• Maxillofacial Plastic and Reconstructive Surgery
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• 제34권4호
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• pp.239-245
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• 2012

Purpose: Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis and lymphangiogenesis including induction of endothelial cell proliferation, migration and capillary tube formation. E7080 (S1164, Selleck chemical, Houston, TX, USA) is a muti-targeted kinase inhibitor, which targets VEGF receptor-2, 3 (VEGFR-2, 3) and inhibits survival and proliferation of tumor cell. The purpose of this study was to determine the anti-tumor effect of E7080 on oral squamous cell carcinoma. Methods: An oral squamous cell carcinoma cell line, SCC-9 was used in this study. E7080 was applied to SCC-9 cells by 3 different concentrations (1, 5, 10 ${\mu}g/mL$). Control means no application of E7080. The cellular growth was evaluated by real-time cell electronic sensing and MTT assay. The signal transduction was evaluated by Western blotting. Results: In experimental group, SCC-9 cell proliferation was decreased and the VEGFR-3 downstream pathways were inhibited compared with control. Furthermore, increasing the concentration of E7080, the ability of E7080 to disturbance of SCC-9 cell proliferation was increased. Conclusion: Proliferation of SCC-9 cells was inhibited by E7080, which was through by inhibition of VEGFR-3 downstream pathway. In vivo study with E7080 will be required to provide therapeutic benefits in oral squamous cell carcinoma.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제46권5호
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• pp.341-347
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• 2020

Objectives: Oral squamous cell carcinoma (OSCC) is one of the most common types of head and neck cancer. MicroRNAs, as new biomarkers, are recommended for diagnosis and treatment of different types of cancers. Bevacizumab, sold under the trade name Avastin, is a humanized whole monoclonal antibody that targets and blocks VEGF-A (vascular endothelial growth factor A; angiogenesis) and oncogenic signaling pathways. Materials and Methods: This study comprised 50 cases suffering from OSCC and 50 healthy participants. Peripheral blood samples were collected in glass test tubes, and RNA extraction was started immediately. Expression levels of miR-155, miR-191, and miR-494 biomarkers in the peripheral blood of OSCC-affected individuals and healthy volunteers in vivo were evaluated using real-time PCR. The influence of Avastin on the expression levels of the aforementioned biomarkers in vitro and in the HN5 cell line was also investigated. Results: Expression levels of miR-155, miR-191, and miR-494 in the peripheral blood of individuals affected by OSCC were higher than in those who were healthy. Moreover, Avastin at a concentration of 400 μM caused a decrease in the expression levels of the three biomarkers and a 1.5-fold, 3.5-fold, and 4-fold increase in apoptosis in the test samples compared to the controls in the HN5 cell line after 24, 48, and 72 hours, respectively. Conclusion: The findings of this study demonstrate that overexpression of miR-155, miR-191, and miR-494 is associated with OSCC, and Avastin is able to regulate and downregulate the expression of those biomarkers and increase apoptosis in cancerous cells in the HN5 cell line.

• 대한예방한의학회지
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• 제13권2호
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• pp.39-50
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• 2009

Objectives : In order to evaluate the cytotoxicity of 3,4,5-trihydroxybenzoic acid and related compounds on the growth of normal cell lines and human oral epithelioid cell line, cell viability, cell adhesion ability, and morphological changes of cells were examined. Methods : We measured the cytotoxicity of 3,4,5-trihydroxybenzoic acid and related compounds with 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyltetrazolium bromide-[MTT), and 2,3-bis-[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium -5-caboxanilide-[XTT) methods. Results : The cytotoxicity of 3,4,5-trihydroxybenzoic acid($IC_{50}$, $2,552.40\;{\mu}M$) was low according to the toxic criteria. Cytotoxic effect of 3,4,5-trihydroxybenzoic acid and related compounds against $IC_{50}$ value in cell morphology increased in a concentration-dependent manner. In light microscopy, $100\;{\mu}M$ 3,4,5-trihydroxy-benzoic acid showed th highest cytotoxic activity. Conclusions : These results suggest that 3,4,5-trihydroxybenzoic acid may have a potential anticancer activity.

