title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 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.
  
  
  CONCLUSIONS
  These data indicate that BGT226 is a potential drug in the treatment of head and neck cancer.
authors: Institute of Clinical Medicine, Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors: Kwang-Yu
authors: KY
authors: Chang
authors: Shan-Yin
authors: SY
authors: Tsai
authors: Ching-Ming
authors: CM
authors: Wu
authors: Chia-Jui
authors: CJ
authors: Yen
authors: Bin-Fay
authors: BF
authors: Chuang
authors: Jang-Yang
authors: JY
authors: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C570852:8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one; D000970:Antineoplastic Agents; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases