Unifying mechanisms of action of the anticancer activities of triterpenoids and synthetic analogs.
Unifying mechanisms of action of the anticancer activities of triterpenoids and synthetic analogs.
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DOI：
10.2174/187152012803833099
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发表时间：
2012-12
影响因子：
2.8
通讯作者：
Jutooru I
中科院分区：
文献类型：
--
作者：
Safe SH;Prather PL;Brents LK;Chadalapaka G;Jutooru I
三萜如白桦酸（BA）和齐墩果酸的合成类似物[2-氰基-3,12-二氧齐墩酸-1,9-二烯-28-酸（CDDO）]和甘草次酸[2-氰基-3,11-二氧齐墩酸-18β- 1,12-二烯-30-酸（CDODA）]是有效的抗癌药物，具有抗增殖、抗血管生成、抗炎和促凋亡活性。虽然它们对多种途径的影响已被报道，但统一的作用机制尚未报道。本实验室的研究表明，几种三萜包括BA及其衍生物、雷公藤酚、熊茄酸甲酯、β-乳香酸衍生物，以及合成的类似物CDDO、CDODA及其酯，在多种癌细胞中降低特异性蛋白（Sp）转录因子和几种促癌Sp调控基因的表达。这种反应的机制既依赖于化合物，也依赖于细胞环境，包括蛋白酶体依赖性和非依赖性途径的激活。目前，三萜介导的活性氧（ROS）诱导已被认为是Sp转录因子下调的一个重要的蛋白酶体非依赖性途径。ROS降低了microRNA-27a （miR-27a）和miR-20a/miR-17-5p的表达，从而分别诱导了“Sp-repressor”转录因子ZBTB10和ZBTB4的表达，进而下调Sp和Sp-regulated基因。三萜还激活或失活核受体和g蛋白偶联受体，这些途径有助于它们的抗肿瘤活性，也可能在靶向Sp1， Sp3和Sp4中发挥作用，这些Sp1， Sp3和Sp4在多种癌症中高度过表达，似乎对维持癌症表型很重要。
Triterpenoids such as betulinic acid (BA) and synthetic analogs of oleanolic acid [2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)] and glycyrrhetinic acid [2-cyano-3,11-dioxo-18β-oleana-1,12-dien-30-oc acid (CDODA)] are potent anticancer agents that exhibit antiproliferative, antiangiogenic, anti-inflammatory and pro-apoptotic activities. Although their effects on multiple pathways have been reported, unifying mechanisms of action have not been reported. Studies in this laboratory have now demonstrated that several triterpenoids including BA and some derivatives, celastrol, methyl ursolatee, β-boswellic acid derivatives, and the synthetic analogs CDDO, CDODA and their esters decreased expression of specificity protein (Sp) transcription factors and several pro-oncogenic Sp-regulated genes in multiple cancer cell lines. The mechanisms of this response are both compound- and cell context-dependent and include activation of both proteasome-dependent and -independent pathways. Triterpenoid-mediated induction of reactive oxygen species (ROS) has now been characterized as an important proteasome-independent pathway for downregulation of Sp transcription factors. ROS decreases expression of microRNA-27a (miR-27a) and miR-20a/miR-17-5p and this results in the induction of the transcriptional “Sp-repressors” ZBTB10 and ZBTB4, respectively, which in turn downregulate Sp and Sp-regulated genes. Triterpenoids also activate or deactive nuclear receptors and G-protein coupled receptors, and these pathways contribute to their antitumorigenic activity and may also play a role in targeting Sp1, Sp3 and Sp4 which are highly overexpressed in multiple cancers and appear to be important for maintaining the cancer phenotype.