The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling
The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling
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DOI：
10.1158/0008-5472.can-04-4539
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发表时间：
2005-06-01
期刊：
影响因子：
11.2
通讯作者：
Sporn, MB
中科院分区：
文献类型：
--
作者：
Liby, K;Hock, T;Sporn, MB
合成的三萜类化合物2-氰基-3，12-二氧代齐墩果-1，9（11）-二烯-28-酸（CDDO）及其衍生物1-[2-氰基-3，12-二氧代齐墩果-1，9（11）-二烯-28-酰基]咪唑（CDDO-Im）是具有有效的抗增殖、分化和抗炎活性的多功能分子。在纳摩尔浓度下，这些药物在体外和体内迅速增加细胞保护性血红素加氧酶-1（HO-1）的表达。使用一系列报告构建体的转染研究表明，由三萜类激活人HO-1启动子需要抗氧化反应元件（ARE），环AMP反应元件和E盒序列。这些响应元件之一单独失活部分降低HO-1诱导，但所有三个序列中的突变完全消除响应三萜类的启动子活性。CDDO-Im治疗还提高了Nrf 2（一种先前被证明与ARE序列结合的转录因子）的蛋白水平，并增加了受Nrf 2调节的许多抗氧化和解毒基因的表达。三萜类化合物还减少了用叔丁基过氧化氢攻击的细胞中活性氧的形成，但这种细胞保护活性在Nrf 2缺陷细胞中不存在。这些研究是第一次调查诱导HO-1和Nrf 2/ARE途径的CDDO和CDDO-Im，我们的结果表明，需要进一步的体内研究，以探索化学预防和化疗的三萜类化合物的潜力。
The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its derivative 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are multifunctional molecules with potent antiproliferative, differentiating, and anti-inflammatory activities. At nano-molar concentrations' these agents rapidly increase the expression of the cytoprotective heme oxygenase-1 (HO-1) enzyme in vitro and in vivo. Transfection studies using a series of reporter constructs show that activation of the human HO-1 promoter by the triterpenoids requires an antioxidant response element (ARE), a cyclic AMP response element, and an E Box sequence. Inactivation of one of these response elements alone partially reduces HO-I induction, but mutations in all three sequences entirely eliminate promoter activity in response to the triterpenoids. Treatment with CDDO-Im also elevates protein levels of Nrf2, a transcription factor previously shown to bind ARE sequences, and increases expression of a number of antioxidant and detoxification genes regulated by Nrf2. The triterpenoids also reduce the formation of reactive oxygen species in cells challenged with tert-butyl hydroperoxide, but this cytoprotective activity is absent in Nrf2 deficient cells. These studies are the first to investigate the induction of the HO-1 and Nrf2/ARE pathways by CDDO and CDDO-Im, and our results suggest that further in vivo studies are needed to explore the chemopreventive and chemotherapeutic potential of the triterpenoids.