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Prostate cancer (PCa) is the leading cause of cancer-related deaths in elderly men in US; ACS’ statistical estimates for 2011 report ∼240,890 new PCa cases and 33,720 associated deaths. In recent years, transgenic adenocarcinoma of the mouse prostate (TRAMP) has been the most frequently employed PCa model to evaluate chemopreventive efficacy of various agents. This model closely mimics human form of the disease, wherein prostate carcinogenesis progresses in a step-wise manner with the age of the mouse. The well defined stages of prostate tumor growth, progression and angiogenesis in TRAMP model provide unique opportunity to assess ‘stage specific’ preventive efficacy of an agent. Accordingly, employing TRAMP model, here we assessed stage-specific efficacy of inositol hexaphosphate (IP6) feeding on PCa initiation and growth, progression and angiogenesis, and elucidated the molecular events involved in IP6 effects during these stages. Different groups of male TRAMP mice starting at 4, 12, 20 and 30 weeks of age were fed with regular drinking water or 2% IP6 in regular drinking water for 8-10 weeks. At the end of the study, histopathological analysis of prostate showed that all the mice fed with IP6 at different time-points display less severe prostatic lesions compared to non-IP6 fed positive control mice. During early stages of prostate tumor development, IP6 mediated its chemopreventive effect mostly via anti-proliferative and pro-apoptotic mechanisms. Feeding of IP6 to animals burdened with higher stages of prostate tumor significantly decreased tumor grade via anti-proliferative effect and inhibition of angiogenesis as evidenced by decreased expression of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD-31), vascular endothelial growth factor (VEGF) hypoxia-inducible factor-1a (HIF-1a) and inducible nitric oxide synthase (iNOS). These effects of IP6 also correlated with an alteration of epithelial-mesenchymal transition (EMT) as was evidenced by a decreased expression of mesenchymal markers Snail-1 in the prostatic tissue and retention of epithelial characteristics determined by localization of E-cadherin. Together, the findings in the present study are both novel and highly significant in establishing the dual efficacy of IP6, where it inhibits initiation and progression of primary prostatic tumor and also exerts protective efficacy against angiogenesis. These effects of IP6 should have potential implications to control PCa growth and improve the morbidity and survival time in PCa patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5421. doi:1538-7445.AM2012-5421

Prostate cancer (PCa) is the second leading cause of cancer-associated deaths in elderly males in Western world, suggesting that newer approaches are needed to prevent/control PCa. Herein, for the first time, by employing anatomical and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), we evaluated non-invasively, the in vivo chemopreventive efficacy of inositol hexaphosphate (IP6), a major constituent of high fiber diets, against prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The study was conducted on a longitudinal basis to simultaneously assess both prostate sizes and changes in tumor vascularization (perfusion and permeability) due to IP6 feeding. Male TRAMP mice, beginning 4 weeks of age, were fed with 1, 2 or 4% (w/v) IP6 in drinking water or only drinking water till 28 weeks of age and monitored using MRI over the course of treatment. Longitudinal assessment of volumes of prostate and seminal vesicles showed profound effect of 2% and 4% IP6 doses on selectively reducing prostate volume without noticeable changes in seminal vesicles. Further, gadolinium-based DCE-MRI showed decreased tumor perfusion and permeability, indicative of anti-angiogenic effects of IP6 treatment. Histopathological analysis at the end of the study corroborated the MRI results, and showed that IP6-fed mice had less severe prostatic lesions compared to positive controls. Specifically, the mice in IP6-fed groups showed higher incidence of prostatic intraepithelial neoplasia (PIN) at the expense of a strong decrease in adenocarcinoma incidence. Importantly, the mice in IP6-fed groups also had prostatic regions with typical normal histology, which was totally absent in positive controls. IHC and WB results indicated anti-proliferative, pro-apoptotic, and anti-angiogenic effect of IP6 feeding, as evidenced by decreased number of PCNA-, PECAM-1/CD-31-, VEGF- and iNOS- positive cells, together with increased number of TUNEL positive cells. As potential mechanisms of IP6 efficacy, decrease in the expression of glucose transporter (GLUT) proteins together with an increase in phosphorylated levels of AMP-activated kinase (AMPKTh172) and acetyl-CoA carboxylase (ACCSer79) were observed in the prostatic tissue of mice from IP6 fed-groups. Since phosphorylation results in decreased activity of ACC which is an essential enzyme for fatty acid synthesis, our findings suggest that IP6 is interfering with the metabolic events occurring in TRAMP prostate tumor tissue. Together, these findings show that oral IP6 feeding blocks PCa growth and progression in TRAMP mouse model via modulation of metabolic events involved in tumor sustenance and thereby results in energy deprivation within the tumor, suggesting its practical and translational potential in suppressing growth and progression of PCa in humans (NCI RO1 grant CA116636). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 950.