A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis

Oncotarget. 2015 Apr 20;6(11):9295-312. doi: 10.18632/oncotarget.3261.

Abstract

Here we showed that ursolic acid (UA), a pentacyclic triterpene natural product, and its novel prodrug derivative US597 suppressed cancer cells adhesion, invasion and migration. This effect was accompanied by inhibition of focal adhesion signaling pathway including alterations in ICAM-1, VCAM-1, E-selectin, P-selectin, integrin α6β1, FAK, Src, paxillin and PTEN. While oral administration of UA or US597 increases survival rate of melanoma lung metastasis in C57BL/6 mice, US597 treatment extend the survival rate above that of UA. Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis. We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities. Thus, UA and US597 are potential drug candidates for preventing cancer metastasis. Molecular and cellular study data suggest that UA and US597 modulate expression of cell adhesion molecules within focal adhesion signaling pathway leading to cancer cell motility.

Keywords: anti-metastasis; cell adhesion molecules; focal adhesion; integrin; ursolic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Products / pharmacology
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cells, Cultured
  • HT29 Cells
  • Hep G2 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Neoplasm Metastasis
  • Neoplasms / pathology*
  • Neoplasms / prevention & control*
  • Pentacyclic Triterpenes / pharmacology
  • Prodrugs / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Triterpenes / pharmacology*

Substances

  • 3-acetoxyurs-12-en-28-oic acid hexamethylenediamine
  • Biological Products
  • Pentacyclic Triterpenes
  • Prodrugs
  • Triterpenes
  • ursolic acid