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

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...

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Main Authors:	Tiago Ferreira, Sandra Campos, Mónica G. Silva, Rita Ribeiro, Susana Santos, José Almeida, Maria João Pires, Rui Miguel Gil da Costa, Cláudia Córdova, António Nogueira, Maria João Neuparth, Rui Medeiros, Margarida Maria da Silva Monteiro Bastos, Isabel Gaivão, Francisco Peixoto, Maria Manuel Oliveira, Paula Alexandra Oliveira
Format:	Article
Language:	English
Published:	MDPI AG 2019-08-01
Series:	International Journal of Molecular Sciences
Subjects:	COX-2 NSAID in vivo K14HPV16
Online Access:	https://www.mdpi.com/1422-0067/20/16/3902

id	doaj-fb0a10c1a2bf4b78a5dbcc63964c7a33
record_format	Article
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Tiago Ferreira Sandra Campos Mónica G. Silva Rita Ribeiro Susana Santos José Almeida Maria João Pires Rui Miguel Gil da Costa Cláudia Córdova António Nogueira Maria João Neuparth Rui Medeiros Margarida Maria da Silva Monteiro Bastos Isabel Gaivão Francisco Peixoto Maria Manuel Oliveira Paula Alexandra Oliveira
spellingShingle	Tiago Ferreira Sandra Campos Mónica G. Silva Rita Ribeiro Susana Santos José Almeida Maria João Pires Rui Miguel Gil da Costa Cláudia Córdova António Nogueira Maria João Neuparth Rui Medeiros Margarida Maria da Silva Monteiro Bastos Isabel Gaivão Francisco Peixoto Maria Manuel Oliveira Paula Alexandra Oliveira The Cyclooxigenase-2 Inhibitor Parecoxib Prevents Epidermal Dysplasia in HPV16-Transgenic Mice: Efficacy and Safety Observations International Journal of Molecular Sciences COX-2 NSAID in vivo K14HPV16
author_facet	Tiago Ferreira Sandra Campos Mónica G. Silva Rita Ribeiro Susana Santos José Almeida Maria João Pires Rui Miguel Gil da Costa Cláudia Córdova António Nogueira Maria João Neuparth Rui Medeiros Margarida Maria da Silva Monteiro Bastos Isabel Gaivão Francisco Peixoto Maria Manuel Oliveira Paula Alexandra Oliveira
author_sort	Tiago Ferreira
title	The Cyclooxigenase-2 Inhibitor Parecoxib Prevents Epidermal Dysplasia in HPV16-Transgenic Mice: Efficacy and Safety Observations
title_short	The Cyclooxigenase-2 Inhibitor Parecoxib Prevents Epidermal Dysplasia in HPV16-Transgenic Mice: Efficacy and Safety Observations
title_full	The Cyclooxigenase-2 Inhibitor Parecoxib Prevents Epidermal Dysplasia in HPV16-Transgenic Mice: Efficacy and Safety Observations
title_fullStr	The Cyclooxigenase-2 Inhibitor Parecoxib Prevents Epidermal Dysplasia in HPV16-Transgenic Mice: Efficacy and Safety Observations
title_full_unstemmed	The Cyclooxigenase-2 Inhibitor Parecoxib Prevents Epidermal Dysplasia in HPV16-Transgenic Mice: Efficacy and Safety Observations
title_sort	cyclooxigenase-2 inhibitor parecoxib prevents epidermal dysplasia in hpv16-transgenic mice: efficacy and safety observations
publisher	MDPI AG
series	International Journal of Molecular Sciences
issn	1422-0067
publishDate	2019-08-01
description	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<sup>−/−</sup>, <i>n</i> = 10, parecoxib-treated); II (HPV16<sup>−/−</sup> <i>n</i> = 11, untreated); III (HPV16<sup>+/−</sup>, <i>n</i> = 11, parecoxib-treated) and IV (HPV16<sup>+/−</sup>, <i>n</i> = 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<sup>+/−</sup> treated animals (0% versus 64% in HPV16<sup>+/−</sup> untreated, <i>p</i> = 0.027). Parecoxib decreases lipid peroxidation (LPO) and superoxide dismutase (SOD) activity and increases the GSH:GSSG ratio in HPV16<sup>+/−</sup> 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.
topic	COX-2 NSAID in vivo K14HPV16
url	https://www.mdpi.com/1422-0067/20/16/3902
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spelling	doaj-fb0a10c1a2bf4b78a5dbcc63964c7a332020-11-25T02:35:12ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-08-012016390210.3390/ijms20163902ijms20163902The Cyclooxigenase-2 Inhibitor Parecoxib Prevents Epidermal Dysplasia in HPV16-Transgenic Mice: Efficacy and Safety ObservationsTiago Ferreira0Sandra Campos1Mónica G. Silva2Rita Ribeiro3Susana Santos4José Almeida5Maria João Pires6Rui Miguel Gil da Costa7Cláudia Córdova8António Nogueira9Maria João Neuparth10Rui Medeiros11Margarida Maria da Silva Monteiro Bastos12Isabel Gaivão13Francisco Peixoto14Maria Manuel Oliveira15Paula Alexandra Oliveira16Department 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, PortugalDepartment 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, PortugalCQVR, Chemistry Department, University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, PortugalCQVR, Chemistry Department, University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, PortugalDepartment 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, PortugalDepartment 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, PortugalDepartment 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, PortugalDepartment 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, PortugalSchool of Health Dr. Lopes Dias, IPC, 6000 Castelo Branco, PortugalMountain Research Centre (CIMO), IPB, 5300 Bragança, PortugalAdvanced Polytechnic and University Cooperative (CESPU), Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), 4585 Gandra, PortugalMolecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO-Porto), 4000 Porto, PortugalMolecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO-Porto), 4000 Porto, PortugalDepartment of Genetics and Biotechnology and Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, PortugalCQVR, Biology and Environment Department, University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, PortugalCQVR, Chemistry Department, University of Trás-os-Montes and Alto Douro (UTAD), 5000 Vila Real, PortugalDepartment 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, PortugalCarcinogenesis 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<sup>−/−</sup>, <i>n</i> = 10, parecoxib-treated); II (HPV16<sup>−/−</sup> <i>n</i> = 11, untreated); III (HPV16<sup>+/−</sup>, <i>n</i> = 11, parecoxib-treated) and IV (HPV16<sup>+/−</sup>, <i>n</i> = 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<sup>+/−</sup> treated animals (0% versus 64% in HPV16<sup>+/−</sup> untreated, <i>p</i> = 0.027). Parecoxib decreases lipid peroxidation (LPO) and superoxide dismutase (SOD) activity and increases the GSH:GSSG ratio in HPV16<sup>+/−</sup> 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.https://www.mdpi.com/1422-0067/20/16/3902COX-2NSAIDin vivoK14HPV16

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

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