• Journal of Life Science
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• v.27 no.9
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• pp.1059-1063
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• 2017

Angiogenesis is an essential step in tumoral growth and metastasis and is regulated by a balance between stimulators and inhibitors. Recently, antiangiogenic target therapy has shown promise as a new type of chemotherapy. Natural products have attracted widespread attention worldwide as a useful source of novel therapeutic compounds. The balloon-flower has long been used as a traditional medicinal material and food in Asia. In this study, we investigated whether extract of balloon-flower would inhibit in vitro angiogenesis and vascular-like network formation in human umbilical vein endothelial cells (HUVECs). The extract of Balloon-flower did not affect the viability of HUVECs. However, treatment with the Balloon-flower extract suppressed tube formation of HUVECs. In addition, after treatment with the Balloon-flower extract, cell migration decreased about 80%, and cell invasion was almost completely inhibited. Taken together, these results suggest that extract of Balloon-flower may have potential as an angiogenic inhibitor and that it could be developed as an anticancer agent.

• 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.

• IMMUNE NETWORK
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• v.3 no.1
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• pp.38-46
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• 2003

Background: Platelet-activating factor (PAF) induces nuclear factor $(NF)-{\kappa}B$ activation and angiogenesis and increases tumor growth and pulmonary tumor metastasis in vivo. The role of $NF-{\kappa}B$ activation in PAF-induced angiogenesis in a mouse model of Matrigel implantation, and in PAF-mediated pulmonary tumor metastasis were investigated. Methods: Angiogenesis using Matrigel and experimental pulmonary tumor metastasis were tested in a mouse model. Electrophoretic mobility shift assay was done for the assessment of $NF-{\kappa}B$ translocation to the nucleus. Expression of angiogenic factors, such as tumor necrosis factor $(TNF)-{\alpha}$, interleukin $(IL)-1{\alpha}$, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) were tested by RT-PCR and ELISA. Results: PAF induced a dose- and time-dependent angiogenic response. PAF-induced angiogenesis was significantly blocked by PAF antagonist, CV6209, and inhibitors of $NF-{\kappa}B$ expression or action, including antisense oligonucleotides to p65 subunit of $NF-{\kappa}B$ (p65 AS) and antioxidants such as ${\alpha}$-tocopherol and N-acetyl-L-cysteine. In vitro, PAF activated the transcription factor, $NF-{\kappa}B$ and induced mRNA expression of $TNF-{\alpha}$, $IL-1{\alpha}$, bFGF, VEGF, and its receptor, KDR. The PAF-induced expression of the above mentioned factors was inhibited by p65 AS or antioxidants. Also, protein synthesis of VEGF was increased by PAF and inhibited by p65 AS or antioxidants. The angiogenic effect of PAF was blocked when anti-VEGF antibodies was treated or antibodies against $TNF-{\alpha}$, $IL-1{\alpha}$, and bFGF was co-administrated, but not by antibodies against $TNF-{\alpha}$, $IL-1{\alpha}$, and bFGF each alone. PAF-augmented pulmonary tumor metastasis was inhibited by p65 AS or antioxidants. Conclusion: These data indicate that PAF increases angiogenesis and pulmonary tumor metastasis through $NF-{\kappa}B$ activation and expression of $NF-{\kappa}B$-dependent angiogenic factors.

• Molecules and Cells
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• v.46 no.11
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• pp.675-687
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• 2023

Accumulation of pathogenic amyloid-β disrupts the tight junction of retinal pigment epithelium (RPE), one of its senescence-like structural alterations. In the clearance of amyloid-β, the autophagy-lysosome pathway plays the crucial role. In this context, mammalian target of rapamycin (mTOR) inhibits the process of autophagy and lysosomal degradation, acting as a potential therapeutic target for age-associated disorders. However, efficacy of targeting mTOR to treat age-related macular degeneration remains largely elusive. Here, we validated the therapeutic efficacy of the mTOR inhibitors, Torin and PP242, in clearing amyloid-β by inducing the autophagy-lysosome pathway in a mouse model with pathogenic amyloid-β with tight junction disruption of RPE, which is evident in dry age-related macular degeneration. High concentration of amyloid-β oligomers induced autophagy-lysosome pathway impairment accompanied by the accumulation of p62 and decreased lysosomal activity in RPE cells. However, Torin and PP242 treatment restored the lysosomal activity via activation of LAMP2 and facilitated the clearance of amyloid-β in vitro and in vivo. Furthermore, clearance of amyloid-β by Torin and PP242 ameliorated the tight junction disruption of RPE in vivo. Overall, our findings suggest mTOR inhibition as a new therapeutic strategy for the restoration of tight junctions in age-related macular degeneration.

• BMB Reports
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• v.57 no.4
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• pp.188-193
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• 2024

Gastric cancer (GC), a leading cause of cancer-related mortality, remains a significant challenge despite recent therapeutic advancements. In this study, we explore the potential of targeting cell surface glucose-regulated protein 94 (GRP94) with antibodies as a novel therapeutic approach for GC. Our comprehensive analysis of GRP94 expression across various cancer types, with a specific focus on GC, revealed a substantial overexpression of GRP94, highlighting its potential as a promising target. Through in vitro and in vivo efficacy assessments, as well as toxicological analyses, we found that K101.1, a fully human monoclonal antibody designed to specifically target cell surface GRP94, effectively inhibits GC growth and angiogenesis without causing in vivo toxicity. Furthermore, our findings indicate that K101.1 promotes the internalization and concurrent downregulation of cell surface GRP94 on GC cells. In conclusion, our study suggests that cell surface GRP94 may be a potential therapeutic target in GC, and that antibody-based targeting of cell surface GRP94 may be an effective strategy for inhibiting GRP94-mediated GC growth and angiogenesis.

