Document Detail


MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825.
MedLine Citation:
PMID:  17218385     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Interactions between MEK1/2 inhibitors and the dual Abl/Src kinase inhibitor dasatinib (BMS-354825) were examined in chronic myeloid leukemia (CML) cell lines and primary specimens. Cotreatment of K562 or LAMA cells with subtoxic or marginally toxic concentrations of PD184352 (or U0126) and dasatinib synergistically potentiated mitochondrial damage, caspase activation, and apoptosis. Similar interactions were observed in CD34(+) cells from one CML patient-derived but not in a normal human CD34(+) bone marrow cell specimen. These interactions were associated with multiple perturbations in survival signaling pathways, including inactivation of Bcr/Abl, STAT5, and ERK1/2; down-regulation of Bcl-x(L) and Mcl-1; and dephosphorylation/activation of Bim. They were also associated with BAX/BAK conformational change, mitochondrial dysfunction, and caspase activation. Bim knockdown by shRNA suppressed BAX and BAK conformational change and protected cells from dasatinib/PD184352 lethality. Conversely, K562 cells ectopically expressing Mcl-1 or Bcl-x(L) were significantly less susceptible to dasatinib/PD184352 toxicity. Notably, the dasatinib/PD184352 regimen was active against leukemic cells exhibiting various forms of imatinib mesylate resistance, including Bcr/Abl overexpression, Lyn activation, and several Bcr/Abl kinase domain mutations (eg, E255K, M351T), but not T315I. Together, these findings suggest that strategies combining dasatanib with MEK1/2 inhibitors warrant further investigation in Bcr/Abl(+) malignancies, particularly in the setting of imatinib mesylate-resistant disease.
Authors:
Tri K Nguyen; Mohamed Rahmani; Hisashi Harada; Paul Dent; Steven Grant
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Publication Detail:
Type:  Clinical Trial; Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2007-01-11
Journal Detail:
Title:  Blood     Volume:  109     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2007 May 
Date Detail:
Created Date:  2007-04-23     Completed Date:  2007-06-05     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4006-15     Citation Subset:  AIM; IM    
Affiliation:
Department of Medicine, Massey Cancer Center, Virginia Commonwealth University, 401 College Street, Richmond, VA 23298, USA.
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MeSH Terms
Descriptor/Qualifier:
Benzamides / agonists,  pharmacology
Butadienes / agonists,  pharmacology
Drug Resistance, Neoplasm / drug effects,  genetics
Drug Screening Assays, Antitumor
Drug Synergism
Fusion Proteins, bcr-abl / antagonists & inhibitors*,  metabolism
Gene Expression Regulation, Leukemic / drug effects,  genetics
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy,  enzymology*,  genetics
MAP Kinase Kinase 1 / antagonists & inhibitors*,  metabolism
MAP Kinase Kinase 2 / antagonists & inhibitors*,  metabolism,  pharmacology
Nitriles / agonists,  pharmacology
Piperazines / pharmacology,  therapeutic use
Protein Kinase Inhibitors / agonists,  pharmacology*
Pyrimidines / agonists,  pharmacology*,  therapeutic use
Thiazoles / agonists,  pharmacology*
src-Family Kinases / antagonists & inhibitors,  metabolism
Grant Support
ID/Acronym/Agency:
CA 100866/CA/NCI NIH HHS; CA 63753/CA/NCI NIH HHS; CA 72955/CA/NCI NIH HHS; CA 88906/CA/NCI NIH HHS; CA 93738/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; 0/Benzamides; 0/Butadienes; 0/Fusion Proteins, bcr-abl; 0/Nitriles; 0/Piperazines; 0/Protein Kinase Inhibitors; 0/Pyrimidines; 0/Thiazoles; 0/U 0126; BKJ8M8G5HI/imatinib; EC 2.7.1.-/MAP2K2 protein, human; EC 2.7.10.2/src-Family Kinases; EC 2.7.12.2/MAP Kinase Kinase 1; EC 2.7.12.2/MAP Kinase Kinase 2; RBZ1571X5H/dasatinib
Comments/Corrections

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