Unifying Mechanisms of Action of the Anticancer Activities of Triterpenoids and Synthetic Analogs

Abstract

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.

Advances in Preventive Therapy for Estrogen-Receptor-Negative Breast Cancer

“…Natural triterpenoids are abundantly found in marine sources, for example marine sponges, sea cucumbers, or marine algae [103], and have antiproliferative, antiangiogenic, anti-inflammatory, and pro-apoptotic activity [104]. CDDO esters and CDDO-Me have been shown to delay ER-negative mammary tumor formation in animal studies (Table 1) [70, 105].…”

Anticancer Activities of the Quinone-Methide Triterpenes Maytenin and 22-β-hydroxymaytenin Obtained from Cultivated Maytenus ilicifolia Roots Associated with Down-Regulation of miRNA-27a and miR-20a/miR-17-5p

“…Since effects on monolayer cell culture can differ considerably from those obtained in a three-dimensional (3D) environment, we also assessed the effect of the compounds in spheroids derived from immortalized cell lines. Since microRNAs (miRNAs) have been implicated in the mechanisms of action of triterpenoids in association with the induction of ROS [6], we investigated the effects of maytenin and 22-β-hydroxymaytenin on the expression of miRNAs in normal oral keratinocytes and a HNSCC cell line using DNA microarrays.…”

MicroRNA-Specificity Protein (Sp) Transcription Factor Interactions and Significance in Carcinogenesis

“…Not surprisingly, miR-27 antagomirs also induced apoptosis, inhibited breast cancer cell growth and cell cycle progression and this was due not only to ZBTB10-mediated repression of Sp TFs and Sp-regulated genes but also activation of Myt-1 which inhibited cells at the G2/M phase of the cell cycle. The role of miR-27a:ZBTB10 in the maintenance of high levels of Sp1, Sp3 and Sp4 has been observed in breast, pancreatic, colon, rhabdomyosarcoma and bladder cancer cell lines (13-15, 46, 51-61). …”