Therapeutic Efficacy of Seliciclib in Combination with Ionizing Radiation for Human Nasopharyngeal Carcinoma
Therapeutic Efficacy of Seliciclib in Combination with Ionizing Radiation for Human Nasopharyngeal Carcinoma
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DOI：
10.1158/1078-0432.ccr-08-2790
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发表时间：
2009-06-01
影响因子：
11.5
通讯作者：
Liu, Fei-Fei
中科院分区：
文献类型：
--
作者：
Hui, Angela B. Y.;Yue, Shijun;Liu, Fei-Fei
目的：Seliciclib是一种小分子细胞周期蛋白依赖性激酶抑制剂，据报道可诱导EBV阴性鼻咽癌细胞系凋亡和细胞周期阻滞。由于大多数鼻咽癌患者携带EBV，我们继续评估seliciclib在EBV阳性鼻咽癌模型中的细胞毒性作用。实验设计：在EBV阳性细胞系C666-1和C666 -1和C15异种移植模型中研究seliciclib的细胞毒性。流式细胞仪检测Caspase活性和细胞周期。Seliciclib联合放射治疗的疗效也evaluated.Results：Seliciclib在C666-1细胞中以时间和剂量依赖性方式引起显著的细胞毒性，细胞聚集在sub-G（1）和G（2）-M期，分别表示凋亡和细胞周期阻滞。Caspase-2、-3、-8和-9活性均增加，其中Caspase-3在处理后48 h活化最显著。这些细胞还显示出Mcl-1 mRNA和蛋白水平的降低。seliciclib与放疗联合治疗显示出协同作用，增强了C666-1细胞的细胞毒性，并延迟了双链DNA断裂的修复。对于体内模型，观察到C666-1和C15肿瘤的肿瘤生长显著延迟，这与通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记和免疫组织化学分析确定的增强的细胞凋亡相关。Seliciclib增强了EBV阳性鼻咽癌放疗的抗肿瘤疗效，其特征是G（2）-M阻滞和细胞凋亡，与半胱天冬酶活性的诱导相关。该过程通过Mcl-1表达的减少和双链DNA断裂修复的减弱来介导。
Purpose: Seliciclib is a small-molecule cyclin-dependent kinase inhibitor, which has been reported to induce apoptosis and cell cycle arrest in EBV-negative nasopharyngeal carcinoma cell lines. Because most nasopharyngeal carcinoma patients harbor EBV, we proceeded to evaluate the cytotoxic effects of seliciclib in EBV-positive nasopharyngeal carcinoma models.Experimental Design: Cytotoxicity of seliciclib was investigated in the EBV-positive cell line C666-1 and the C666-1 and C15 xenograft models. Caspase activities and cell cycle analyses were measured by flow cytometry. Efficacy of combined treatment of seliciclib with radiation therapy was also evaluated.Results: Seliciclib caused significant cytotoxicity in the C666-1 cells in a time- and dose-dependent manner, with accumulation of cells in both sub-G(1) and G(2)-M phases, indicative of apoptosis and cell cycle arrest, respectively. Caspase-2, -3, -8, and -9 activities were all increased, with caspase-3 being the most significantly activated at 48 h after treatment. These cells also showed a reduction of Mcl-1 mRNA and protein levels. Combined treatment of seliciclib with radiation therapy showed a synergistic interaction with enhanced cytotoxicity in C666-1 cells and delayed repair of double-strand DNA breaks. For in vivo models, significant delays in tumor growth were observed for both C666-1 and C15 tumors, which were associated with enhanced apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and immunohistochemistry analyses.Conclusions: Seliciclib enhanced the antitumor efficacy of radiation therapy in EBV-positive nasopharyngeal carcinoma, characterized by G(2)-M arrest, and apoptosis, associated with an induction in caspase activity. This process is mediated by reduction in Mcl-1 expression and by attenuation of double-strand DNA break repair.