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

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.

• Authors: Keliang Wang, Jie Luo, Shuyuan Yeh, Bosen You, Jialin Meng, Philip Chang, Yuanjie Niu, Gonghui Li, Changxue Lu, Yezi Zhu, Emmanuel S Antonarakis, Jun Luo, Chi-Ping Huang, Wanhai Xu, Chawnshang Chang
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 2689 (06 01 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32483206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AR protein, human
• Benzamides
• Monoamine Oxidase Inhibitors
• Nitriles
• Receptors, Androgen
• Phenylthiohydantoin
• enzalutamide
• Monoamine Oxidase
• monoamine oxidase A, human
• Clorgyline
• Phenelzine

Topics

• Alternative Splicing
• Animals
• Benzamides
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Clorgyline (pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Enzyme Stability
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice
• Mice, Nude
• Mice, SCID
• Monoamine Oxidase (chemistry, genetics, metabolism)
• Monoamine Oxidase Inhibitors (pharmacology)
• Neoplastic Cells, Circulating (metabolism)
• Nitriles
• Phenelzine (pharmacology)
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, metabolism)
• Receptors, Androgen (genetics, metabolism)
• Signal Transduction (drug effects)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays