Bardoxolone-Methyl (CDDO-Me) Suppresses Androgen Receptor and Its Splice-Variant AR-V7 and Enhances Efficacy of Enzalutamide in Prostate Cancer Cells

Abstract

Androgen receptor (AR) signaling is fundamental to prostate cancer (PC) progression, and hence, androgen deprivation therapy (ADT) remains a mainstay of treatment. However, augmented AR signaling via both full length AR (AR-FL) and constitutively active AR splice variants, especially AR-V7, is associated with the recurrence of castration resistant prostate cancer (CRPC). Oxidative stress also plays a crucial role in anti-androgen resistance and CRPC outgrowth. We examined whether a triterpenoid antioxidant drug, Bardoxolone-methyl, known as CDDO-Me or RTA 402, can decrease AR-FL and AR-V7 expression in PC cells. Nanomolar (nM) concentrations of CDDO-Me rapidly downregulated AR-FL in LNCaP and C4-2B cells, and both AR-FL and AR-V7 in CWR22Rv1 (22Rv1) cells. The AR-suppressive effect of CDDO-Me was evident at both the mRNA and protein levels. Mechanistically, acute exposure (2 h) to CDDO-Me increased and long-term exposure (24 h) decreased reactive oxygen species (ROS) levels in cells. This was concomitant with an increase in the anti-oxidant transcription factor, Nrf2. The anti-oxidant N-acetyl cysteine (NAC) could overcome this AR-suppressive effect of CDDO-Me. Co-exposure of PC cells to CDDO-Me enhanced the efficacy of a clinically approved anti-androgen, enzalutamide (ENZ), as evident by decreased cell-viability along with migration and colony forming ability of PC cells. Thus, CDDO-Me which is in several late-stage clinical trials, may be used as an adjunct to ADT in PC patients.

Stevia Eupatoria and Stevia Pilosa Extracts Inhibit the Proliferation and Migration of Prostate Cancer Cells

“…Quercetin is able to reduce the migration and invasion of human skin melanoma cells SK-MEL-28, increasing the expression of epithelial markers and decreasing mesenchymal markers [32]. The combination of Stevia pilosa and Stevia eupatoria with enzalutamide did not induce an antagonist effect on the migration of cells, which is consistent with wound-healing assay with enzalutamide alone reported by Khurana, et al [33], and different from the antagonist effect reported by the same group with enzalutamide and sulforaphane in resistant cells [34]. Based on the above, we suggest that the extracts could affect some of these mechanisms, however, additional studies are needed.…”

Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo

“…The remaining compounds either showed a lower level of bioactivity compared to SM (pi-153) or were unable to affect motility of tumor cells at all (TM, pi-156). The obtained results are in line with published data: recently, we found that SM at identical concentration (0.5 µM) effectively inhibited migration of RAW264.7 macrophages [64]; furthermore, SM's structural analog CDDO-Me and its derivatives significantly reduced motility of both malignant [65][66][67][68][69] and non-malignant [70][71][72] cells at submicromolar concentrations (0.05-1 µM). Revealed differences in the level of inhibitory activity of investigated compounds against tumor cell motility are consistent with the level of their cytotoxicity.…”

Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer

“…ABT263 drug could increase ubiquitin/proteasome-dependent degradation of AR and AR-v7 proteins through the ROS/USP26 axis, enhancing CRPC cell sensitivity to Enzalutamide [ 130 ]. Besides, acute exposure (2 h) to CDDO-Me increased ROS levels to suppresses AR and its splice-variant AR-V7 at both the transcriptional and translational levels [ 131 ].…”