2. Academic Validation
  3. The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer

The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer

  • Nat Commun. 2020 Jun 1;11(1):2689. doi: 10.1038/s41467-020-15396-5.
Keliang Wang  # 1 2,  Jie Luo  # 2,  Shuyuan Yeh  # 2,  Bosen You 1 2,  Jialin Meng 2,  Philip Chang 3,  Yuanjie Niu 4,  Gonghui Li 5,  Changxue Lu 6,  Yezi Zhu 6,  Emmanuel S Antonarakis 6,  Jun Luo 6,  Chi-Ping Huang 7,  Wanhai Xu 8,  Chawnshang Chang 9 10
Affiliations

Affiliations

  • 1 Department of Urology, The 4th Affiliated Hospital of Harbin Medical University, NHC Key Lab of Molecular Probes and Targeted Diagnosis and Therapy, Harbin, 150001, China.
  • 2 George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • 3 Department of Neurology, Kaiser Permanente Santa Clara Medical Center, Santa Clara, CA, 95051, USA.
  • 4 Tianjin Institute of Urology, Tianjin Medical University, Tianjin, 300211, China.
  • 5 Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
  • 6 Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center, and James Buchanan Brady Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
  • 7 Sex Hormone Research Center, Department of Urology, China Medical University and Hospital, Taichung, 404, Taiwan.
  • 8 Department of Urology, The 4th Affiliated Hospital of Harbin Medical University, NHC Key Lab of Molecular Probes and Targeted Diagnosis and Therapy, Harbin, 150001, China. [email protected].
  • 9 George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA. [email protected].
  • 10 Sex Hormone Research Center, Department of Urology, China Medical University and Hospital, Taichung, 404, Taiwan. [email protected].
  • # Contributed equally.
PMID: 32483206 DOI: 10.1038/s41467-020-15396-5
Abstract

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate Cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the Androgen Receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.

Figures
Products