Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFSCAR |
Texto Completo: | https://repositorio.ufscar.br/handle/ufscar/14337 |
Resumo: | Cancer is a term used for diseases in which abnormal cells divide uncontrolled, spread, and invade other tissues through the blood and lymphatic systems. Breast cancer is one of the most common and with higher mortality among women. Its heterogeneity represents a critical challenge in the clinic, as it requires specific treatment for each subtype of the disease. The treatments used for breast cancer have a high resistance rate and low selectivity for tumor cells, causing several side effects. The development of antitumor metal-based compounds started with the discovery of antitumor activity of cisplatin and is currently among the most widely used antitumor drugs in the clinic to treat various types of tumors, such as ovary, breast, head, and neck. Ruthenium complexes have attracted significant attention because they have unique properties that can justify their antitumor potential, such as mimicking the iron for binding several biomolecules, including transferrin and albumin, making it more specific to tumor cells. This work aimed to select among different complexes a new ruthenium complex, which would be the candidate for antitumor drug, and evaluate the effects of the selected complex through in vitro studies on breast cells and in vivo through the spontaneous metastases of syngenic an orthotopic model. The results demonstrated that the complex Ru(Amsal) was the most selective against breast tumor cells MDA-MB-231 among the six complexes tested. Morphological studies showed that the Ru(Amsal) complex promoted more significant changes in the morphology of breast cancer cells MDA-MB-231 compared to other cell lines tested and, besides, the complex was able to act in the colony formation process, reducing the number and size of the colonies. In the metastatic cascade assays, the complex Ru(Amsal) inhibited migration, invasion, and take and altered the organization of the cytoskeleton of breast cancer cells MDA-MB-231. The complex also induced cell death by apoptosis, DNA damage, nuclear fragmentation, and mitochondrial membrane potential depolarization. Furthermore, it changed the cell cycle of breast tumor cells MDA-MB-231, increasing the percentage of these cells in the sub-G1 phase. An analysis of the effect of the complex Ru(Amsal) synthesized on a microemulsion (Ru(Amsal)ME) in vivo in a spontaneous metastases syngenic and orthotopic model demonstrated that this complex was able to inhibit pulmonary and bone metastases. Also, there were no signs of acute toxicity in animals treated with the complex. Therefore, the results indicate that the complex Ru(Amsal) has promising properties and might be a good alternative drug for breast cancer treatment. |
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Popolin, Cecília PatríciaCominetti, Márcia Reginahttp://lattes.cnpq.br/3725318894555272http://lattes.cnpq.br/5598104335028847568812a5-9faa-4834-a83f-0b80c2e259722021-06-03T10:58:17Z2021-06-03T10:58:17Z2021-04-30POPOLIN, Cecília Patrícia. Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados. 2021. Tese (Doutorado em Ciências Fisiológicas) – Universidade Federal de São Carlos, São Carlos, 2021. Disponível em: https://repositorio.ufscar.br/handle/ufscar/14337.https://repositorio.ufscar.br/handle/ufscar/14337Cancer is a term used for diseases in which abnormal cells divide uncontrolled, spread, and invade other tissues through the blood and lymphatic systems. Breast cancer is one of the most common and with higher mortality among women. Its heterogeneity represents a critical challenge in the clinic, as it requires specific treatment for each subtype of the disease. The treatments used for breast cancer have a high resistance rate and low selectivity for tumor cells, causing several side effects. The development of antitumor metal-based compounds started with the discovery of antitumor activity of cisplatin and is currently among the most widely used antitumor drugs in the clinic to treat various types of tumors, such as ovary, breast, head, and neck. Ruthenium complexes have attracted significant attention because they have unique properties that can justify their antitumor potential, such as mimicking the iron for binding several biomolecules, including transferrin and albumin, making it more specific to tumor cells. This work aimed to select among different complexes a new ruthenium complex, which would be the candidate for antitumor drug, and evaluate the effects of the selected complex through in vitro studies on breast cells and in vivo through the spontaneous metastases of syngenic an orthotopic model. The results demonstrated that the complex Ru(Amsal) was the most selective against breast tumor cells MDA-MB-231 among the six complexes tested. Morphological studies showed that the Ru(Amsal) complex promoted more significant changes in the morphology of breast cancer cells MDA-MB-231 compared to other cell lines tested and, besides, the complex was able to act in the colony formation process, reducing the number and size of the colonies. In the metastatic cascade assays, the complex Ru(Amsal) inhibited migration, invasion, and take and altered the organization of the cytoskeleton of breast cancer cells MDA-MB-231. The complex also induced cell death by apoptosis, DNA damage, nuclear fragmentation, and mitochondrial membrane potential depolarization. Furthermore, it changed the cell cycle of breast tumor cells MDA-MB-231, increasing the percentage of these cells in the sub-G1 phase. An analysis of the effect of the complex Ru(Amsal) synthesized on a microemulsion (Ru(Amsal)ME) in vivo in a spontaneous metastases syngenic and orthotopic model demonstrated that this complex was able to inhibit pulmonary and bone metastases. Also, there were no signs of acute toxicity in animals treated with the complex. Therefore, the results indicate that the complex Ru(Amsal) has promising properties and might be a good alternative drug for breast cancer treatment.O câncer é um termo utilizado para doenças em que células anormais se dividem sem controle e são capazes de se espalhar e invadir outros órgãos e tecidos através dos sistemas sanguíneo e linfático. O câncer de mama apresenta maior incidência e mortalidade entre as mulheres. Sua heterogeneidade representa um grande desafio na clínica, pois requer planos de tratamentos específicos para cada subtipo da doença. Os fármacos utilizados atualmente para o tratamento do câncer de mama apresentam alta taxa de resistência e baixa seletividade para as células tumorais, causando diversos efeitos colaterais. O desenvolvimento de compostos antitumorais a base de metais iniciou-se com a descoberta da atividade antitumoral da cisplatina, que atualmente está entre os fármacos antitumorais mais utilizados na clínica para o tratamento de diversos tipos de tumores, como de ovário, mama, cabeça e pescoço. Os complexos de rutênio têm atraído grande atenção por apresentarem propriedades únicas que podem justificar seu potencial antitumoral como a capacidade de imitar o ferro na ligação a muitas biomoléculas, incluindo a transferrina e albumina, tornando-o mais específico para as células tumorais. O objetivo deste trabalho foi selecionar dentre diferentes complexos um novo complexo de rutênio contendo ácido salicílico e derivados, o qual pudesse ser candidato a medicamento antitumoral, e avaliar os efeitos do complexo selecionado através de estudos in vitro em células de mama e in vivo através do modelo de metástase espontâneo singênico ortotópico. Os resultados demonstraram que o complexo Ru(Amsal) foi o mais seletivo para as células tumorais de mama da linhagem MDA-MB-231 entre os seis complexos testados. Estudos morfológicos mostraram que o complexo Ru(Amsal) promoveu maiores alterações na morfologia das células MDA-MB-231 quando comparado a outras linhagens testadas e além disso, o complexo foi capaz de atuar no processo de formação de colônias, diminuindo o número de tamanho das mesmas. Nos ensaios relacionados a cascata metastática, o complexo Ru(Amsal) inibiu a migração, invasão, adesão, e alterou a organização do citoesqueleto de células da linhagem MDA-MB-231. O complexo também induziu a morte celular por apoptose, casou danos ao DNA, fragmentação nuclear e despolarização do potencial de membrana da mitocôndria. Ainda, foi capaz de alterar o ciclo celular das células tumorais MDA-MB-231, aumentando a porcentagem dessas células na fase sub-G1. A análise do efeito do complexo Ru(Amsal) incorporado em microemulsão (Ru(Amsal)ME) in vivo em modelo de metástase espontâneo singênico ortotópico, demonstrou que este complexo foi capaz de inibir metástases pulmonares e ósseas. Além disso, não houve sinais de toxicidade nos animais tratados com o complexo. Portanto, os resultados indicam que o complexo Ru(Amsal) apresenta propriedades promissoras e que pode ser uma nova alternativa de fármaco para o tratamento do câncer de mama.