Cilengitide inhibits attachment and invasion of malignant pleural mesothelioma cells through antagonism of integrins αvβ3 and αvβ5

PLoS One. 2014 Mar 3;9(3):e90374. doi: 10.1371/journal.pone.0090374. eCollection 2014.

Abstract

Malignant pleural mesothelioma (MPM) is an almost invariably fatal, asbestos-related malignancy arising from the mesothelial membrane lining the thoracic cavities. Despite some improvements in treatment, therapy is not considered curative and median survival following diagnosis is less than 1 year. Although still classed as a rare cancer, the incidence of MPM is increasing, and the limited progress in treating the disease makes the identification of new therapies a priority. As there is evidence for expression of the integrins αvβ3 and αvβ5 in MPM, there is a rationale for investigating the effects on MPM of cilengitide, a synthetic peptide inhibitor of integrin αv heterodimer with high specificity for αvβ3 and αvβ5. In mesothelial cells (MC) and 7 MPM cell lines, growth inhibition by cilengitide was associated with the expression level of its target integrins. Furthermore, cilengitide caused cell detachment and subsequent death of anoikis-sensitive cells. It also suppressed invasion of MPM cells in monolayer and three-dimensional cultures. Gene knockdown experiments indicated that these effects of cilengitide were, at least partly, due to antagonism of αvβ3 and αvβ5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / drug effects*
  • Cell Line, Tumor
  • Humans
  • Integrin alphaVbeta3 / antagonists & inhibitors*
  • Mesothelioma / pathology*
  • Neoplasm Invasiveness / prevention & control*
  • Pleural Neoplasms / pathology*
  • Receptors, Vitronectin / antagonists & inhibitors*
  • Snake Venoms / pharmacology*

Substances

  • Integrin alphaVbeta3
  • Receptors, Vitronectin
  • Snake Venoms
  • integrin alphaVbeta5
  • Cilengitide

Grants and funding

This study was funded by a Cancer Institute NSW grant (11/TPG/3–06) to NvZ and GR, and an investigator initiated study grant (4501161930) from Merck to GR and NvZ. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.