• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제27권4호
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• pp.330-336
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• 2001

Angiogenesis is an essential process for the growth, invasion and metastasis of cancer. However, it is uncertain that antiangiogenic effects can be a major treatment strategy of oral cancer. The aim of this study was to investigate whether thalidomide, which is known to be a potent inhibitor of angiogenesis, have inhibitory effect on the growth and antiangiogenic effects of oral squamous cell carcinoma(OSCC) xenografted in nude mice and whether antiangiogenesis of thalidomide can be included as a major treatment strategy of oral cancer. After human oral squamous cell carcinoma strain KB was subcutaneously implanted in 20 nude mice, the volume of tumor was measured every three days. When the tumor mass reached $75{\sim}100mm^3$, thalidomide(200mg/kg/d) was administered into 10 experimental nude mice and the same volume of distilled water was administered into 10 control nude mice and the tumor volume was measured every three days. The excised tumor masses on the 30th day after administration were frozen and processed for immunohistochemistry using vascular endothelial growth factor(VEGF) and CD31. We evaluated microvessel density and VEGF expression. The results were as follows ; 1. Thalidomide retarded the growth of human OSCC as compared with the control group, but it was not statistically significant. 2. A statistically significant lower microvessel density was observed in the thalidomide-treated group than in the control group(p<0.01) and thalidomide significantly reduced VEGF expression (p<0.01). Thalidomide exhibited significantly antiangiogenic effect, but did not inhibit the growth of human OSCC effectively. Antiangiogenic therapy of thalidomide alone is not likely to be effective in the treatment of human OSCC, but might be regarded as adjuvant chemotherapeutic strategy.

• 생명과학회지
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• 제33권9호
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• pp.703-712
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• 2023

기존 혈관에서 새로운 혈관을 형성하는 혈관 신생은 혈관 신생 조절인자에 의해 조절되는 다단계 과정이며 배아 발달, 만성 염증 및 상처 복구를 포함한 다양한 생리학적 과정에 필수적이다. 혈관 신생의 조절장애는 암, 자가 면역 질환, 류마티스 관절염, 심혈관 질환 및 상처 치유 지연과 같은 많은 질병을 유발한다. 그러나 효과적인 혈관신생 억제 약물은 제한되어 있으며, 최근 연구에서는 천연 자원에서 잠재적인 약물후보를 식별하는 데 중점을 두고 있다. 예를 들어, 해양 천연물은 항암, 항산화, 항염증, 항바이러스 및 상처 치유 효과를 입증했다. 따라서 본 연구에서는 톳(갈조류) 추출물의 혈관 신생 억제 효과를 확인했습니다. H. fusiformis 추출물은 인간 제대 정맥 내피 세포(HUVECs)에서 세포 이동, 침윤 및 관 형성을 억제하며, 동시에 Matrigel 겔 플러그 분석을 통해 생체 내 혈관 신생을 억제를 확인했다. 또한, 톳 추출물 처리 후 VEGF, Erk, Akt의 활성이 감소하는 것을 확인했다. 이 결과를 토대로 H. fusiformis 추출물이 in vitro 및 in vivo 혈관 신생을 억제함을 시사한다.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.167-174
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• 2014

Tumor angiogenesis, growth and metastasis are three closely related processes. We therefore investigated the effects of barbigerone on all three in the B16F10 tumor model established in both zebrafish and mouse models, and explored underlying molecular mechanisms. In vitro, barbigerone inhibited B16F10 cell proliferation, survival, migration and invasion and suppressed human umbilical vascular endothelial cell migration, invasion and tube formation in concentration-dependent manners. In the transgenic zebrafish model, treatment with $10{\mu}M$ barbigerone remarkably inhibited angiogenesis and tumor-associated angiogenesis by reducing blood vessel development more than 90%. In vivo, barbigerone significantly suppressed angiogenesis as measured by H and E staining of matrigel plugs and CD31 staining of B16F10 melanoma tumors in C57BL/6 mice. Furthermore, it exhibited highly potent activity at inhibiting tumor growth and metastasis to the lung of B16F10 melanoma cells injected into C57BL/6 mice. Western blotting revealed that barbigerone inhibited phosphorylation of AKT, FAK and MAPK family members, including ERK, JNK, and p38 MAPKs, in B16F10 cells mainly through the MEK3/6/p38 MAPK signaling pathway. These findings suggested for the first time that barbigerone could inhibit tumor-angiogenesis, tumor growth and lung metastasis via downregulation of the MEK3/6/p38 MAPK signaling pathway. The findings support further investigation of barbigerone as a potential anti-cancer drug.

