Abstract 188: 4-methylumbelliferone: Dietary supplement turned chemo-preventive and anti-metastatic agent for prostate cancer.

Abstract

Abstract INTRODUCTION: Hyaluronic acid (HA), a glycosaminoglycan, is associated with prostate cancer (PCa) progression and metastasis. 4-methylumbelliferone (4-MU) is a HA-synthesis inhibitor and 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 the 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), 12 (adenocarcinoma) and 22 (invasive carcinoma) 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: 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; 8 wk: 0.43±0.14; 12 wk: 0.35±0.04; 22 wk: 1.0±0.35 g. The P+SV weight in TRAMP mice at 22 wks of age was 0.9±0.04, showing that late stage administration of 4-MU halted further tumor progression. Animals in 8 and 12 wk groups 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. 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. CONCLUSION: 4-MU is a promising non-toxic, oral chemopreventive agent, which inhibits PCa growth and metastasis by plausibly abrogating HA-signaling and reversing EMT. Support: R01 CA 123063-04 (VBL); R01 CA 72821-11 (VBL) Citation Format: Travis Yates, Luis Lopez, Marie Hupe, Nicolas Ortiz, Vinata B. Lokeshwar. 4-methylumbelliferone: Dietary supplement turned chemo-preventive and anti-metastatic agent for prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 188. doi:10.1158/1538-7445.AM2013-188