dextrose medium at 30$^{\circ}C$ for 24 h, and cell-free extracts were than digested with pepsin for 4 h at 37$^{\circ}C$. The anti-angiogenic agent was further purified by ultrafiltration, Sephadex G-25 gel permeation chromatography and reverse-phase HPLC, and the anti-angiogenic activity of the final purified preparation was 72.7% at 10 $\mu$M/egg. The purified anti-angiogenic agent was found to originate from the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) molecule of Saccharomyces cerevisiae K-7, and its peptide sequence was Val-Ser-Trp-Tyr-Asp-Asn-Glu-Tyr-Gly-Tyr-Ser-Thr-Arg-Val-Val-Asp. In the MTT assay, the shape of the HT-l 080 cell was clearly changed to a circular type at 0.2 mM purified anti-angiogenic agent. This result indicated that the growth of the HT-I080 cell was significantly inhibited at 0.2 mM of the purified anti-angiogenic agent. The MMP activity of the treated HT-l080 cells was not affected, evidenced by the gelatin zymography, indicating that the anti-angiogenic mechanism of the purified anti-angiogenic agent is not mediated through MMP activity.

• Archives of Pharmacal Research
• /
• v.24 no.5
• /
• pp.397-401
• /
• 2001

In the search for new naturally occurring angiogenic inhibitory we found that culture broths from two unidentified fungal strains exerted potent inhibitory activities on capillary-like tube formation of human umbilical vein endothelial cells (HUVEC) in vitro. Two active compounds were isolated by bioassay-guided separation and their structures were identified as gliotoxin (1) and its derivative methylthiogliotoxin (2) by spectroscopic analyses. These compounds significantly inhibited the migration of HUVEC assessed by in vitro wounding migration assay and exhibited at least 10 times more potent inhibition of proliferation of HUVECs as compared with that of cancer cell lines such as HeLa, MCF-7, and KB 3-1 cells. Especially, gliotoxin having disulfide group exerted more potent activities than methylthiogliotoxin, suggesting that gliotoxin could be a useful compound for further study as an anti-angiogenic agent.

• Bulletin of the Korean Chemical Society
• /
• v.26 no.4
• /
• pp.619-628
• /
• 2005

We attempted to replace a benzopyran ring of 4-[(N-imidazol-2-ylmethyl)-4-chloroanilino]benzopyran, previously discovered as anti-angiogenic agent with antitumor activity, with pyranopyridines. The [3,2-c]-, [3,2-b]-, [2,3-c]-, and [2,3-b]-pyranopyridines with -(imidazol-2-ylmethyl)aniline moiety at the 4-position, were synthesized respectively, and evaluated for primary anti-angiogenic properties through primary cultured HUVEC tube formation assay. From this study, we found that the pyranopyridine ring, especially [3,2-b]- and [2,3-c]-isomer, can replace the benzopyran ring of the compound 1 and can be optimized through the introduction of substituents both on the pyranopyridine ring and the aniline moiety for the identification of a novel anti-angiogenic agent.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.19 no.5
• /
• pp.1363-1369
• /
• 2005

Previously we have shown that shikonin has strong anti-tumor activities via inducing apoptosis and suppressing metastasis on LLC cells in vivo and in vitro. Here we have investigated anti-angiogenic potential of shikonin and its possible mechanism of action in HSE cells. Shikonin inhibited the proliferation of HSE cells in a concentration-dependent manner. It was shown that this proliferation inhibition was caused by apoptosis induced by shikonin via BrdU incorporation and Western blotting analysis. Shikonin treatment was caused that decrease of activation of caspases and cleavage of PARP. And shikonin induced that the activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38. Moreover, shikonin showed anti-angiogenic activities inhibiting tube-like formation of HSE cells in vitro and vascular formation of LLC cells in vivo. These findings suggest that shikonin may a possible candidate not only anti-metastatic agent but also anti-angiogenic agent.

• Journal of Microbiology and Biotechnology
• /
• v.32 no.3
• /
• pp.302-306
• /
• 2022

A chemical investigation of a culture extract from Streptomyces sp. RK85-270 led to the isolation and characterization of two new oxindoles, RK-270D (1) and E (2). The structures of 1 and 2 were determined by analyzing spectroscopic and spectrometric data from 1D and 2D NMR and High-resolution electrospray ionization mass spectrometry (HRESIMS) experiments. Compound 1 exhibited anti-angiogenic activities against human umbilical vein endothelial cells (HUVECs) without cytotoxicity. Results of Western blot analysis revealed that 1 inhibits VEGF-induced angiogenesis in the HUVECs via VEGFR2/ p38 MAPK-mediated pathway.

