PMID- 15784722
OWN - NLM
STAT- MEDLINE
DCOM- 20060217
LR  - 20211203
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 19
IP  - 8
DP  - 2005 Jun
TI  - Identification of mTOR as a novel bifunctional target in chronic myeloid 
      leukemia: dissection of growth-inhibitory and VEGF-suppressive effects of 
      rapamycin in leukemic cells.
PG  - 960-2
AB  - The mammalian target of rapamycin (mTOR) has recently been described to be 
      constitutively activated in Bcr-Abl-transformed cells and to mediate 
      rapamycin-induced inhibition of growth in respective cell lines. We have recently 
      shown that rapamycin down-regulates expression of vascular endothelial growth 
      factor (VEGF), a mediator of leukemia-associated angiogenesis, in primary CML 
      cells. In the present study, we analyzed growth-inhibitory in vitro and in vivo 
      effects of rapamycin on primary CML cells and asked whether rapamycin-induced 
      suppression of VEGF in leukemic cells is related to growth inhibition. Rapamycin 
      dose dependently inhibited growth of primary CML cells obtained from patients 
      with imatinib-responsive or imatinib-resistant disease as well as growth of 
      Bcr-Abl-transformed imatinib-resistant cell lines. Moreover, we observed potent 
      cytoreductive effects of rapamycin in a patient with imatinib-resistant Bcr-Abl+ 
      leukemia. The growth-inhibitory effects of rapamycin on CML cells were found to 
      be associated with G1 cell cycle arrest and with induction of apoptosis. In all 
      cell types tested, rapamycin was found to down-regulate expression of VEGF. 
      However, exogenously added VEGF did not counteract the rapamycin-induced decrease 
      in proliferation. In conclusion, rapamycin inhibits growth of CML cells in vitro 
      and in vivo and, in addition, down-regulates expression of VEGF. Both effects may 
      contribute to the antileukemic activity of the drug in CML.
FAU - Mayerhofer, Matthias
AU  - Mayerhofer M
AD  - Department of Internal Medicine I, Division of Hematology and Hemostaseology, 
      Medical University of Vienna, Austria. matthias.mayerhofer@univie.ac.at
FAU - Aichberger, Karl J
AU  - Aichberger KJ
FAU - Florian, Stefan
AU  - Florian S
FAU - Krauth, Maria-Theresa
AU  - Krauth MT
FAU - Hauswirth, Alexander W
AU  - Hauswirth AW
FAU - Derdak, Sophia
AU  - Derdak S
FAU - Sperr, Wolfgang R
AU  - Sperr WR
FAU - Esterbauer, Harald
AU  - Esterbauer H
FAU - Wagner, Oswald
AU  - Wagner O
FAU - Marosi, Christine
AU  - Marosi C
FAU - Pickl, Winfried F
AU  - Pickl WF
FAU - Deininger, Michael
AU  - Deininger M
FAU - Weisberg, Ellen
AU  - Weisberg E
FAU - Druker, Brian J
AU  - Druker BJ
FAU - Griffin, James D
AU  - Griffin JD
FAU - Sillaber, Christian
AU  - Sillaber C
FAU - Valent, Peter
AU  - Valent P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20050322
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (Piperazines)
RN  - 0 (Pyrimidines)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Benzamides
MH  - Cell Cycle/drug effects
MH  - Cell Division/*drug effects
MH  - Cell Survival
MH  - Drug Resistance, Neoplasm
MH  - Flow Cytometry
MH  - Fusion Proteins, bcr-abl/analysis/genetics
MH  - G1 Phase/drug effects
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Imatinib Mesylate
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism/*pathology
MH  - Piperazines/pharmacology
MH  - Point Mutation
MH  - Protein Kinases/analysis/*physiology
MH  - Pyrimidines/pharmacology
MH  - Recombinant Proteins/pharmacology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A/*antagonists & 
      inhibitors/genetics/pharmacology
EDAT- 2005/03/24 09:00
MHDA- 2006/02/18 09:00
CRDT- 2005/03/24 09:00
PHST- 2005/03/24 09:00 [pubmed]
PHST- 2006/02/18 09:00 [medline]
PHST- 2005/03/24 09:00 [entrez]
AID - 04-1973fje [pii]
AID - 10.1096/fj.04-1973fje [doi]
PST - ppublish
SO  - FASEB J. 2005 Jun;19(8):960-2. doi: 10.1096/fj.04-1973fje. Epub 2005 Mar 22.