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J Cancer Res Clin Oncol. 2010 Nov;136(11):1761-71. doi: 10.1007/s00432-010-0835-6. Epub 2010 Mar 4.

Targeting monoamine oxidase A in advanced prostate cancer.

Author information

1
Department of Urology, Stanford Medical Center, Stanford University School of Medicine, Stanford, CA 94305-5118, USA.

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.

PMID:
20204405
PMCID:
PMC2945406
DOI:
10.1007/s00432-010-0835-6
[Indexed for MEDLINE]
Free PMC Article

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