• Journal of Microbiology and Biotechnology
• /
• v.28 no.8
• /
• pp.1332-1338
• /
• 2018

In the course of studies to discover natural products with anti-angiogenic properties, two cyclic octapeptides, octaminomycins A (1) and B (2), were isolated from the cultures of Streptomyces sp. RK85-270. Octaminomycins suppressed the vascular endothelial growth factor (VEGF)-induced proliferation, adhesion, tube formation, migration, and invasion of HUVECs. Anti-angiogenic activity was futher confirmed in vivo by the chicken chorioallantoic membrane assay. We also identified that 1 and 2 inhibited the phosphorylation of VEGF receptor 2, AKT, and ERK1/2 and the expression and activities of MMP-2 and MMP-9. These results suggest that 1 and 2 may serve as potential scaffolds for the development of therapeutic agents to angiogenesis-dependent diseases.

• Archives of Pharmacal Research
• /
• v.25 no.4
• /
• pp.500-504
• /
• 2002

Propolis, obtained from honeybee hives, has been used in Oriental folk medicine as an anti-inflammatory, anti-carcinogenic, and immunomodulatory agent. There is considerable evidence suggesting that angiogenesis and chronic inflammation are codependent. Blockage of angiogenesis results in an anti-inflammatory effect. Ethanol (EEP) and ether extracts of propolis (REP), and caffeic acid phenethyl ester (CAPE), an active component of propolis, were examined for their anti-angiogenic activities using the chick embryo chorioallantoic membrane (CAM), and the calf pulmonary arterial endothelial (CPAE) cell proliferation, assays. The presence of EEP, REP and CAPE inhibited angiogenesis in the CAM assay and the proliferation of CPAE cells. The results suggest that anti-angiogenic activities of EEP, REP and CAPE are also responsible for their anti-inflammatory effect.

• Biomolecules & Therapeutics
• /
• v.29 no.5
• /
• pp.506-518
• /
• 2021

The imprinted tumour suppressor NOEY2 is downregulated in various cancer types, including ovarian cancers. Recent data suggest that NOEY2 plays an essential role in regulating the cell cycle, angiogenesis and autophagy in tumorigenesis. However, its detailed molecular function and mechanisms in ovarian tumours remain unclear. In this report, we initially demonstrated the inhibitory effect of NOEY2 on tumour growth by utilising a xenograft tumour model. NOEY2 attenuated the cell growth approximately fourfold and significantly reduced tumour vascularity. NOEY2 inhibited the phosphorylation of the signalling components downstream of phosphatidylinositol-3'-kinase (PI3K), including phosphoinositide-dependent protein kinase 1 (PDK-1), tuberous sclerosis complex 2 (TSC-2) and p70 ribosomal protein S6 kinase (p70S6K), during ovarian tumour progression via direct binding to vascular endothelial growth factor receptor-2 (VEGFR-2). Particularly, the N-terminal domain of NOEY2 (NOEY2-N) had a potent anti-angiogenic activity and dramatically downregulated VEGF and hypoxia-inducible factor-1α (HIF-1α), key regulators of angiogenesis. Since no X-ray or nuclear magnetic resonance structures is available for NOEY2, we constructed the three-dimensional structure of this protein via molecular modelling methods, such as homology modelling and molecular dynamic simulations. Thereby, Lys15 and Arg16 appeared as key residues in the N-terminal domain. We also found that NOEY2-N acts as a potent inhibitor of tumorigenesis and angiogenesis. These findings provide convincing evidence that NOEY2-N regulates endothelial cell function and angiogenesis by interrupting the VEGFR-2/PDK-1/GSK-3β signal transduction and thus strongly suggest that NOEY2-N might serve as a novel anti-tumour and anti-angiogenic agent against many diseases, including ovarian cancer.

• YAKHAK HOEJI
• /
• v.37 no.5
• /
• pp.532-537
• /
• 1993

Angiogenesis refers to the formation of new capillary blood vessels, or neovascularization occurring under various physical conditions, such as development of the embryo, formation of corpus luteum, wound healing and pathological conditions including tumor growth and metastases, hemangiomas, diabetic retinopathy, rheumatoid arthritis. There are many evidences that angiogenesis is important for the progressive growth of solid tumors and also permits the shedding of metastatic tumors from the primary site. Thus, treatment of angiogenesis inhibitors might be a novel strategy for tumor growth inhibition. Normal vascular endothelial cells are in a state of differentiation and angiogenic endothelial cells migrate and proliferate, and they subsequently differentiate into vessel-forming quiescent phenotype cells, Therfore, it was speculated that a modifier of cell differentiation could also affect angiogenesis. In order to identify new antiangiogenic factors, the research was conducted to estimate the inhibitory activities of cell differentiation agents by means of chick embryo chorioallantoic membrane(CAM) assay. Hence, we have established the CAM assay for the screening of antiangiogenic agents. Using the CAM assay, we found that ursolic acid, a tumor cell differentiation-inducing agent, showed a markedly inhibitory effect on chick embryonic angiogenesis.

• Bulletin of the Korean Chemical Society
• /
• v.33 no.9
• /
• pp.2925-2929
• /
• 2012