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ABSTRACT: Tumor necrosis factor-alpha (TNF-α) is released in a variety of pathological states in the inner ear. Inducible nitric oxide synthase (iNOS) can be induced by cytokines and other inflammatory factors, and is generally thought to be associated with inflammation and other pathological processes in the cochlea. The purpose of the present study was to reveal that TNF-α could induce apoptosis in the auditory cell line and to investigate the role of nitric oxide (NO) in TNF-α-induced auditory cell death.
Experimental study.
UB-OC1 cells and zebrafish were exposed to TNF-α. Flow cytometry, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) assay, assay of mitochondrial membrane potential (MMP), and electron microscopy were used to show that TNF-α could induce apoptosis. Western blot was used to measure iNOS expression and mitogen-activated protein kinase pathway.
Flow cytometric analysis, TUNEL assay, MMP, and electron microscopy all demonstrated that TNF-α could induce apoptosis in UB-OC1 cells. TNF-α significantly increased NO generation and iNOS expression. Pretreatment with iNOS blocker NG-methyl-L-arginine (NMA) attenuated TNF-α-induced cell death and caspase-3 activation. Also, TNF-α treatment increased p-p38 and p-ERK, and pretreatment of NMA reduced this increased expression of p-p38 and p-ERK.
TNF-α can induce apoptosis in the auditory cell line, and NO production in response to TNF-α is essential for apoptosis. Laryngoscope, 2012.
The Laryngoscope 07/2012; 122(10):2256-64. · 1.75 Impact Factor
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ABSTRACT: Hepatocyte growth factor (HGF) and c-Met have recently attracted a great deal of attention as prognostic indicators of patient outcome, and they are important in the control of tumor growth and invasion. Epigallocatechin-3-gallate (EGCG) has been shown to modulate multiple signal pathways in a manner that controls the unwanted proliferation and invasion of cells, thereby imparting cancer chemopreventive and therapeutic effects. In this study, we investigated the effects of EGCG in inhibiting HGF-induced tumor growth and invasion of oral cancer in vitro and in vivo. We examined the effects of EGCG on HGF-induced cell proliferation, migration, invasion, induction of apoptosis and modulation of HGF/c-Met signaling pathway in the KB oral cancer cell line. We investigated the antitumor effect and inhibition of c-Met expression by EGCG in a syngeneic mouse model (C3H/HeJ mice, SCC VII/SF cell line). HGF promoted cell proliferation, migration, invasion and induction of MMP (matrix metalloproteinase)-2 and MMP-9 in KB cells. EGCG significantly inhibited HGF-induced phosphorylation of Met and cell growth, invasion and expression of MMP-2 and MMP-9. EGCG blocked HGF-induced phosphorylation of c-Met and that of the downstream kinases AKT and ERK, and inhibition of p-AKT and p-ERK by EGCG was associated with marked increases in the phosphorylation of p38, JNK, cleaved caspase-3 and poly-ADP-ribose polymerase. In C3H/HeJ syngeneic mice, as an in vivo model, tumor growth was suppressed and apoptosis was increased by EGCG. Our results suggest that EGCG may be a potential therapeutic agent to inhibit HGF-induced tumor growth and invasion in oral cancer.
The Journal of nutritional biochemistry 02/2011; 22(11):1074-83. · 4.29 Impact Factor
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Young Chang Lim,
Ki Woong Cho,
Hak Cheol Kwon,
Sung Un Kang,
Jung Hee Pyun, Mi Hye Lee,
Hye Sook Hwang,
Jang Hee Kim,
Ha Neul Lee,
Eun Chang Choi,
Chul-Ho Kim
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ABSTRACT: To determine whether a novel marine micro-organism with anticancer properties, H31, the metabolic product of Bacillus SW31, has anti-tumor effects on head and neck cancer, and potential for apoptotic-enhancing anti-cancer treatment of affected patients.
The cell viability and apoptosis assays were performed. Changes in the signal pathway related to apoptosis were investigated. Then, the therapeutic effects of H31 were explored in mouse xenograft model and drug toxicity of H31 was examined in zebrafish model.
