Cidofovir: A Novel Antitumor Agent for Glioblastoma

Abstract

Purpose Cidofovir (CDV) is a FDA approved nucleoside antiviral agent used to treat severe human cytomegalovirus (HCMV) infection. Until now, no clear therapeutic effects of CDV have been reported outside of the setting of viral infection, including a potential role for CDV as an antineoplastic agent for the treatment of brain tumors. Experimental Design We investigated CDV cytotoxicity against glioblastoma (GBM) cells, U87MG and primary SF7796, in vitro and in vivo, using an intracranial xenograft model. Standard techniques for cell culturing, immunohistochemistry, Western blotting, and real-time PCR were employed. The survival of athymic mice (n= 8–10 per group) bearing GBM tumors, treated with CDV alone or in combination with radiation, was analyzed by the Kaplan-Meier method and evaluated with a two-sided log-rank test. Results CDV possesses potent antineoplastic activity against HCMV infected GBM cells. This activity is associated with inhibition of HCMV gene expression and with activation of cellular apoptosis. Surprisingly, we also determined that CDV induces GBM cell death in the absence of HCMV infection. CDV is incorporated into tumor cell DNA, which promotes double-stranded DNA breaks and induces apoptosis. In the setting of ionizing radiation treatment (RT), the standard of care for GBM in humans, CDV augments radiation-induced DNA damage and further promotes tumor cell death. Combined CDV and RT treatment significantly extended the survival of mice bearing intracranial GBM tumors. Conclusion We have identified a novel anti-glioma property of the FDA approved drug CDV, which heightens RT cytotoxic effect, the standard of care therapy for GBM.

Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia

“…Recently, these findings were confirmed by P. Hadaczek and co-workers who also found that CDV is incorporated into cellular DNA activating DNA damage response pathways due to increased DNA breaks that prompt elevated tumor cell apoptotic response in glioblastoma cells (Hadaczek et al, 2013).…”

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

“…The drug potentiated the effects of radiation, but the mechanism was not dependent on HCMV. 31 Thus, antiviral therapy may be a promising alternative for treating patients with GBMs and may provide both anti-viral and off-target effects.…”

Cytomegalovirus and glioblastoma; controversies and opportunities

“…This is supported by a recent pre-clinical animal study on cidofovir, another anti-viral nucleoside analog [47]. Cidofovir synergized with irradiation in vitro independent of CMV infection status, and synergized with irradiation in animal glioblastoma models in the absence of CMV to give a significant survival benefit.…”

“…Indeed the NIH has recently proposed performing studies to validate key results [55], and this type of argument could be resolved by such a process. The valganciclovir question can only be resolved by conducting a randomized trial, and effects of valganciclovir on standard therapies should also be evaluated, as this may influence conventional therapies as was shown for the anti-viral agent cidofovir [47].…”