PMID- 23271044
OWN - NLM
STAT- MEDLINE
DCOM- 20130812
LR  - 20211203
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 3
IP  - 12
DP  - 2012 Dec
TI  - A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as 
      a new therapeutic option for patients with acute myeloid leukemia.
PG  - 1615-28
AB  - Signaling through the phosphatidylinositol 3-kinase (PI3K) pathway and its 
      downstream effectors, Akt and mechanistic target of rapamycin (mTOR), is 
      aberrantly activated in acute myeloid leukemia (AML) patients, where it 
      contributes to leukemic cell proliferation, survival, and drug-resistance. Thus, 
      inhibiting mTOR signaling in AML blasts could enhance their sensitivity to 
      cytotoxic agents. Preclinical data also suggest that allosteric mTOR inhibition 
      with rapamycin impaired leukemia initiating cells (LICs) function. In this study, 
      we assessed the therapeutic potential of a combination consisting of temsirolimus 
      [an allosteric mTOR complex 1 (mTORC1) inhibitor] with clofarabine, a nucleoside 
      analogue with potent inhibitory effects on both ribonucleotide reductase and DNA 
      polymerase. The drug combination (CLO-TOR) displayed synergistic cytotoxic 
      effects against a panel of AML cell lines and primary cells from AML patients. 
      Treatment with CLO-TOR induced a G(0)/G(1)-phase cell cycle arrest, apoptosis, and 
      autophagy. CLO-TOR was pro-apoptotic in an AML patient blast subset 
      (CD34(+)/CD38(-)/CD123(+)), which is enriched in putative leukemia initiating cells 
      (LICs). In summary, the CLO-TOR combination could represent a novel valuable 
      treatment for AML patients, also in light of its efficacy against LICs.
FAU - Chiarini, Francesca
AU  - Chiarini F
AD  - Institute of Molecular Genetics, National Research Council, Bologna, Italy.
FAU - Lonetti, Annalisa
AU  - Lonetti A
FAU - Teti, Gabriella
AU  - Teti G
FAU - Orsini, Ester
AU  - Orsini E
FAU - Bressanin, Daniela
AU  - Bressanin D
FAU - Cappellini, Alessandra
AU  - Cappellini A
FAU - Ricci, Francesca
AU  - Ricci F
FAU - Tazzari, Pier Luigi
AU  - Tazzari PL
FAU - Ognibene, Andrea
AU  - Ognibene A
FAU - Falconi, Mirella
AU  - Falconi M
FAU - Pagliaro, Pasqualepaolo
AU  - Pagliaro P
FAU - Iacobucci, Ilaria
AU  - Iacobucci I
FAU - Martinelli, Giovanni
AU  - Martinelli G
FAU - Amadori, Sergio
AU  - Amadori S
FAU - McCubrey, James A
AU  - McCubrey JA
FAU - Martelli, Alberto M
AU  - Martelli AM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Adenine Nucleotides)
RN  - 0 (Antigens, CD34)
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Arabinonucleosides)
RN  - 0 (Eukaryotic Initiation Factor-4F)
RN  - 0 (IL3RA protein, human)
RN  - 0 (Interleukin-3 Receptor alpha Subunit)
RN  - 0 (MYC protein, human)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 624KN6GM2T (temsirolimus)
RN  - 762RDY0Y2H (Clofarabine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.2.2.5 (CD38 protein, human)
RN  - EC 3.2.2.6 (ADP-ribosyl Cyclase 1)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Cell Cycle. 2013 Jun 15;12(12):1815-6. PMID: 23708511
MH  - ADP-ribosyl Cyclase 1/metabolism
MH  - Adenine Nucleotides/pharmacology
MH  - Allosteric Regulation
MH  - Antigens, CD34/metabolism
MH  - Antimetabolites, Antineoplastic/pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Apoptosis/drug effects
MH  - Arabinonucleosides/pharmacology
MH  - Autophagy/drug effects
MH  - Cell Line, Tumor
MH  - Clofarabine
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Eukaryotic Initiation Factor-4F/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - G1 Phase Cell Cycle Checkpoints/drug effects
MH  - Humans
MH  - Interleukin-3 Receptor alpha Subunit/metabolism
MH  - Leukemia, Myeloid, Acute/*drug therapy/enzymology/immunology/pathology
MH  - Membrane Glycoproteins/metabolism
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Proto-Oncogene Proteins c-myc/metabolism
MH  - STAT3 Transcription Factor/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Time Factors
MH  - Tumor Cells, Cultured
PMC - PMC3681499
COIS- The authors have no conflict of interest to disclose.
EDAT- 2012/12/29 06:00
MHDA- 2013/08/13 06:00
PMCR- 2012/12/01
CRDT- 2012/12/29 06:00
PHST- 2012/12/29 06:00 [entrez]
PHST- 2012/12/29 06:00 [pubmed]
PHST- 2013/08/13 06:00 [medline]
PHST- 2012/12/01 00:00 [pmc-release]
AID - 762 [pii]
AID - 10.18632/oncotarget.762 [doi]
PST - ppublish
SO  - Oncotarget. 2012 Dec;3(12):1615-28. doi: 10.18632/oncotarget.762.