We identified the anticancer activity of H31, a novel metabolic product of Bacillus SW31. Bacillus SW31, a new marine micro-organism, has 70% homology with Bacillus firmus and contains potent cytotoxic bioactivity in head and neck cancer cells using MTT assay. Combined with c-JUN, p53, cytochrome C, and caspase-3, H31 induced apoptosis of KB cells, a head and neck cancer cell line. In a separate in vivo model, tumor growth in C3H/HeJ syngeneic mice was suppressed by H31. In addition, in a zebrafish model used for toxicity testing, a considerable dose of H31 did not result in embryo or neurotoxicity.
Growth inhibition and apoptosis were achieved both in vitro and in vivo in head and neck cancer cells after exposure to H31, a metabolite from the marine Bacillus species, without any significant toxicity effects even at considerable H31 dose concentrations.
Clinical and Experimental Otorhinolaryngology 12/2010; 3(4):217-25. · 0.92 Impact Factor
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ABSTRACT: Development of vitiligo-like hypopigmentary lesions associated with topical imiquimod has been reported. We hypothesized that mode of action of imiquimod in melanocytes may include triggering of apoptosis resulted in loss of cells, which may be a possible mechanism of imiquimod-induced hypopigmentary lesions. Therefore, we investigated whether imiquimod induces apoptosis of human melanocytes and also whether it modulates expression of apoptosis-related molecules in human melanocytes. Imiquimod treatment induced apoptosis of melanocytes, which was observed by TUNEL assay and Hoechst 33258 staining. Imiquimod-induced apoptosis was further shown by measuring mitochondrial membrane potential in melanocytes. The apoptotic activity of imiquimod was associated with caspase-3, Bcl-2 and mitogen-activated protein kinase expression in melanocytes. These results indicated that imiquimod induces apoptosis of melanocytes. These findings may provide a clue to understand pathogenesis of imiquimod-induced vitiligo-like hypopigmentary lesions.
Archives for Dermatological Research 05/2010; 302(4):301-6. · 2.28 Impact Factor
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ABSTRACT: Hepatocyte growth factor (HGF) has recently attracted a considerable amount of attention as a stromal-derived mediator in tumor-stromal interactions, particularly because of its close involvement in cancer invasion and metastasis, and (-)-epigallocatechin-3-gallate (EGCG) can modulate the cell signaling associated with angiogenesis, metastasis, and migration of cancer cells. In the present study, we have investigated the effects of HGF on invasion and metastasis of hypopharyngeal carcinoma cells and the effect of EGCG on blocking HGF-induced invasion and metastasis in these cells. We found that HGF promoted the autophosphorylation of c-Met, HGF receptor, and that HGF-induced proliferation, colony dispersion, migration and invasion of tumors. We also observed that HGF enhanced the activity of matrix metalloproteinase (MMP)-9 and urokinase-type plasminogen activator (uPA) in hypopharyngeal carcinoma cells. In addition, HGF-induced the activation of Akt and Erk pathway as a downstreaming pathway of invasion. On the other hand, EGCG at physiologically relevant concentration (1 microM) suppressed HGF-induced tumor motility and MMP-9 and uPA activities, and the suppression of Akt and Erk pathway by EGCG was one of the downstream mechanisms to facilitate EGCG-induced anti-invasion effects. These results suggest that EGCG may serve as a therapeutic agent to inhibit HGF-induced invasion in hypopharyngeal carcinoma patients.
Cancer letters 11/2008; 271(1):140-52. · 4.86 Impact Factor
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ABSTRACT: Cisplatin, a chemotherapeutic drug that is widely used to treat various cancers, promotes ototoxicity at higher doses. In this study, the effect of epicatechin (EC) on cisplatin-induced hair cell death was investigated in a cochlear organ of Corti-derived cell line, HEI-OC1, and in vivo in zebrafish. Cisplatin promoted apoptosis and altered mitochondrial membrane potential (MMP) in HEI-OC1 cells. EC inhibited cisplatin-induced apoptosis and intracellular reactive oxygen species (ROS) generation. Labeling of zebrafish lateral line hair cells by the fluorescent dye YO-PRO1 was lost upon exposure to cisplatin, and EC protected against this cisplatin-induced loss of labeling in a dose-dependent manner. Scanning and transmission electron micrographs showed that treatment with EC protected against cisplatin-induced loss of kinocilium and stereocilia in zebrafish neuromasts. These results suggest that EC prevents cisplatin-induced ototoxicity by blocking ROS generation and by preventing changes in MMP.
Apoptosis 10/2008; 13(9):1184-94. · 4.07 Impact Factor
