Bortezomib-mediated proteasome inhibition as a potential strategy for the treatment of rhabdomyosarcoma

Eur J Cancer. 2008 Apr;44(6):876-84. doi: 10.1016/j.ejca.2008.02.022. Epub 2008 Mar 14.

Abstract

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, divided into two major histological subtypes, embryonal (ERMS) and alveolar (ARMS). To explore the possibility that the proteasome could be a target of therapeutic value in rhabdomyosarcoma, we treated several RMS cell lines with the proteasome inhibitor bortezomib (Velcade or PS-341) at a concentration of 13-26 nM. RMS cells showed high sensitivity to the drug, whereas no toxic effect was observed in primary human myoblasts. In both ERMS and ARMS cells bortezomib promoted apoptosis, activation of caspase 3 and 7 and induced a dose-dependent reduction of anchorage-independent growth. Furthermore, bortezomib induced activation of the stress response, cell cycle arrest and the reduction of NF-kappaB transcriptional activity. Finally, bortezomib decreased tumour growth and impaired cells viability, proliferation and angiogenesis in a xenograft model of RMS. In conclusion, our data indicate that bortezomib could represent a novel drug against RMS tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Cell Proliferation
  • Cell Survival / drug effects
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / prevention & control
  • Protease Inhibitors / therapeutic use*
  • Proteasome Inhibitors*
  • Pyrazines / therapeutic use*
  • Rhabdomyosarcoma / drug therapy*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • Angiogenesis Inhibitors
  • Boronic Acids
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrazines
  • Bortezomib