Abstract 2681: 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 dietary supplement that inhibits HA-synthesis. In this study we evaluated chemopreventive and therapeutic efficacy of 4-MU to prevent PCa growth and metastasis in three PCa models. METHODS: Efficacy of daily oral gavage of 4-MU was evaluated in 3 PCa models: Model 1: TRAMP mice (n = 8-20/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. Model 2: Mice were treated with 4-MU (200 mg/kg or 450 mg/kg) following intracardiac injection of Luciferase expressing PC3-ML cells. 3. Palpable DU145 xenografts were treated with 4-MU (200 and 450 mg/kg). Effect of 4-MU on EMT markers, HA receptors was evaluated by Q-PCR, immunoblotting and/or immunohistochemistry in PCa cells and xenograft tissues. HA add back and overexpression studies were conducted to evaluate the mechanism of action of 4-MU. RESULTS: In the TRAMP model, at 28 wks, 100% of vehicle treated mice developed PCa, 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, 12 and 22 wk groups remained tumor free until 52, 44 and 34 wks respectively, even after stopping treatment at 28 wks. While 55% of vehicle treated animals developed metastasis, none of the treated groups had metastasis. In the PC3-ML intracardiac model, 100% of the mice in the vehicle group but none in the treatment group developed skeletal metastasis. In the DU145 model, 4-MU inhibited tumor growth. No serum/organ toxicity or weight loss was observed in any treatment groups. In all models, 4-MU treatment downregulated HA, HA receptors (CD44, RHAMM) and EMT markers (β-catenin, Zeb2) by >2-fold) but up-regulated E-cadherin. HA addition and overexpression of myristoylated AKt inhibited 4-MU effects. CONCLUSION: 4-MU is a potent non-toxic, oral chemopreventive agent, which inhibits PCa growth and metastasis by abrogating HA-signaling and reversing EMT. Support: R01 CA 123063-04 (VBL); R01 CA 72821-11 (VBL) Note: This abstract was not presented at the meeting. Citation Format: Travis Yates, David Alonzo, Soum Lokeshwar, Kelly Hoye, Luis E. Lopez, Marie Hupe, Vinata Lokeshwar. 4-methylumbelliferone: Dietary supplement turned chemo-preventive and anti-metastatic agent for prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2681. doi:10.1158/1538-7445.AM2014-2681