Inhibition of the invasion capacity of carcinoma cells by WX-UK1, a novel synthetic inhibitor of the urokinase-type plasminogen activator system

Int J Cancer. 2004 Jul 20;110(6):815-24. doi: 10.1002/ijc.20192.

Abstract

The overall survival rate of patients suffering from carcinomas has remained poor and nearly unchanged over the last decades. This is mainly due to the so-called minimal residual disease, i.e., remaining tumor cells that overcome surgery and/or radiotherapy and are the cause of locoregional and distant metastases. To metastasize, tumor cells take advantage of proteases to invade and remodel surrounding tissues. Here, we analyzed the efficiency of WX-UK1, a novel 3-amidinophenylalanine-based inhibitor of the uPA system, at inhibiting the invasive capacity of carcinoma cells. First, uPAR expression was characterized in different carcinoma cell lines, including SCCHN, breast and cervical carcinoma. Thereafter, the invasive potential of these cell lines was determined using Matrigel invasion chambers and a spheroid cocultivation model with human fibroblasts. uPAR expression levels correlated positively with invasion capacity, which could be significantly inhibited by WX-UK1. A decrease of tumor cell invasion by up to 50% was achieved in both models with the SCCHN line FaDu and the cervical carcinoma line HeLa after treatment with WX-UK1. Thus, our results demonstrate the potential of WX-UK1 in vitro as a promising adjuvant antimetastatic therapy of carcinomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / toxicity
  • Breast Neoplasms
  • Cell Line, Tumor
  • Collagen
  • Drug Combinations
  • Female
  • Flow Cytometry
  • HeLa Cells
  • Humans
  • Laminin
  • Neoplasm Invasiveness / prevention & control*
  • Neoplasm Metastasis / prevention & control
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / pharmacology*
  • Proteoglycans
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / physiology*
  • Receptors, Urokinase Plasminogen Activator
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
  • Uterine Cervical Neoplasms

Substances

  • Antineoplastic Agents
  • Drug Combinations
  • Laminin
  • PLAUR protein, human
  • Proteoglycans
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • matrigel
  • Phenylalanine
  • Collagen
  • Urokinase-Type Plasminogen Activator
  • N-alpha-(2,4,6-triisopropyl-phenylsulfonyl)-3-amidino-(L)-phenyl-alanine-4-ethoxycarbonyl-piperazide hydrochloride