Abstract
BackgroundInsights into the mechanisms associated with chemotherapy-resistance are important for implementation of therapeutic strategies and for unraveling the mode of action of chemotherapeutics. Although cidofovir (CDV) has proven efficacious in the treatment of human papillomavirus (HPV)-induced proliferation, no studies concerning the development of resistance to CDV in HPV-positive tumor cells have been performed yet.MethodsFrom the cervical carcinoma SiHa cells (SiHaparental), which are HPV-16 positive, cidofovir-resistant cells (SiHaCDV) were selected, and differential gene expression profiles were analyzed by means of microarrays. We examined in vitro phenotyping of resistant cells compared to parental cells as well as tumorigenicity and pathogenicity in a mouse-xenograft model.ResultsSiHaCDV had a resistant phenotype and a reduced growth both in vitro and in vivo. A markedly diminished inflammatory response (as measured by production of host- and tumor-derived cytokines and number of neutrophils and macrophages in spleen) was induced by SiHaCDV than by SiHaparental in the xenograft model. Gene expression profiling identified several genes with differential expression upon acquisition of CDV-resistance and pointed to a diminished induction of inflammatory response in SiHaCDV compared to SiHaparental.ConclusionsOur results indicate that acquisition of resistance to cidofovir in SiHa cells is linked to reduced pathogenicity. The present study contributes to our understanding on the antiproliferative effects of CDV and on the mechanisms involved, the inflammatory response playing a central role.
Highlights
Insights into the mechanisms associated with chemotherapy-resistance are important for implementation of therapeutic strategies and for unraveling the mode of action of chemotherapeutics
We have recently shown that besides inhibition of tumor growth, intratumoral CDV administration had a beneficial effect on the pathology associated with the growth of cervical carcinoma cells in athymic nude mice as demonstrated by a favorable effect on body weight gain, reduced splenomegaly and lower inflammatory state in animals that received the compound versus the placebotreated group [24]
We focused on the analysis of functions and pathways involved in the inflammatory response that changed in SiHa cells following acquisition of CDV-resistance
Summary
Insights into the mechanisms associated with chemotherapy-resistance are important for implementation of therapeutic strategies and for unraveling the mode of action of chemotherapeutics. Three acyclic nucleoside phosphonate analogues (ANPs), i.e. tenofovir (PMPA), adefovir (PMEA) and cidofovir (CDV), are approved for the treatment of viral infections [1,2]. CDV is formally licensed for treatment of cytomegalovirus retinitis in AIDS patients, it is often Besides their well-recognized antiviral properties, some ANPs have shown anticancer potency. A close correlation between the cytostatic activities of PME derivatives and the inhibitory effects of their active metabolites (diphosphate forms) on cellular DNA polymerases α, δ, and ε has been established. In these studies, PMEG-diphosphate (PMEGpp) emerged as the most potent chain-terminating inhibitor of cellular DNA polymerases [12,13]. The utility of PMEG as an anticancer agent is limited by poor cellular permeability and toxicity [13,14] and prodrugs, such as GS-9191 and GS9219, were designed to increase the permeability and accumulation of PMEGpp in the cells [10,13]
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