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

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          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 (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.

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          Nucleoside analogues: mechanisms of drug resistance and reversal strategies.

          C Dumontet, Carlos M. Galmarini, Aaron J. Mackey (2001)
          Nucleoside analogues (NA) are essential components of AML induction therapy (cytosine arabinoside), effective treatments of lymphoproliferative disorders (fludarabine, cladribine) and are also used in the treatment of some solid tumors (gemcitabine). These important compounds share some general common characteristics, namely in terms of requiring transport by specific membrane transporters, metabolism and interaction with intracellular targets. However, these compounds differ in regard to the types of transporters that most efficiently transport a given compound, and their preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumors and others on neoplasia with a more protracted evolution. In this review, we analyze the available data concerning mechanisms of action of and resistance to NA, with particular emphasis on recent advances in the characterization of nucleoside transporters and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to these compounds. We performed an extensive search of published in vitro and clinical data in which the levels of expression of nucleoside-activating or inactivating enzymes have been correlated with tumor response or patient outcome. Strategies aiming to increase the intracellular concentrations of active compounds are presented.
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            Human UMP-CMP kinase 2, a novel nucleoside monophosphate kinase localized in mitochondria.

            Yunjian Xu, Magnus Johansson, Anna Karlsson (2008)
            Enzyme deficiency in the salvage pathway of deoxyribonucleotide synthesis in mitochondria can cause mtDNA depletion syndromes. We have identified a human mitochondrial UMP-CMP kinase (UMP-CMPK, cytidylate kinase; EC 2.7.4.14), designated as UMP-CMP kinase 2 (UMP-CMPK2). The C-terminal domain of this 449-amino acid protein contains all consensus motifs of a nucleoside monophosphate kinase. Phylogenetic analysis showed that UMP-CMPK2 belonged to a novel nucleoside monophosphate kinase family, which was closer to thymidylate kinase than to cytosolic UMP-CMP kinase. Subcellular localization with green fluorescent protein fusion proteins illustrated that UMP-CMPK2 was localized in the mitochondria of HeLa cells and that the mitochondrial targeting signal was included in the N-terminal 22 amino acids. The enzyme was able to phosphorylate dUMP, dCMP, CMP, and UMP with ATP as phosphate donor, but the kinetic properties were different compared with the cytosolic UMP-CMPK. Its efficacy to convert dUMP was highest, followed by dCMP, whereas CMP and UMP were the poorest substrates. It also phosphorylated the monophosphate forms of the nucleoside analogs ddC, dFdC, araC, BVDU, and FdUrd, which suggests that UMP-CMPK2 may be involved in mtDNA depletion caused by long term treatment with ddC or other pyrimidine analogs. UMP-CMPK2 mRNA expression was exclusively detected in chronic myelogenous leukemia K-562 and lymphoblastic leukemia MOLT-4 among eight studied cancer cell lines. Particular high expression in leukemia cells, dominant expression in bone marrow, and tight correlation with macrophage activation and inflammatory response suggest that UMP-CMPK2 may have other functions in addition to the supply of substrates for mtDNA synthesis.
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              Acquired resistance to drugs targeting receptor tyrosine kinases.

              Steven A. Rosenzweig (2012)
              Development of resistance to chemotherapeutic drugs represents a significant hindrance to the effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over half a century and have revealed the lack of a single cause. Rather, a multitude of mechanisms have been delineated ranging from induction and expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system and altered metabolism to name a few. Treatment of cancer patients/cancer cells with chemotherapeutic agents and/or molecularly targeted drugs is accompanied by acquisition of resistance to the treatment administered. Chemotherapeutic agent resistance was initially assumed to be due to induction of mutations leading to a resistant phenotype. This has also been true for molecularly targeted drugs. Considerable experience has been gained from the study of agents targeting the Bcr-Abl tyrosine kinase including imatinib, dasatinib and sunitinib. It is clear that mutations alone are not responsible for the many resistance mechanisms in play. Rather, additional mechanisms are involved, ranging from epigenetic changes, alternative splicing and the induction of alternative/compensatory signaling pathways. In this review, resistance to receptor tyrosine kinase inhibitors (RTKIs), RTK-directed antibodies and antibodies that inactivate ligands for RTKs are discussed. New approaches and concepts aimed at avoiding the generation of drug resistance will be examined. The recent observation that many RTKs, including the IGF-1R, are dependence receptors that induce apoptosis in a ligand-independent manner will be discussed and the implications this signaling paradigm has on therapeutic strategies will be considered. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 1 March 2016
                Publication date (Electronic): 25 January 2016
                Volume: 7
                Issue: 9
                Pages: 10386-10401
                Affiliations
                1 Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium
                2 Sorbonne 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
                3 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of The Czech Republic, v.v.i., CZ-166 10 Prague 6, Czech Republic
                Author notes
                Correspondence to: Dimitri Topalis, dimitrios.topalis@ 123456rega.kuleuven.be
                Article
                Publisher ID: 7006
                DOI: 10.18632/oncotarget.7006
                PMC ID: 4891127
                PubMed ID: 26824416
                SO-VID: 464dd3da-bb31-402b-8693-44113b80bb72
                Copyright © Copyright: © 2016 Topalis et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 9 July 2015
                Date accepted : 5 January 2016
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: human papillomavirus,cervical carcinoma,ump-cmp kinase,cidofovir,ntp metabolism
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: human papillomavirus, cervical carcinoma, ump-cmp kinase, cidofovir, ntp metabolism

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