Targeting monoamine oxidase A in advanced prostate cancer

Abstract

Purpose Inhibitors of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine, are commonly used to treat neurological conditions including depression. Recently, we and others identified high expression of MAOA in normal basal prostatic epithelium and high-grade primary prostate cancer (PCa). In contrast, MAOA is low in normal secretory prostatic epithelium and low-grade PCa. An irreversible inhibitor of MAOA, clorgyline, induced secretory differentiation in primary cultures of normal basal epithelial cells and high-grade PCa. Furthermore, clorgyline inhibited several oncogenic pathways in PCa cells, suggesting clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high-risk PCa. Here, we extended our studies to a model of advanced PCa, VCaP cells, which were derived from castration-resistant metastatic PCa and express a high level of MAOA. Methods Growth of VCaP cells in the presence or absence of clorgyline was evaluated in vitro and in vivo. Gene expression changes in response to clorgyline were determined by microarray and validated by quantitative real-time polymerase chain reaction. Results Treatment with clorgyline in vitro inhibited growth and altered the transcriptional pattern of VCaP cells in a manner consistent with the pro-differentiation and anti-oncogenic effects seen in treated primary PCa cells. Src, beta-catenin, and MAPK oncogenic pathways, implicated in androgen-independent growth and metastasis, were significantly downregulated. Clorgyline treatment of mice bearing VCaP xenografts slowed tumor growth and induced transcriptome changes similar to those noted in vitro. Conclusion Our results support the possibility that anti-depressant drugs that target MAOA might find a new application in treating PCa.

Identification of Distinct Gene Expression Profiles between Esophageal Squamous Cell Carcinoma and Adjacent Normal Epithelial Tissues

“…It has been recently reported that high expression of monoamine oxidase A (MAOA) was found in normal basal prostatic epithelium and high-grade primary prostate cancer. On the contrary, both normal secretory prostatic epithelium and low-grade prostate cancer had low expression of MAOA (Flamand et al 2010). In this study, we also found that MAOA was down-regulated markedly in ESCC when compared with normal esophageal mucosae.…”

The Monoamine Oxidase A Inhibitor Clorgyline Is a Broad-Spectrum Inhibitor of Fungal ABC and MFS Transporter Efflux Pump Activities Which Reverses the Azole Resistance of Candida albicans and Candida glabrata Clinical Isolates

“…The clorgyline concentration required for chemosensitizing activity (Ն5 M) was ϳ10 fold greater than its reported activity (IC 50 0.54 M) against MAO-A (12). However, concentrations of up to 50 M have been demonstrated to be nontoxic to cultured human cells (11), and clorgyline is under investigation as a lead compound for treatment of heart failure (17) and also for prostate cancer (11). Another key finding was that clorgyline is not a substrate of fungal efflux pumps; therefore, the inhibitory activity observed is not a result of competition with the substrates (R6G or azoles) used in the secondary assays.…”

Effects of the monoamine oxidase inhibitors pargyline and tranylcypromine on cellular proliferation in human prostate cancer cells

“…In recent years, MAO inhibitors such as pargyline, tranylcypromine and clorgyline (11,12,14–16,21) began to be tested for cancer cell treatment. In the present study, we found that pargyline efficiently inhibited the proliferation of prostate cancer cells.…”