Document Detail


ABT-737 overcomes resistance to immunotoxin-mediated apoptosis and enhances the delivery of pseudomonas exotoxin-based proteins to the cell cytosol.
MedLine Citation:
PMID:  20587662     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Roberta Traini; Gal Ben-Josef; Diana V Pastrana; Elizabeth Moskatel; Ashima K Sharma; Antonella Antignani; David J Fitzgerald
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2010-06-29
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  9     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-09     Completed Date:  2010-11-04     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2007-15     Citation Subset:  IM    
Copyright Information:
(c)2010 AACR.
Affiliation:
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
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MeSH Terms
Descriptor/Qualifier:
Activating Transcription Factor 4 / 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:
Z01 BC008757-20/BC/NCI NIH HHS
Chemical
Reg. No./Substance:
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

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