Resistance to the nucleotide analogue cidofovir in HPV(+) cells: a multifactorial process involving UMP/CMP kinase 1

Human papillomavirus (HPV) is responsible for cervical cancer, and its role in head and neck carcinoma has been reported. No drug is approved for the treatment of HPV-related diseases but cidofovir (CDV) exhibits selective antiproliferative activity. In this study, we analyzed the effects of CDV-resistance (CDV(R)) in two HPV(+) (SiHa(CDV) and HeLa(CDV)) and one HPV(−) (HaCaT(CDV)) tumor cell lines. Quantification of CDV metabolites and analysis of the sensitivity profile to chemotherapeutics was performed. Transporters expression related to multidrug-resistance (MRP2, P-gp, BCRP) was also investigated. Alterations of CDV metabolism in SiHa(CDV) and HeLa(CDV,) but not in HaCaT(CDV,) emerged via impairment of UMP/CMPK1 activity. Mutations (P64T and R134M) as well as down-regulation of UMP/CMPK1 expression were observed in SiHa(CDV) and HeLa(CDV,) respectively. Altered transporters expression in SiHa(CDV) and/or HeLa(CDV,) but not in HaCaTCDV, was also noted. Taken together, these results indicate that CDV(R) in HPV(+) tumor cells is a multifactorial process.