Avaliação dos efeitos de calcogenonucleosídeos derivados da zidovudina usando células sanguíneas como alvo toxicológico
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/20160 |
Resumo: | Zidovudine (AZT), a thymidine derivative, is widely used in antiretroviral regimens and more recently it has been indicated, in combination with other chemotherapeutics, for the treatment of some types of cancer. Patients under therapy with zidovudine (AZT) have experienced several side effects, highlighting the hematopoietic abnormalities. Consequently, the synthesis of new molecules modified from the structure of AZT that may present high therapeutic efficacy and low toxicity has attracted the interest of the scientific community in recent years. Taking into consideration these perspectives, we performed a screening to evaluate and compare the toxicity of three new compounds derived from the AZT molecule containing portions of selenium, the chalcogenonucleosides 5 '-(4-Chlorophenylselene)zidovudine (SZ1), 5'- (Phenylselene)zidovudine (SZ2) and 5 '-(4-Methylphenylselene)zidovudine (SZ3) in resting and stimulated mononuclear cells and erythrocytes isolated from human blood. PBMCs were exposed to AZT and derivatives at concentrations of 10 to 200μM for 24 and 72h. For erythrocytes and isolated membranes (Ghosts), the exposure occurred for 3 and 12h at concentrations ranging from 10 to 500μM. Cell viability, cell death, oxidative stress and inflammatory parameters were evaluated after the respective treatments. In order to analyze the toxicity of the compounds in vivo, adult mice received a single dose of AZT and derivatives (100μmol/kg, s.c.) and 72h after the administration, liver and renal biomarkers were analyzed. Exposure to SZ1 caused loss of viability, increased production of reactive species, delayed cell cycle, apoptosis and increased expression and production of proinflammatory cytokines in quiescent PBMCs. Most of these effects were also induced by SZ2. AZT and SZ3 did not cause significant toxicity in quiescent PBMCs. Similar results were found in PBMCs stimulated with phytohemagglutinin. In erythrocytes, SZ1 induced hemolysis and increased membrane fragility. Reactive species generation and lipid peroxidation in erythrocytes ghosts were also significantly increased in cells after exposure to the highest concentrations of SZ1. The activity of δ-ALA-D and Na+/ K+-ATPase enzymes was inhibited by SZ1 and SZ2. In addition, both derivatives caused eriptosis, cell death characterized by the translocation of phosphatidylserine to the membrane surface. AZT and SZ3 did not induce significant toxic effects on erythrocytes. In vivo, exposure to AZT and derivatives did not alter the body weight of mice and serum biochemical markers indicative of renal and hepatic function. However, the relative weights of liver, kidney and spleen were modified in animals treated with AZT, SZ1 and SZ2. These results show that derivatives SZ1 and SZ2, containing portions of chlorophenylselene and phenylselene, respectively, were toxic to PBMCs in different stages of division, as well as to erythrocytes, provoking cellular responses associated with redox imbalance, apoptosis and inflammation. On the other hand, SZ3 derivative exhibited AZT-like properties, emerging as a promising candidate to be tested in studies focusing on viral infections and/or cancer, where AZT is considered the therapeutic model. |
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2020-11-25T08:47:21Z2020-11-25T08:47:21Z2018-02-23http://repositorio.ufsm.br/handle/1/20160Zidovudine (AZT), a thymidine derivative, is widely used in antiretroviral regimens and more recently it has been indicated, in combination with other chemotherapeutics, for the treatment of some types of cancer. Patients under therapy with zidovudine (AZT) have experienced several side effects, highlighting the hematopoietic abnormalities. Consequently, the synthesis of new molecules modified from the structure of AZT that may present high therapeutic efficacy and low toxicity has attracted the interest of the scientific community in recent years. Taking into consideration these perspectives, we performed a screening to evaluate and compare the toxicity of three new compounds derived from the AZT molecule containing portions of selenium, the chalcogenonucleosides 5 '-(4-Chlorophenylselene)zidovudine (SZ1), 5'- (Phenylselene)zidovudine (SZ2) and 5 '-(4-Methylphenylselene)zidovudine (SZ3) in resting and stimulated mononuclear cells and erythrocytes isolated from human blood. PBMCs were exposed to AZT and derivatives at concentrations of 10 to 200μM for 24 and 72h. For erythrocytes and isolated membranes (Ghosts), the exposure occurred