title: Inositol hexaphosphate inhibits tumor growth, vascularity, and metabolism in TRAMP mice: a multiparametric magnetic resonance study.
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.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Komal
authors.initials: K
authors.lastname: Raina
authors.forename: Kameswaran
authors.initials: K
authors.lastname: Ravichandran
authors.forename: Subapriya
authors.initials: S
authors.lastname: Rajamanickam
authors.forename: Kendra M
authors.initials: KM
authors.lastname: Huber
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D001835:Body Weight; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010833:Phytic Acid / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control
chemical_list: D014408:Biomarkers, Tumor; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; D010833:Phytic Acid; D055372:AMP-Activated Protein Kinases