4-Methylumbelliferone Decreases the Hyaluronan-rich Extracellular Matrix and Increases the Effectiveness of 5-Fluorouracil

Anticancer Res. 2018 Oct;38(10):5799-5804. doi: 10.21873/anticanres.12919.


Background/aim: Pancreatic cancer responds poorly to most chemotherapeutic agents. Several studies have reported that hyaluronan (HA)-rich extracellular matrix (ECM) is a biological barrier against chemotherapeutic agents. 4-methylumbelliforone (MU) led to inhibition of HA synthesis and its preservation in ECM, which may enhance 5-fluorouracil (5-FU) cytotoxicity. Thus, new therapy with MU and 5-FU may be developed for pancreatic cancer.

Materials and methods: A 5-fluorouracil (5-FU) concentration and 4-methylumbelliferone (MU) dosage was analyzed by high-performance liquid chromatography (HPLC). Change in antitumor efficacy of 5-FU in combination with MU was also examined in vivo and in vitro.

Results: Combined 5-FU and MU treatment inhibited cell proliferation better than 5-FU alone; 0.01 mM 5-FU alone decreased cell proliferation by 37.7 %, while 0.01 mM 5-FU with 0.5 mM MU decreased cell proliferation by 57.4%. MU enhanced the intracellular concentration of 5-FU by 47.3% compared to control. Mice tumors treated with 5-FU and MU decreased in size and animal survival was prolonged. Moreover, MU decreased cohesiveness of the intercellular space.

Conclusion: Combination therapy of 5-FU with MU was effective. A novel therapy can be designed for pancreatic cancer by using ECM modulation.

Keywords: 4-methylumbelliferone; 5-fluorouracil; Pancreatic cancer; antitumor effect; extracellular modulation; hyaluronan.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Drug Synergism*
  • Extracellular Matrix / metabolism*
  • Fluorouracil / pharmacology*
  • Humans
  • Hyaluronic Acid / metabolism*
  • Hymecromone / pharmacology*
  • Indicators and Reagents / pharmacology
  • Mice
  • Mice, SCID
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antimetabolites, Antineoplastic
  • Indicators and Reagents
  • Hymecromone
  • Hyaluronic Acid
  • Fluorouracil