for 3 and 12h at concentrations ranging from 10 to 500μM. Cell viability, cell death, oxidative stress and inflammatory parameters were evaluated after the respective treatments. In order to analyze the toxicity of the compounds in vivo, adult mice received a single dose of AZT and derivatives (100μmol/kg, s.c.) and 72h after the administration, liver and renal biomarkers were analyzed. Exposure to SZ1 caused loss of viability, increased production of reactive species, delayed cell cycle, apoptosis and increased expression and production of proinflammatory cytokines in quiescent PBMCs. Most of these effects were also induced by SZ2. AZT and SZ3 did not cause significant toxicity in quiescent PBMCs. Similar results were found in PBMCs stimulated with phytohemagglutinin. In erythrocytes, SZ1 induced hemolysis and increased membrane fragility. Reactive species generation and lipid peroxidation in erythrocytes ghosts were also significantly increased in cells after exposure to the highest concentrations of SZ1. The activity of δ-ALA-D and Na+/ K+-ATPase enzymes was inhibited by SZ1 and SZ2. In addition, both derivatives caused eriptosis, cell death characterized by the translocation of phosphatidylserine to the membrane surface. AZT and SZ3 did not induce significant toxic effects on erythrocytes. In vivo, exposure to AZT and derivatives did not alter the body weight of mice and serum biochemical markers indicative of renal and hepatic function. However, the relative weights of liver, kidney and spleen were modified in animals treated with AZT, SZ1 and SZ2. These results show that derivatives SZ1 and SZ2, containing portions of chlorophenylselene and phenylselene, respectively, were toxic to PBMCs in different stages of division, as well as to erythrocytes, provoking cellular responses associated with redox imbalance, apoptosis and inflammation. On the other hand, SZ3 derivative exhibited AZT-like properties, emerging as a promising candidate to be tested in studies focusing on viral infections and/or cancer, where AZT is considered the therapeutic model.A zidovudina (AZT), um análogo do nucleosídeo timidina, é amplamente usado nos esquemas antirretrovirais e mais recentemente foi indicado, em associação com outros quimioterápicos, para o tratamento de alguns tipos de câncer. Pacientes em terapia com AZT vivenciam diversos efeitos colaterais ao longo do tratamento, a destacar as anormalidades hematopoiéticas. Em decorrência disso, a síntese de novas moléculas modificadas a partir da estrutura do AZT que exibam eficácia terapêutica e baixa toxicidade tem atraído o interesse da comunidade científica nos últimos anos. Com tais perspectivas, neste trabalho realizamos uma triagem para avaliar e comparar a toxicidade de três novos compostos derivados da molécula do AZT contendo porções de selênio, os calcogenonucleosídeos 5’-(4-Clorofenilseleno)zidovudina (SZ1), 5’-(Fenilseleno)zidovudina (SZ2) e 5’-(4-Metilfenilseleno)zidovudina (SZ3) em células mononucleares de sangue periférico (PBMCs) quiescentes e estimuladas com fitohemaglutinina (PHA) e em eritrócitos isolados de sangue humano. As PBMCs foram expostas aos análogos e ao AZT nas concentrações de 10 a 200μM por 24 e 72h. Para eritrócitos e membranas isoladas (Ghosts), a exposição foi de 3 e 12h em concentrações que variaram de 10 a 500μM. Parâmetros inflamatórios, de viabilidade celular, morte celular e estresse oxidativo foram avaliados após os respectivos tratamentos. A fim de analisar a toxicidade dos compostos in vivo, camundongos adultos receberam uma única dose dos análogos e do AZT (100μmol/kg, s.c.) e 72h após a administração, biomarcadores hepáticos/renais foram analisados. A exposição ao SZ1 causou perda de viabilidade, aumento da produção de espécies reativas, atraso no ciclo celular, apoptose e aumento na expressão e produção de citocinas pró-inflamatórias em PBMCs quiescentes. A maioria desses efeitos também foi observado nas células expostas ao SZ2. O AZT e o SZ3 não causaram toxicidade significativa em PBMCs quiescentes. Achados similares foram encontrados em PBMCs estimuladas com fitohemaglutinina. Em eritrócitos, o SZ1 induziu hemólise e aumentou a fragilidade da membrana. A geração de espécies reativas e a peroxidação lipídica em ghosts também foram significativamente aumentadas nas células após exposição às concentrações mais altas de SZ1. A atividade das enzimas δ-ALA-D e Na+/ K+-ATPase foi inibida pelo SZ1 e SZ2. Além disso, ambos os derivados causaram eriptose, morte celular caracterizada pela translocação de fosfatidilserina para a superfície da membrana. O AZT e o SZ3 também não induziram efeitos tóxicos significativos em eritrócitos. In vivo, a exposição ao AZT e análogos não alterou o peso corporal dos animais e marcadores bioquímicos séricos de função renal e hepática. No entanto, o peso relativo do fígado, rins e baço foi alterado nos animais tratados com AZT, SZ1 e SZ2. Os resultados obtidos nesta pesquisa mostram que os derivados SZ1 e SZ2, contendo porções de clorofenilseleno e fenilseleno, respectivamente, foram tóxicos para PBMCs em diferentes fases de divisão, assim como para eritrócitos, provocando respostas celulares associadas com desbalanço redox, apoptose e inflamação. Por outro lado, o análogo SZ3 exibiu um perfil de efeitos similar ao AZT, emergindo assim como um promissor candidato para a ser testado em pesquisas com infecções virais e/ou câncer, onde o AZT é considerado o terapêutico modelo.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de Santa MariaCentro de Ciências Naturais e ExatasPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBrasilBioquímicaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessNucleosídeosZidovudinaCalcogenonucleosídeosSelênioCélulas mononuclearesEritrócitosNucleosidesZidovudineChalcogenonucleosidesSeleniumMononuclear cellsErythrocytesCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAAvaliação dos efeitos de calcogenonucleosídeos derivados da zidovudina usando células sanguíneas como alvo toxicológicoEvaluation of the effects of zidovudine derivatives calcogenonucleosides using blood cells as toxicological targetinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisBarbosa, Nilda Berenice de Vargashttp://lattes.cnpq.br/5901511067144019Fachinetto, Roseleihttp://lattes.cnpq.br/7203076675431306Schuch, André Passagliahttp://lattes.cnpq.br/4932611269622766Bem, Andreza Fabro dehttp://lattes.cnpq.br/0383092486694460Tuana, Florencia María Barbéhttp://lattes.cnpq.br/0541621833997095http://lattes.cnpq.br/4444454127603145Ecker, Assis20080000000260087b11d6d-46b4-49bc-b979-5342a4cd48ff29645bcd-7ba6-425e-97c7-af6b1de6846fd4a64262-0e7e-45c5-910e-0b0aee907c10eef91c04-f210-4292-b081-55f0e964ea25345b9516-6fba-4add-8d9a-ef8e90d61d01a18090c9-e872-4666-8044-debb8bad3ef4reponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGBT_2018_ECKER_ASSIS.pdfTES_PPGBT_2018_ECKER_ASSIS.pdfTese de Doutoradoapplication/pdf12705397http://repositorio.ufsm.br/bitstream/1/20160/1/TES_PPGBT_2018_ECKER_ASSIS.pdf2427088ccb7791532125fc8808db48d6MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Avaliação dos efeitos de calcogenonucleosídeos derivados da zidovudina usando células sanguíneas como alvo toxicológico |
dc.title.alternative.eng.fl_str_mv |
Evaluation of the effects of zidovudine derivatives calcogenonucleosides using blood cells as toxicological target |
title |
Avaliação dos efeitos de calcogenonucleosídeos derivados da zidovudina usando células sanguíneas como alvo toxicológico |
spellingShingle |
Avaliação dos efeitos de calcogenonucleosídeos derivados da zidovudina usando células sanguíneas como alvo toxicológico Ecker, Assis Nucleosídeos Zidovudina Calcogenonucleosídeos Selênio Células mononucleares Eritrócitos Nucleosides Zidovudine Chalcogenonucleosides Selenium Mononuclear cells Erythrocytes CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Avaliação dos efeitos de calcogenonucleosídeos derivados da zidovudina usando células sanguíneas como alvo toxicológico |
title_full |
Avaliação dos efeitos de calcogenonucleosídeos derivados da zidovudina usando células sanguíneas como alvo toxicológico |
title_fullStr |
Avaliação dos efeitos de calcogenonucleosídeos derivados da zidovudina usando células sanguíneas como alvo toxicológico |
title_full_unstemmed |
Avaliação dos efeitos de calcogenonucleosídeos derivados da zidovudina usando células sanguíneas como alvo toxicológico |
title_sort |
Avaliação dos efeitos de calcogenonucleosídeos derivados da zidovudina usando células sanguíneas como alvo toxicológico |
author |
Ecker, Assis |
author_facet |
Ecker, Assis |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Barbosa, Nilda Berenice de Vargas |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/5901511067144019 |
dc.contributor.referee1.fl_str_mv |
Fachinetto, Roselei |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/7203076675431306 |
dc.contributor.referee2.fl_str_mv |
Schuch, André Passaglia |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/4932611269622766 |
dc.contributor.referee3.fl_str_mv |
Bem, Andreza Fabro de |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/0383092486694460 |
dc.contributor.referee4.fl_str_mv |
Tuana, Florencia María Barbé |
dc.contributor.referee4Lattes.fl_str_mv |
http://lattes.cnpq.br/0541621833997095 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/4444454127603145 |
dc.contributor.author.fl_str_mv |
