Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa (E-CA).</p> <p>Methods</p> <p>We systematically assessed gene expression changes induced by clorgyline in E-CA cells using high-density oligonucleotide microarrays. Genes differentially expressed in treated and control cells were identified by Significance Analysis of Microarrays. Expression of genes of interest was validated by quantitative real-time polymerase chain reaction.</p> <p>Results</p> <p>The expression of 156 genes was significantly increased by clorgyline at all time points over the time course of 6 – 96 hr identified by Significance Analysis of Microarrays (SAM). The list is enriched with genes repressed in 7 of 12 oncogenic pathway signatures compiled from the literature. In addition, genes downregulated ≥ 2-fold by clorgyline were significantly enriched with those upregulated by key oncogenes including beta-catenin and ERBB2, indicating an anti-oncogenic effect of clorgyline. Another striking effect of clorgyline was the induction of androgen receptor (AR) and classic AR target genes such as prostate-specific antigen together with other secretory epithelial cell-specific genes, suggesting that clorgyline promotes differentiation of cancer cells. Moreover, clorgyline downregulated EZH2, a critical component of the Polycomb Group (PcG) complex that represses the expression of differentiation-related genes. Indeed, many genes in the PcG repression signature that predicts PCa outcome were upregulated by clorgyline, suggesting that the differentiation-promoting effect of clorgyline may be mediated by its downregulation of EZH2.</p> <p>Conclusion</p> <p>Our results suggest that inhibitors of MAO-A, already in clinical use to treat depression, may have potential application as therapeutic PCa drugs by inhibiting oncogenic pathway activity and promoting differentiation.</p

Artemisia Annua as Phytogenic Feed Additive in the Diet of Broilers (14-35 Days) Reared under Heat Stress (32 ºC)

ABSTRACT The 21 days feeding trial was conducted on 90, Cobb 500 broilers (aged 14 days), assigned to 3 groups (C, E1 and E2) housed in an experimental hall at 32° C constant temperature and 23 h light regimen. During the growth period (14-35 days), the conventional diet (C) had corn and soybean meal as basic ingredients. Unlike the conventional diet formulation (C), the diet formulations for the experimental groups also included 0.005% Artemisia annua oil (E1) and 0.005% Artemisia annua oil plus 1% Artemisia annua powder (E2). Six broilers per group were slaughtered at 35 days of age in order to measure the weight of the carcass and internal organs of broilers, and samples of intestinal and caecal content were collected for bacteriological assessment (Enterobacteriaceae, E. coli, staphylococci, Lactobacilli, Salmonella spp.).The following parameters were monitored during the experimental period: bodyweight (g); average daily feed intake (g feed/broiler/day); average daily weight gain (g/broiler/day); feed conversion ratio (g feed/g gain). Under heat stress (32 ºC), E2 broilers (mixture of A. annua oil and powder) had a significantly (p<0.05) higher average of daily feed intake than the broilers receiving the C diet or the diet supplemented just with A. annua oil (E1). Both samples of intestinal and caecal content, showed the lowest count (p<0.05) of Enterobacteriaceae, E. coli and staphylococcus colony forming units in E2 broilers. Diet with A. annua oil and powder provided proper conditions for lactic acid bacteria proliferation in the intestine and caecum of heat stressed broilers