• 대한한방종양학회지
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• 제5권1호
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• pp.61-75
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• 1999

To examine the effect of Xuefuzhuyutang on the metastasis of cancer, the following experiments were carried out. Before the main experiments, the cytotoxicity was measured by putting Xuefuzhuyutant sample in HT1080. Then zymography was made to examine the change of gelatinolytic activity. Western blotting was carried out to examine the changes of Fos, Jun, Ets, Erk, md JNK. In vitro invasion assay with transwells coated by collagen and matrigel was carried out. From the above results the following conclusions were obtained. 1. The experimental result about cytotoxicity of Xuefuzhuyutang agaitst HT1080 was a below. The stained cell count after being treated by by Xuefuzhuyutang sample $400{\mu}g/ml$ for 24 hours was 0.9% of total cells, and the stained cell count by Xuefuzhuyutang sample $100{\mu}g/ml$ was 1.5% of total cells. Both were near the level of control group which showed 0.6% stained. 2. The result of collagenase assay was as below. In Xuefuzhuyutang sample $400{\mu}g/ml$, MMP2 was reduced as compared with TPA control group, and the band of MMP-9 induced by TPA disapappeared. In Xuefuzhuyutang samle $800{\mu}g/ml$ both bands of MMP-2 and MMP-9 disapeared. 3. The results of western blots for Jun, Fos, Ets, Erk, JNK were a below. In Xuefuzhuyutang sample $200{\mu}g/ml$, Ets was reduced, and Jun, Fos were increased. 4 The result of invasion assay was as below. The number of cells which migrated across transwell membrane in Xuefuzhuyutang-treated group was less than that of control(+TPA) group. From the above results, it was concluded that Xuefuzhuyutang might inhibit the activity of collagenase not by the MMP-2, MMP-9 promoter but by the other way.

• Asian Pacific Journal of Cancer Prevention
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• 제14권1호
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• pp.173-177
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• 2013

Backgrounds: Tanshinone IIA (TIIA), a phenanthrenequinone derivative extracted from Salvia miltiorrhiza BUNGE, has been reported to be a natural anti-cancer agent in a variety of tumor cells. However, the effect of TIIA on gastric cancer cells remains unknown. In the present study, we investigated the influence of TIIA on the malignant phenotype of SGC7901 gastric cancer cells. Methods: Cells cultured in vitro were treated with TIIA (0, 1, 5, $10{\mu}g/ml$) and after incubation for different periods, cell proliferation was measured by MTT method and cell apoptosis and cell cycling were assessed by flow cytometry (FCM). The sensitivity of SGC7901 gastric cancer cells to anticancer chemotherapy was investigated with the MTT method, while cell migration and invasion were examined by wound-healing and transwell assays, respectively. Results: TIIA (1, 5, $10{\mu}g/ml$) exerted powerful inhibitory effects on cell proliferation (P < 0.05, and P < 0.01), and this effect was time- and dose-dependent. FCM results showed that TIIA induced apoptosis of SGC7901 cells, reduced the number of cells in S phase and increased those in G0/G1 phase. TIIA also significantly increased the sensitivity of SGC7901 gastric cancer cells to ADR and Fu. Moreover, wound-healing and transwell assays showed that TIIA markedly decreased migratory and invasive abilities of SGC7901 cells. Conclusions: TIIA can reverse the malignant phenotype of SGC7901 gastric cancer cells, indicating that it may be a promising therapeutic agent.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제29권6호
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• pp.365-373
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• 2003

