PMID- 23838676
OWN - NLM
STAT- MEDLINE
DCOM- 20140318
LR  - 20211203
IS  - 1473-5741 (Electronic)
IS  - 0959-4973 (Linking)
VI  - 24
IP  - 9
DP  - 2013 Oct
TI  - A dual mTORC1 and mTORC2 inhibitor shows antitumor activity in esophageal 
      squamous cell carcinoma cells and sensitizes them to cisplatin.
PG  - 889-98
LID - 10.1097/CAD.0b013e328363c64e [doi]
AB  - The mammalian target of rapamycin (mTOR) signaling pathway is critical for the 
      growth and proliferation of various malignant tumors, including esophageal 
      squamous cell carcinoma (ESCC). Therefore, targeting of mTOR protein is a 
      promising strategy for therapy in this disease. In the present study, we examined 
      the antitumor effects of a specific mTOR kinase inhibitor, PP242, which blocks 
      both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) pathways, in two ESCC 
      cell lines: Eca-109 and TE-1. We showed that PP242, but not rapamycin, attenuated 
      the activities of both mTORC1 and mTORC2 signaling in ESCC. PP242 inhibited 
      4E-binding protein-1 phosphorylation and abrogated mTORC1-dependent PI3K/Akt 
      feedback activation. Significantly, PP242 effectively suppressed ESCC cell 
      proliferation, induced apoptosis, and arrested the cell cycle. Furthermore, PP242 
      promoted cisplatin-induced apoptosis and enhanced the antitumor efficacy of 
      cisplatin in ESCC cells, which was likely to be associated with inhibition of Akt 
      activity. Our results show that simultaneous targeting of both mTORC1 and mTORC2 
      pathways leads to effective antitumor actions in ESCC, and strongly suggest that 
      dual mTORC1/2 inhibitors should be developed as potential agents for the 
      treatment of ESCC.
FAU - Huang, Yu
AU  - Huang Y
AD  - Cancer Center of Tongji Hospital, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan, China.
FAU - Xi, Qingsong
AU  - Xi Q
FAU - Chen, Yu
AU  - Chen Y
FAU - Wang, Jing
AU  - Wang J
FAU - Peng, Ping
AU  - Peng P
FAU - Xia, Shu
AU  - Xia S
FAU - Yu, Shiying
AU  - Yu S
LA  - eng
PT  - Journal Article
PL  - England
TA  - Anticancer Drugs
JT  - Anti-cancer drugs
JID - 9100823
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Indoles)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Purines)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - H5669VNZ7V (PP242)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Carcinoma, Squamous Cell/*drug therapy/enzymology/metabolism
MH  - Cell Cycle/drug effects
MH  - Cell Cycle Proteins
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cisplatin/*pharmacology
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Esophageal Neoplasms/*drug therapy/enzymology/metabolism
MH  - Esophageal Squamous Cell Carcinoma
MH  - Feedback, Physiological/drug effects
MH  - Humans
MH  - Indoles/pharmacology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Molecular Targeted Therapy
MH  - Multiprotein Complexes/*antagonists & inhibitors/metabolism
MH  - Neoplasm Proteins/antagonists & inhibitors/metabolism
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Protein Processing, Post-Translational/drug effects
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism
MH  - Purines/pharmacology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
EDAT- 2013/07/11 06:00
MHDA- 2014/03/19 06:00
CRDT- 2013/07/11 06:00
PHST- 2013/07/11 06:00 [entrez]
PHST- 2013/07/11 06:00 [pubmed]
PHST- 2014/03/19 06:00 [medline]
AID - 10.1097/CAD.0b013e328363c64e [doi]
PST - ppublish
SO  - Anticancer Drugs. 2013 Oct;24(9):889-98. doi: 10.1097/CAD.0b013e328363c64e.