Pleiotropic effects of fenretinide in neuroblastoma cell lines and multicellular tumor spheroids

Roos Cuperus, Godelieve A.M. Tytgat, René Leen, Pedro Brites, Johannes Bras, Huib N. Caron, André B.P. Van Kuilenburg

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

The efficacy and mechanism of action of fenretinide (4-HPR), a vitamin A analogue, was investigated in a panel of six neuroblastoma cell lines and multicellular tumor spheroids. The latter are three dimensional cell aggregates and as such, a model for micrometastases. In all cell lines, the production of reactive oxygen species (ROS) increased with 163-680% after 1 h of treatment with 4-HPR. In addition, a decrease of the mitochondrial membrane potential of 30-75% was observed after 4 h of incubation with 4-HPR. A 6-12-fold difference was observed between the IC50 values for cell proliferation and viability between the most sensitive (IMR32) and most resistant (NASS) cell line towards 4-HPR. Flow cytometric analysis showed an increased amount of apoptotic bodies and no cell-cycle arrest. The antioxidant Trolox completely inhibited the accumulation of 4HPR-induced ROS and prevented the 4HPR-associated cytotoxicity. In all neuroblastoma spheroids, 4-HPR induced a complete cytostasis at clinical relevant concentrations (3-10 μM). Immunohistochemical analysis of 4-HPR-treated spheroids showed a decreased staining for proliferation marker Ki-67 and an increased staining for cleaved-PARP, a marker of apoptosis. Our results suggest that 4-HPR might be a promising agent for the treatment of micrometastases and high-risk neuroblastoma.

Original languageEnglish
Pages (from-to)1011-1019
Number of pages9
JournalInternational Journal of Oncology
Volume32
Issue number5
DOIs
Publication statusPublished - May 2008
Externally publishedYes

Keywords

  • Apoptosis
  • Fenretinide
  • Mitochondrial membrane potential
  • Neuroblastoma
  • Oxidative stress
  • Spheroids

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