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Int J Mol Sci. 2019 Aug 10;20(16). pii: E3902. doi: 10.3390/ijms20163902.

The Cyclooxigenase-2 Inhibitor Parecoxib Prevents Epidermal Dysplasia in HPV16-Transgenic Mice: Efficacy and Safety Observations.

Author information

1
Department of Veterinary Sciences, Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, Portugal.
2
CQVR, Chemistry Department, University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, Portugal.
3
Laboratory for Process Engineering, Environment, Biotechnology and Energy, (LEPABE) Chemical Engineering Department, Faculty of Engineering, University of Porto (FEUP), 4000 Porto, Portugal.
4
Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO-Porto), 4000 Porto, Portugal.
5
School of Health Dr. Lopes Dias, IPC, 6000 Castelo Branco, Portugal.
6
Mountain Research Centre (CIMO), IPB, 5300 Bragança, Portugal.
7
Advanced Polytechnic and University Cooperative (CESPU), Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), 4585 Gandra, Portugal.
8
Research Center in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sports, University of Porto, 4000 Porto, Portugal.
9
Faculty of Medicine, University of Porto (FMUP), 4000 Porto, Portugal.
10
CEBIMED, Faculty of Health Sciences, Fernando Pessoa University, 4000 Porto, Portugal.
11
LPCC Research Department, Portuguese League against Cancer (NRNorte), 4000 Porto, Portugal.
12
Department of Genetics and Biotechnology and Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, Portugal.
13
CQVR, Biology and Environment Department, University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, Portugal.
14
CQVR, Chemistry Department, University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, Portugal. mmso@utad.pt.
15
Department of Veterinary Sciences, Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, Portugal. pamo@utad.pt.

Abstract

Carcinogenesis induced by high-risk human papillomavirus (HPV) involves inflammatory phenomena, partially mediated by cyclooxigenase-2. In pre-clinical models of HPV-induced cancer, cyclooxygenase-2 inhibitors have shown significant efficacy, but also considerable toxicity. This study addresses the chemopreventive effect and hepatic toxicity of a specific cyclooxigensase-2 inhibitor, parecoxib, in HPV16-transgenic mice. Forty-three 20 weeks-old female mice were divided into four groups: I (HPV16-/-, n = 10, parecoxib-treated); II (HPV16-/- n = 11, untreated); III (HPV16+/-, n = 11, parecoxib-treated) and IV (HPV16+/-, n = 11, untreated). Parecoxib (5.0 mg/kg once daily) or vehicle was administered intraperitoneally for 22 consecutive days. Skin lesions were classified histologically. Toxicological endpoints included genotoxic parameters, hepatic oxidative stress, transaminases and histology. Parecoxib completely prevented the onset of epidermal dysplasia in HPV16+/- treated animals (0% versus 64% in HPV16+/- untreated, p = 0.027). Parecoxib decreases lipid peroxidation (LPO) and superoxide dismutase (SOD) activity and increases the GSH:GSSG ratio in HPV16+/- treated animals meaning that oxidative stress is lower. Parecoxib increased genotoxic stress parameters in wild-type and HPV16-transgenic mice, but didn't modify histological or biochemical hepatic parameters. These results indicate that parecoxib has chemopreventive effects against HPV16-induced lesions while maintaining an acceptable toxicological profile in this model.

KEYWORDS:

COX-2; K14HPV16; NSAID; in vivo

PMID:
31405112
PMCID:
PMC6720853
DOI:
10.3390/ijms20163902
[Indexed for MEDLINE]
Free PMC Article

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