Dietary supplement 4-methylumbelliferone: an effective chemopreventive and therapeutic agent for prostate cancer

J Natl Cancer Inst. 2015 Apr 13;107(7):djv085. doi: 10.1093/jnci/djv085. Print 2015 Jul.

Abstract

Background: Prevention and treatment of advanced prostate cancer (PCa) by a nontoxic agent can improve outcome, while maintaining quality of life. 4-methylumbelliferone (4-MU) is a dietary supplement that inhibits hyaluronic acid (HA) synthesis. We evaluated the chemopreventive and therapeutic efficacy and mechanism of action of 4-MU.

Methods: TRAMP mice (7-28 per group) were gavaged with 4-MU (450mg/kg/day) in a stage-specific treatment design (8-28, 12-28, 22-28 weeks). Efficacy of 4-MU (200-450mg/kg/day) was also evaluated in the PC3-ML/Luc(+) intracardiac injection and DU145 subcutaneous models. PCa cells and tissues were analyzed for HA and Phosphoinositide 3-kinase (PI-3K)/Akt signaling and apoptosis effectors. HA add-back and myristoylated Akt (mAkt) overexpression studies evaluated the mechanism of action of 4-MU. Data were analyzed with one-way analysis of variance and unpaired t test or Tukey's multiple comparison test. All statistical tests were two-sided.

Results: While vehicle-treated transgenic adenocarcinoma of the prostate (TRAMP) mice developed prostate tumors and metastases at 28 weeks, both were abrogated in treatment groups, without serum/organ toxicity or weight loss; no tumors developed at one year, even after stopping the treatment at 28 weeks. 4-MU did not alter the transgene or neuroendocrine marker expression but downregulated HA levels. However, 4-MU decreased microvessel density and proliferative index (P < .0001,). 4-MU completely prevented/inhibited skeletal metastasis in the PC3-ML/Luc(+) model and DU145-tumor growth (85-90% inhibition, P = .002). 4-MU also statistically significantly downregulated HA receptors, PI-3K/CD44 complex and activity, Akt signaling, and β-catenin levels/activation, but upregulated GSK-3 function, E-cadherin, and apoptosis effectors (P < .001); HA addition or mAkt overexpression rescued these effects.

Conclusion: 4-MU is an effective nontoxic, oral chemopreventive, and therapeutic agent that targets PCa development, growth, and metastasis by abrogating HA signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Anticarcinogenic Agents / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor / metabolism
  • Bone Neoplasms / prevention & control*
  • Bone Neoplasms / secondary
  • Dietary Supplements*
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hyaluronic Acid / antagonists & inhibitors
  • Hyaluronic Acid / metabolism
  • Hymecromone / pharmacology*
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Staging
  • Neovascularization, Pathologic / prevention & control
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Signal Transduction / drug effects
  • Time Factors
  • Treatment Outcome

Substances

  • Anticarcinogenic Agents
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Phosphoinositide-3 Kinase Inhibitors
  • Hymecromone
  • Hyaluronic Acid