• International Journal of Oral Biology
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• 제34권2호
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• pp.61-72
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• 2009

Chios gum mastic (CGM) is a resin produced from the stem and leaves of Pistiacia lentiscus L var chia, a plant which grows only on Chios Island in Greece. CGM has been used for many centuries as a dietary supplement and folk medicine for stomach and duodenal ulcers in many Mediterranean countries and is known also to induce cell cycle arrest and apoptosis in some cancer cells. In this study, we further investigated the induction and mechanisms underlying the apoptotic response to CGM treatment in the SCC25 human tongue squamous cell carcinoma cell line. The viability of SCC25 cells, human normal keratinocytes (HaCaT cells) and human gingival fibroblasts (HGF-1 cells), and the growth inhibition of SCC25 cells were assessed by MTT assay and clonogenic assay, respectively. Staining with Hoechst and hemacolor dyes and TUNEL assays were employed to detect SCC25 cells undergoing apoptosis. SCC25 cells were treated with CGM, and this was followed by western blotting, immunocytochemistry, confocal microscopy, FACScan flow cytometry, MMP activity and proteasome activity analyses. CGM treatment of SCC25 cells was found to result in a time- and dosedependent decrease in cell viability, a dose-dependent inhibition of cell growth, and apoptotic cell death. Interestingly, CGM showed a remarkable level of cytotoxicity in SCC25 cells but not in normal cells. Tested SCC25 cells also showed several lines of apoptotic manifestation. Taken together, our present findings demonstrate that CGM strongly inhibits cell proliferation by modulating the expression of G1 cell cycle-related proteins and induces apoptosis via the proteasome, mitochondria and caspase cascades in SCC25 cells.

• International Journal of Oral Biology
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• 제46권4호
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• pp.176-183
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• 2021

Oral squamous cell carcinoma (OSCC) metastasis is characterized by distant metastasis and local recurrence. Combined chemotherapy with cisplatin and 5-fluorouracil is routinely used to treat patients with OSCC, and the combined use of gefitinib with cytotoxic drugs has been reported to enhance the sensitivity of cancer cells in vitro. However, the development of drug resistance because of prolonged chemotherapy is inevitable, leading to a poor prognosis. Therefore, understanding alterations in signaling pathways and gene expression is crucial for overcoming the development of drug resistance. However, the altered characterization of Ca²⁺ signaling in drug-resistant OSCC cells remains unclear. In this study, we investigated alterations in intracellular Ca²⁺ ([Ca²⁺]_i) mobilization upon the development of gefitinib resistance in human tongue squamous carcinoma cell line (HSC)-3 and HSC-4 using ratiometric analysis. This study demonstrated the presence of altered epidermal growth factor- and purinergic agonist-mediated [Ca²⁺]_i mobilization in gefitinib-resistant OSCC cells. Moreover, Ca²⁺ content in the endoplasmic reticulum, store-operated calcium entry, and lysosomal Ca²⁺ release through the transient receptor potential mucolipin 1, were confirmed to be significantly reduced upon the development of apoptosis resistance. Consistent with [Ca²⁺]_i mobilization, we identified modified expression levels of Ca²⁺ signaling-related genes in gefitinib-resistant cells. Taken together, we propose that the regulation of [Ca²⁺]_i mobilization and related gene expression can be a new strategy to overcome drug resistance in patients with cancer.

• Animal cells and systems
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• 제15권2호
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• pp.139-146
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• 2011

Secretory leukocyte protease inhibitor (SLPI) plays an important role in promoting the invasion and metastasis of a range of cancer cells. However, there are no reports of the expression and function of SLPI in oral carcinoma cells. In this study, the oral carcinoma cell line KB was used to determine whether SLPI affects the proliferation, migration and invasion of oral carcinoma cells. RT-PCR and Western blotting revealed high levels of endogenous SLPI expression in KB cells as well as a strong increase in SLPI secretion after wounding compared to immortalized normal oral keratinocytes (INOK). The wound healing assay revealed more migration of KB cells than INOK cells, and the SLPI treatment increased the migration of KB cells. KB cell proliferation was increased significantly by the SLPI protein but decreased by SLPI-siRNA. SLPI strongly increased the migration and invasion of KB cells. On the other hand, SLPI-siRNA decreased the migration and invasion of KB cells. This suggests that SLPI plays an important role in the metastasis of oral carcinoma cells.

• Biomolecules & Therapeutics
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• 제25권5호
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• pp.553-558
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• 2017

Paclitaxel (PTX) is one of the most frequently used anticancer agent for treating refractory ovarian cancer, metastatic breast cancer and non-small cell lung cancer. However, its oral administration is impeded by very low bioavailability (<5%) due to the P-glycopprotein (P-gp) efflux pump effect. This study investigated in vitro and in vivo P-gp inhibitory effects of adamantyl derivatives AC-603 and AC-786 in rats. Two adamantyl derivatives tested in this study increased the cytotoxicity of daunomycin (DNM) in P-gp overexpressed cell line by inhibiting P-gp efflux function. Pharmacokinetics of PTX with orally co-administered P-gp inhibitors were assessed in rats to improve PTX absorption. The pharmacokinetic parameters of PTX were determined in rats after intravenous (2 mg/kg) or oral (25 mg/kg) administration in the presence or absence of verapamil (a positive control), AC-603 or AC-786 (0.5 mg/kg or 5 mg/kg). Compared to control group (PTX alone), experimental groups (PTX with AC-603 or AC-786) significantly increased the area under the plasma concentration-time curve of PTX following oral administration by 1.7-2.2 fold. The volume of distribution and total clearance of PTX were decreased, while other parameters were not significantly changed. In conclusion, co-administration of AC-603 or AC-786 enhanced the relative bioavailability of orally administered PTX as compared to control.

• 한국식품영양과학회지
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• 제32권5호
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• pp.758-763
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• 2003

구강 편평 세포암종 KB 세포를 이용하여 아미노산 수송계 L억제제인 BCH의 세포 성장억제에 미치는 효과를 밝히기 위해, KB세포에서 uptake실험, MTT분석 및 DNA frag-mentation분석 등을 시행하여 다음과 같은 결과를 얻었다. KB 세포에서는 아미노산 수송계 L 중에서 LAT1과 그 보조인자 4F2hc를 통해 BCH및 중성 아미노산들이 수송되었다. BCH는 시간과 농도에 의존적으로 KB세포의 성장을 억제시켰다. BCH를 처리한 실험군에서 DNA fragmentation 현상은 볼 수 없었다. 본 연구의 결과로서 구강암 세포주인 구강 편평세포암종 KB 세포에서 LAT1과 그 보조인자 4F2hc를 통해 BCH및 중성 아미노산의 수송이 이루어지고 있다는 것을 확인할 수 있었으며 BCH는 이 LAT1을 차단하여 중성 아미노산들의 세포 내 고갈을 유도함으로서 KB 세포 성장의 억제를 유도하는 것으로 사료된다.

• International Journal of Oral Biology
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• 제37권4호
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• pp.189-195
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• 2012

Resistance to the induction of apoptosis is a possible mechanism by which tumor cells can survive anti-neoplastic treatments. Melanoma is notoriously resistant to anti-neoplastic therapy. Previous studies have demonstrated focal adhesion kinase (FAK) overexpression in melanoma cell lines. Given its probable role in mediating resistance to apoptosis, many researchers have sought to determine whether the downregulation of FAK in melanoma cells would confer a greater sensitivity to anti-neoplastic agents. Genistein is a known inhibitor of protein-tyrosine kinase (PTK), which may attenuate the growth of cancer cells by inhibiting the PTK-mediated signaling pathway. This present study was undertaken to investigate the effect of genistein on the expression of FAK and cell cycle related proteins in the G361 melanoma cell line. Genistein was found to have a preferential cytotoxic effect on G361 melanoma cells over HaCaT normal keratinocytes. Genistein decreased the expression of 125 kDa phosphotyrosine kinase and the FAK protein in particular. Genistein treatment did not affect the expression of p53 in G361 cells in which p21 is upregulated. The expression of cyclin B and cdc2 was downregulated by genistein treatment. Taken together, our data indicate that genistein induces the decreased proliferation of G361 melanoma cells via the inhibition of FAK expression and regulation of cell cycle genes. This suggests that the use of genistein may be a viable approach to future melanoma treatments.

• BMB Reports
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• 제50권3호
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• pp.150-155
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• 2017

Non-small-cell lung cancer (NSCLC) is the third most common cancer that spreads to the bone, resulting in osteolytic lesions caused by hyperactivation of osteoclasts. Activating mutations in epidermal growth factor receptor-tyrosine kinase (EGF-TK) are frequently associated with NSCLC, and afatinib is a first-line therapeutic drug, irreversibly targeting EGF-TK. However, the effects of afatinib on osteoclast differentiation and activation as well as the underlying mechanism remain unclear. In this study, afatinib significantly suppressed receptor activator of nuclear factor ${\kappa}B$ (RANK) ligand (RANKL)-induced osteoclast formation in bone marrow macrophages (BMMs). Consistently, afatinib inhibited the expression of osteoclast marker genes, whereas, it upregulated the expression of negative modulator genes. The bone resorbing activity of osteoclasts was also abrogated by afatinib. In addition, afatinib significantly inhibited RANKL-mediated Akt/protein kinase B and c-Jun N-terminal kinase phosphorylation. These results suggest that afatinib substantially suppresses osteoclastogenesis by downregulating RANK signaling pathways, and thus may reduce osteolysis after bone metastasis.