PMID- 21835141
OWN - NLM
STAT- MEDLINE
DCOM- 20120521
LR  - 20211203
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 56
IP  - 1
DP  - 2012 Jan
TI  - Dual targeting of mTORC1/C2 complexes enhances histone deacetylase 
      inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in 
      vivo.
PG  - 176-83
LID - 10.1016/j.jhep.2011.07.013 [doi]
AB  - BACKGROUND & AIMS: The mammalian target of rapamycin (mTOR) plays a pivotal role 
      in hepatocellular carcinoma (HCC). Previous studies indicated that inhibition of 
      mTORC1 enhanced histone deacetylase inhibitors (HDACis)-mediated anti-tumor 
      activity, accompanied with feedback activation of AKT. Therefore, dual targeting 
      of mTORC1/C2 should be more efficient in suppressing AKT activity and in 
      enhancing the anti-tumor activity of HDACi in HCC. METHODS: The interactions 
      between mTOR kinase inhibitors (mTORKis) (i.e., Pp242, AZD8055, OSI027) and 
      HDACis (i.e., SAHA, LBH589) were examined in vitro using HCC cell lines and in 
      vivo using patient-derived primary HCC xenografts on SCID mice. RESULTS: mTORKis 
      significantly enhanced HDACi-induced apoptosis in HCC cells. The inhibition of 
      both mTORC1/2 not only efficiently blocked mTORC1 signaling, but also abrogated 
      AKT-feedback activation caused by selective mTORC1 inhibition. The co-treatment 
      of mTORKi and HDACi further inhibited AKT signaling and upregulated Bim. 
      Dysfunction of mTORC2 by shRNA significantly lowered the threshold of 
      HDACi-induced cytotoxicity by abrogating AKT activation. Knockdown of AKT1 
      sensitized Pp242/HDACi-induced apoptosis and ectopic expression of constitutively 
      active AKT1 abrogated the combination-induced cytotoxicity, indicating AKT plays 
      a vital role in the combination-induced effects. Knockdown of Bim prevented 
      Pp242/HDACis-induced cytotoxicity in HCC. Lastly, in vivo studies indicated that 
      the combination of AZD8055 and SAHA almost completely inhibited tumor-growth, 
      without obvious adverse effects, by abrogating AKT and upregulating Bim; while 
      either agent alone shows only 30% inhibition in primary HCC xenografts. 
      CONCLUSIONS: Our findings suggest that a combining-regimen of mTORKi and HDACi 
      may be an effective therapeutic strategy for HCC.
CI  - Copyright (c) 2011 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Shao, Huanjie
AU  - Shao H
AD  - Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
FAU - Gao, Chun
AU  - Gao C
FAU - Tang, Haikuo
AU  - Tang H
FAU - Zhang, Hao
AU  - Zhang H
FAU - Roberts, Lewis R
AU  - Roberts LR
FAU - Hylander, Bonnie L
AU  - Hylander BL
FAU - Repasky, Elizabeth A
AU  - Repasky EA
FAU - Ma, Wen W
AU  - Ma WW
FAU - Qiu, Jingxin
AU  - Qiu J
FAU - Adjei, Alex A
AU  - Adjei AA
FAU - Dy, Grace K
AU  - Dy GK
FAU - Yu, Chunrong
AU  - Yu C
LA  - eng
PT  - Journal Article
DEP - 20110809
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BCL2L11 protein, human)
RN  - 0 (Bcl-2-Like Protein 11)
RN  - 0 (Bcl2l11 protein, mouse)
RN  - 0 (CRTC2 protein, human)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Membrane Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Transcription Factors)
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 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis Regulatory Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Base Sequence
MH  - Bcl-2-Like Protein 11
MH  - Carcinoma, Hepatocellular/*drug therapy/genetics/metabolism/pathology
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Histone Deacetylase Inhibitors/*administration & dosage
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Membrane Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Mice
MH  - Mice, SCID
MH  - Multiprotein Complexes
MH  - Proteins/*antagonists & inhibitors
MH  - Proto-Oncogene Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/genetics/metabolism
MH  - RNA, Small Interfering/genetics
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/*antagonists & inhibitors
MH  - Xenograft Model Antitumor Assays
EDAT- 2011/08/13 06:00
MHDA- 2012/05/23 06:00
CRDT- 2011/08/13 06:00
PHST- 2011/02/06 00:00 [received]
PHST- 2011/07/05 00:00 [revised]
PHST- 2011/07/07 00:00 [accepted]
PHST- 2011/08/13 06:00 [entrez]
PHST- 2011/08/13 06:00 [pubmed]
PHST- 2012/05/23 06:00 [medline]
AID - S0168-8278(11)00575-7 [pii]
AID - 10.1016/j.jhep.2011.07.013 [doi]
PST - ppublish
SO  - J Hepatol. 2012 Jan;56(1):176-83. doi: 10.1016/j.jhep.2011.07.013. Epub 2011 Aug 
      9.