Cyclosporine A and its non-immunosuppressive derivative NIM811 induce apoptosis of malignant melanoma cells in in vitro and in vivo studies

Authors

  • Iwona Ciechomska,

    1. Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warsaw, Poland
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  • Magdalena Legat,

    1. Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warsaw, Poland
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  • Jakub Golab,

    1. Department of Immunology, Centre of Biostructure Research, Medical University of Warsaw, Poland
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  • Aleksandra Wesolowska,

    1. Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warsaw, Poland
    2. Department of Transplantation Medicine and Nephrology, Transplantation Institute, Warsaw, Poland
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  • Zuzanna Kurzaj,

    1. Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warsaw, Poland
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  • Andrzej Mackiewicz,

    1. University School of Medical Sciences at Great Poland Cancer Center, Poznan, Poland
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  • Bozena Kaminska

    Corresponding author
    1. Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warsaw, Poland
    • Dept. Cell Biology, Nencki Institute of Experimental Biology, 3 Pasteur Str., 02-093 Warsaw, Poland
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    • Fax: +48-22-822-53-42


Abstract

Advanced melanoma is a highly malignant tumor with an increasing incidence that has a poor prognosis due to resistance to common therapeutic strategies. We have demonstrated previously that cyclosporine A (CsA) induces apoptosis of rat glioma cells, reactive astrocytes, and fibroblasts. In our present study, we investigated effects of CsA and its nonimmunosuppressive derivative NIM811 on survival of human and murine melanoma cells. We demonstrated that CsA and NIM811 affect survival of human and murine melanoma cells and induce morphological changes, alterations in nuclear morphology and an internucleosomal DNA fragmentation, consistent with an apoptotic type of death. Western blot analysis showed an activation of caspases 9, 7, 3 and PARP cleavage detectable at 24 hr after exposure of human melanoma cells to the drugs. CsA and NIM811 induced a significant increase in subG1 population of murine B16F10 melanoma cells indicative of apoptotic DNA fragmentation. Studies in murine model of melanoma showed that NIM811, but not CsA, retards tumor progression and significantly decreases tumor volume after intratumoral application. Our findings indicate that CsA and its derivatives may be new candidates for the treatment of melanoma patients. © 2005 Wiley-Liss, Inc.

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