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Apoptosis

, Volume 12, Issue 8, pp 1533–1541 | Cite as

Doxorubicin enhances TRAIL-induced cell death via ceramide-enriched membrane platforms

  • Claudia Alexandra Dumitru
  • Alexander Carpinteiro
  • Tanja Trarbach
  • Ulrich R. Hengge
  • Erich GulbinsEmail author
Original Paper

Abstract

Previous studies indicated that signalling via CD95 and DR5 is greatly enhanced by the formation of ceramide-enriched membrane platforms. Here, we employed this concept to convert doses of subtherapeutic TRAIL that were unable to release ceramide and kill leukemic B-cells or ex vivo T lymphocytes, into a very effective apoptotic stimulus. Ceramide production was induced by application of sub-toxic doses of doxorubicin that resulted in an activation of the acid sphingomyelinase (ASM), release of ceramide and formation of ceramide-enriched membrane platforms. The latter served DR5 to cluster after application of very low doses of TRAIL in combination with doxorubicin. Genetic deficiency of the ASM abrogated doxorubicin-induced ceramide release, as well as clustering of DR5 and apoptosis induced by the combined treatment of doxorubicin and TRAIL. These data show that local release of ceramide potentiates very low, otherwise inactive doses of TRAIL that may represent a novel therapeutic concept to treat tumors.

Keywords

Acid sphingomyelinase Apoptosis Ceramide Chemotherapy 

Notes

Acknowledgements

The study was supported by DFG Graduiertenkolleg 1045/1 to E.G. and Deutsche Krebshilfe grant 102238-Gu2 to T.T., U.H. and E.G.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Claudia Alexandra Dumitru
    • 1
  • Alexander Carpinteiro
    • 1
    • 2
  • Tanja Trarbach
    • 3
  • Ulrich R. Hengge
    • 4
  • Erich Gulbins
    • 1
    Email author
  1. 1.Department of Molecular BiologyUniversity of Duisburg-EssenEssenGermany
  2. 2.Clinic of HematologyUniversity of Duisburg-EssenEssenGermany
  3. 3.Department of Internal Medicine/Hematology Oncology (West German Cancer Center)University of Duisburg-EssenEssenGermany
  4. 4.Department of DermatologyUniversity of DuesseldorfDuesseldorfGermany

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