DescriptionProstate cancer is the one of the most common cancers in the world, and the incidence of this disease increases annually. Many phytochemicals have been shown to be potent inhibitors in preventing prostate cancer disease initiation, progression or inhibit metastasis. Cancer chemoprevention by relatively non-toxic commonly consumed dietary phytochemicals or synthetic compounds would be a logical approach in reducing cancer incidence, and progression to advanced-resistant cancer cells. Synthetic oleanane triterpenoids have been shown to be effective compounds in prostate cancer chemoprevention. The nuclear E2-factor related factor 2 (Nrf2) is the master regulator of many detoxifying and antioxidant enzymes. It is considered the most important chemopreventive signaling pathway in inhibiting cancer initiation and progression. In this study, two synthetic triterpenoids CDDO-Im and CDDO-EA were used to investigate their effects on the activation of Nrf2 and Nrf2-mediated downstream target genes. These compounds were first tested on HepG2-C8 cells stably transfected with ARE-luciferase reporter gene, for cell toxicity and their potential to induce the Nrf2/ARE pathway. CDDO-Im and CDDO-EA were found to could induce ARE-luciferase activities at relatively low and non-toxic concentrations. Using quantitative PCR (qPCR) and western blotting, the transcription of Nrf2 downstream genes HO-1 and SOD1 were significantly induced by drug treatments, corresponding with the increase in their protein levels in human prostate LNCaP cells. These results suggest that CDDO-Im and CDDO-EA could elicit their chemopreventive effect via the activation of Nrf2 pathway. Emerging evidence suggests epigenetic mechanism such as DNA methylation and histone modifications could potentially be involved in the regulation of Nrf2 pathway. In this study, the effects of CDDO-Im and CDDO-EA on histone deacetylases (HDAC) were investigated by using qPCR. Both compounds show inhibitory effects on HDAC1, HDAC2 and HDAC3 which are considered the highly expressed type of HDACs in prostate cancer. Both compounds can also inhibit HDAC6 at low concentrations. In summary, this study shows that CDDO-Im and CDDO-EA are potentially interesting compounds for prostate cancer chemoprevention via activating Nrf2/ARE signaling pathway as well as epigenetic regulation.