Tamoxifen is an selective estrogen receptor antagonist widely used in the management of patients with breast cancer for more than 30 years. It was thought to act primarily through occupying the estrogen receptor sites in ER positive breast cancer cells and directly on cancer cell proper. These inhibitory effects, which have been shown to be independent of the ER, highlight new mechanism of therapeutic action of tamoxifen. The purposes of this study were to identify ER in oral carcinoma cell lines and to evaluate ER independent cytotoxic effect of tamoxifen. KB(SCC), HSC-3(SCC) and A253(ACC) cell line were used and capacity of cell proliferation, apoptosis, in vitro invasion and gelatin zymography were tested. ER expression of each cell line were detected by RT-PCR and immunocytochemistry. Dose dependent inhibition of cell proliferation and inhibition of gelatinolytic activity were observed in all oral carcinoma cell lines and significant difference of apoptotic index were observed in A253 and KB. Tamoxifen inhibited in vitro invasion in all experimental groups. ER expression was detected in KB and A253. These data suggest that tamoxifen may play a role in management of oral carcinoma by independent cytotoxic effect and more advanced research must processed confirming ER-dependent cytotoxicity.

• 생명과학회지
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• 제19권9호
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• pp.1200-1208
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• 2009

Tight junctions (TJs)은 인접된 세포 사이의 전해질 및 거대분자 확산 조절에 관여하는 paracellular permeability의 장벽 역할을 한다. 본 연구에서는 MCF-7 및 MDA-MB-231 인체유방암세포에서 대두의 대표적인 생리활성물인 genistein에 의한 암세포의 침윤 억제에서 TJs의 견고성 및 투과성과의 연관성을 조사하였다. 본 연구의 결과에 의하면 genistein에 의한 유방암세포의 증식 억제, 암세포 이동성의 저하 및 침윤성의 억제는 TJs의 증가된 견고성과 연관이 있었으며, 이를 transepithelial electrical resistance의 증가 및 paracellular permeability의 감소로 확인하였다. Genistein은 두 유방암세포에서 TJs의 주요 조절 단백질로서 paracellular transport 조절에 중요한 역할을 하는 claudin-3 및 claudin-4의 발현을 억제시켰다. 그리고 genistein은 암세포의 전이 조절 관련 유전자들인 like growth factor-1 receptor 및 snail의 발현을 억제하였으며, thrombospondin-1 및 E-cadherin의 발현은 증가시켰다. 또한 small interfering RNA를 이용하여 genistein의 유방암세포의 침윤 억제에서 claudin-3단백질의 중요성을 확인하였다. 결론적으로 genistein이 TJs의 견고성 증가를 통하여 암세포의 침윤성을 억제할 수 있었으며, 이 과정에서 아마도 claudin 단백질의 발현 증가가 중요한 역할을 하고 있음을 알 수 있었다. 본 연구의 결과는 genistein이 종양 전이억제를 효과적으로 차단할 수 있음을 보여주는 것이다.

• 생명과학회지
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• 제20권2호
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• pp.275-280
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• 2010

