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Open AccessArticle

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

1
Department of Urology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA
2
Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA
3
Department of Internal Medicine-Medical Oncology, Washington University in St. Louis Medical Campus, 660 S Euclid Ave, St. Louis, MO 63110-1010, USA
4
Department of Microbiology, Lincoln Memorial University—Debusk College of Osteopathic Medicine, 9737 Coghill Drive, Knoxville, TN 37932, USA
*
Authors to whom correspondence should be addressed.
Antioxidants 2020, 9(1), 68; https://doi.org/10.3390/antiox9010068
Received: 4 December 2019 / Revised: 2 January 2020 / Accepted: 7 January 2020 / Published: 12 January 2020
(This article belongs to the Special Issue Free Radical Research in Cancer)
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. View Full-Text
Keywords: bardoxolone methyl; prostate cancer; castration-resistant prostate cancer; androgen receptor (AR), AR-V7; anti-androgen; enzalutamide; androgen deprivation therapy bardoxolone methyl; prostate cancer; castration-resistant prostate cancer; androgen receptor (AR), AR-V7; anti-androgen; enzalutamide; androgen deprivation therapy
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Khurana, N.; Chandra, P.K.; Kim, H.; Abdel-Mageed, A.B.; Mondal, D.; Sikka, S.C. Bardoxolone-Methyl (CDDO-Me) Suppresses Androgen Receptor and Its Splice-Variant AR-V7 and Enhances Efficacy of Enzalutamide in Prostate Cancer Cells. Antioxidants 2020, 9, 68.

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