Mechanism of action and development of selective aryl hydrocarbon receptor modulators for treatment of hormone-dependent cancers (Review).
Mechanism of action and development of selective aryl hydrocarbon receptor modulators for treatment of hormone-dependent cancers (Review).
复制标题
DOI：
10.3892/ijo.20.6.1123
复制
发表时间：
2002-06
影响因子：
5.2
通讯作者：
S. Safe;A. McDougal
中科院分区：
文献类型：
--
作者：
S. Safe;A. McDougal
配体活化受体被广泛用作开发用于治疗包括癌症在内的多种疾病的组织选择性药物的靶标。芳烃受体（AhR）是一种碱性螺旋-环-螺旋转录因子，其结合合成化学物质如2，3，7，8-四氯二苯并-对-二恶英（TCDD）和天然存在的植物化学物质、甾醇和血红素分解产物。高亲和力配体TCDD诱导几种AhR介导的基因表达变化，组织/物种特异性毒性，以及致瘤和抗癌反应，包括抑制雌激素依赖性乳腺和子宫肿瘤的形成和生长。该实验室的研究表明，TCDD通过复合抑制AhR-雌激素受体（ER）串扰抑制啮齿动物子宫和乳腺肿瘤（生长抑制）以及乳腺癌和子宫内膜癌细胞系中E2诱导的反应。6-烷基-1，3，8-三氯二苯并呋喃和取代的二吲哚基甲烷代表两种结构类型的选择性AhR调节剂（SAhRM）。这些化合物相对无毒，抑制ER阳性和ER阴性乳腺肿瘤生长，并与他莫昔芬协同抑制乳腺癌生长，阻断他莫昔芬诱导的子宫内雌激素活性。初步研究还表明，SAhRM抑制前列腺癌细胞生长，并有证据表明抑制AhR-雄激素受体串扰。SAhRM代表了一类用于治疗乳腺癌依赖性癌症的新型药物，SAhRM与他莫昔芬和其他选择性ER调节剂（SERM）的联合疗法提供了治疗患有乳腺癌的女性的新方法。
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.