PMID- 27107695
OWN - NLM
STAT- MEDLINE
DCOM- 20170510
LR  - 20211204
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 474
IP  - 2
DP  - 2016 May 27
TI  - MEK-ERK inhibition potentiates WAY-600-induced anti-cancer efficiency in 
      preclinical hepatocellular carcinoma (HCC) models.
PG  - 330-337
LID - S0006-291X(16)30604-0 [pii]
LID - 10.1016/j.bbrc.2016.04.099 [doi]
AB  - The search for novel anti-hepatocellular carcinoma (HCC) agents is important. 
      Mammalian target of rapamycin (mTOR) hyper-activation plays a pivotal role in 
      promoting HCC tumorigenesis and chemoresistance. The current preclinical study 
      evaluated the potential anti-HCC activity by a potent mTOR kinase inhibitor, 
      WAY-600. We showed that WAY-600 inhibited survival and proliferation of HCC cell 
      lines (HepG2 and Huh7) and primary human HCC cells. Caspase-dependent apoptosis 
      was activated by WAY-600 in above HCC cells. Reversely, caspase inhibitors 
      largely attenuated WAY-600's lethality against HCC cells. At the signaling level, 
      WAY-600 blocked mTOR complex 1/2 (mTORC1/2) assemble and activation, yet 
      activated MEK-ERK pathway in HCC cells. MEK-ERK inhibitors, PD-98059 and MEK-162, 
      or MEK1/2 shRNA significantly potentiated WAY-600's cytotoxicity in HCC cells. 
      Further studies showed that WAY-600 intraperitoneal (i.p.) administration in nude 
      mice inhibited p-AKT Ser-473 and displayed significant anti-cancer activity 
      against HepG2 xenografts. Remarkably, co-administration of MEK-162 further 
      potentiated WAY-600's anti-HCC activity in vivo. These preclinical results 
      demonstrate the potent anti-HCC activity by WAY-600, either alone or with MEK-ERK 
      inhibitors.
CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
FAU - Wang, Kaifeng
AU  - Wang K
AD  - Cancer center, the Affiliated Hospital of Hangzhou Normal University, Hangzhou, 
      China. Electronic address: kaifeng_wangdr@sina.com.
FAU - Fan, Yaohua
AU  - Fan Y
AD  - Oncology Department, No. 1 Hospital of Jiaxing, Zhejiang Province, Jiaxing, 
      China.
FAU - Chen, Gongying
AU  - Chen G
AD  - Oncology Department, The Affiliated Hospital Hangzhou Normal University, 
      Hangzhou, China.
FAU - Wang, Zhengrong
AU  - Wang Z
AD  - Taizhou Hospital, Zhejiang Province, Taizhou, China.
FAU - Kong, Dexin
AU  - Kong D
AD  - Oncology Department, Sir Run Run Shaw Hospital, Medical School, Zhejiang 
      University, Hangzhou, China.
FAU - Zhang, Peng
AU  - Zhang P
AD  - Oncology Department, Sir Run Run Shaw Hospital, Medical School, Zhejiang 
      University, Hangzhou, China.
LA  - eng
PT  - Journal Article
DEP - 20160421
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyridines)
RN  - 0 (pyrazolo(3,4-b)pyridine)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Female
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/*metabolism/pathology
MH  - MAP Kinase Signaling System/*drug effects
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Middle Aged
MH  - Pyrazoles/*administration & dosage
MH  - Pyridines/*administration & dosage
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Treatment Outcome
OTO - NOTNLM
OT  - Combined treatment
OT  - Hepatocellular carcinoma (HCC)
OT  - MEK-ERK
OT  - WAY-600
OT  - mTOR
EDAT- 2016/04/25 06:00
MHDA- 2017/05/11 06:00
CRDT- 2016/04/25 06:00
PHST- 2016/04/15 00:00 [received]
PHST- 2016/04/19 00:00 [accepted]
PHST- 2016/04/25 06:00 [entrez]
PHST- 2016/04/25 06:00 [pubmed]
PHST- 2017/05/11 06:00 [medline]
AID - S0006-291X(16)30604-0 [pii]
AID - 10.1016/j.bbrc.2016.04.099 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2016 May 27;474(2):330-337. doi: 
      10.1016/j.bbrc.2016.04.099. Epub 2016 Apr 21.