• The Journal of Korean Medicine
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• v.22 no.2
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• pp.22-30
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• 2001

This study was attempted to investigate the anti-tumor and anti-metastatic effects of Sobokchukeotang(SBCT) and Kamisobokchukeotang(KSBCT). Cytotoxicity against various cancer cell lines, anti-adhesion, pulmonary colonization, anti-angiogenesis, and T/C% were evaluated. SBCT and KSBCT exhibited no cytotoxicity against HT-1080, A549, SK-OV-3, B16-F10 and SK-Mel-2 cell lines. In inhibitory effect on DNA topoisomerase I, the $IC_{50S}$ were shown $250-500{\;}\mu\textrm{g}/ml$ of SBCT and $62.5-125{\;}\mu\textrm{g}/ml$ of KSBCT respectively. In the in vivo experiments, SBCT(135.98%) and KSBCT(151.92%) apparently increased the life span of mice bearing sarcoma-180. KSBCT significantly inhibited the adhesion of HT-1080 to complex extracellular matrix in a dose-dependent manner in contrast to SBCT. In pulmonary colonization assay by B16-F10, a number of colonies in the lungs were decreased more significantly in KSBCT group than those in SBCT group. In vitro neovascularization and CAM assay, angiogenesis was more significantly inhibited in KSBCT-treated group than in SBCT- treated group. Above results suggests that KSBCT is more effectively applied to prevention and treatment of cancer than SBCT.

• Molecules and Cells
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• v.21 no.2
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• pp.213-217
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• 2006

Although AIMP1 (previously known as p43) is one of three auxiliary proteins bound to a macromolecular aminoacyl tRNA complex, it is also secreted as a cytokine controlling both angiogenesis and immune responses. Here we show that systemically administered purified recombinant human AIMP1 had anti-tumor activity in mouse xenograft models. In Meth A-bearing Balb/c mice, tumor volume increased about 28 fold in the vehicle treatment group, while an increase of about 16.7 fold was observed in the AIMP1-treated group. We also evaluated the anti-tumor activity of AIMP1 in combination with a sub-clinical dose of the cytotoxic anti-tumor drug, paclitaxel. The growth of NUGC-3 human stomach cancer cells was suppressed by 84% and 94% by the combinations of 5 mg/kg paclitaxel + 25 mg/kg AIMP1 (p = 0.03), and 5 mg/kg paclitaxel + 50 mg/kg AIMP1 (p = 0.02), respectively, while 5 mg/kg paclitaxel alone suppressed growth by only 54% (p = 0.02). A similar cooperative effect of AIMP1 and paclitaxel was observed in a lung cancer xenograft model. These results suggest that AIMP1 may be useful as a novel anti-tumor agent.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.20
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• pp.9039-9043
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• 2014

There is a continuing need for innovative alternative therapies for liver cancer. DNA vaccines for hormone/growth factor immune deprivation represent a feasible and attractive approach for cancer treatment. We reported a preventive effect of a DNA vaccine based on six copies of the B cell epitope GRP18-27 with optimized adjuvants against H22 hepatocarcinoma. Vaccination with pCR3.1-VS-HSP65-TP-GRP6-M2 (vaccine) elicited much higher level of anti-GRP antibodies and proved efficacious in preventing growth of transplanted hepatocarcinoma cells. The tumor size and weight were significantly lower (p<0.05) in the vaccine subgroup than in the control pCR3.1-VS-TP-HSP65-TP-GRP6, pCR3.1-VS-TP-HSP65-TP-M2 or saline subgroups. In addition, significant reduction of tumor-induced angiogenesis associated with intradermal tumors of H22 cells was observed. These potent effects may open ways towards the development of new immunotherapeutic approaches in the treatment of liver cancer.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.202.4-203
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• 2003

The present study was carried out to clarify whether isoflavonoids isolated from Belamcandae Rhizoma (Iridaceae) inhibit inflammation and angiogenesis by the experimental methods in vitro and in vivo. Among the isolated isoflavonoids, such as irigenin, irisflorentine, and iristectorene B inhibited nitric oxide (NO) production, as measured by nitrite formation at 3-30 ${\mu}M$. Also these compounds reduced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) enzyme expression in a concentration dependent manner, when measured by western blotting, at 3-30 ${\mu}M$. Irigenin, irisflorentine and iristectoren B decreased angiogenesis of chick embryos in the chorioallantoic membrane assay. These compounds also reduced the proliferation of calf pulmonary arterial endothelial (CPAE) cells and found to possess relatively weak gelatinase/collagenase inhibitory activity in vitro. These compounds, when administered subcataneously at the dose of 30mg/kg for 20 days to mice implanted with murine Lewis lung carcinoma (LLC), caused a significant inhibition of tumor volume. Therefore, antiangiogenic activities of isoflavonoids from Belamcandae Rhizoma might be due to antiproliferative activities under inhibition the induction of COX-2 and iNOS enzyme.

• 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.