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Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases

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Abstract

Disease progression in patients suffering from malignant melanomas is often determined by metastatic spreading into brain parenchyma. Systemic chemotherapy regimens are, therefore, mandatory for successful treatment. Most recently, inhibitors of histone deacetylases (HDACi) have been shown to significantly inhibit melanoma progression. Here, mouse as well as human melanoma cells were transplanted into rodent hippocampal slice cultures in order to translate and microscopically confirm promising in vitro chemotherapeutic propensities of HDACi within the organotypic brain environment. In our ex vivo model, tumor progression was significantly inhibited by administration of low micromolar concentrations of second generation HDACi MS-275 over a period of 8 days. In contrast, HDACi treatment with suberoylanilide hydroxamic acid was less efficient ex vivo, although both compounds were successful in the treatment of tumor cell monolayer cultures. Protein levels of the cell cycle inhibitor p21WAF1 were significantly increased after HDACi treatment, which points to enhanced G1 arrest of tumor cells as confirmed by cytofluorometric analysis. Considering the ability of MS-275 to cross the blood–brain barrier, our experimental model identifies the benzamide MS-275 as a promising therapeutic compound for targeting epigenetic chromatin modulation as systemic treatment of metastatic melanomas.

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Acknowledgments

We kindly acknowledge Dr P. Rohwer, Nikolaus-Fiebiger-Center of Molecular Medicine, University of Erlangen-Nuremberg for assistance with fluorescence tumor cell sorting. We thank Tajana Jungbauer, Ina Jeske, Silke Gutmann and Birte Rings for technical support.

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Authors and Affiliations

  1. Department of Neuropathology, University of Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054, Erlangen, Germany

    Annett Hölsken, Rolf Buslei, Eric Hahnen, Ingmar Blümcke & Florian A. Siebzehnrübl

  2. Department of Neurosurgery, University of Erlangen-Nuremberg, Erlangen, Germany

    Ilker Y. Eyüpoglu

  3. Department of Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany

    Mike Lueders

  4. Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Bonn, Germany

    Christian Tränkle

  5. Department of Dermatology, University of Erlangen-Nuremberg, Erlangen, Germany

    Detlef Dieckmann

  6. Institute of Human Genetics, Institute of Genetics and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany

    Eric Hahnen

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  1. Annett Hölsken
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Correspondence to Ingmar Blümcke.

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Hölsken, A., Eyüpoglu, I.Y., Lueders, M. et al. Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases. Acta Neuropathol 112, 205–215 (2006). https://doi.org/10.1007/s00401-006-0082-8

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  • DOI: https://doi.org/10.1007/s00401-006-0082-8

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