PMID- 21976531
OWN - NLM
STAT- MEDLINE
DCOM- 20120325
LR  - 20230815
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 17
IP  - 22
DP  - 2011 Nov 15
TI  - 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.
PG  - 7116-26
LID - 10.1158/1078-0432.CCR-11-0796 [doi]
AB  - PURPOSE: 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. 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 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.
FAU - Chang, Kwang-Yu
AU  - Chang KY
AD  - Institute of Clinical Medicine, Department of Cell Biology and Anatomy, College 
      of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
FAU - Tsai, Shan-Yin
AU  - Tsai SY
FAU - Wu, Ching-Ming
AU  - Wu CM
FAU - Yen, Chia-Jui
AU  - Yen CJ
FAU - Chuang, Bin-Fay
AU  - Chuang BF
FAU - Chang, Jang-Yang
AU  - Chang JY
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111005
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 
      (8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Drug Evaluation, Preclinical
MH  - Head and Neck Neoplasms/drug therapy
MH  - Humans
MH  - Imidazoles/*therapeutic use
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Quinolines/*therapeutic use
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Xenograft Model Antitumor Assays
EDAT- 2011/10/07 06:00
MHDA- 2012/03/27 06:00
CRDT- 2011/10/07 06:00
PHST- 2011/10/07 06:00 [entrez]
PHST- 2011/10/07 06:00 [pubmed]
PHST- 2012/03/27 06:00 [medline]
AID - 1078-0432.CCR-11-0796 [pii]
AID - 10.1158/1078-0432.CCR-11-0796 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2011 Nov 15;17(22):7116-26. doi: 10.1158/1078-0432.CCR-11-0796. 
      Epub 2011 Oct 5.