Departments of Medicine and Pharmacology, Dartmouth Medical School, Hanover, NH 03755, USA.
Pharmacol Rev. 2012 Oct;64(4):972-1003. doi: 10.1124/pr.111.004846. Epub 2012 Sep 10.
We review the rationale for the use of synthetic oleanane triterpenoids (SOs) for prevention and treatment of disease, as well as extensive biological data on this topic resulting from both cell culture and in vivo studies. Emphasis is placed on understanding mechanisms of action. SOs are noncytotoxic drugs with an excellent safety profile. Several hundred SOs have now been synthesized and in vitro have been shown to: 1) suppress inflammation and oxidative stress and therefore be cytoprotective, especially at low nanomolar doses, 2) induce differentiation, and 3) block cell proliferation and induce apoptosis at higher micromolar doses. Animal data on the use of SOs in neurodegenerative diseases and in diseases of the eye, lung, cardiovascular system, liver, gastrointestinal tract, and kidney, as well as in cancer and in metabolic and inflammatory/autoimmune disorders, are reviewed. The importance of the cytoprotective Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1/nuclear factor (erythroid-derived 2)-like 2/antioxidant response element (Keap1/Nrf2/ARE) pathway as a mechanism of action is explained, but interactions with peroxisome proliferator-activated receptor γ (PARPγ), inhibitor of nuclear factor-κB kinase complex (IKK), janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT), human epidermal growth factor receptor 2 (HER2)/ErbB2/neu, phosphatase and tensin homolog (PTEN), the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, mammalian target of rapamycin (mTOR), and the thiol proteome are also described. In these interactions, Michael addition of SOs to reactive cysteine residues in specific molecular targets triggers biological activity. Ultimately, SOs are multifunctional drugs that regulate the activity of entire networks. Recent progress in the earliest clinical trials with 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) methyl ester (bardoxolone methyl) is also summarized.
我们回顾了合成齐墩果酸三萜（SOs）用于预防和治疗疾病的基本原理，以及大量关于该主题的细胞培养和体内研究的生物学数据。重点放在对作用机制的理解上。SOs 是一种非细胞毒性药物，具有极好的安全性。现在已经合成了数百种 SOs，体外实验表明：1）抑制炎症和氧化应激，因此具有细胞保护作用，尤其是在低纳摩尔剂量下，2）诱导分化，3）在较高微摩尔剂量下阻止细胞增殖并诱导细胞凋亡。综述了 SOs 在神经退行性疾病、眼病、肺部疾病、心血管系统疾病、肝脏疾病、胃肠道疾病和肾脏疾病以及癌症、代谢和炎症/自身免疫性疾病中的应用的动物数据。解释了 Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1/nuclear factor (erythroid-derived 2)-like 2/antioxidant response element (Keap1/Nrf2/ARE) 通路作为作用机制的重要性，但也描述了与过氧化物酶体增殖物激活受体 γ（PPARγ）、核因子-κB 激酶复合物（IKK）抑制剂、Janus 酪氨酸激酶/信号转导和转录激活剂（JAK/STAT）、人表皮生长因子受体 2（HER2）/ErbB2/neu、磷酸酶和张力蛋白同系物（PTEN）、磷脂酰肌醇 3-激酶/蛋白激酶 B（PI3K/Akt）通路、哺乳动物雷帕霉素靶蛋白（mTOR）和硫醇蛋白质组的相互作用。在这些相互作用中，SOs 与特定分子靶标中的反应性半胱氨酸残基的迈克尔加成触发了生物学活性。最终，SOs 是调节整个网络活性的多功能药物。还总结了 2-氰基-3,12-二氧代齐墩果酸-1,9(11)-二烯-28-酸甲酯（CDDO 甲基酯）（ bardoxolone 甲基）最早的临床试验的最新进展。
