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Article

Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor

  • Authors:
    • Steven G. Gray
    • Anne-Marie Baird
    • Fardod O'Kelly
    • Georgios Nikolaidis
    • Malin Almgren
    • Armelle Meunier
    • Eilis Dockry
    • Donal Hollywood
    • Tomas J. Ekström
    • Antoinette S. Perry
    • Kenneth J. O'Byrne
  • View Affiliations / Copyright

    Affiliations: Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Republic of Ireland, Prostate Molecular Oncology, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Republic of Ireland, Roy Castle Lung Cancer Research Program, Department of Molecular and Clinical Cancer Medicine, University of Liverpool Cancer Research Centre, Liverpool L3 9TA, UK, Department of Clinical Neuroscience, Karolinska Institute, Center for Molecular Medicine, SE-17176 Stockholm, Sweden
  • Pages: 1505-1511
    |
    Published online on: September 21, 2012
       https://doi.org/10.3892/ijmm.2012.1138
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Abstract

Gemcitabine is indicated in combination with cisplatin as first-line therapy for solid tumours including non-small cell lung cancer (NSCLC), bladder cancer and mesothelioma. Gemcitabine is an analogue of pyrimidine cytosine and functions as an anti-metabolite. Structurally, however, gemcitabine has similarities to 5-aza-2-deoxycytidine (decitabine/Dacogen®), a DNA methyltransferase inhibitor (DNMTi). NSCLC, mesothelioma and prostate cancer cell lines were treated with decitabine and gemcitabine. Reactivation of epigenetically silenced genes was examined by RT-PCR/qPCR. DNA methyltransferase activity in nuclear extracts and recombinant proteins was measured using a DNA methyl­transferase assay, and alterations in DNA methylation status were examined using methylation-specific PCR (MS-PCR) and pyrosequencing. We observe a reactivation of several epigenetically silenced genes including GSTP1, IGFBP3 and RASSF1A. Gemcitabine functionally inhibited DNA methyltransferase activity in both nuclear extracts and recombinant proteins. Gemcitabine dramatically destabilised DNMT1 protein. However, DNA CpG methylation was for the most part unaffected by gemcitabine. In conclusion, gemcitabine both inhibits and destabilises DNA methyltransferases and reactivates epigenetically silenced genes having activity equivalent to decitabine at concentrations significantly lower than those achieved in the treatment of patients with solid tumours. This property may contribute to the anticancer activity of gemcitabine.
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Copy and paste a formatted citation
Spandidos Publications style
Gray SG, Baird A, O'Kelly F, Nikolaidis G, Almgren M, Meunier A, Dockry E, Hollywood D, Ekström TJ, Perry AS, Perry AS, et al: Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor. Int J Mol Med 30: 1505-1511, 2012.
APA
Gray, S.G., Baird, A., O'Kelly, F., Nikolaidis, G., Almgren, M., Meunier, A. ... O'Byrne, K. . (2012). Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor. International Journal of Molecular Medicine, 30, 1505-1511. https://doi.org/10.3892/ijmm.2012.1138
MLA
Gray, S. G., Baird, A., O'Kelly, F., Nikolaidis, G., Almgren, M., Meunier, A., Dockry, E., Hollywood, D., Ekström, T. J., Perry, A. S., O'Byrne, K. ."Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor". International Journal of Molecular Medicine 30.6 (2012): 1505-1511.
Chicago
Gray, S. G., Baird, A., O'Kelly, F., Nikolaidis, G., Almgren, M., Meunier, A., Dockry, E., Hollywood, D., Ekström, T. J., Perry, A. S., O'Byrne, K. ."Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor". International Journal of Molecular Medicine 30, no. 6 (2012): 1505-1511. https://doi.org/10.3892/ijmm.2012.1138
Copy and paste a formatted citation
x
Spandidos Publications style
Gray SG, Baird A, O'Kelly F, Nikolaidis G, Almgren M, Meunier A, Dockry E, Hollywood D, Ekström TJ, Perry AS, Perry AS, et al: Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor. Int J Mol Med 30: 1505-1511, 2012.
APA
Gray, S.G., Baird, A., O'Kelly, F., Nikolaidis, G., Almgren, M., Meunier, A. ... O'Byrne, K. . (2012). Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor. International Journal of Molecular Medicine, 30, 1505-1511. https://doi.org/10.3892/ijmm.2012.1138
MLA
Gray, S. G., Baird, A., O'Kelly, F., Nikolaidis, G., Almgren, M., Meunier, A., Dockry, E., Hollywood, D., Ekström, T. J., Perry, A. S., O'Byrne, K. ."Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor". International Journal of Molecular Medicine 30.6 (2012): 1505-1511.
Chicago
Gray, S. G., Baird, A., O'Kelly, F., Nikolaidis, G., Almgren, M., Meunier, A., Dockry, E., Hollywood, D., Ekström, T. J., Perry, A. S., O'Byrne, K. ."Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor". International Journal of Molecular Medicine 30, no. 6 (2012): 1505-1511. https://doi.org/10.3892/ijmm.2012.1138
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