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

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18 Citations (Scopus)


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
Issue number5
Publication statusPublished - May 2008
Externally publishedYes


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


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