• Journal of Ginseng Research
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• 제40권4호
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• pp.431-436
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• 2016

Background: Although numerous studies of the anticancer activities of Korean Red Ginseng (KRG) have been performed, the therapeutic effect of KRG on leukemia has not been fully elucidated. In this study, we investigated the antileukemia activities of KRG and its cellular and molecular mechanisms. Methods: An established leukemia tumor model induced by xenografted T cell lymphoma (RMA cells) was used to test the therapeutic activity of KRG water extract (KRG-WE). Direct cytotoxic activity of KRG-WE was confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The immunomodulatory activities of KRG-WE were verified by immunohistochemistry, nitric oxide production assay. The inhibitory effect of KRG-WE on cell survival signaling was also examined. Results: Orally administered KRG-WE reduced the sizes of tumor masses. Levels of apoptosis regulatory enzymes and cleaved forms of caspases-3 and -8 were increased by this extract. In addition, expression of matrix metalloproteinase-9, a metastasis regulatory enzyme, was decreased by KRG-WE treatment. The proportion of CD11c+ cells was remarkably increased in the KRG-treated group compared to the control group. However, KRG-WE did not show significant direct cytotoxicity against RMA cells. Conclusion: Our results strongly suggest that the KRG might have antileukemia activity through CD11c+ cell-mediated antitumor immunity.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제31권1호
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• pp.8-17
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• 2009

Purpose: We determined the therapeutic effect of an epidermal growth factor receptor (EGFR)-specific monoclonal antibody (mAb), cetuximab (Erbitux) on the growth of oral squamous cell carcinoma (OSCC) xenografted in athymic nude mice. Experimental Design: We induced subcutaneous tumors by inoculating human tumor cell suspension into the right flank of nude mice. Nude mice with subcutaneous tumors were randomized to receive cetuximab alone, paclitaxel alone, cetuximab plus paclitaxel, or a placebo (control). Antitumor mechanisms of cetuximab were determined by immunohistochemical and apoptosis assays. Results: Cetuximab, paclitaxel, and cetuximab/paclitaxel combined therapy resulted in 50%, 52%, 67% in vivo inhibition of tumor proliferation, respectively. Tumors of mice treated with cetuximab plus paclitaxel demonstrated decreased PCNA-positive tumor cells and increased apoptotic tumor cells, which slowed growth of the murine tumors. Conclusion: These data show that EGFR can be a molecular target for the treatment of OSCC. And combination therapy with cetuximab and paclitaxel warrants further clinical study.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제32권2호
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• pp.118-125
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• 2010

Background and Purpose: Bone metastases rarely occur in patients with oral squamous cell carcinoma (OSCC), so the molecular mechanisms of bone metastasis of OSCC remains unclear. Studies with animal models allow progresses in understanding the molecular events for bone metastasis and provide new targets for therapy. So we tried to establish a murine model for bone metastasis of oral squamous cell carcinoma. Materials and Methods: Human OSCC cells (KB cell line) were xenografted to nude mice via direct inoculation into the tibial marrow. Mice with tibial tumors were sacrificed once a week, until seven weeks after the injection of human tumor cells. Growth of tibial tumors were observed by histology. Expression of TGF-$\beta$ and CXCR-4 in bone OSCC (experimental) and subcutaneous tumor (control) was also evaluated by immunohistochemical staining. Results: Bone OSCC was successfully induced by intra-tibial injection of KB cells. Tumor mass was developed in the marrow tissues of tibia and finally invade the endosteum of tibia. Immunohistochemical staining showed higher expression of TGF-$\beta$ in bone tumors than in subcutaneous tumors. Conclusion: A murine model of bone metastasis of OSCC was suggested that imitated the clinical findings of distant vascular metastasis. This bone tumor model should facilitate understanding of the molecular pathogenesis of OSCC bone metastasis, and aid in the developement of treatment strategies against OSCC bone metastasis.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제30권6호
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• pp.529-539
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• 2008

Background and Purpose : Oral squamous cell carcinoma (OSCC) is one of the most aggressive tumors of the head and neck area. OSCC is known to preferentially metastasize via lymphatic system, and resulting cervical lymph node metastasis is the most reliable of treatment failure. But the biological mechanism of the regional nodal metastasis is not clear. So, we determined metastasis-related factors in orthotopic nude mouse models of OSCC. Experimental Design : Two cell lines-KB and YD-10B cells, established from human oral mucosal squamous cell carcinoma, were xenografted into the tissue space of athymic murine mouth floor. The mice were followed for tumor development and growth, the murine tumors were examined histopathologically for local invasion or regional or distant metastasis. Finally, we performed immunohistochemical assays with antiepithelial growth factor (EGF), EGF receptor (EGFR), phosphorylated EGFR (pEGFR), and anti-vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-2, phosphorylated VEGFR-2/3 (pVEGFR-2/3) antibodies. We also determined the microvessel density. Results : Transplantation of human OSCC tumor cells into the mouth floor successfully resulted in the formation of orthotopic tumors. KB cell line showed significantly higher tumor proliferation and higher nodal metastatic potential than YD-10B cell line. Furthermore, immunohistochemical staining demonstrated higher expression of EGFR/pEGFR, VEGF, and pVEGFR-2/3 as well as higher microvessel density in KB murine tumors than in YD-10B murine tumors. Conclusion : An orthotopic model of OSCC in athymic mice was established which copies the cervical lymph nodal metastasis of human OSCC. Our mouth floor model should facillitate the understanding of the molecular pathogenesis of cervical nodal metastasis of OSCC.

• 대한핵의학회지
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• 제38권2호
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• pp.152-160
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• 2004

Radioiodide uptake in thyroid follicular epithelial cells, mediated by a plasma membrane transporter, sodium iodide symporter (NIS), provides a first step mechanism for thyroid cancer detection by radioiodide injection and effective radioiodide treatment for patients with invasive, recurrent, and/or metastatic thyroid cancers after total thyroidectomy. NIS gene transfer to tumor cells may significantly and specifically enhance internal radioactive accumulation of tumors following radioiodide administration, and result in better tumor control. NIS gene transfers have been successfully performed in a variety of tumor animal models by either plasmid-mediated transfection or virus (adenovirus or retrovirus)-mediated gene delivery. These animal models include nude mice xenografted with human melanoma, glioma, breast cancer or prostate cancer, rats with subcutaneous thyroid tumor implantation, as well as the rat intracranial glioma model. In these animal models, non-invasive imaging of in vivo tumors by gamma camera scintigraphy after radioiodide or technetium injection has been performed successfully, suggesting that the NIS can serve as an imaging reporter gene for gene therapy trials. In addition, the tumor killing effects of I-131, ReO4-188 and At-211 after NIS gene transfer have been demonstrated in in vitro clonogenic assays and in vivo radioiodide therapy studies, suggesting that NIS gene can also serve as a therapeutic agent when combined with radioiodide injection. Better NIS-mediated imaging and tumor treatment by radioiodide requires a more efficient and specific system of gene delivery with better retention of radioiodide in tumor. Results thus far are, however, promising, and suggest that NIS gene transfer followed by radioiodide treatment will allow non-invasive in vivo imaging to assess the outcome of gene therapy and provide a therapeutic strategy for a variety of human diseases.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제33권1호
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• pp.1-9
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• 2011

Purpose: Tumor associated angiogenesis and/or lymphangiogenesis are known to be linked by VEGFR signaling pathways. These processes are regulated by several growth factors including VEGFR-2, VEGFR-3. E7080 is an orally active inhibitor of multiple tyrosine kinases including VEGFR-2, 3. Therefore, it was proposed that E7080 may inhibit angiogenesis and lymphangiogenesis. The aim of this study was to determine the effect of E7080 in a nude mouse model of OSCC. Methods: KB cells were xenografted into the submucosal tissue of the mouth floor of athymic mice. Seven days after the xenograft, the mice were randomized into 2 groups. E7080 were administered orally to the experimental group once per day. The mice were sacrificed 3 weeks after the treatment. The tumors were examined histopathologically. Immunohistochemical assays with anti- VEGF-C, VEGFR-2, VEGFR-3, phosphorylated VEGFR-2/3 (pVEGFR-2/3), and D2-40 antibodies were then performed. Results: The transplantation of human OSCC tumor cells into the mouth floor resulted in the formation of orthotopic tumors. The experimental (E7080 treatment) group showed a slowly increased tumor volume. Moreover, immunohistochemical staining demonstrated higher levels of VEGF-C, VEGFR-2, VEGFR-3, pVEGFR-2/3 and D2-40 expression in the control group than in the experimental group. Conclusion: These results suggest that E7080 may provide therapeutic benefits in OSCC.

