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The histone deacetylase inhibitor vorinostat induces calreticulin exposure in childhood brain tumour cells in vitro

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Abstract

Purpose

It has recently been recognised that anticancer chemotherapy can elicit an immunogenic form of apoptosis characterised by the exposure of calreticulin (CRT) on the surface of dying tumour cells, entailing an immune response that contributes to the therapeutic outcome. CRT exposure has been found to be induced by anthracyclins and oxaliplatin, but not by other proapoptotic antineoplastic agents including etoposide, camptothecin and cisplatin. In this study, we examined the histone deacetylase inhibitor vorinostat for its capability to stimulate CRT exposure in tumour cells.

Methods

Childhood tumour cells, i.e. the brain tumour cell lines PFSK and DAOY and the Ewing’s sarcoma cell line CADO-ES-1, were treated with vorinostat, and CRT exposure was determined by flow cytometric analysis of CRT immunofluorescence. Combination effects of vorinostat/TRAIL and vorinostat/bortezomib were also assessed.

Results

Vorinostat treatment induced CRT exposure in PFSK and DAOY cells, but not in caspase-8-deficient CADO-ES-1 cells. CRT exposure could be prevented by the pan-caspase inhibitor z-VAD-fmk and by brefeldin A, an inhibitor of Golgi-mediated transport.

Conclusion

Vorinostat has the capacity to elicit CRT exposure, suggesting its usefulness as immunogenic antitumour agent.

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Fig. 1
Fig. 2

Abbreviations

CRT:

Calreticulin

ER:

Endoplasmatic reticulum

HDACi:

Histone deacetylase inhibitor

sPNET:

Supratentorial primitive neuroectodermal tumour

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Acknowledgments

We gratefully acknowledge the input and discussions of Barbara Bröker (Institute for Immunology, University of Greifswald). This work was supported by a grant from the “Wilhelm Sander-Stiftung, Neustadt/Donau”. S.G. received a fellowship from the “IZKF des Universitätsklinikum Jena”; M.S. received a fellowship from the “Alfried Krupp Wissenschaftskolleg Greifswald der Alfried Krupp von Bohlen und Halbach-Stiftung”.

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Authors and Affiliations

  1. Department of Paediatric Haematology and Oncology, University Children’s Hospital Jena, Jena, Germany

    Jürgen Sonnemann, Stephanie Greßmann, Sabine Becker, Susan Wittig & James F. Beck

  2. Institute for Immunology and Transfusion Medicine, Ernst Moritz Arndt University, Greifswald, Germany

    Mareike Schmudde

  3. Klinik für Kinder- und Jugendmedizin, Friedrich-Schiller-Universität Jena, Kochstr. 2, 07745, Jena, Germany

    Jürgen Sonnemann

Authors
  1. Jürgen Sonnemann
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  2. Stephanie Greßmann
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  3. Sabine Becker
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  4. Susan Wittig
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  5. Mareike Schmudde
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  6. James F. Beck
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Correspondence to Jürgen Sonnemann.

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Sonnemann, J., Greßmann, S., Becker, S. et al. The histone deacetylase inhibitor vorinostat induces calreticulin exposure in childhood brain tumour cells in vitro. Cancer Chemother Pharmacol 66, 611–616 (2010). https://doi.org/10.1007/s00280-010-1302-4

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  • DOI: https://doi.org/10.1007/s00280-010-1302-4

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