PMID- 28366631
OWN - NLM
STAT- MEDLINE
DCOM- 20170704
LR  - 20211204
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 487
IP  - 3
DP  - 2017 Jun 3
TI  - The anti-hepatocellular carcinoma cell activity by a novel mTOR kinase inhibitor 
      CZ415.
PG  - 494-499
LID - S0006-291X(17)30633-2 [pii]
LID - 10.1016/j.bbrc.2017.03.156 [doi]
AB  - Dysregulation of mammalian target of rapamycin (mTOR) in hepatocellular carcinoma 
      (HCC) represents a valuable treatment target. Recent studies have developed a 
      highly-selective and potent mTOR kinase inhibitor, CZ415. Here, we showed that nM 
      concentrations of CZ415 efficiently inhibited survival and induced apoptosis in 
      HCC cell lines (HepG2 and Huh-7) and primary-cultured human HCC cells. Meanwhile, 
      CZ415 inhibited proliferation of HCC cells, more potently than mTORC1 inhibitors 
      (rapamycin and RAD001). CZ415 was yet non-cytotoxic to the L02 human hepatocytes. 
      Mechanistic studies showed that CZ415 disrupted assembly of mTOR complex 1 
      (mTORC1) and mTORC2 in HepG2 cells. Meanwhile, activation of mTORC1 (p-S6K1) and 
      mTORC2 (p-AKT, Ser-473) was almost blocked by CZ415. In vivo studies revealed 
      that oral administration of CZ415 significantly suppressed HepG2 xenograft tumor 
      growth in severe combined immuno-deficient (SCID) mice. Activation of mTORC1/2 
      was also largely inhibited in CZ415-treated HepG2 tumor tissue. Together, these 
      results show that CZ415 blocks mTORC1/2 activation and efficiently inhibits HCC 
      cell growth in vitro and in vivo.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Zhang, Wei
AU  - Zhang W
AD  - Department of Gastrointestinal Pancreatic Surgery, Zhejiang Provincial People's 
      Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China; 
      Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory 
      of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital 
      of Hangzhou medical College, Hangzhou, China.
FAU - Chen, Bingyu
AU  - Chen B
AD  - Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory 
      of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital 
      of Hangzhou medical College, Hangzhou, China.
FAU - Zhang, Yu
AU  - Zhang Y
AD  - Clinical Research Institute, Zhejiang Provincial People's Hospital, People's 
      Hospital of Hangzhou medical College, Hangzhou, China.
FAU - Li, Kaiqiang
AU  - Li K
AD  - Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory 
      of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital 
      of Hangzhou medical College, Hangzhou, China.
FAU - Hao, Ke
AU  - Hao K
AD  - Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory 
      of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital 
      of Hangzhou medical College, Hangzhou, China.
FAU - Jiang, Luxi
AU  - Jiang L
AD  - Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory 
      of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital 
      of Hangzhou medical College, Hangzhou, China.
FAU - Wang, Ying
AU  - Wang Y
AD  - Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory 
      of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital 
      of Hangzhou medical College, Hangzhou, China.
FAU - Mou, Xiaozhou
AU  - Mou X
AD  - Clinical Research Institute, Zhejiang Provincial People's Hospital, People's 
      Hospital of Hangzhou medical College, Hangzhou, China.
FAU - Xu, Xiaodong
AU  - Xu X
AD  - Department of Gastrointestinal Pancreatic Surgery, Zhejiang Provincial People's 
      Hospital, People's Hospital of Hangzhou medical College, Hangzhou, China. 
      Electronic address: drxxklzjsry@163.com.
FAU - Wang, Zhen
AU  - Wang Z
AD  - Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory 
      of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital 
      of Hangzhou medical College, Hangzhou, China; Clinical Research Institute, 
      Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou medical 
      College, Hangzhou, China. Electronic address: drzwklzjsry@163.com.
LA  - eng
PT  - Journal Article
DEP - 20170330
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CZ415 compound)
RN  - 0 (Cyclic S-Oxides)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Apoptosis/drug effects
MH  - Carcinoma, Hepatocellular/drug therapy/*enzymology/*pathology
MH  - Cell Cycle/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cyclic S-Oxides/chemical synthesis/chemistry/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Drug Screening Assays, Antitumor
MH  - Hep G2 Cells
MH  - Humans
MH  - Liver Neoplasms/drug therapy/*enzymology/*pathology
MH  - Phenylurea Compounds/chemical synthesis/chemistry/*pharmacology
MH  - Protein Kinase Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Tumor Cells, Cultured
OTO - NOTNLM
OT  - Apoptosis
OT  - CZ415
OT  - Hepatocellular carcinoma
OT  - Mammalian target of rapamycin (mTOR)
EDAT- 2017/04/04 06:00
MHDA- 2017/07/05 06:00
CRDT- 2017/04/04 06:00
PHST- 2017/03/23 00:00 [received]
PHST- 2017/03/29 00:00 [accepted]
PHST- 2017/04/04 06:00 [pubmed]
PHST- 2017/07/05 06:00 [medline]
PHST- 2017/04/04 06:00 [entrez]
AID - S0006-291X(17)30633-2 [pii]
AID - 10.1016/j.bbrc.2017.03.156 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2017 Jun 3;487(3):494-499. doi: 
      10.1016/j.bbrc.2017.03.156. Epub 2017 Mar 30.