| ABT-737 overcomes resistance to immunotoxin-mediated apoptosis and enhances the delivery of pseudomonas exotoxin-based proteins to the cell cytosol. | |
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MedLine Citation:
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PMID: 20587662 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Pseudomonas exotoxin (PE)-based immunotoxins (antibody-toxin fusion proteins) have achieved frequent complete remissions in patients with hairy cell leukemia but far fewer objective responses in other cancers. To address possible mechanisms of resistance, we investigated immunotoxin activity in a model system using the colon cancer cell line, DLD1. Despite causing complete inhibition of protein synthesis, there was no evidence that an immunotoxin targeted to the transferrin receptor caused apoptosis in these cells. To address a possible protective role of prosurvival Bcl-2 proteins, the BH3-only mimetic, ABT-737, was tested alone or in combination with immunotoxins. Neither the immunotoxin nor ABT-737 alone activated caspase 3, whereas the combination exhibited substantial activation. In other epithelial cell lines, ABT-737 enhanced the cytotoxicity of PE-related immunotoxins by as much as 20-fold, but did not enhance diphtheria toxin or cycloheximide. Because PE translocates to the cytosol via the endoplasmic reticulum (ER) and the other toxins do not, ABT-737-mediated effects on the ER were investigated. ABT-737 treatment stimulated increased levels of ER stress response factor, ATF4. Because of its activity in the ER, ABT-737 might be particularly well suited for enhancing the activity of immunotoxins that translocate from the ER to the cell cytosol. |
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Authors:
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Roberta Traini; Gal Ben-Josef; Diana V Pastrana; Elizabeth Moskatel; Ashima K Sharma; Antonella Antignani; David J Fitzgerald |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural Date: 2010-06-29 |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 9 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-09 Completed Date: 2010-11-04 Revised Date: 2011-08-01 |
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: 2007-15 Citation Subset: IM |
Copyright Information:
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(c)2010 AACR. |
Affiliation:
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Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland 20892, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Activating Transcription Factor 4
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metabolism Apoptosis / drug effects* Biphenyl Compounds / pharmacology* Blotting, Western Caspases / metabolism Cell Line, Tumor Cell Survival / drug effects Cytosol / drug effects, metabolism Dose-Response Relationship, Drug Drug Resistance, Neoplasm / drug effects Drug Synergism Endoplasmic Reticulum / metabolism Exotoxins / metabolism, pharmacology Humans Immunotoxins / pharmacology* Neoplasms / drug therapy, metabolism, pathology Nitrophenols / pharmacology* Piperazines / pharmacology Protein Biosynthesis / drug effects Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors, metabolism Pseudomonas / metabolism Sulfonamides / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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Z01 BC008757-20/BC/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ABT-737; 0/ATF4 protein, human; 0/Biphenyl Compounds; 0/Exotoxins; 0/Immunotoxins; 0/Nitrophenols; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Sulfonamides; 145891-90-3/Activating Transcription Factor 4; EC 3.4.22.-/Caspases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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