Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane

Chen, Ichen; McDougal, Andrew; Fan, Wei; Safe, Stephen

doi:10.1093/carcin/19.9.1631

Cited by 269 publications

(193 citation statements)

References 42 publications

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“…Acid condensation products of I3C that bind and activate Ahr may also inhibit the transcription of ER-responsive genes by competing for coactivators or increasing ER degradation [81,89]. In contrast, some studies in cell culture [90,91] and animal models [92] have found that acid condensation products of I3C enhance the transcription of ER-responsive genes.…”

Section: Effects Of Indole-3-carbinol On Estrogen Receptor Activitymentioning

confidence: 99%

Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis

Higdon

Delage

Williams

et al. 2007

Pharmacological Research

917

697

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Cruciferous vegetables are a rich source of glucosinolates and their hydrolysis products, including indoles and isothiocyanates, and high intake of cruciferous vegetables has been associated with lower risk of lung and colorectal cancer in some epidemiological studies. Glucosinolate hydrolysis products alter the metabolism or activity of sex hormones in ways that could inhibit the development of hormone-sensitive cancers, but evidence of an inverse association between cruciferous vegetable intake and breast or prostate cancer in humans is limited and inconsistent. Organizations such as the National Cancer Institute recommend the consumption of 5-9 servings of fruits and vegetables daily, but separate recommendations for cruciferous vegetables have not been established. Isothiocyanates and indoles derived from the hydrolysis of glucosinolates, such as sulforaphane and indole-3-carbinol (I3C), have been implicated in a variety of anticarcinogenic mechanisms, but deleterious effects also have been reported in some experimental protocols, including tumor promotion over prolonged periods of exposure. Epidemiological studies indicate that human exposure to isothiocyanates and indoles through cruciferous vegetable consumption may decrease cancer risk, but the protective effects may be influenced by individual genetic variation (polymorphisms) in the metabolism and elimination of isothiocyanates from the body. Cooking procedures also affect the bioavailability and intake of glucosinolates and their derivatives. Supplementation with I3C or the related dimer 3,3′-diindolylmethane (DIM) alters urinary estrogen metabolite profiles in women, but the effects of I3C and DIM on breast cancer risk are not known. Small preliminary trials in humans suggest that I3C supplementation may be beneficial in treating conditions related to human papilloma virus infection, such as cervical intraepithelial neoplasia and recurrent respiratory papillomatosis, but larger randomized controlled trials are needed.

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Section: Effects Of Indole-3-carbinol On Estrogen Receptor Activitymentioning

confidence: 99%

Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis

Higdon

Delage

Williams

et al. 2007

Pharmacological Research

917

697

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“…DIM is reported to modulate aryl hydrocarbon receptor (AhR), as evidenced in multiple breast cancer cell lines. 31 Aryl hydrocarbon receptor is a ubiquitous cytoplasmic receptor that, when activated and transported to the nucleus, promotes transcription of genes that stimulate the expression of detoxification enzymes, including the phase I cytochrome P450 (CYP) family. Cellular responses to AhR signaling can either promote or diminish inflammation.…”

Section: Initiation Of Breast Tumorsmentioning

confidence: 99%

Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

Thomson

Ström

2016

Nutr Rev

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Diet is a modifiable factor associated with the risk of several cancers, with convincing evidence showing a link between diet and breast cancer. The role of bioactive compounds of food origin, including those found in cruciferous vegetables, is an active area of research in cancer chemoprevention. This review focuses on 3,3 0 -diindolylmethane (DIM), the major bioactive indole in crucifers. Research of the cancerpreventive activity of DIM has yielded basic mechanistic, animal, and human trial data. Further, this body of evidence is largely supported by observational studies. Bioactive DIM has demonstrated chemopreventive activity in all stages of breast cancer carcinogenesis. This review describes current evidence related to the metabolism and mechanisms of DIM involved in the prevention of breast cancer. Importantly, this review also focuses on current evidence from human observational and intervention trials that have contributed to a greater understanding of exposure estimates that will inform recommendations for DIM intake.

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“…The major active metabolite of I3C, diindolylmethane (DIM), induces expression of GADD45a, a DNA damage-responsive gene and putative tumour suppressor (Carter et al, 2002). Indole-3-carbinol can activate two pathways linked to cancer prevention: (1) aryl hydrocarbon receptor (AhR) signalling (which leads to expression of phase I enzymes (e.g., CYP1A1) via the xenobiotic response element) and (2) antioxidant/electrophilic response element signalling (resulting in expression of phase II detoxifying enzymes: e.g., oxido-reductases and glutathione-S-transferases) (Chen et al, 1998;Hayes and McMahon, 2001;Kwak et al, 2002). Thus, the ability of I3C to induce enzymes that metabolise genotoxic agents may contribute to cancer prevention.…”

mentioning

confidence: 99%

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

et al. 2006

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Indole-3-carbinol (I3C) and genistein are naturally occurring chemicals derived from cruciferous vegetables and soy, respectively, with potential cancer prevention activity for hormone-responsive tumours (e.g., breast and prostate cancers). Previously, we showed that I3C induces BRCA1 expression and that both I3C and BRCA1 inhibit oestrogen (E2)-stimulated oestrogen receptor (ER-a) activity in human breast cancer cells. We now report that both I3C and genistein induce the expression of both breast cancer susceptibility genes (BRCA1 and BRCA2) in breast (MCF-7 and T47D) and prostate (DU-145 and LNCaP) cancer cell types, in a time-and dosedependent fashion. Induction of the BRCA genes occurred at low doses of I3C (20 mM) and genistein (0.5 -1.0 mM), suggesting potential relevance to cancer prevention. A combination of I3C and genistein gave greater than expected induction of BRCA expression. Studies using small interfering RNAs (siRNAs) and BRCA expression vectors suggest that the phytochemical induction of BRCA2 is due, in part, to BRCA1. Functional studies suggest that I3C-mediated cytoxicity is, in part, dependent upon BRCA1 and BRCA2. Inhibition of E2-stimulated ER-a activity by I3C and genistein was dependent upon BRCA1; and inhibition of ligand-inducible androgen receptor (AR) activity by I3C and genistein was partially reversed by BRCA1-siRNA. Finally, we provide evidence suggesting that the phytochemical induction of BRCA1 expression is due, in part, to endoplasmic reticulum stress response signalling. These findings suggest that the BRCA genes are molecular targets for some of the activities of I3C and genistein.

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Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane

Cited by 269 publications

References 42 publications

Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis

Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis

Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

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