PMID- 24394624
OWN - NLM
STAT- MEDLINE
DCOM- 20141209
LR  - 20161125
IS  - 1638-6183 (Electronic)
IS  - 0300-9084 (Linking)
VI  - 101
DP  - 2014 Jun
TI  - Inhibition of hedgehog signaling by GANT58 induces apoptosis and shows 
      synergistic antitumor activity with AKT inhibitor in acute T cell leukemia cells.
PG  - 50-9
LID - S0300-9084(13)00469-0 [pii]
LID - 10.1016/j.biochi.2013.12.019 [doi]
AB  - The hedgehog (Hh) signaling pathways have a crucial role in cell proliferation 
      and survival, and the de-regulation of these pathways can lead to tumorigenesis. 
      Here we investigated the expression and function of these pathways in acute T 
      lymphocytic leukemia cells (T-ALL). Profiling of Hh pathway members revealed 
      common expression of key Hh signaling effectors in all T-ALL cells. We found that 
      T-ALL cells were insensitive to specific Smoothened (SMO) inhibition following 
      the use of low concentrations of the SMO antagonist cyclopamine. In contrast, 
      treatment with the novel GLI antagonist GANT58 reduced expression of the target 
      gene Patched 1 as well as GLI family zinc finger 1 (GLI1) and preferentially 
      decreased the viability of T-ALL cells. We also found perifosine, a novel AKT 
      inhibitor, down-regulated GLI1 protein by dephosphorylation of AKT and GSK3beta 
      dose-dependently and that pre-treatment with PD98059, a MEK/ERK pathway 
      inhibitor, enhanced this down-regulation by 20%-30%. Then we questioned whether 
      use of both GANT58 and AKT inhibitor together could confer a synergistic effect 
      to decrease T-ALL cell viability. By applying the Chou-Talalay method, low 
      concentration of GANT58 induced T-ALL cell death in a synergism fashion with 
      perifosine or GSK690693 when used simultaneously. These findings indicate that 
      the combined use of GANT58 and AKT inhibitor could help treat a broad range of 
      malignant tumors in conjunction with existing cancer treatments.
CI  - Copyright (c) 2014 Elsevier Masson SAS. All rights reserved.
FAU - Hou, Xiaoming
AU  - Hou X
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China. Electronic address: 
      houxiaoming11111@hotmail.com.
FAU - Chen, Xing
AU  - Chen X
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China.
FAU - Zhang, Ping
AU  - Zhang P
AD  - Department of Neurosurgery, Qi Lu Hospital, Shandong University, Jinan, PR China.
FAU - Fan, Youfei
AU  - Fan Y
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China.
FAU - Ma, Aihua
AU  - Ma A
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China.
FAU - Pang, Tingting
AU  - Pang T
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China.
FAU - Song, Zhao
AU  - Song Z
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China.
FAU - Jin, Youpeng
AU  - Jin Y
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China.
FAU - Hao, Wei
AU  - Hao W
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China.
FAU - Liu, Fengqin
AU  - Liu F
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China.
FAU - Wang, Wei
AU  - Wang W
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China.
FAU - Wang, Yulin
AU  - Wang Y
AD  - Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, 
      Shandong University, Jinan, PR China. Electronic address: 
      shandongwanghou@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140103
PL  - France
TA  - Biochimie
JT  - Biochimie
JID - 1264604
RN  - 0 (Antineoplastic Agents)
RN  - 0 (GANT58)
RN  - 0 (GLI1 protein, human)
RN  - 0 (GSK690693)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Oxadiazoles)
RN  - 0 (Pyridines)
RN  - 0 (Thiophenes)
RN  - 0 (Transcription Factors)
RN  - 0 (Veratrum Alkaloids)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - 107-73-3 (Phosphorylcholine)
RN  - 2GWV496552 (perifosine)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - ZH658AJ192 (cyclopamine)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Drug Screening Assays, Antitumor
MH  - Drug Synergism
MH  - Hedgehog Proteins/metabolism
MH  - Humans
MH  - Jurkat Cells
MH  - MAP Kinase Signaling System
MH  - Oxadiazoles/*pharmacology
MH  - Phosphorylcholine/*analogs & derivatives/pharmacology
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors
MH  - Pyridines/*pharmacology
MH  - Thiophenes/*pharmacology
MH  - Transcription Factors/antagonists & inhibitors/metabolism
MH  - Veratrum Alkaloids/pharmacology
MH  - Zinc Finger Protein GLI1
OTO - NOTNLM
OT  - AKT inhibitor
OT  - Apoptosis
OT  - GANT58
OT  - GLI1
OT  - T-ALL
EDAT- 2014/01/08 06:00
MHDA- 2014/12/15 06:00
CRDT- 2014/01/08 06:00
PHST- 2013/06/05 00:00 [received]
PHST- 2013/12/19 00:00 [accepted]
PHST- 2014/01/08 06:00 [entrez]
PHST- 2014/01/08 06:00 [pubmed]
PHST- 2014/12/15 06:00 [medline]
AID - S0300-9084(13)00469-0 [pii]
AID - 10.1016/j.biochi.2013.12.019 [doi]
PST - ppublish
SO  - Biochimie. 2014 Jun;101:50-9. doi: 10.1016/j.biochi.2013.12.019. Epub 2014 Jan 3.