TY - JOUR
T1 - Mechanism of action and development of selective aryl hydrocarbon receptor modulators for treatment of hormone-dependent cancers (Review).
AU - Safe, Stephen
AU - McDougal, Andrew
PY - 2002/6
Y1 - 2002/6
N2 - Ligand-activated receptors are extensively used as targets for developing tissue-selective drugs for treatment of multiple diseases including cancers. The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix transcription factor that binds both synthetic chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and naturally-occurring phytochemicals, sterols and heme breakdown products. The high affinity ligand TCDD induces several AhR-mediated changes in gene expression, tissue/species-specific toxicities, and both tumorigenic and anticarcinogenic responses including inhibition of estrogen-dependent mammary and uterine tumor formation and growth. Research in this laboratory has demonstrated that TCDD inhibits E2-induced responses in the rodent uterus and mammary tumors (growth inhibition) and in breast and endometrial cancer cell lines through complex inhibitory AhR-estrogen receptor (ER) crosstalk. 6-Alkyl-1,3,8-trichlorodibenzofurans and substituted diindolylmethanes represent two structural classes of selective AhR modulators (SAhRMs). These compounds are relatively non-toxic and inhibit ER-positive and ER-negative mammary tumor growth, and synergize with tamoxifen to inhibit breast cancer growth and block tamoxifen-induced estrogenic activity in the uterus. Preliminary studies also indicate that SAhRMs inhibit prostate cancer cell growth, and there is evidence for inhibitory AhR-androgen receptor crosstalk. SAhRMs represent a novel class of drugs for treatment of hormone-dependent cancers, and combined therapies of SAhRMs with tamoxifen and other selective ER modulators (SERMs) provides a new approach for treating women with breast cancer.
AB - Ligand-activated receptors are extensively used as targets for developing tissue-selective drugs for treatment of multiple diseases including cancers. The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix transcription factor that binds both synthetic chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and naturally-occurring phytochemicals, sterols and heme breakdown products. The high affinity ligand TCDD induces several AhR-mediated changes in gene expression, tissue/species-specific toxicities, and both tumorigenic and anticarcinogenic responses including inhibition of estrogen-dependent mammary and uterine tumor formation and growth. Research in this laboratory has demonstrated that TCDD inhibits E2-induced responses in the rodent uterus and mammary tumors (growth inhibition) and in breast and endometrial cancer cell lines through complex inhibitory AhR-estrogen receptor (ER) crosstalk. 6-Alkyl-1,3,8-trichlorodibenzofurans and substituted diindolylmethanes represent two structural classes of selective AhR modulators (SAhRMs). These compounds are relatively non-toxic and inhibit ER-positive and ER-negative mammary tumor growth, and synergize with tamoxifen to inhibit breast cancer growth and block tamoxifen-induced estrogenic activity in the uterus. Preliminary studies also indicate that SAhRMs inhibit prostate cancer cell growth, and there is evidence for inhibitory AhR-androgen receptor crosstalk. SAhRMs represent a novel class of drugs for treatment of hormone-dependent cancers, and combined therapies of SAhRMs with tamoxifen and other selective ER modulators (SERMs) provides a new approach for treating women with breast cancer.
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U2 - 10.3892/ijo.20.6.1123
DO - 10.3892/ijo.20.6.1123
M3 - Article
C2 - 12011988
AN - SCOPUS:0036615860
VL - 20
SP - 1123
EP - 1128
JO - International Journal of Oncology
JF - International Journal of Oncology
SN - 1019-6439
IS - 6
ER -