Title:Unifying Mechanisms of Action of the Anticancer Activities of Triterpenoids and Synthetic Analogs
VOLUME: 12 ISSUE: 10
Author(s):Stephen H. Safe, Paul L. Prather, Lisa K. Brents, Gayathri Chadalapaka and Indira Jutooru
Affiliation:Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466.
Keywords:Sp transcription factors, Downregulation, Reactive oxygen species, TRITERPENOIDS, biphenylamine carboxylic acids, glycyrrhetinic acid, Proteasome-dependent, anti-inflammatory agents, NATURAL PRODUCTS, HISTONE
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 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 Spregulated
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 “Sprepressors”
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.
