PMID- 21331075
OWN - NLM
STAT- MEDLINE
DCOM- 20110809
LR  - 20211203
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 25
IP  - 5
DP  - 2011 May
TI  - Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has 
      cytotoxic effects in T-cell acute lymphoblastic leukemia.
PG  - 781-91
LID - 10.1038/leu.2011.20 [doi]
AB  - The mammalian Target Of Rapamycin (mTOR) serine/threonine kinase belongs to two 
      multi-protein complexes, referred to as mTORC1 and mTORC2. mTOR-generated signals 
      have critical roles in leukemic cell biology by controlling mRNA translation of 
      genes that promote proliferation and survival. However, allosteric inhibition of 
      mTORC1 by rapamycin has only modest effects in T-cell acute lymphoblastic 
      leukemia (T-ALL). Recently, ATP-competitive inhibitors specific for the mTOR 
      kinase active site have been developed. In this study, we have explored the 
      therapeutic potential of active-site mTOR inhibitors against both T-ALL cell 
      lines and primary samples from T-ALL patients displaying activation of mTORC1 and 
      mTORC2. The inhibitors affected T-ALL cell viability by inducing cell-cycle 
      arrest in G(0)/G(1) phase, apoptosis and autophagy. Western blot analysis 
      demonstrated a Ser 473 Akt dephosphorylation (indicative of mTORC2 inhibition) 
      and a dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found 
      a marked inhibition of mRNA translation in T-ALL cell lines treated with 
      active-site mTOR inhibitors. The inhibitors strongly synergized with both 
      vincristine and the Bcl-2 inhibitor, ABT-263. Remarkably, the drugs targeted a 
      putative leukemia-initiating cell sub-population (CD34(+)/CD7(-)/CD4(-)) in 
      patient samples. In conclusion, the inhibitors displayed remarkable anti-leukemic 
      activity, which emphasizes their future development as clinical candidates for 
      therapy in T-ALL.
FAU - Evangelisti, C
AU  - Evangelisti C
AD  - Department of Human Anatomy, University of Bologna, Bologna, Italy.
FAU - Ricci, F
AU  - Ricci F
FAU - Tazzari, P
AU  - Tazzari P
FAU - Tabellini, G
AU  - Tabellini G
FAU - Battistelli, M
AU  - Battistelli M
FAU - Falcieri, E
AU  - Falcieri E
FAU - Chiarini, F
AU  - Chiarini F
FAU - Bortul, R
AU  - Bortul R
FAU - Melchionda, F
AU  - Melchionda F
FAU - Pagliaro, P
AU  - Pagliaro P
FAU - Pession, A
AU  - Pession A
FAU - McCubrey, J A
AU  - McCubrey JA
FAU - Martelli, A M
AU  - Martelli AM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110218
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (CRTC2 protein, human)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Autophagy/*drug effects
MH  - Blotting, Western
MH  - Catalytic Domain
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Flow Cytometry
MH  - Humans
MH  - Immunosuppressive Agents/pharmacology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Multiprotein Complexes
MH  - Phosphorylation/drug effects
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug 
      therapy/metabolism/*pathology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proteins/*antagonists & inhibitors/metabolism
MH  - RNA, Messenger/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/*antagonists & inhibitors/metabolism
EDAT- 2011/02/19 06:00
MHDA- 2011/08/10 06:00
CRDT- 2011/02/19 06:00
PHST- 2011/02/19 06:00 [entrez]
PHST- 2011/02/19 06:00 [pubmed]
PHST- 2011/08/10 06:00 [medline]
AID - leu201120 [pii]
AID - 10.1038/leu.2011.20 [doi]
PST - ppublish
SO  - Leukemia. 2011 May;25(5):781-91. doi: 10.1038/leu.2011.20. Epub 2011 Feb 18.