| Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. | |
MedLine Citation:
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PMID: 19190119 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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:
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Vanessa Milano; Yuji Piao; Tiffany LaFortune; John de Groot |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-02-03 |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 8 ISSN: 1535-7163 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2009 Feb |
Date Detail:
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Created Date: 2009-02-12 Completed Date: 2009-03-24 Revised Date: 2013-06-03 |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 394-406 Citation Subset: IM |
Affiliation:
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Brain Tumor Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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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:
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5P30CA016672-29/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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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