Dietary Supplement 4-Methylumbelliferone

An Effective Chemopreventive and Therapeutic Agent for Prostate Cancer

Travis J. Yates, Luis E. Lopez, Soum D. Lokeshwar, Nicolas Ortiz, Georgios Kallifatidis, Andre Jordan, Kelly Hoye, Norman Altman, Vinata B Lokeshwar

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberdjv085
JournalJournal of the National Cancer Institute
Volume107
Issue number7
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

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Hymecromone
Dietary Supplements
Prostatic Neoplasms
Hyaluronic Acid
Therapeutics
Prostate
1-Phosphatidylinositol 4-Kinase
Neoplasm Metastasis
Adenocarcinoma
Down-Regulation
Apoptosis
Glycogen Synthase Kinase 3
Catenins
Neoplasms
Cadherins
Subcutaneous Injections
Microvessels
Transgenes
Growth and Development
Weight Loss

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dietary Supplement 4-Methylumbelliferone : An Effective Chemopreventive and Therapeutic Agent for Prostate Cancer. / Yates, Travis J.; Lopez, Luis E.; Lokeshwar, Soum D.; Ortiz, Nicolas; Kallifatidis, Georgios; Jordan, Andre; Hoye, Kelly; Altman, Norman; Lokeshwar, Vinata B.

In: Journal of the National Cancer Institute, Vol. 107, No. 7, djv085, 01.07.2015.

Research output: Contribution to journalArticle

Yates, Travis J. ; Lopez, Luis E. ; Lokeshwar, Soum D. ; Ortiz, Nicolas ; Kallifatidis, Georgios ; Jordan, Andre ; Hoye, Kelly ; Altman, Norman ; Lokeshwar, Vinata B. / Dietary Supplement 4-Methylumbelliferone : An Effective Chemopreventive and Therapeutic Agent for Prostate Cancer. In: Journal of the National Cancer Institute. 2015 ; Vol. 107, No. 7.
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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.",
author = "Yates, {Travis J.} and Lopez, {Luis E.} and Lokeshwar, {Soum D.} and Nicolas Ortiz and Georgios Kallifatidis and Andre Jordan and Kelly Hoye and Norman Altman and Lokeshwar, {Vinata B}",
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T2 - An Effective Chemopreventive and Therapeutic Agent for Prostate Cancer

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AU - Lopez, Luis E.

AU - Lokeshwar, Soum D.

AU - Ortiz, Nicolas

AU - Kallifatidis, Georgios

AU - Jordan, Andre

AU - Hoye, Kelly

AU - Altman, Norman

AU - Lokeshwar, Vinata B

PY - 2015/7/1

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N2 - 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.

AB - 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.

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