Institute of Clinical Medicine, Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
Clin Cancer Res. 2011 Nov 15;17(22):7116-26. doi: 10.1158/1078-0432.CCR-11-0796. Epub 2011 Oct 5.
Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway frequently accounts for the tumorigenesis in head and neck cancer. To develop a new treatment, we investigated the effect of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in head and neck cancer cells.
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.
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 G(0)-G(1) 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.
These data indicate that BGT226 is a potential drug in the treatment of head and neck cancer.
磷酸肌醇 3-激酶（PI3K）/AKT/mTOR 信号通路的失调常常导致头颈部癌症的发生。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）对头颈部癌细胞的作用。
在各种癌细胞系中测定 BGT226 的体外抗肿瘤作用。还应用动物模型来检查药物效力。分析 BGT226 对 PI3K/AKT/mTOR 信号通路的抑制能力。
生长抑制试验表明 BGT226 对头颈部癌症所有测试的细胞系均有活性。在顺铂耐药细胞系中没有观察到交叉耐药性。BGT226 以浓度和时间依赖性方式抑制 AKT/mTOR 信号级联的激活。流式细胞术分析显示细胞在 G0-G1 期积累，同时 S 期减少。末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）测定和 caspase 3/7 和 PARP 的分析结果表明，BGT226 通过非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 的基因沉默或自噬体抑制剂 3-甲基腺嘌呤的共处理抑制了 BGT226 诱导的自噬，并导致集落存活的恢复。在异种移植动物模型中，BGT226 以剂量依赖性方式显著延迟肿瘤生长，同时抑制细胞质中 p-p70 S6 激酶的表达和自噬体的形成。
这些数据表明 BGT226 是治疗头颈部癌症的一种潜在药物。
