The Effects of Cruciferous Vegetable Derived Bioactive Compounds on the Modulation of Human Prostate Cancer

Prostate cancer is the most common non-skin cancer type in American males. Poor diet quality may have profound negative consequences on disease outcome. Diets consisting of low cruciferous vegetable and high red meat intake were found to be significant, yet modifiable risk factors. Currently, there are no effective cures for prostate cancer. As a result, improved diet quality through the promoted use of natural products is commonly sought after complementary health approach to disease prevention and cancer risk reduction. Phenethyl isothiocyanate (PEITC) and indole-3-carbinol (I3C), naturally occurring bioactive compounds in cruciferous vegetables, are considered ideal chemopreventive candidates. This dissertation focused on examining biological efficacy and identifying distinctive biological mechanisms utilized by PEITC and I3C to modulate human prostate cancer growth in a xenograft mouse model. When treated with PEITC, mice were found to be differentially responsive. Tissue analysis revealed a significant decrease in tumor burden with no observable toxic effects. PEITC exerted minimal effects on androgen responsive pathways within tumors. However, cell proliferation and macrophage presence were significantly reduced and insulin-like growth factor binding protein-3 expression was increased in the treatment group fed PEITC. Previous studies have shown an overlap in no effect and chemopreventive I3C dosage levels. Therefore, physiological and biological sensitivity to I3C in a commonly used xenograft model was examined. Mice were biologically responsive to doses exceeding 10 µmoles I3C/g diets. Viability was significantly affected at the highest concentration unless mice were switched to the control diet without I3C after first detection of stress. The intestine appeared to be the target of I3C toxicity as noted by changes in number and width of intestinal villi, proliferation, and apoptosis. Changes to xenobiotic metabolism were indicated within the livers of the treatment mice, supporting involvement of aryl hydrocarbon receptor-mediated pathway in the metabolism of I3C. Biological efficacy of low, physiologically relevant doses of I3C was also examined. Following exposure to low concentrations of I3C, tumor volume, xenobiotic metabolism, and cell motility were altered in tumorigenic mice. Collectively, findings from this study highlighted unique, yet complicated, pleiotropic responses of cruciferous-derived compounds in prostate cancer

Inhibition of Tumor Growth by Dietary Indole-3-Carbinol in a Prostate Cancer Xenograft Model May Be Associated with Disrupted Gut Microbial Interactions

Accumulated evidence suggests that the cruciferous vegetables-derived compound indole-3-carbinol (I3C) may protect against prostate cancer, but the precise mechanisms underlying its action remain unclear. This study aimed to verify the hypothesis that the beneficial effect of dietary I3C may be due to its modulatory effect on the gut microbiome of mice. Athymic nude mice (5–7 weeks old, male, Balb c/c nu/nu) with established tumor xenografts were fed a basal diet (AIN-93) with or without 1 µmoles I3C/g for 9 weeks. The effects of dietary I3C on gut microbial composition and microbial species interactions were then examined by 16s rRNA gene-based sequencing and co-occurrence network analysis. I3C supplementation significantly inhibited tumor growth (p < 0.0001) and altered the structure of gut microbiome. The abundance of the phylum Deferribacteres, more specifically, Mucispirillum schaedleri, was significantly increased by dietary I3C. Additionally, I3C consumption also changed gut microbial co-occurrence patterns. One of the network modules in the control group, consisting of seven bacteria in family S-27, was positively correlated with tumor size (p < 0.009). Moreover, dietary I3C disrupted microbial interactions and altered this association between specific microbial network and tumor development. Our results unraveled complex relationships among I3C ingestion, gut microbiota, and prostate tumor development and may provide a novel insight into the mechanism for the chemopreventive effect of dietary I3C on prostate cancer