• BMB Reports
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• 제47권12호
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• pp.697-702
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• 2014

Recently, the interest in natural products for the treatment of cancer is increasing because they are the pre-screened candidates. In the present study, we demonstrate the therapeutic effect of celastrol, a triterpene extracted from the root bark of Chinese medicine on gastric cancer. The proliferation of AGS and YCC-2 cells were most sensitively decreased in six kinds of gastric cancer cell lines after the treatment with celastrol. Celastrol inhibited the cell migration and increased G1 arrest in cell-cycle populations in both cell lines. The treatment with celastrol significantly induced autophagy and apoptosis and increased the expression of autophagy and apoptosis-related proteins. We also found an increase in phosphorylated AMPK following a decrease in all phosphorylated forms of AKT, mTOR and S6K after the treatment with celastrol. Moreover, gastric tumor burdens were reduced in a dose-dependent manner by celastrol administration in a xenografted mice model. Taken together, celastrol distinctly inhibits the gastric cancer cell proliferation and induces autophagy and apoptosis.

• 대한한의학회지
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• 제31권3호
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• pp.34-46
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• 2010

Objective: This experimental study was performed to examine if Hang-Am-Dan non-boiled water extracts (HAD-N) induce apoptosis in human lung carcinoma NCI-H460 cells in vitro and inhibits the growth of NCI-H460 cell-transplanted solid tumor in vivo. Materials and Methods: We cultured NCI-H460 cell lines and xenografted them to nude mice. The mice were divided into 3 groups, NCI-H460 cell alone, NCI-H460 + 90 mg/kg HAD-N treated group, and NCI-H460 + 180 mg/kg HAD-N treated group, with seven mice per group. HAD-N was orally administrated every day for four weeks. We checked their body weight and tumor weight and volumes two times a week and their absolute organ weight and biochemical blood analysis at the final day by sacrificing them. We also calculated their tumor inhibition rate (IR), mean survival time and percent increase in life span (% ILS). Results: In this study, we observed that all of the HAD-N treated mice got smaller tumors. The more doses of HAD-N used, the less IR showed at the 8th day after starting this experiment. Tumor weight and volume of HAD-N treatment groups also decreased. Mean survival time and percent increase in life span (% ILS) in the high-dose HAD-N treatment groups were higher than those of other groups. The test substances in the blood level UN results showed reduction in the significance in both HAD-N 90 mg/kg and HAD-N 180 mg/kg (p<0.01). The blood level phosphatase results in HAD-N 90 mg/kg group compared to NCI-H460 cell alone group showed a reduction in significance (p<0.05). AST levels HAD-N 180 mg/kg group compared to NCI-H460 cell alone group significance as well (p<0.05). Conclusion: We suggest that the results of the in vivo study showed that HAD-N may have potential as a growth inhibitor of tumor-induced NCI-H460 of nude mice in spite of the shortcomings of this study. More studies to overcome those shortcomings and to find out significant antitumor mechanism will be needed.

