title: Resistance to the nucleotide analogue cidofovir in HPV(+) cells: a multifactorial process involving UMP/CMP kinase 1.
abstract: 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 (CDVR) in two HPV(+) (SiHaCDV and HeLaCDV) and one HPV(-) (HaCaTCDV) 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 SiHaCDV and HeLaCDV, but not in HaCaTCDV, emerged via impairment of UMP/CMPK1 activity. Mutations (P64T and R134M) as well as down-regulation of UMP/CMPK1 expression were observed in SiHaCDV and HeLaCDV, respectively. Altered transporters expression in SiHaCDV and/or HeLaCDV, but not in HaCaTCDV, was also noted. Taken together, these results indicate that CDVR in HPV(+) tumor cells is a multifactorial process.
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Topalis
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Tatiane C
authors.initials: TC
authors.lastname: Nogueira
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: De Schutter
authors.affiliation: Sorbonne Universités, UPMC University Paris 06, UMR 8256, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular and Functional Enzymology, Paris, France.
authors.forename: Chahrazade
authors.initials: C
authors.lastname: El Amri
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of The Czech Republic, v.v.i., Prague, Czech Republic.
authors.forename: Marcela
authors.initials: M
authors.lastname: Krečmerová
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D045744:Cell Line, Tumor; D000077404:Cidofovir; D003570:Cytidine Triphosphate / Q000096:biosynthesis; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D009703:Nucleoside-Phosphate Kinase / Q000096:biosynthesis / Q000378:metabolism*; D063065:Organophosphonates / Q000494:pharmacology*; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000188:drug therapy*; D010766:Phosphorylation; D000070590:Solute Carrier Proteins / Q000096:biosynthesis; D014544:Uridine Triphosphate / Q000096:biosynthesis; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D063065:Organophosphonates; D000070590:Solute Carrier Proteins; D003570:Cytidine Triphosphate; D003596:Cytosine; C019979:cytidylate kinase; D009703:Nucleoside-Phosphate Kinase; D000077404:Cidofovir; D014544:Uridine Triphosphate
keywords: NTP metabolism; UMP-CMP kinase; cervical carcinoma; cidofovir; human papillomavirus
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