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Influence of multidrug resistance on 18F-FCH cellular uptake in a glioblastoma model

  • Claire Vanpouille
  • Nathalie Le Jeune
  • David Kryza
  • Anthony Clotagatide
  • Marc Janier
  • Francis Dubois
  • Nathalie Perek
Original Article

Abstract

Purpose

Multidrug resistance, aggressiveness and accelerated choline metabolism are hallmarks of malignancy and have motivated the development of new PET tracers like 18F-FCH, an analogue of choline. Our aim was to study the relationship of multidrug resistance of cultured glioma cell lines and 18F-FCH tracer uptake.

Methods

We used an in vitro multidrug-resistant (MDR) glioma model composed of sensitive parental U87MG and derived resistant cells U87MG-CIS and U87MG-DOX. Aggressiveness, choline metabolism and transport were studied, particularly the expression of choline kinase (CK) and high-affinity choline transporter (CHT1). FCH transport studies were assessed in our glioblastoma model.

Results

As expected, the resistant cell lines express P-glycoprotein (Pgp), multidrug resistance-associated protein isoform 1 (MRP1) and elevated glutathione (GSH) content and are also more mobile and more invasive than the sensitive U87MG cells. Our results show an overexpression of CK and CHT1 in the resistant cell lines compared to the sensitive cell lines. We found an increased uptake of FCH (in % of uptake per 200,000 cells) in the resistant cells compared to the sensitive ones (U87MG: 0.89 ± 0.14; U87MG-CIS: 1.27 ± 0.18; U87MG-DOX: 1.33 ± 0.13) in line with accelerated choline metabolism and aggressive phenotype.

Conclusions

FCH uptake is not influenced by the two ATP-dependant efflux pumps: Pgp and MRP1. FCH would be an interesting probe for glioma imaging which would not be effluxed from the resistant cells by the classic MDR ABC transporters. Our results clearly show that FCH uptake reflects accelerated choline metabolism and is related to tumour aggressiveness and drug resistance.

Keywords

Choline metabolism Glioblastoma Drug resistance Tumour aggressiveness 18F-Fluorocholine 

Notes

Acknowledgements

This work was supported by grants from Region Rhône-Alpes (Programme Thématiques Prioritaires Région), Cancéropole Lyon Auvergne Rhône-Alpes (CLARA) and Rhône-Alpes Genopole.

We thank Mr. Philip Lawrence for the manuscript’s English revision.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Claire Vanpouille
    • 1
  • Nathalie Le Jeune
    • 1
  • David Kryza
    • 2
  • Anthony Clotagatide
    • 1
  • Marc Janier
    • 3
  • Francis Dubois
    • 1
  • Nathalie Perek
    • 1
    • 4
  1. 1.Université de Lyon, Université Jean Monnet-Cancer Research Group IFRESIS 143Saint-EtienneFrance
  2. 2.CREATIS, UMR CNRS 5515Hospice Civils de Lyon, Quai Des CelestinsLyonFrance
  3. 3.CREATIS, UMR CNRS 5515Hospice Civils de Lyon, Quai Des CelestinsLyonFrance
  4. 4.Laboratoire de Biophysique, Faculté de MédecineSaint-Etienne Cedex 02France

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