title: Dietary supplement 4-methylumbelliferone: an effective chemopreventive and therapeutic agent for prostate cancer.
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.
  
  
  CONCLUSIONS
  4-MU is an effective nontoxic, oral chemopreventive, and therapeutic agent that targets PCa development, growth, and metastasis by abrogating HA signaling.
authors: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (TJY, AJ, KH), Department of Urology (LEL, NO, GK, VBL), Honors Program in Medical Education (SDL), Department of Pathology (NA), Department of Cell Biology (VBL), Clinical Translational Science Institute (VBL), University of Miami-Miller School of Medicine, Miami, FL.Current affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA (TJY).
authors: Travis J
authors: TJ
authors: Yates
authors: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (TJY, AJ, KH), Department of Urology (LEL, NO, GK, VBL), Honors Program in Medical Education (SDL), Department of Pathology (NA), Department of Cell Biology (VBL), Clinical Translational Science Institute (VBL), University of Miami-Miller School of Medicine, Miami, FL.Current affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA (TJY).
authors: Luis E
authors: LE
authors: Lopez
authors: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (TJY, AJ, KH), Department of Urology (LEL, NO, GK, VBL), Honors Program in Medical Education (SDL), Department of Pathology (NA), Department of Cell Biology (VBL), Clinical Translational Science Institute (VBL), University of Miami-Miller School of Medicine, Miami, FL.Current affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA (TJY).
authors: Soum D
authors: SD
authors: Lokeshwar
authors: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (TJY, AJ, KH), Department of Urology (LEL, NO, GK, VBL), Honors Program in Medical Education (SDL), Department of Pathology (NA), Department of Cell Biology (VBL), Clinical Translational Science Institute (VBL), University of Miami-Miller School of Medicine, Miami, FL.Current affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA (TJY).
authors: Nicolas
authors: N
authors: Ortiz
authors: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (TJY, AJ, KH), Department of Urology (LEL, NO, GK, VBL), Honors Program in Medical Education (SDL), Department of Pathology (NA), Department of Cell Biology (VBL), Clinical Translational Science Institute (VBL), University of Miami-Miller School of Medicine, Miami, FL.Current affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA (TJY).
authors: Georgios
authors: G
authors: Kallifatidis
authors: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (TJY, AJ, KH), Department of Urology (LEL, NO, GK, VBL), Honors Program in Medical Education (SDL), Department of Pathology (NA), Department of Cell Biology (VBL), Clinical Translational Science Institute (VBL), University of Miami-Miller School of Medicine, Miami, FL.Current affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA (TJY).
authors: Andre
authors: A
authors: Jordan
authors: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (TJY, AJ, KH), Department of Urology (LEL, NO, GK, VBL), Honors Program in Medical Education (SDL), Department of Pathology (NA), Department of Cell Biology (VBL), Clinical Translational Science Institute (VBL), University of Miami-Miller School of Medicine, Miami, FL.Current affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA (TJY).
authors: Kelly
authors: K
authors: Hoye
authors: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (TJY, AJ, KH), Department of Urology (LEL, NO, GK, VBL), Honors Program in Medical Education (SDL), Department of Pathology (NA), Department of Cell Biology (VBL), Clinical Translational Science Institute (VBL), University of Miami-Miller School of Medicine, Miami, FL.Current affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA (TJY).
authors: Norman
authors: N
authors: Altman
authors: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (TJY, AJ, KH), Department of Urology (LEL, NO, GK, VBL), Honors Program in Medical Education (SDL), Department of Pathology (NA), Department of Cell Biology (VBL), Clinical Translational Science Institute (VBL), University of Miami-Miller School of Medicine, Miami, FL.Current affiliation: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA (TJY). vlokeshw@med.miami.edu.
authors: Vinata B
authors: VB
authors: Lokeshwar
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D019587:Dietary Supplements; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D006923:Hymecromone / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006820:Hyaluronic Acid; D006923:Hymecromone; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors