PMID- 27863431
OWN - NLM
STAT- MEDLINE
DCOM- 20180221
LR  - 20211204
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 51
DP  - 2016 Dec 20
TI  - Synergistic antitumor activity of the combination of salubrinal and rapamycin 
      against human cholangiocarcinoma cells.
PG  - 85492-85501
LID - 10.18632/oncotarget.13408 [doi]
AB  - Less is known about the roles of eukaryotic initiation factor alpha (eIF2alpha) in 
      cholangiocarcinoma (CCA). Here, we report that eIF2alpha inhibitor salubrinal 
      inhibits the proliferation of human CCA cells. Clinical application of mammalian 
      target of rapamycin (mTOR) inhibitors only has moderate antitumor efficacy. 
      Therefore, combination approaches may be required for effective clinical use of 
      mTOR inhibitors. Here, we investigated the efficacy of the combination of 
      salubrinal and rapamycin in the treatment of CCA. Our data demonstrate a 
      synergistic antitumor effect of the combination of salubrinal and rapamycin 
      against CCA cells. Rapamycin significantly inhibits the proliferation of CCA 
      cells. However, rapamycin initiates a negative feedback activation of Akt. 
      Inhibition of Akt by salubrinal potentiates the efficacy of rapamycin both in 
      vitro and in vivo. Additionally, rapamycin treatment results in the up-regulation 
      of Bcl-xL in a xenograft mouse model. It is notable that salubrinal inhibits 
      rapamycin-induced Bcl-xL up-regulation in vivo. Taken together, our data suggest 
      that salubrinal and rapamycin combination might be a new and effective strategy 
      for the treatment of CCA.
FAU - Zhao, Xiaofang
AU  - Zhao X
AD  - Department of Biochemistry and Molecular Biology, Southwest Medical University, 
      Luzhou, Sichuan, China.
FAU - Zhang, Chunyan
AU  - Zhang C
AD  - Department of Biochemistry and Molecular Biology, Southwest Medical University, 
      Luzhou, Sichuan, China.
FAU - Zhou, Hong
AU  - Zhou H
AD  - Department of Biochemistry and Molecular Biology, Southwest Medical University, 
      Luzhou, Sichuan, China.
FAU - Xiao, Bin
AU  - Xiao B
AD  - Department of Biochemistry and Molecular Biology, Southwest Medical University, 
      Luzhou, Sichuan, China.
FAU - Cheng, Ying
AU  - Cheng Y
AD  - Department of Biochemistry and Molecular Biology, Southwest Medical University, 
      Luzhou, Sichuan, China.
FAU - Wang, Jinju
AU  - Wang J
AD  - Department of Hepatobiliary Surgery of the Affiliated Hospital, Southwest Medical 
      University, Luzhou, Sichuan, China.
FAU - Yao, Fuli
AU  - Yao F
AD  - Department of Biochemistry and Molecular Biology, Southwest Medical University, 
      Luzhou, Sichuan, China.
FAU - Duan, Chunyan
AU  - Duan C
AD  - Department of Biochemistry and Molecular Biology, Southwest Medical University, 
      Luzhou, Sichuan, China.
FAU - Chen, Run
AU  - Chen R
AD  - Department of Public Health, Southwest Medical University, Luzhou, Sichuan, 
      China.
FAU - Liu, Youping
AU  - Liu Y
AD  - Department of Hepatobiliary Surgery of the Affiliated Hospital, Southwest Medical 
      University, Luzhou, Sichuan, China.
FAU - Feng, Chunhong
AU  - Feng C
AD  - Department of Hepatobiliary Surgery of the Affiliated Hospital, Southwest Medical 
      University, Luzhou, Sichuan, China.
FAU - Li, Hong
AU  - Li H
AD  - Department of Biochemistry and Molecular Biology, Southwest Medical University, 
      Luzhou, Sichuan, China.
FAU - Li, Jing
AU  - Li J
AD  - Department of Hepatobiliary Surgery of the Affiliated Hospital, Southwest Medical 
      University, Luzhou, Sichuan, China.
FAU - Dai, Rongyang
AU  - Dai R
AD  - Department of Biochemistry and Molecular Biology, Southwest Medical University, 
      Luzhou, Sichuan, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (BCL2L1 protein, human)
RN  - 0 (Cinnamates)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (bcl-X Protein)
RN  - 0 (salubrinal)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - GYV9AM2QAG (Thiourea)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Bile Duct Neoplasms/*drug therapy/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cholangiocarcinoma/*drug therapy/metabolism/pathology
MH  - Cinnamates/*pharmacology
MH  - Drug Synergism
MH  - Eukaryotic Initiation Factor-2/antagonists & inhibitors/metabolism
MH  - Humans
MH  - Male
MH  - Mice, Nude
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Thiourea/*analogs & derivatives/pharmacology
MH  - Time Factors
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
MH  - bcl-X Protein/metabolism
PMC - PMC5356752
OTO - NOTNLM
OT  - Akt
OT  - Bcl-xL
OT  - cholangiocarcinoma
OT  - rapamycin
OT  - salubrinal
COIS- CONFLICTS OF INTEREST No potential conflicts of interest were disclosed.
EDAT- 2016/11/20 06:00
MHDA- 2018/02/22 06:00
PMCR- 2016/12/20
CRDT- 2016/11/19 06:00
PHST- 2016/08/20 00:00 [received]
PHST- 2016/10/27 00:00 [accepted]
PHST- 2016/11/20 06:00 [pubmed]
PHST- 2018/02/22 06:00 [medline]
PHST- 2016/11/19 06:00 [entrez]
PHST- 2016/12/20 00:00 [pmc-release]
AID - 13408 [pii]
AID - 10.18632/oncotarget.13408 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Dec 20;7(51):85492-85501. doi: 10.18632/oncotarget.13408.