Document Detail

The unhydrolyzable fenretinide analogue 4-hydroxybenzylretinone induces the proapoptotic genes GADD153 (CHOP) and Bcl-2-binding component 3 (PUMA) and apoptosis that is caspase- dependent and independent of the retinoic acid receptor.
MedLine Citation:
PMID:  17616685     Owner:  NLM     Status:  MEDLINE    
The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) induces apoptosis in a variety of cell lines and has shown promise as an anticancer agent both in vitro and in vivo. The clinical dose of 4-HPR, however, is limited by residual-associated toxicities, indicating a need for a less toxic drug. In this study, we show that 4-hydroxybenzylretinone (4-HBR), the unhydrolyzable analogue of 4-HPR, is effective in producing apoptosis in a variety of 4-HPR-sensitive cell lines, including breast cancer, neuroblastoma, and leukemia cells. We also show through the use of a pan-caspase inhibitor that this 4-HBR-induced apoptosis is dependent, at least in part, on caspase activity. 4-HBR is shown to exhibit binding to the retinoic acid receptors (RAR) at concentrations necessary to induce cell death and induces expression of all-trans-retinoic acid-responsive genes that can be blocked by a RAR pan-antagonist. However, through the use of this RAR pan-antagonist, 4-HBR-induced apoptosis and cell death is shown to be independent of the RAR signaling pathway. To further characterize the mechanism of action of 4-HBR, expression of the endoplasmic reticulum stress-induced genes GADD153 and Bcl-2-binding component 3 was examined. These mRNAs are shown to be rapidly induced in 4-HBR-treated and 4-HPR-treated breast cancer cells, and this up-regulation is also shown to be independent of the RARs. These results suggest that a stress-mediated apoptotic cascade is involved in the mechanism of action of these retinoids.
Allyson L Anding; Jason S Chapman; Derek W Barnett; Robert W Curley; Margaret Clagett-Dame
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Cancer research     Volume:  67     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-07-09     Completed Date:  2007-07-27     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6270-7     Citation Subset:  IM    
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
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MeSH Terms
Apoptosis Regulatory Proteins / biosynthesis*
Caspases / metabolism
Cell Line, Tumor
Cell Proliferation
Fenretinide / analogs & derivatives*
HL-60 Cells
Leukemia / metabolism
Proto-Oncogene Proteins / biosynthesis*
RNA, Messenger / metabolism
Receptors, Retinoic Acid / metabolism*
Retinoids / metabolism
Transcription Factor CHOP / biosynthesis*
Vitamin A / analogs & derivatives*,  pharmacology
Grant Support
Reg. No./Substance:
0/4-hydroxybenzylretinone; 0/Apoptosis Regulatory Proteins; 0/BBC3 protein, human; 0/Proto-Oncogene Proteins; 0/RNA, Messenger; 0/Receptors, Retinoic Acid; 0/Retinoids; 11103-57-4/Vitamin A; 147336-12-7/Transcription Factor CHOP; 65646-68-6/Fenretinide; EC 3.4.22.-/Caspases

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