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

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 EBVexpressing 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 virusrelated 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 radiationinduced 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.

Ribonucleotide reductase inhibitors enhance cidofovir‐induced apoptosis in EBV‐positive nasopharyngeal carcinoma xenografts

“…16 Widespread apoptosis was produced in all 3 types of tumors. Thus, the data suggest that apoptosis was dependent on neither p53 nor LMP1 expression in contrast to the results of Abdulkarim et al 16,38 We had also reported previously that PARP cleavage was induced by cidofovir in NPC-KT cells, which do not express LMP1. 17 Although LMP1 signaling might be partially involved, the main pathway of cidofovir-induced apoptosis may be LMP1-independent.…”

“…Abdulkarim et al 38 showed that cidofovir induced a downregulation of the EBV oncoprotein latent membrane protein-1 (LMP1) associated with a decrease of the antiapoptotic Bcl-2 and an increase of the proapoptotic Bax protein in NPC C15. 38 Previously, we showed that local or systemic administration of cidofovir produced striking effects on growth of LMP1-expressing NPC C15 xenografts.…”

“…38 Previously, we showed that local or systemic administration of cidofovir produced striking effects on growth of LMP1-expressing NPC C15 xenografts. Similar effects were produced in C17 and C18 xenografts, which are EBV-positive, but do not express detectable LMP1 protein; unlike most primary NPC, the latter NPCs have mutations in the p53 gene.…”

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

“…This suggests a promising nontoxic and effective therapy for EBV-positive lymphoproliferative diseases. Abdulkarim et al (2003) also demonstrated that treatment with Cidofovir combined with ionizing radiation leads to tumor remission without increasing toxicity in EBV-positive cells (Raji and C15) in nude mice. This approach is likely to greatly improve conventional cancer therapies.…”

Effect of EBV LMP1 targeted DNAzymes on cell proliferation and apoptosis

“…28 Abdulkarim et al 29 reported that antiviral agent Cidofovir could downregulate the EBV oncoprotein LMP1 expression, which was associated with a decrease in antiapoptotic Bcl-2 protein and an increase of the proapoptotic Bax protein in Raji (BL) and C15 (NPC) cells. However, the mechanism of Codofovir's effect on the LMP1 and bcl-2 protein expression was not defined.…”