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.

Targeting the glucocorticoid receptor signature gene Mono Amine Oxidase-A enhances the efficacy of chemo- and anti-androgen therapy in advanced prostate cancer

“…5E, F ). Observed effects of MAO-A knockdown on cell viability and cell proliferation are in concordance with already published in vitro and in vivo data using different PCa cell lines [ 17 , 25 – 27 ]. To further evaluate the potential use of MAO-A targeting for a clinical approach, pharmacological MAO-A inhibition was performed.…”

Mechanisms of enzalutamide resistance in castration‐resistant prostate cancer and therapeutic strategies to overcome it

“…This rational drug design provides an efficient strategy for the development of novel agents for enzalutamide-resistant castration-resistant prostate cancer (Table 1 and Figure 2). AR splice variants lncRNA Malat1 (Stone, 2017;Tummala, Lou, Gao, & Nadiminty, 2017;Zhao et al, 2018) ACK1/pY88-H4/WDR5/MLL2/AR, AR-V7 (Mahajan et al, 2017) AR-V7/MAO-A Phenelzine/clorgyline (Wang, Luo, et al, 2020) AR-V7…”

Imipramine Inhibits Migration and Invasion in Metastatic Castration-Resistant Prostate Cancer PC-3 Cells via AKT-Mediated NF-κB Signaling Pathway

“…Several classes of antidepressants exist, such as nonselective monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, nonselective monoamine oxidase inhibitors, monoamine oxidase A (MAO-A) inhibitors, and other antidepressants including tricyclic antidepressants (TCAs) [ 14 , 15 ]. Among these, MAO-A inhibitors are known for their efficacy and mechanisms of prostate cancer suppression [ 16 , 17 ]. MAO-A inhibitors, including clogyline and mocrobemide, suppressed the activation of Shh-interleukin 6-receptor activator of nuclear factor kappaB ligand (Shh–IL6–RANKL) signaling, further suppressed the metastasis of CRPC cells, and prolonged overall survival in patients in preclinical studies [ 16 ].…”

“…MAO-A inhibitors, including clogyline and mocrobemide, suppressed the activation of Shh-interleukin 6-receptor activator of nuclear factor kappaB ligand (Shh–IL6–RANKL) signaling, further suppressed the metastasis of CRPC cells, and prolonged overall survival in patients in preclinical studies [ 16 ]. In addition, antiandrogen enzalutamide-resistant mCRPC cells derived by chronic exposure to enzalutamide could be re-sensitized to enzalutamide by treatment with MAO-A inhibitors such as phenelzine and clorgyline [ 17 ]. However, the efficacy and mechanisms of action of TCAs in mCRPC cells have been poorly studied.…”