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-res...

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Bibliographic Details
Published in:Oncotarget 2016-03, Vol.7 (9), p.10386-10401
Main Authors: Topalis, Dimitri, Nogueira, Tatiane C, De Schutter, Tim, El Amri, Chahrazade, Krečmerová, Marcela, Naesens, Lieve, Balzarini, Jan, Andrei, Graciela, Snoeck, Robert
Format: Article
Language:English
Subjects:
ATP-Binding Cassette Transporters - biosynthesis
Cancer
Cell Line, Tumor
Cytidine Triphosphate - biosynthesis
Cytosine - analogs & derivatives
Cytosine - pharmacology
Drug Resistance, Neoplasm - genetics
Female
Gynecology and obstetrics
HeLa Cells
Human health and pathology
Humans
Life Sciences
Microbial Sensitivity Tests
Nucleoside-Phosphate Kinase - biosynthesis
Nucleoside-Phosphate Kinase - metabolism
Organophosphonates - pharmacology
Papillomaviridae
Papillomavirus Infections - drug therapy
Phosphorylation
Research Paper
Solute Carrier Proteins - biosynthesis
Uridine Triphosphate - biosynthesis
Uterine Cervical Neoplasms - drug therapy
Uterine Cervical Neoplasms - pathology
Uterine Cervical Neoplasms - virology
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.7006