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 ursolate, 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.

译文

:三萜类化合物,例如桦木酸(BA)和齐墩果酸[2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid(CDDO)]和甘草次酸[2-cyano-3, 11-二氧代-18β-oleana-1,12-dien-30-oc酸(CDODA)]是有效的抗癌剂,具有抗增殖,抗血管生成,抗炎和促凋亡的活性。尽管已经报道了它们对多种途径的作用,但尚未报道统一的作用机理。现在,该实验室的研究表明,三萜类化合物包括BA和某些衍生物,天青素,尿酸甲酯,β-乳香酸衍生物,以及合成类似物CDDO,CDODA及其酯可降低特异性蛋白(Sp)转录因子的表达,并且一些多种癌细胞系中致癌的Sp调控基因。这种反应的机制既取决于化合物又取决于细胞,并且包括蛋白酶体依赖性和非依赖性途径的激活。三萜类化合物介导的活性氧(ROS)的诱导现已被表征为下调Sp转录因子的重要的蛋白酶体独立途径。 ROS降低了microRNA-27a(miR-27a)和miR-20a / miR-17-5p的表达,这分别导致了转录“ Sp阻遏物” ZBTB10和ZBTB4的诱导,进而下调了Sp和Sp-调控基因。三萜类化合物还激活或失活的核受体和G蛋白偶联受体,这些通路有助于其抗肿瘤发生活性,并且还可能在靶向Sp1,Sp3和Sp4方面发挥作用,而Sp1,Sp3和Sp4在多种癌症中过度表达,对于维持肿瘤的发生很重要。癌症表型。

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