Document Detail

The hydroxyl functional group of N-(4-hydroxyphenyl)retinamide mediates cellular uptake and cytotoxicity in premalignant and malignant human epithelial cells.
MedLine Citation:
PMID:  20923701     Owner:  NLM     Status:  MEDLINE    
In a previous study, we demonstrated that the anticancer synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) redox cycles at the mitochondrial enzyme dihydroorotate dehydrogenase to trigger anomalous reactive oxygen species (ROS) production and attendant apoptosis in transformed human epithelial cells. Furthermore, we speculated that the hydroxyl functional group of 4HPR was required for this pro-oxidant property. In this study, we investigated the role of the hydroxyl functional group in the in vitro cytotoxicity of 4HPR. Using 4HPR, its primary in vivo metabolite N-(4-methoxyphenyl)retinamide (4MPR), and the synthetic derivative N-(4-trifluoromethylphenyl)retinamide (4TPR), we examined the pro-oxidant and apoptotic effects, as well as the cellular uptake, of these three N-(4-substituted-phenyl)retinamides in premalignant and malignant human skin, prostate, and breast epithelial cells. Compared to 4HPR, both 4MPR and 4TPR were ineffective in promoting conspicuous cellular ROS production, mitochondrial disruption, or DNA fragmentation in these transformed cells. Interestingly, both 4MPR and 4TPR were not particularly cell permeative relative to 4HPR in skin or breast epithelial cells, which implied an additional role for the hydroxyl functional group in the cellular uptake of 4HPR. Moreover, the short-term uptake of 4HPR was directly proportional to cell size, but this characteristic, in obvious contrast to cellular bioenergetic status and/or dihydroorotate dehydrogenase expression, was not fundamentally influential in the overall sensitivity to the promotion of cellular ROS production and apoptosis induction by this agent. Together, these results strongly implicate the hydroxyl functional group in the cytotoxic effects of 4HPR.
Numsen Hail; Ping Chen; Michael F Wempe
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-10-23
Journal Detail:
Title:  Free radical biology & medicine     Volume:  49     ISSN:  1873-4596     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-14     Completed Date:  2011-08-18     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2001-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Department of Pharmaceutical Sciences, University of Colorado School of Pharmacy, Aurora, CO 80045, USA.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Transformed
Cell Line, Tumor
Cell Shape / drug effects
Cell Transformation, Neoplastic / metabolism,  pathology
DNA Fragmentation / drug effects
Electron Transport Complex IV / metabolism
Epithelial Cells / drug effects*,  enzymology,  metabolism
Fenretinide / pharmacology*
Hydroxides / metabolism,  pharmacology*
Mitochondria / drug effects
Oxidoreductases Acting on CH-CH Group Donors / metabolism
Reactive Oxygen Species / metabolism
Tretinoin / analogs & derivatives*,  pharmacology
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/Hydroxides; 0/N-(4-trifluoromethylphenyl)retinamide; 0/Reactive Oxygen Species; 302-79-4/Tretinoin; 65646-68-6/Fenretinide; EC 1.3.-/Oxidoreductases Acting on CH-CH Group Donors; EC dehydrogenase; EC 1.9.3.-/cytochrome C oxidase subunit II; EC Transport Complex IV

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