Document Detail

Aryl hydrocarbon receptor (AHR)-active pharmaceuticals are selective AHR modulators in MDA-MB-468 and BT474 breast cancer cells.
MedLine Citation:
PMID:  22879383     Owner:  NLM     Status:  MEDLINE    
Leflunomide, flutamide, nimodipine, mexiletine, sulindac, tranilast, 4-hydroxytamoxifen, and omeprazole are pharmaceuticals previously characterized as aryl hydrocarbon receptor (AHR) agonists in various cell lines and animal models. In this study, the eight AHR-active pharmaceuticals were investigated in highly aggressive aryl hydrocarbon (Ah)-responsive BT474 and MDA-MB-468 breast cancer cell lines, and their effects on AHR protein, CYP1A1 (protein and mRNA), CYP1B1 (mRNA), and cell migration were determined. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was used as a positive control. The AHR agonist activities of the pharmaceuticals depended on structure, response, and cell context. Most compounds induced one or more AHR-mediated responses in BT474 cells, whereas in Ah-responsive MDA-MB-468 cells effects of the AHR-active pharmaceuticals were highly variable. 4-Hydroxytamoxifen, mexiletine, and tranilast did not induce CYP1A1 in MDA-MB-468 cells; moreover, in combination with TCDD, mexiletine was a potent AHR antagonist, tranilast was a partial antagonist, and 4-hydroxytamoxifen also exhibited some AHR antagonist activity. Omeprazole and, to a lesser extent, sulindac and leflunomide were full and partial AHR agonists, respectively, in both breast cancer cell lines. These data indicate that the AHR-active pharmaceuticals are selective AHR modulators, and applications of these drugs for targeting the AHR must be confirmed by studies using the most relevant cell context.
Un-Ho Jin; Syng-ook Lee; Stephen Safe
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-09
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  343     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-16     Completed Date:  2012-12-31     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  333-41     Citation Subset:  IM    
Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
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MeSH Terms
Antineoplastic Agents / pharmacology
Blotting, Western
Breast Neoplasms / drug therapy*,  pathology
Carcinogens / pharmacology
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Chromatin Immunoprecipitation
Cytochrome P-450 CYP1A1 / biosynthesis,  genetics,  metabolism
Drug Delivery Systems
RNA, Messenger / biosynthesis,  genetics
Real-Time Polymerase Chain Reaction
Receptors, Aryl Hydrocarbon / antagonists & inhibitors,  drug effects*
Tetrachlorodibenzodioxin / pharmacology
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/Carcinogens; 0/RNA, Messenger; 0/Receptors, Aryl Hydrocarbon; 1746-01-6/Tetrachlorodibenzodioxin; EC P-450 CYP1A1

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