Ecker, Assis |
contributor_str_mv |
Barbosa, Nilda Berenice de Vargas Fachinetto, Roselei Schuch, André Passaglia Bem, Andreza Fabro de Tuana, Florencia María Barbé |
dc.subject.por.fl_str_mv |
Nucleosídeos Zidovudina Calcogenonucleosídeos Selênio Células mononucleares Eritrócitos |
topic |
Nucleosídeos Zidovudina Calcogenonucleosídeos Selênio Células mononucleares Eritrócitos Nucleosides Zidovudine Chalcogenonucleosides Selenium Mononuclear cells Erythrocytes CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.eng.fl_str_mv |
Nucleosides Zidovudine Chalcogenonucleosides Selenium Mononuclear cells Erythrocytes |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
Zidovudine (AZT), a thymidine derivative, is widely used in antiretroviral regimens and more recently it has been indicated, in combination with other chemotherapeutics, for the treatment of some types of cancer. Patients under therapy with zidovudine (AZT) have experienced several side effects, highlighting the hematopoietic abnormalities. Consequently, the synthesis of new molecules modified from the structure of AZT that may present high therapeutic efficacy and low toxicity has attracted the interest of the scientific community in recent years. Taking into consideration these perspectives, we performed a screening to evaluate and compare the toxicity of three new compounds derived from the AZT molecule containing portions of selenium, the chalcogenonucleosides 5 '-(4-Chlorophenylselene)zidovudine (SZ1), 5'- (Phenylselene)zidovudine (SZ2) and 5 '-(4-Methylphenylselene)zidovudine (SZ3) in resting and stimulated mononuclear cells and erythrocytes isolated from human blood. PBMCs were exposed to AZT and derivatives at concentrations of 10 to 200μM for 24 and 72h. For erythrocytes and isolated membranes (Ghosts), the exposure occurred for 3 and 12h at concentrations ranging from 10 to 500μM. Cell viability, cell death, oxidative stress and inflammatory parameters were evaluated after the respective treatments. In order to analyze the toxicity of the compounds in vivo, adult mice received a single dose of AZT and derivatives (100μmol/kg, s.c.) and 72h after the administration, liver and renal biomarkers were analyzed. Exposure to SZ1 caused loss of viability, increased production of reactive species, delayed cell cycle, apoptosis and increased expression and production of proinflammatory cytokines in quiescent PBMCs. Most of these effects were also induced by SZ2. AZT and SZ3 did not cause significant toxicity in quiescent PBMCs. Similar results were found in PBMCs stimulated with phytohemagglutinin. In erythrocytes, SZ1 induced hemolysis and increased membrane fragility. Reactive species generation and lipid peroxidation in erythrocytes ghosts were also significantly increased in cells after exposure to the highest concentrations of SZ1. The activity of δ-ALA-D and Na+/ K+-ATPase enzymes was inhibited by SZ1 and SZ2. In addition, both derivatives caused eriptosis, cell death characterized by the translocation of phosphatidylserine to the membrane surface. AZT and SZ3 did not induce significant toxic effects on erythrocytes. In vivo, exposure to AZT and derivatives did not alter the body weight of mice and serum biochemical markers indicative of renal and hepatic function. However, the relative weights of liver, kidney and spleen were modified in animals treated with AZT, SZ1 and SZ2. These results show that derivatives SZ1 and SZ2, containing portions of chlorophenylselene and phenylselene, respectively, were toxic to PBMCs in different stages of division, as well as to erythrocytes, provoking cellular responses associated with redox imbalance, apoptosis and inflammation. On the other hand, SZ3 derivative exhibited AZT-like properties, emerging as a promising candidate to be tested in studies focusing on viral infections and/or cancer, where AZT is considered the therapeutic model. |
publishDate |
2018 |
dc.date.issued.fl_str_mv |
2018-02-23 |
dc.date.accessioned.fl_str_mv |
2020-11-25T08:47:21Z |
dc.date.available.fl_str_mv |
2020-11-25T08:47:21Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/20160 |
url |
http://repositorio.ufsm.br/handle/1/20160 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
200800000002 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
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eu_rights_str_mv |
openAccess |
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Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
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Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Bioquímica |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
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