Sulforaphane은 십자가화 채소에 존재하는 화합물로 항염증, 항암 및 신생혈관 생성의 억제 효과가 알려짐으로써 최근 많은 연구가 활발히 이루어지고 있으나, LPS에 의한 MMP-9 활성 조절에 대한 연구는 매우 미흡한 편이다. 따라서 본 연구에서 sulforaphane이 LPS 유도에 의한 MMP-9 활성에 미치는 영향에 대해서 조사해 보았다. Raw 264.7 세포에 sulforaphane을 전처리 한 후 LPS를 처리하여 gelatin zymography를 실시해 본 결과, LPS에 의해 유도된 MMP-9 활성 증가가 sulforaphane 농도 의존적으로 감소됨을 확인 하였다. 또한 RT-PCR과 MMP-9의 luciferase assay를 통한 실험에서 sulforaphane의 MMP-9 억제효과가 전사단계에서 조절됨을 추측 할 수 있었다. MMP-9 promoter 부위에 여러 가지의 전사조절인자 결합부위가 존재한다. 특히 AP-1과 NF-${\kappa}B$가 중요 전사조절인자로 작용하여 MMP-9 발현조절에 관여한다. 본 실험에서 sulforaphane에 의한 MMP-9 억제효과 기전에 이들 전사조절인자들의 중요한 역할을 조사하였다. AP-1과 NF-${\kappa}B$ 결합부위를 변형 시킨 vector를 transfection하여 MMP-9의 promoter 활성을 측정한 결과, 정상 vector에 비해 그 활성도가 현저히 떨어짐을 확인하였고, LPS에 의해 증가되는 AP-1과 NF-${\kappa}B$의 basal promoter 활성 또한 sulforaphane에 의해 감소됨을 관찰 할 수 있었다. 이상의 결과에서 sulforaphane의 MMP-9 활성억제효과는 AP-1과 NF-${\kappa}B$와 같은 전사인자들이 MMP-9의 전사를 조절함으로써 일어나는 것임을 알 수 있었다. 그리고 sulforaphane은 세포의 invasion능력 또한 효과적으로 억제시킴을 관찰 할 수 있었는데 이는 MMP-9 활성억제효과와 밀접한 관련이 있음을 추측 할 수 있었다.

• Advances in Traditional Medicine
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• 제5권4호
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• pp.283-293
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• 2005

Our previous study showed that a novel synthetic shikonin derivative, 6-(1-hydroxyimino-4-methylpentyl)5,8-dimethyoxy 1,4-naphthoquinone S-52 (DMNQ S-52) induced apoptosis. In the present study, we investigated its anti-metastatic activities as compared with shikonin because DMNQ S-52 was synthesized for overcoming weak points of shikonin such as high toxicity, low solubility and deleterious effects. DMNQ S-52 showed the weaker cytotoxicity $(IC_{50};\;12.3{\pm}1.6\;{\mu}M)$ against Lewis lung carcinoma (LLC) cells than that of shikonin $(IC_{50};\;4.2{\pm}1.1\;{\mu}M)$. DMNQ S-52, at non-toxic concentrations $(less\;than\;10\;{\mu}M)$, significantly inhibited the invasion and migration of LLC cells. DMNQ S-52 also significantly inhibited the production of MMP-9, MTl-MMP and uPAR. Moreover, daily i.p. administration of DMNQ S-52 at dose of 5 mg/kg in mice resulted in a potent inhibition of the primary tumor size of LLC in the lung as well as the metastasis of lymph nodes. These findings suggest that the DMNQ S-52 has therapeutic potential to inhibit metastasis via inhibition of MMP family and uPA/plasminogen system.

• 약학회지
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• 제46권1호
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• pp.11-17
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• 2002

$\beta$-Immunan, a proteoglycan, was isolated from the mycelium of Canoderma lucidum which belongs to a medicinal mushroom. The effects of $\beta$-Immunan on cell-cell and cell-matrix interactions mediated by carbohydrate-recognition and the mechanism responsible for the inhibition of experimental metastasis of Bl6-F10 and B16/BL6 murine melanoma were studied. The results showed that $\beta$-Immunan inhibited Bl6-Fl melanoma cell's adhesion to laminin and asialofetuin-induced homotypic aggregation and reduced invasion against Bl6-F10 murine melanoma cells through matrigel in vivo assay. When $\beta$-Immunan was intraperitoneally administrated to C57B/6 mice bearing B16/BL6 murine melanoma cells, it was decreased the number of pulmonary metastatic colony by the dose dependent manner ranging from 20 to 100 mg/kg/day. The results indirectly indicate that clinical treatment with $\beta$-Immunan might be expected to exhibit anti-metastatic effect. In the pulmonary metastasis, the number of pulmonary metastatic colony of melanoma when $\beta$-Immunan was intraperitoneally administrated to C57BL/6 mice bearing B16/BL6 murine melanoma cells by intravenous injection were decreased by the dose dependent manner ranging from 20 to 100 mg/kg/day.