495 CHEMOPREVENTION OF TUMOR PROGRESSION AND METASTASIS IN PROSTATE CANCER BY NUTRACEUTICAL, 4-METHYLUMBELLIFERONE

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research (III)1 Apr 2013495 CHEMOPREVENTION OF TUMOR PROGRESSION AND METASTASIS IN PROSTATE CANCER BY NUTRACEUTICAL, 4-METHYLUMBELLIFERONE Nicolas Ortiz, Travis Yates, Luis Lopez, Marie Hupe, and Vinata Lokeshwar Nicolas OrtizNicolas Ortiz Miami, FL More articles by this author , Travis YatesTravis Yates Miami, FL More articles by this author , Luis LopezLuis Lopez Miami, FL More articles by this author , Marie HupeMarie Hupe Miami, FL More articles by this author , and Vinata LokeshwarVinata Lokeshwar Miami, FL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1889AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Hyaluronic acid (HA), a glycosaminoglycan, is associated with prostate cancer (PCa) progression and metastasis. 4-methylumbelliferone (4-MU), is a HA-synthesis inhibitor. We have shown antitumor and anti-invasive effects of 4-MU on PCa cells in vitro and in xenografts. In this study we evaluated the efficacy of 4-MU to prevent PCa growth and metastasis in the TRAMP model. We also evaluated effects of 4-MU on epithelial-mesenchymal transition (EMT). METHODS TRAMP mice (n = 8-11/group) were treated with vehicle or 4-MU (450 mg/kg) by starting stage-specific treatment at 8 (PIN stage; Gr1), 12 (adenocarcinoma; Gr2) and 22 (invasive carcinoma; Gr3) wks of age. At 28 wks, 50% of animals in 4-MU treated groups were sacrificed and the other 50% were left untreated up to 52 wks. At necropsy, prostate (P) and seminal vesicles (SV) were weighed, tissues were analyzed by histology, immunohistochemistry and quantitative PCR for EMT markers and serum chemistry was evaluated. PC3-ML cells treated with 4-MU were analyzed for EMT markers. RESULTS In the TRAMP model, at 28 wks, 100% of vehicle treated mice developed prostate tumors, but tumor growth and progression was inhibited in all 4-MU treated groups; P+SV weight (g): vehicle: 3.2±2.9; 4-MU treated: Gr1: 0.43±0.14; Gr2: 0.35±0.04; Gr3: 1.0±0.35 g. P+SV weight in control TRAMP mice at 22 wks of age was 0.9±0.04. Animals in Gr1 and Gr2 remained tumor free until 52 wk and 44 wk respectively. While 55% of vehicle treated animals developed metastasis, none of the treated groups had metastasis or SV invasion. No serum/organ toxicity or weight loss was observed in the treatment groups. HA, HA receptors (CD44, RHAMM) and EMT markers (β-catenin, Zeb2) were downregulated (>2-fold), but E-cadherin was upregulated (4-fold) in the treatment groups. 4-MU treatment (0-60 μg/ml) similarly modulated the expression of EMT markers and HA receptors in PC3-ML cells. CONCLUSIONS 4-MU is a promising non-toxic, oral chemopreventive agent, which inhibits PCa growth and metastasis by plausibly abrogating HA-signaling and reversing EMT. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e203 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nicolas Ortiz Miami, FL More articles by this author Travis Yates Miami, FL More articles by this author Luis Lopez Miami, FL More articles by this author Marie Hupe Miami, FL More articles by this author Vinata Lokeshwar Miami, FL More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...