Carcinogenesis, Vol 19, 1631-1639, Copyright © 1998 by Oxford University Press
I Chen, A McDougal, F Wang and S Safe
Phytochemicals such as indole-3-carbinol (I3C) and sulforaphane are
components of cruciferous vegetables which exhibit antitumorigenic activity
associated with altered carcinogen metabolism and detoxification.
Diindolylmethane (DIM) is a major acid-catalyzed metabolite of I3C formed
in the gut that binds to the aryl hydrocarbon receptor (AhR) and treatment
of MCF-7 human breast cancer cells with 10- 50 microM DIM resulted in rapid
formation of the nuclear AhR complex and induction of CYP1A1 gene
expression was observed at concentrations >50 microM. Previous studies
have demonstrated that 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), a high
affinity AhR ligand, inhibits 17beta-estradiol (E2)-induced responses in
MCF-7 cells and growth of E2-dependent 7,12-dimethylbenzanthracene
(DMBA)-induced mammary tumors in female Sprague-Dawley rats. Results of
this study show that like TCDD, DIM inhibits E2-induced proliferation of
MCF-7 cells, reporter gene activity in cells transiently transfected with
an E2-responsive plasmid (containing a frog vitellogenin A2 gene promoter
insert) and down-regulates the nuclear estrogen receptor. Moreover, DIM (5
mg/kg every other day) also inhibits DMBA-induced mammary tumor growth in
Sprague-Dawley rats and this was not accompanied by induction of hepatic
CYP1A1-dependent activity. Thus, DIM represents a new class of relatively
non-toxic AhR-based antiestrogens that inhibit E2- dependent tumor growth
in rodents and current studies are focused on development of analogs for
clinical treatment of breast cancer.
ARTICLES
Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466, USA.
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R. Duan, W. Porter, I. Samudio, C. Vyhlidal, M. Kladde, and S. Safe Transcriptional Activation of c-fos Protooncogene by 17{beta}-Estradiol: Mechanism of Aryl Hydrocarbon Receptor-Mediated Inhibition Mol. Endocrinol., September 1, 1999; 13(9): 1511 - 1521. [Abstract] [Full Text]
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K. Ramamoorthy, M. S. Gupta, G. Sun, A. McDougal, and S. H. Safe 3,3',4,4'-Tetrachlorobiphenyl exhibits antiestrogenic and antitumorigenic activity in the rodent uterus and mammary cells and in human breast cancer cells Carcinogenesis, January 1, 1999; 20(1): 115 - 123. [Abstract] [Full Text] [PDF]
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E. J. Cram, B. D. Liu, L. F. Bjeldanes, and G. L. Firestone Indole-3-carbinol Inhibits CDK6 Expression in Human MCF-7 Breast Cancer Cells by Disrupting Sp1 Transcription Factor Interactions with a Composite Element in the CDK6 Gene Promoter J. Biol. Chem., June 15, 2001; 276(25): 22332 - 22340. [Abstract] [Full Text] [PDF]
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