Abstract
Herein, employing anatomical and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), we evaluated noninvasively, 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. Male TRAMP mice, beginning at 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 study. Longitudinal assessment of prostate volumes by conventional MRI and tumor vascularity by gadolinium-based DCE-MRI showed a profound reduction in tumor size, partly due to antiangiogenic effects by IP6 treatment. As potential mechanisms of IP6 efficacy, decrease in the expression of glucose transporter GLUT-4 protein together with an increase in levels of phospho-AMP-activated kinase (AMPK(Th172)) were observed in prostate tissues of mice from IP6 fed-groups, suggesting that IP6 is interfering with the metabolic events occurring in TRAMP prostate. Investigative metabolomics study using quantitative high-resolution (1)H-NMR on prostate tissue extracts showed that IP6 significantly decreased glucose metabolism and membrane phospholipid synthesis, in addition to causing an increase in myoinositol levels in the prostate. Together, these findings show that oral IP6 supplement blocks growth and angiogenesis of prostate cancer in the TRAMP model in conjunction with metabolic events involved in tumor sustenance. This results in energy deprivation within the tumor, suggesting a practical and translational potential of IP6 treatment in suppressing growth and progression of prostate cancer in humans.
Highlights
Prostate cancer is the most frequently diagnosed malignancy in elderly American men; its incidence varies dramatically on a global level; both incidence and associated mortality are lower in the Asian compared with Western countries [1]
In the 4%–IP6-fed group, mice showed lower fluid consumption compared with other groups, which could be attributed to the taste of the highly concentrated IP6 solution
Mouse prostate consisting of a combination of anatomical proton density-weighted imaging for longitudinal tumor growth and dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) for tumor perfusion and permeability, to evaluate the IP6 effect on prostate tumorigenesis as a function of time. This noninvasive imaging technique showed that 1% IP6 dose was not significantly effective, but 2% and 4% IP6 doses showed a significant decrease in prostate volume after 16 weeks of mouse age, they were ineffective in inhibiting tumorigenesis before this time www.aacrjournals.org point
Summary
Prostate cancer is the most frequently diagnosed malignancy in elderly American men; its incidence varies dramatically on a global level; both incidence and associated mortality are lower in the Asian compared with Western countries [1]. The incidence of the occult/indolent form of PCa is similar globally despite dramatic difference in the occurrence of clinical malignancy [2]. One possible explanation for this enigma could be the aging process, which inadvertently causes slow histopathologic changes in the prostate, while environmental/dietary. In an effort to identify such etiologic factors, several studies indicate that 1 of the possible causes is the Western diet that includes highly processed foods [4,5,6]. IP6 is already marketed as a dietary supplement because of its antioxidant property and known beneficial effects, such as prevention of the formation of kidney stone, high cholesterol, and heart and liver diseases [5, 6, 8, 9]
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