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

Topalis, Dimitrios; Nogueira, Tatiane C; Schutter, Tim De; Amri, Chahrazade El; Krečmerová, Marcela; Naesens, Lieve; Balzarini, Jan; Andrei, Gracíela; Snoeck, Robert

doi:10.18632/oncotarget.7006

Cited by 6 publications

(5 citation statements)

References 45 publications

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“…The first phosphorylation is catalyzed by the cytosolic UMP-CMP kinase, producing CDV-monophosphate (CDVp) which is then phosphorylated by a nucleoside diphosphate kinase, pyruvate kinase or creatine kinase to the diphosphate form (CDVpp). The intracellular depot form of CDV, cidofovir monophosphocholine (CDVp-choline) is formed by choline-phosphate cytidylyltransferase [29–31]. CDVpp is the active metabolite and can be incorporated into DNA instead of the natural substrate dCTP [17].…”

Section: Introductionmentioning

confidence: 99%

Cidofovir is active against human papillomavirus positive and negative head and neck and cervical tumor cells by causing DNA damage as one of its working mechanisms

et al. 2016

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Human papillomavirus (HPV) causes cervical cancer and a large fraction of head and neck squamous cell carcinomas (HNSCC). Cidofovir (CDV) proved efficacious in the treatment of several HPV-induced benign and malignant hyper proliferations. To provide a better insight into how CDV selectively eradicates transformed cells, HPV+ and HPV− cervical carcinoma and HNSCC cell lines were compared to normal cells for antiproliferative effects, CDV metabolism, drug incorporation into cellular DNA, and DNA damage. Incorporation of CDV into cellular DNA was higher in tumor cells than in normal cells and correlated with CDV antiproliferative effects, which were independent of HPV status. Increase in phospho-ATM levels was detected following CDV exposure and higher levels of γ-H2AX (a quantitative marker of double-strand breaks) were measured in tumor cells compared to normal cells. A correlation between DNA damage and CDV incorporation into DNA was found but not between DNA damage and CDV antiproliferative effects. These data indicate that CDV antiproliferative effects result from incorporation of the drug into DNA causing DNA damage. However, the anti-tumor effects of CDV cannot be exclusively ascribed to DNA damage. Furthermore, CDV can be considered a promising broad spectrum anti-cancer agent, not restricted to HPV+ lesions.

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Section: Introductionmentioning

confidence: 99%

Cidofovir is active against human papillomavirus positive and negative head and neck and cervical tumor cells by causing DNA damage as one of its working mechanisms

et al. 2016

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“…In recent years, the clinical indications of CDV have been expanded. However, there are few studies focusing on using CDV as antiviral therapy (14). …”

Section: Discussionmentioning

confidence: 99%

Inhibition of antiviral drug cidofovir on proliferation of human papillomavirus-infected cervical cancer cells

Yang

Dai

Chen

et al. 2016

Experimental and Therapeutic Medicine

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In order to evaluate the potential application value of cidofovir (CDV) in the prevention of human papillomavirus (HPV) infection and treatment of cervical cancer, the inhibitory effect of CDV on the proliferation of HPV 18-positive HeLa cells in cervical cancer was preliminarily investigated, using cisplatin (DDP) as a positive control. An MTT assay was used to analyze the effects of CDV and DDP on HeLa cell proliferation. In addition, clone formation assay and Giemsa staining were used to examine the extent of HeLa cell apoptosis caused by CDV and DDP. Flow cytometry was also used to detect the shape and size of apoptotic cells following propidium iodide staining, while western blot analysis identified the expression levels of of E6 and p53 proteins in HeLa cells. A cell climbing immunofluorescence technique was used to locate the subcellular position of p53 in HeLa cells. The results demonstrated that CDV and DDP inhibited the proliferation of HeLa cells in a concentration- and time-dependent manner. Flow cytometry showed that CDV and DDP treatments resulted in cell arrest in the S-phase, and triggered programmed cell death. Furthermore, western blot analysis revealed that CDV and DDP inhibited E6 protein expression and activated p53 expression in HeLa cells. Finally, the immunofluorescence results indicated that CDV and DDP inhibited the nuclear export of p53 by E6 protein, which is required for degradation of endogenous p53 by MDM2 and human papilloma virus E6. In conclusion, CDV and DDP inhibited HeLa cell proliferation in a concentration- and time-dependent manner, reduced the expression of E6 protein, and reinstated p53 protein activity. Thus, CDV regulates cell cycle arrest and apoptosis, and may be a potential cervical cancer therapeutic strategy.

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“…They inhibit transcription and/or replication of different RNA and DNA viruses by targeting components of the viral replication machinery. However, it is established that numerous viruses eventually mutate and develop resistance to these molecules 11-13 . To circumvent this limitation, newly designed BSA overtake the drug resistance problem by targeting host cellular pathways hijacked by the virus to replicate instead of viral factors themselves.…”

Section: Introductionmentioning

confidence: 99%

Replication of Equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors

Valle-Casuso

Gaudaire

Martin-Faivre

et al. 2020

Preprint

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26RNA viruses are responsible for a large variety of animal infections. Equine Arteritis Virus (EAV) is a 27 positive single-stranded RNA virus member of the family Arteriviridae from the order Nidovirales like 28 the Coronaviridae. EAV causes respiratory and reproductive diseases in equids. Although two 29 vaccines are available, the vaccination coverage of the equine population is largely insufficient to 30 prevent new EAV outbreaks around the world. In this study, we present a high-throughput in vitro 31 assay suitable for testing candidate antiviral molecules on equine dermal cells infected by EAV. Using 32 this assay, we identified three molecules that impair EAV infection in equine cells: the broad-spectrum 33 antiviral and nucleoside analog ribavirin, and two compounds previously described as inhibitors of 34 dihydroorotate dehydrogenase (DHODH), the fourth enzyme of the pyrimidine biosynthesis pathway. 35 These molecules effectively suppressed cytopathic effects associated to EAV infection, and strongly 36 inhibited viral replication and production of infectious particles. Since ribavirin is already approved in 37 human and small animal, and that several DHODH inhibitors are in advanced clinical trials, our results 38 open new perspectives for the management of EAV outbreaks. 39 40 41 Keywords: Antiviral activity, equine arteritis virus, dihydroorotate dehydrogenase, pyrimidine 42 biosynthesis inhibitor, ribavirin. 43 44 45 46 47 48

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

Cited by 6 publications

References 45 publications

Cidofovir is active against human papillomavirus positive and negative head and neck and cervical tumor cells by causing DNA damage as one of its working mechanisms

Cidofovir is active against human papillomavirus positive and negative head and neck and cervical tumor cells by causing DNA damage as one of its working mechanisms

Inhibition of antiviral drug cidofovir on proliferation of human papillomavirus-infected cervical cancer cells

Replication of Equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors

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