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.
MeSH terms
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Animals
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Antiviral Agents / pharmacology*
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Antiviral Agents / therapeutic use
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Apoptosis / drug effects
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Apoptosis / radiation effects
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Burkitt Lymphoma / drug therapy
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Burkitt Lymphoma / pathology
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Burkitt Lymphoma / radiotherapy*
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Burkitt Lymphoma / virology
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Carcinoma / drug therapy
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Carcinoma / pathology
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Carcinoma / radiotherapy*
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Carcinoma / virology
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Caspase 3
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Caspase 9
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Caspases / metabolism
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Cell Division / drug effects
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Cidofovir
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Combined Modality Therapy
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Cytosine / analogs & derivatives*
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Cytosine / pharmacology*
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Cytosine / therapeutic use
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Enzyme Activation / drug effects
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Enzyme Activation / radiation effects
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Epstein-Barr Virus Infections / drug therapy
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Epstein-Barr Virus Infections / pathology
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Epstein-Barr Virus Infections / radiotherapy*
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Female
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Gene Expression Regulation, Viral / drug effects*
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Genes, bcl-2
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Herpesvirus 4, Human / drug effects*
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Herpesvirus 4, Human / metabolism
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Humans
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Mice
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Mice, Nude
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Nasopharyngeal Neoplasms / drug therapy
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Nasopharyngeal Neoplasms / pathology
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Nasopharyngeal Neoplasms / radiotherapy*
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Nasopharyngeal Neoplasms / virology
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Oncogene Proteins, Viral / biosynthesis*
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Oncogene Proteins, Viral / genetics
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Organophosphonates*
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Organophosphorus Compounds / pharmacology*
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Organophosphorus Compounds / therapeutic use
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
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Radiation Tolerance / drug effects*
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Remission Induction
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Tumor Cells, Cultured / radiation effects
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Tumor Cells, Cultured / transplantation
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Tumor Cells, Cultured / virology
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Tumor Stem Cell Assay
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Tumor Virus Infections / drug therapy
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Tumor Virus Infections / pathology
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Tumor Virus Infections / radiotherapy*
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Tumor Virus Infections / virology
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Viral Matrix Proteins / biosynthesis
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Viral Matrix Proteins / genetics
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Xenograft Model Antitumor Assays
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bcl-2-Associated X Protein
Substances
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Antiviral Agents
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BAX protein, human
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Bax protein, mouse
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EBV-associated membrane antigen, Epstein-Barr virus
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Oncogene Proteins, Viral
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Organophosphonates
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Organophosphorus Compounds
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Viral Matrix Proteins
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bcl-2-Associated X Protein
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Cytosine
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CASP3 protein, human
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CASP9 protein, human
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Casp3 protein, mouse
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Casp9 protein, mouse
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Caspase 3
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Caspase 9
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Caspases
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Cidofovir