PMID- 23415012
OWN - NLM
STAT- MEDLINE
DCOM- 20130725
LR  - 20211203
IS  - 1756-8722 (Electronic)
IS  - 1756-8722 (Linking)
VI  - 6
DP  - 2013 Feb 18
TI  - SNS-032 inhibits mTORC1/mTORC2 activity in acute myeloid leukemia cells and has 
      synergistic activity with perifosine against Akt.
PG  - 18
LID - 10.1186/1756-8722-6-18 [doi]
AB  - BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disorder with 
      aberrant regulation of a variety of signal pathways. Therefore, simultaneous 
      targeting of two or even more deregulated signal transduction pathways is needed 
      to overcome drug resistance. Previously, it was reported that SNS-032, a 
      selective cyclin-dependent kinase inhibitor, is an effective agent for treatment 
      of AML; however, the molecular mechanisms of SNS-032-induced cell death of AML 
      cells are not yet fully understood. The aim of the study was to characterize the 
      effects in vitro of SNS-032, used alone and in combination with an Akt inhibitor 
      perifosine, against AML cells and to identify the mechanism involved. RESULTS: 
      SNS-032 significantly induced cytotoxicity in human AML cell lines and blasts 
      from patients with newly diagnosed or relapsed AML. However, Kasumi-1 cells and 
      some of leukemic samples (14.9%) from AML patients were resistant to 
      SNS-032-mediated cell death. Western blot analysis showed that SNS-032 strongly 
      inhibited the phosphorylation of mammalian target of rapamycin (mTOR) on Ser 2448 
      and Ser2481, and that removal of SNS-032 resulted in partial recovery of cell 
      death and reactivation of phosphorylation of mTOR. Moreover, exogenous 
      insulin-like growth factor-1 (IGF-1) did not reverse SNS-032-induced cell growth 
      inhibition and downregualtion of phosphor-mTOR at Ser2448 and Ser2481 although 
      slight suppression of IGF-1R expression was triggered by the agent. Furthermore, 
      SNS-032 at a lower concentration (60-80 nM) enhanced AML cell cytotoxicity 
      induced by perifosine, an Akt inhibitor. Importantly, SNS-032 treatment reduced 
      colony formation ability of AML cells, which was significantly increased when two 
      agents were combined. This combination therapy led to almost complete inhibition 
      of Akt activity. CONCLUSION: We conclude that SNS-032 might directly target 
      mammalian target of rapamycin complex 1 (mTORC1)/mTORC2. Our results further 
      provide a rationale for combining SNS-032 with perifosine for the treatment of 
      AML.
FAU - Meng, Haitao
AU  - Meng H
AD  - Institute of Hematology, The First Affiliated Hospital, College of Medicine, 
      Zhejiang University, 79# Qingchun Road, Hangzhou, 310003, PR China.
FAU - Jin, Yingming
AU  - Jin Y
FAU - Liu, Hui
AU  - Liu H
FAU - You, Liangshun
AU  - You L
FAU - Yang, Chunmei
AU  - Yang C
FAU - Yang, Xue
AU  - Yang X
FAU - Qian, Wenbin
AU  - Qian W
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130218
PL  - England
TA  - J Hematol Oncol
JT  - Journal of hematology & oncology
JID - 101468937
RN  - 0 (Multiprotein Complexes)
RN  - 0 
      (N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide)
RN  - 0 (Oxazoles)
RN  - 0 (RNA, Messenger)
RN  - 0 (Thiazoles)
RN  - 107-73-3 (Phosphorylcholine)
RN  - 2GWV496552 (perifosine)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Cell Proliferation/drug effects
MH  - Drug Synergism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Flow Cytometry
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*drug therapy/metabolism/pathology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Multiprotein Complexes/*antagonists & inhibitors/genetics/metabolism
MH  - Oxazoles/*pharmacology
MH  - Phosphorylation/drug effects
MH  - Phosphorylcholine/*analogs & derivatives/pharmacology
MH  - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors/genetics/metabolism
MH  - RNA, Messenger/genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism
MH  - Thiazoles/*pharmacology
MH  - Tumor Cells, Cultured
PMC - PMC3599109
EDAT- 2013/02/19 06:00
MHDA- 2013/07/26 06:00
PMCR- 2013/02/18
CRDT- 2013/02/19 06:00
PHST- 2012/11/18 00:00 [received]
PHST- 2013/02/08 00:00 [accepted]
PHST- 2013/02/19 06:00 [entrez]
PHST- 2013/02/19 06:00 [pubmed]
PHST- 2013/07/26 06:00 [medline]
PHST- 2013/02/18 00:00 [pmc-release]
AID - 1756-8722-6-18 [pii]
AID - 10.1186/1756-8722-6-18 [doi]
PST - epublish
SO  - J Hematol Oncol. 2013 Feb 18;6:18. doi: 10.1186/1756-8722-6-18.