Terbinafine inhibits oral squamous cell carcinoma growth through anti-cancer cell proliferation and anti-angiogenesis
Terbinafine inhibits oral squamous cell carcinoma growth through anti-cancer cell proliferation and anti-angiogenesis
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DOI：
10.1002/mc.20800
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发表时间：
2012-05-01
影响因子：
4.6
通讯作者：
Lee, Wen-Sen
中科院分区：
文献类型：
--
作者：
Chien, Ming-Hsien;Lee, Tong-Sheng;Lee, Wen-Sen
特比萘芬（TB）是一种用于治疗浅表真菌病的口服抗真菌剂，据报道对多种癌细胞具有抗肿瘤作用。然而，结核病对口腔癌的影响尚未得到评估。在此，我们证明TB（060μM）浓度依赖性地减少培养的人口腔鳞状细胞癌（OSCC）KB细胞中的细胞数量。在另外两种 OSCC 细胞系 SAS 和 SCC 15 中也观察到 TB 的抗增殖作用。TB (60μM) 没有细胞毒性，并且其对 KB 细胞生长的抑制是可逆的。 [3H]胸苷掺入和流式细胞术分析表明，TB 抑制 DNA 合成并诱导 G0/G1 细胞周期停滞。当细胞周期蛋白依赖性激酶 2 活性受到抑制，同时 p21cip1 和 p27kip1 的蛋白水平增加时，结核病诱导的细胞周期停滞就会发生。当 p21cip1 和 p27kip1 的表达同时被抑制时，TB 诱导的 G0/G1 细胞周期停滞被完全阻断。综上所述，这些结果表明 p21cip1 和 p27kip1 相关信号通路可能参与 TB 诱导的 KB 细胞的抗增殖。在体内，TB（50mg/kg，腹腔注射）显着抑制 KB 肿瘤的大小。在这些经过结核病治疗的肿瘤中，观察到 p21cip1 和 p27kip1 蛋白水平增加，增殖细胞核抗原阳性细胞数量和微血管密度减少。这些发现首次证明结核病可能有潜力作为口腔癌的治疗工具。摩尔。致癌。 (c) 2011 年 Wiley 期刊公司。
Terbinafine (TB), an oral antifungal agent used in the treatment of superficial mycosis, has been reported to exert an anti-tumor effect in various cancer cells. However, the effect of TB on oral cancer has not been evaluated. Herein we demonstrate that TB (060?mu M) concentration-dependently decreased cell number in cultured human oral squamous cell carcinoma (OSCC), KB cells. The anti-proliferation effect of TB was also observed in two other OSCC cell lines, SAS and SCC 15. TB (60?mu M) was not cytotoxic and its inhibition on KB cell growth was reversible. [3H]thymidine incorporation and flow cytometric analyses revealed that TB-inhibited DNA synthesis and induced the G0/G1 cell-cycle arrest. The TB-induced cell-cycle arrest occurred when the cyclin-dependent kinase 2 activity was inhibited just as the protein levels of p21cip1 and p27kip1 were increased. The TB-induced G0/G1 cell-cycle arrest was completely blocked when the expressions of p21cip1 and p27kip1 were knocked-down together. Taken together, these results suggest that the p21cip1- and p27kip1-associated signaling pathways might be involved in the TB-induced anti-proliferation in KB cells. In vivo, TB (50?mg/kg, i.p.) significantly inhibited the KB tumor size. In these TB-treated tumors, increases in the levels of p21cip1 and p27kip1 protein and decreases in the number of proliferating cell nuclear antigen-positive cells and the microvessel density were observed. These findings demonstrate for the first time that TB might have potential to serve as a therapeutic tool in the treatment of oral cancer. Mol. Carcinog. (c) 2011 Wiley Periodicals, Inc.