Journal of Molecular Neuroscience

, Volume 55, Issue 1, pp 51–61 | Cite as

Evaluation of Cytotoxic Properties of a Cyclopamine Glucuronide Prodrug in Rat Glioblastoma Cells and Tumors

  • Souheyla Bensalma
  • Corinne Chadeneau
  • Thibaut Legigan
  • Brigitte Renoux
  • Afsaneh Gaillard
  • Madryssa de Boisvilliers
  • Caroline Pinet-Charvet
  • Sébastien Papot
  • Jean Marc Muller
Article

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Activation of the developmental hedgehog (Hh) pathway is observed in GBM, particularly in the so-called glioma stem cells (GSCs). An inhibitor of this pathway is the steroidal alkaloid cyclopamine, an antagonist of the Hh coreceptor Smoothened (SMO). To limit the toxicity of cyclopamine toward Hh-dependent non-tumor cells, our group previously reported the synthesis of a prodrug (called 1b), designed to deliver cyclopamine in the presence of β-glucuronidase, an enzyme found in the necrotic area of GBM. Here, we aimed to analyze the in vitro, ex vivo, and in vivo cytotoxic properties of this prodrug in the C6 rat GBM cells. In the presence of β-glucuronidase, the activated prodrug 1b was toxic and downregulated expression of Gli1, a Hh target gene, in C6 cells and C6-GSCs, but not in normal rat astrocytes in which the Hh pathway is weakly activated. In the absence of β-glucuronidase, prodrug 1b displayed no obvious toxicity toward rat brain tissue explants while cyclopamine clearly affected brain tissue viability. When administered to rats bearing fluorescent C6-derived GBM, the prodrug 1b reduced the tumor density more efficiently than cyclopamine. Prodrug 1b thus appears as a promising concept to optimize confinement of cyclopamine cytotoxicity within the tumors, with more limited effects in the surrounding normal brain tissue.

Keywords

Hedgehog Cyclopamine Glucuronide prodrug Glioblastoma Glioblastoma stem cells (GSCs) 

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Souheyla Bensalma
    • 1
    • 2
  • Corinne Chadeneau
    • 1
    • 2
  • Thibaut Legigan
    • 3
  • Brigitte Renoux
    • 3
  • Afsaneh Gaillard
    • 4
  • Madryssa de Boisvilliers
    • 1
    • 2
  • Caroline Pinet-Charvet
    • 2
  • Sébastien Papot
    • 3
  • Jean Marc Muller
    • 1
    • 2
  1. 1.“Récepteurs, Régulations et Cellules Tumorales” (2RCT) GroupUniversité de PoitiersPoitiersFrance
  2. 2.CNRS FRE 3511, Université de PoitiersPoitiers Cedex 9France
  3. 3.Institut de Chimie des Milieux et des Matériaux (IC2MP)Université de Poitiers, UMR-CNRS 7285Poitiers Cedex 9France
  4. 4.Laboratoire des Neurosciences Expérimentales et Cliniques (LNEC)Université de Poitiers, INSERM U 1084Poitiers Cedex 9France

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