Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy.
Molecules. 2019 Nov 13;24(22):4097. doi: 10.3390/molecules24224097.
Triterpenoids are natural compounds synthesized by plants through cyclization of squalene, known for their weak anti-inflammatory activity. 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and its C28 modified derivative, methyl-ester (CDDO-Me, also known as bardoxolone methyl), are two synthetic derivatives of oleanolic acid, synthesized more than 20 years ago, in an attempt to enhance the anti-inflammatory behavior of the natural compound. These molecules have been extensively investigated for their strong ability to exert antiproliferative, antiangiogenic, and antimetastatic activities, and to induce apoptosis and differentiation in cancer cells. Here, we discuss the chemical properties of natural triterpenoids, the pathways of synthesis and the biological effects of CDDO and its derivative CDDO-Me. At nanomolar doses, CDDO and CDDO-Me have been shown to protect cells and tissues from oxidative stress by increasing the transcriptional activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2). At doses higher than 100 nM, CDDO and CDDO-Me are able to modulate the differentiation of a variety of cell types, both tumor cell lines or primary culture cell, while at micromolar doses these compounds exert an anticancer effect in multiple manners; by inducing extrinsic or intrinsic apoptotic pathways, or autophagic cell death, by inhibiting telomerase activity, by disrupting mitochondrial functions through Lon protease inhibition, and by blocking the deubiquitylating enzyme USP7. CDDO-Me demonstrated its efficacy as anticancer drugs in different mouse models, and versus several types of cancer. Several clinical trials have been started in humans for evaluating CDDO-Me efficacy as anticancer and anti-inflammatory drug; despite promising results, significant increase in heart failure events represented an obstacle for the clinical use of CDDO-Me.
三萜类化合物是植物通过角鲨烯环化合成的天然化合物，具有较弱的抗炎活性。2-氰基-3,12-二氧代齐墩果酸-1,9(11)-二烯-28-酸（CDDO）及其 C28 修饰衍生物甲酯（CDDO-Me，也称为 bardoxolone 甲酯），是齐墩果酸的两种合成衍生物，于 20 多年前合成，旨在增强天然化合物的抗炎作用。这些分子因其强大的抗增殖、抗血管生成和抗转移活性，以及诱导癌细胞凋亡和分化的能力而被广泛研究。在这里，我们讨论了天然三萜类化合物的化学性质、CDDO 及其衍生物 CDDO-Me 的合成途径和生物学效应。在纳摩尔剂量下，CDDO 和 CDDO-Me 已被证明通过增加核因子（红系衍生 2）样 2（Nrf2）的转录活性来保护细胞和组织免受氧化应激。在高于 100 nM 的剂量下，CDDO 和 CDDO-Me 能够调节多种细胞类型的分化，包括肿瘤细胞系或原代培养细胞，而在微摩尔剂量下，这些化合物通过多种方式发挥抗癌作用；通过诱导外在或内在凋亡途径或自噬细胞死亡，通过抑制端粒酶活性，通过 Lon 蛋白酶抑制破坏线粒体功能，以及通过阻断去泛素化酶 USP7。CDDO-Me 在不同的小鼠模型和多种类型的癌症中表现出其作为抗癌药物的功效。已经在人类中开始了几项临床试验，以评估 CDDO-Me 作为抗癌和抗炎药物的疗效；尽管有有希望的结果，但心力衰竭事件的显著增加代表了 CDDO-Me 临床应用的障碍。
