Inhibition of hyaluronan retention by 4-methylumbelliferone suppresses osteosarcoma cells in vitro and lung metastasis in vivo

Br J Cancer. 2011 Dec 6;105(12):1839-49. doi: 10.1038/bjc.2011.459. Epub 2011 Nov 1.

Abstract

Background: Hyaluronan (HA) plays crucial roles in the tumourigenicity of many types of malignant tumours. 4-Methylumbelliferone (MU) is an inhibitor of HA synthesis. Several studies have shown its inhibitory effects on malignant tumours; however, none have focused on its effects on osteosarcoma.

Methods: We investigated the effects of MU on HA accumulation and tumourigenicity of highly metastatic murine osteosarcoma cells (LM8) that have HA-rich cell-associated matrix, and human osteosarcoma cell lines (MG-63 and HOS).

Results: In vitro, MU inhibited HA retention, thereby reducing the formation of functional cell-associated matrices, and also inhibited cell proliferation, migration, and invasion. Akt phosphorylation was suppressed by MU (1.0 mM). In vivo, although MU showed only a mild inhibitory effect on the growth of the primary tumour, it markedly inhibited (75% reduction) the development of lung metastasis. Hyaluronan retention in the periphery of the primary tumour was markedly suppressed by MU.

Conclusion: These findings suggested that MU suppressed HA retention and cell-associated matrix formation in osteosarcoma cells, resulting in a reduction of tumourigenicity, including lung metastasis. 4-Methylumbelliferone is a promising therapeutic agent targeting both primary tumours and distant metastasis of osteosarcoma, possibly via suppression of HA retention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Hyaluronic Acid / antagonists & inhibitors
  • Hyaluronic Acid / metabolism*
  • Hymecromone / analogs & derivatives*
  • Hymecromone / pharmacology
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • In Vitro Techniques
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Real-Time Polymerase Chain Reaction

Substances

  • Hymecromone
  • Hyaluronic Acid
  • Proto-Oncogene Proteins c-akt