• Toxicological Research
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• 제31권4호
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• pp.331-337
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• 2015

Synthetic pyrethroids (SPs) are the most common pesticides which are recently used for indoor pest control. The widespread use of SPs has resulted in the increased exposure to wild animals and humans. Recently, some SPs are suspected as endocrine disrupting chemicals (EDCs) and have been assessed for their potential estrogenicity by adopting various analyzing assays. In this study, we examined the estrogenic effects of lambda-cyhalothrin (LC) and cypermethrin (CP), the most commonly used pesticides in Korea, using BG-1 ovarian cancer cells expressing estrogen receptors (ERs). To evaluate the estrogenic activities of two SPs, LC and CP, we employed MTT assay and reverse-transcription polymerase chain reaction (RT-PCR) in LC or CP treated BG-1 ovarian cancer cells. In MTT assay, LC ($10^{-6}M$) and CP ($10^{-5}M$) significantly induced the growth of BG-1 cancer cells. LC or CP-induced cell growth was antagonized by addition of ICI 182,720 ($10^{-8}M$), an ER antagonist, suggesting that this effect appears to be mediated by an ER-dependent manner. Moreover, RT-PCR results showed that transcriptional level of cyclin D1, a cell cycle-regulating gene, was significantly up-regulated by LC and CP, while these effects were reversed by co-treatment of ICI 182,780. However, p21, a cyclin D-ckd-4 inhibitor gene, was not altered by LC or CP. Moreover, $ER{\alpha}$ expression was not significantly changed by LC and CP, while down-regulated by E2. Finally, in xenografted mouse model transplanted with human BG-1 ovarian cancer cells, E2 significantly increased the tumor volume compare to a negative control, but LC did not. Taken together, these results suggest that LC and CP may possess estrogenic potentials by stimulating the growth of BG-1 ovarian cancer cells via partially ER signaling pathway associated with cell cycle as did E2, but this estrogenic effect was not found in in vivo mouse model.

• Journal of Korean Neurosurgical Society
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• 제30권5호
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• pp.553-560
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• 2001

Objective : The objective of this study was to determine the photodynamic therapeutic response of U-87 human glioma cell in vitro as well as in the nude rat xenograft model using photofrin as photosensitizer. Material and Method : U-87 cells were cultured on 96-well culture plates, photofrin(Quadralogic Technologies Inc., Vancouver, Canada) was added into the cell culture medium at concentration of $1{\mu}g/ml$, $2.5{\mu}g/ml$, $5{\mu}g/ml$, $10{\mu}g/ml$ and $20{\mu}g/ml$. 24 hour after drug treatment, cells were treated with optical(632nm) irradiation of $100mJ/cm^2$, $200mJ/cm^2$ and $400mJ/cm^2$. Photofrin(12.5mg/kg, i.p.) was administered to 28 nude rats containing intracerebral U-87 human glioma as well as 26 normal nude rats. 48 hours after administration, animals were treated with optical irradiation(632nm) of $35J/cm^2$, $140J/cm^2$ and $280J/cm^2$ to exposed tumor and normal brain. The photofrin concentration was measured in tumor and normal brain in a separate population of animals. Results : By MTT assay, there was 100% cytotoxicity at any dose of photofrin with optical irradiation of $200mJ/cm^2$ and $400mJ/cm^2$. But at the optical irradiation of $100mJ/cm^2$ cells were killed in dose dependent manner 28.5%, 49.1%, 54.4%, 78.2%, and 84.6% at concentration of $1{\mu}g/ml$, $2.5{\mu}g/ml$, $5{\mu}g/ml$, $10{\mu}g/ml$ and $20{\mu}g/ml$, respectively. Dose dependent PDT lesions in both tumor and normal brain were observed. In the tumor lesion, only superficial tissue damage was found with optical irradiation of $35J/cm^2$. However, in the optical irradiation group of $140J/cm^2$ and $280J/cm^2$ the volume of lesions was measured of $7.2mm^3$ and $14.0mm^3$ for treatment at $140J/cm^2$ and $280J/cm^2$, respectively. The U-87 bearing rats showed a photofrin concentration in tumor tissue of $6.53{\pm}2.16{\mu}g/g$, 23 times higher than that found in the contralateral hemisphere of $0.28{\pm}0.15{\mu}g/g$. Conclusion : Our data indicate that the U-87 human glioma in vitro and in the xenografted rats is responsive to PDT. At these doses, a reproducible injury can be delivered to human glioma in this model. Strategies to spare the normal brain collateral damage are being studied.