In vivo and in vitro cytotoxicity of R-etodolac with dexamethasone in glucocorticoid-resistant multiple myeloma cells

Authors

  • Paola Neri,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
    2. VA Boston Healthcare System, Boston, MA, USA
    3. Department of Experimental and Clinical Medicine, University of ‘Magna Græcia’ and Cancer Centre, Catanzaro, Italy
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    • *

      These authors contributed equally to this work.

  • Hiroshi Yasui,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
    2. First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
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    • *

      These authors contributed equally to this work.

  • Teru Hideshima,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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  • Pierfrancesco Tassone,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
    2. VA Boston Healthcare System, Boston, MA, USA
    3. Department of Experimental and Clinical Medicine, University of ‘Magna Græcia’ and Cancer Centre, Catanzaro, Italy
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  • Noopur Raje,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
    2. Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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  • Catley P. Laurence,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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  • Kenji Ishitsuka,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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  • Simona Blotta,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
    2. VA Boston Healthcare System, Boston, MA, USA
    3. Department of Experimental and Clinical Medicine, University of ‘Magna Græcia’ and Cancer Centre, Catanzaro, Italy
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  • Tanyel Kiziltepe,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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  • Enrique M. Ocio,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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  • Mariateresa Fulciniti,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
    2. VA Boston Healthcare System, Boston, MA, USA
    3. Department of Experimental and Clinical Medicine, University of ‘Magna Græcia’ and Cancer Centre, Catanzaro, Italy
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  • Sarath Kanekal,

    1. Salmedix, Inc., San Diego, CA, USA
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  • Gary T. Elliott,

    1. Salmedix, Inc., San Diego, CA, USA
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  • Nikhil C. Munshi,

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
    2. VA Boston Healthcare System, Boston, MA, USA
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  • Kenneth C. Anderson

    1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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Errata

This article is corrected by:

  1. Errata: Erratum Volume 134, Issue 4, 448, Article first published online: 4 July 2006

Kenneth C. Anderson, Dana-Farber Cancer Institute, Mayer 557, 44 Binney Street, Boston, MA 02115, USA.
E-mail: kenneth_anderson@dfci.harvard.edu

Summary

Glucocorticoids have been widely used in the treatment of multiple myeloma (MM) both as single agents and in combination with other drugs. However, primary or acquired glucocorticoid resistance occurs in most cases. It was recently reported that R-etodolac induced in vitro cytotoxicity in MM cell lines and in primary MM cells, as well as synergistically enhanced dexamethasone (Dex)-induced apoptosis in Dex-sensitive MM.1S cells. This study examined the in vitro and in vivo effects of combination treatment with R-etodolac and Dex on Dex-resistant OPM1 cells. Treatment with R-etodolac and Dex was found to enhance cytotoxicity, inhibit nuclear factor κB activity via upregulation of IκBα, as well as enhance Dex-induced caspase activation and poly (ADP)-ribose polymerase cleavage in OPM1 cells. R-etodolac also enhanced Dex cytotoxicity in patient MM cells that were resistant to glucocorticoids. The in vivo anti-tumour effect of this combination on MM cells was evaluated by using severe combined immunodeficient mice engrafted with OPM1. Treatment with R-etodolac or Dex alone did not induce a significant reduction of tumour volume; in contrast, combination treatment with R-etodolac and Dex induced significant synergistic inhibition of tumour growth. These data indicate that R-etodolac overcomes resistance to Dex in glucocorticoid-resistant MM cells, providing the framework for clinical trials of R-etodolac combined with Dex, to improve patient outcome in MM.

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