Resistance to the nucleotide analogue cidofovir in HPV(+) cells: a multifactorial process involving UMP/CMP kinase 1
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Dimitri Topalis1, Tatiane C. Nogueira1,*, Tim De Schutter1,*, Chahrazade El Amri2, Marcela Krečmerová3, Lieve Naesens1, Jan Balzarini1, Graciela Andrei1, Robert Snoeck1
1Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium
2Sorbonne Universités, UPMC University Paris 06, UMR 8256, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular and Functional Enzymology, Paris, 75252 Paris Cedex 05, France
3Institute of Organic Chemistry and Biochemistry, Academy of Sciences of The Czech Republic, v.v.i., CZ-166 10 Prague 6, Czech Republic
*These authors have contributed equally to this work
Dimitri Topalis, e-mail: [email protected]
Keywords: human papillomavirus, cervical carcinoma, UMP-CMP kinase, cidofovir, NTP metabolism
Received: July 09, 2015 Accepted: January 05, 2016 Published: January 25, 2016
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.
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