Novel Phosphoinositide 3-Kinase/mTOR Dual Inhibitor, NVP-BGT226, Displays Potent Growth-Inhibitory Activity against Human Head and Neck Cancer Cells In Vitro and In Vivo
Novel Phosphoinositide 3-Kinase/mTOR Dual Inhibitor, NVP-BGT226, Displays Potent Growth-Inhibitory Activity against Human Head and Neck Cancer Cells In Vitro and In Vivo
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DOI：
10.1158/1078-0432.ccr-11-0796
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发表时间：
2011-11-15
影响因子：
11.5
通讯作者：
Chang, Jang-Yang
中科院分区：
文献类型：
--
作者：
Chang, Kwang-Yu;Tsai, Shan-Yin;Chang, Jang-Yang
目的：磷脂酰肌醇3-激酶(PI3K)/AKT/mTOR信号通路的异常经常与头颈部肿瘤的发生有关。为了开发新的治疗方法，我们研究了新型双重PI3K/mTOR抑制剂NVP-BGT226(BGT226)在头颈部癌细胞中的作用。实验设计：测定BGT226在不同癌细胞系中的体外抗肿瘤作用。动物模型也被用来检验药物效力。结果：生长抑制实验表明，BGT226对所有受试癌细胞株均有抑制作用。顺铂耐药细胞株未观察到交叉耐药。BGT226以浓度和时间依赖的方式抑制AKT/mTOR信号级联的激活。流式细胞仪分析显示G0-G1期细胞聚集，S期细胞丢失。末端脱氧核苷酸转移酶介导的dUTP缺口末端标记(TUNEL)检测和caspase3/7及PARP分析结果表明，BGT226通过非细胞凋亡途径诱导癌细胞死亡。BGT226诱导自噬，表现为微管相关蛋白轻链3B-II的聚集和上调以及p62的降解。Beclin1的基因沉默或自噬小体抑制剂3-甲基腺嘌呤的共同处理可抑制BGT226诱导的自噬，并导致恢复集落存活。在异种移植动物模型中，BGT226以剂量依赖的方式显著延缓肿瘤生长，并抑制p-p70 S6激酶的胞浆表达和自噬小体的形成。结论：BGT226是一种治疗头颈部癌症的潜在药物。临床癌症资源；17(22)；7116-26。(C)2011年AACR。
Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway frequently accounts for the tumorigenesis in head and neck cancer. To develop anew treatment, we investigated the effect of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in head and neck cancer cells.Experimental Design: The in vitro antitumor effect of BGT226 was determined in various cancer cell lines. Animal models were also applied to examine drug potency. The inhibitory ability of BGT226 on the PI3K/AKT/mTOR signaling pathway was analyzed.Results: The growth inhibition assay revealed that BGT226 was active against all tested cancer cell lines. Cross-resistance was not observed in the cisplatin-resistant cell line. The activation of the AKT/mTOR signal cascade was suppressed by BGT226 in a concentration-and time-dependent manner. Flow cytometric analysis revealed an accumulation of cells in the G0-G1 phase with concomitant loss in the S-phase. Results of the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and the analysis of caspase 3/7 and PARP indicated that BGT226 induced cancer cell death through an apoptosis-independent pathway. BGT226 induced autophagy as indicated by the aggregation and upregulation of the microtubule-associated protein light chain 3B-II, and p62 degradation. Gene silencing of Beclin1 or cotreatment of the autophagosome inhibitor, 3-methyladenine, inhibited the BGT226-induced autophagy and led to the retrieval of colony survival. In a xenografted animal model, BGT226 significantly delayed tumor growth in a dose-dependent manner, along with suppressed cytoplasmic expression of p-p70 S6 kinase and the presence of autophagosome formation.Conclusions: These data indicate that BGT226 is a potential drug in the treatment of head and neck cancer. Clin Cancer Res; 17(22); 7116-26. (C) 2011 AACR.