title: 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.
abstract: 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.
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria. matthias.mayerhofer@univie.ac.at
authors.forename: Matthias
authors.initials: M
authors.lastname: Mayerhofer
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Aichberger
authors.forename: Stefan
authors.initials: S
authors.lastname: Florian
authors.forename: Maria-Theresa
authors.initials: MT
authors.lastname: Krauth
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Hauswirth
authors.forename: Sophia
authors.initials: S
authors.lastname: Derdak
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.forename: Oswald
authors.initials: O
authors.lastname: Wagner
authors.forename: Christine
authors.initials: C
authors.lastname: Marosi
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.forename: Michael
authors.initials: M
authors.lastname: Deininger
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: Christian
authors.initials: C
authors.lastname: Sillaber
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000235:genetics; D016193:G1 Phase / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D011494:Protein Kinases / Q000032:analysis / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D011494:Protein Kinases; C546842:MTOR protein, human; D016044:Fusion Proteins, bcr-abl; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus