Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Cancer Institute [Grant R01CA142697] and Texas AgriLife.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- AHR
- aryl hydrocarbon receptor
- SAhRM
- selective AHR modulator
- Ah
- aryl hydrocarbon
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- DRE
- dioxin responsive element
- MCDF
- 6-methyl-1,3,8-trichlorodibenzofuran
- ER
- estrogen receptor
- ErbB2
- epidermal growth factor receptor 2
- DMEM
- Dulbecco's modified Eagle's medium
- FBS
- fetal bovine serum
- ChIP
- chromatin immunoprecipitation
- MTT
- 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
- PCR
- polymerase chain reaction
- DMSO
- dimethyl sulfoxide
- TBP
- TATA-binding protein.
- Received April 6, 2012.
- Accepted August 8, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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