Document Detail


Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma.
MedLine Citation:
PMID:  19190119     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Glioblastoma is defined by its aggressive invasion, microvascular proliferation, and central necrosis. BMS-354825 (dasatinib) is an ATP-competitive small-molecule inhibitor effective in treating drug-resistant tumors with mutant BCR-ABL, KIT, and epidermal growth factor receptor by blocking tyrosine phosphorylation sites that are critical in tumorigenesis. In studying the action of dasatinib in human glioblastoma, we found that levels of phospho-SRC, AKT, and ribosomal protein S6 were decreased in cell lines treated with low nanomolar concentrations of dasatinib at baseline and following stimulation with epidermal growth factor. Furthermore, an increased sensitivity to dasatinib was noted in glioma cells with functional PTEN. Reduction of invasive potential was observed in vitro at concentrations well below the IC(50) of dasatinib, which was corroborated by immunofluorescence staining showing disruption of paxillin localization to focal adhesions and decreases in focal adhesion kinase autophosphorylation. Cell cycle analysis revealed minimal G(1) arrest but a significant increase in autophagic cell death in glioma cells treated with dasatinib as assessed by acridine orange staining and a concomitant increase in light chain 3 expression and processing. Combination treatment of glioma cells with dasatinib and temozolomide resulted in a significant increase in cell cycle disruption and autophagic cell death. Dasatinib in combination with temozolomide more effectively increased the therapeutic efficacy of temozolomide than when dasatinib was combined with carboplatin or irinotecan. These results strongly support the clinical use of dasatinib in the treatment of glioblastoma and provide a rationale for combination therapy with dasatinib and temozolomide.
Authors:
Vanessa Milano; Yuji Piao; Tiffany LaFortune; John de Groot
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-02-03
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  8     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-02-12     Completed Date:  2009-03-24     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  394-406     Citation Subset:  IM    
Affiliation:
Brain Tumor Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects
Autophagy / drug effects*
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Dacarbazine / analogs & derivatives*,  pharmacology
Drug Screening Assays, Antitumor
Drug Synergism
G1 Phase / drug effects
Glioma / enzymology,  pathology*
Humans
PTEN Phosphohydrolase / metabolism
Pyrimidines / pharmacology*
Thiazoles / pharmacology*
Grant Support
ID/Acronym/Agency:
5P30CA016672-29/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Pyrimidines; 0/Thiazoles; 4342-03-4/Dacarbazine; 85622-93-1/temozolomide; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase; RBZ1571X5H/dasatinib

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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