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Antiviral agent Cidofovir decreases Epstein–Barr virus (EBV) oncoproteins and enhances the radiosensitivity in EBV-related malignancies

Oncogene volume 22, pages 2260–2271 (2003)Cite this article

Abstract

The Epstein–Barr virus (EBV) is involved in the carcinogenesis of several human cancers such as nasopharyngeal carcinoma (NPC) and Burkitt lymphoma (BL). Given the consistent role of EBV in transformation and maintenance of malignant phenotype, antiviral strategies provide an attractive approach to target EBV-expressing cells. In that aim, we have tested the Cidofovir, which is an acyclic nucleoside phosphonate analog known to exert an antiproliferative activity in some human virus-related tumors. Here, we show that Cidofovir induces a downregulation of the EBV oncoprotein LMP1 associated with a decrease of the antiapoptotic Bcl-2 and an increase of the proapoptotic Bax protein in Raji (BL) and C15 (NPC) cells. Using BL cell line BL2 B95-8 (BL2 infected with the B95.8 strain of EBV), we addressed the relation between EBV genome expression and modulation of viral oncoproteins by Cidofovir and/or ionizing radiation (IR). Cidofovir was able to significantly reduce LMP1 and EBNA2 mRNA and protein expression. This effect was associated with inhibition of proliferation, stimulation of apoptosis, and decrease of Bcl-2 expression in BL2 B95.8 cells. In addition, Cidofovir enhanced the radiation-induced apoptosis and the radiosensitivity through the proteolytic cleavage of death effectors caspase-9 and -3, which was specifically induced by combined treatment in EBV-positive cells compared to their negative counterparts. Furthermore, the combined treatment in nude mice led to a complete tumor remission without increasing toxicity in two human EBV-related cancer xenografts (Raji and C15). These results provide the basis for a novel anticancer strategy to enhance the therapeutic ratio of IR in EBV-related cancers.

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Acknowledgements

We thank Dr Busson P for providing NPC C15 cells. Institut Fédératif de Recherche (IFR No 54) for animal facilities and technical assistance, Ligue Nationale Contre le Cancer, section du Val de Marne, and section de 1'Essonne.

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Authors and Affiliations

  1. Laboratoire UPRES EA No 27-10 ‘Radiosensibilité des tumeurs & tissus sains’, France

    Bassam Abdulkarim, Eric Deutsch, Valerie Frascogna & Jean Bourhis

  2. NSERM U362, France

    Siham Sabri, Diana Zelenika & William Vainchenker

  3. Institut Gustave-Roussy, Villejuif Cédex, 94805, France

    Siham Sabri, Diana Zelenika & William Vainchenker

  4. Service d'anatomie pathologique, France

    Jerzy Klijanienko

  5. Institut Curie, 3 rue d'Ulm, Paris, France

    Jerzy Klijanienko

  6. Laboratoire de Pharmacologie Experimentale, France

    Irène Joab

  7. Institut de génétique moleculaire, Hopital Saint-Louis, Paris, France

    Irène Joab

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  1. Bassam Abdulkarim
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  2. Siham Sabri
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  9. Jean Bourhis
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Correspondence to Jean Bourhis.

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Abdulkarim, B., Sabri, S., Zelenika, D. et al. Antiviral agent Cidofovir decreases Epstein–Barr virus (EBV) oncoproteins and enhances the radiosensitivity in EBV-related malignancies. Oncogene 22, 2260–2271 (2003). https://doi.org/10.1038/sj.onc.1206402

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