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)CNPq: 142335/2016-9CAPES: Código de Financiamento 001porUniversidade Federal de São CarlosCâmpus São CarlosPrograma Interinstitucional de Pós-Graduação em Ciências Fisiológicas - PIPGCFUFSCarAttribution-NonCommercial-NoDerivs 3.0 Brazilhttp://creativecommons.org/licenses/by-nc-nd/3.0/br/info:eu-repo/semantics/openAccessCâncerCâncer de mamaComplexos de rutênioApoptoseMetástaseCancerBreast cancerRuthenium complexApoptosisMetastasisCIENCIAS BIOLOGICAS::BIOLOGIA GERALAvaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivadosEvaluation of in vitro and in vivo antitumor activity of new ruthenium complexes containing salicylic acid and derivativesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis6006006fbc146e-b953-4aee-ae8e-f34e0b675891reponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINALTESE.pdfTESE.pdfTeseapplication/pdf6533485https://repositorio.ufscar.br/bitstream/ufscar/14337/1/TESE.pdf026b02b78ae0f27f3d90ed3a15888194MD51Carta comprovante (1).pdfCarta comprovante (1).pdfCarta comprovanteapplication/pdf169957https://repositorio.ufscar.br/bitstream/ufscar/14337/2/Carta%20comprovante%20%281%29.pdfef41a352b0dea0501a777f61d4129554MD52CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufscar.br/bitstream/ufscar/14337/3/license_rdfe39d27027a6cc9cb039ad269a5db8e34MD53TEXTTESE.pdf.txtTESE.pdf.txtExtracted texttext/plain198535https://repositorio.ufscar.br/bitstream/ufscar/14337/4/TESE.pdf.txt054a8048321cd76bd74518e9f6dffe84MD54Carta comprovante (1).pdf.txtCarta comprovante (1).pdf.txtExtracted texttext/plain1853https://repositorio.ufscar.br/bitstream/ufscar/14337/6/Carta%20comprovante%20%281%29.pdf.txtcabfd69c9c31bad90d7cc9a469cc128cMD56THUMBNAILTESE.pdf.jpgTESE.pdf.jpgIM Thumbnailimage/jpeg7118https://repositorio.ufscar.br/bitstream/ufscar/14337/5/TESE.pdf.jpg6940f9183859942faf8ba8185160e236MD55Carta comprovante (1).pdf.jpgCarta comprovante (1).pdf.jpgIM Thumbnailimage/jpeg5344https://repositorio.ufscar.br/bitstream/ufscar/14337/7/Carta%20comprovante%20%281%29.pdf.jpg2ada3516e60b37ebb9a11eb57d56f244MD57ufscar/143372023-09-18 18:32:11.365oai:repositorio.ufscar.br:ufscar/14337Repositório InstitucionalPUBhttps://repositorio.ufscar.br/oai/requestopendoar:43222023-09-18T18:32:11Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR)false |
dc.title.por.fl_str_mv |
Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados |
dc.title.alternative.eng.fl_str_mv |
Evaluation of in vitro and in vivo antitumor activity of new ruthenium complexes containing salicylic acid and derivatives |
title |
Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados |
spellingShingle |
Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados Popolin, Cecília Patrícia Câncer Câncer de mama Complexos de rutênio Apoptose Metástase Cancer Breast cancer Ruthenium complex Apoptosis Metastasis CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
title_short |
Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados |
title_full |
Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados |
title_fullStr |
Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados |
title_full_unstemmed |
Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados |
title_sort |
Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados |
author |
Popolin, Cecília Patrícia |
author_facet |
Popolin, Cecília Patrícia |
author_role |
author |
dc.contributor.authorlattes.por.fl_str_mv |
http://lattes.cnpq.br/5598104335028847 |
dc.contributor.author.fl_str_mv |
Popolin, Cecília Patrícia |
dc.contributor.advisor1.fl_str_mv |
Cominetti, Márcia Regina |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/3725318894555272 |
dc.contributor.authorID.fl_str_mv |
568812a5-9faa-4834-a83f-0b80c2e25972 |
contributor_str_mv |
Cominetti, Márcia Regina |
dc.subject.por.fl_str_mv |
Câncer Câncer de mama Complexos de rutênio Apoptose Metástase |
topic |
Câncer Câncer de mama Complexos de rutênio Apoptose Metástase Cancer Breast cancer Ruthenium complex Apoptosis Metastasis CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
dc.subject.eng.fl_str_mv |
Cancer Breast cancer Ruthenium complex Apoptosis Metastasis |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
description |
Cancer is a term used for diseases in which abnormal cells divide uncontrolled, spread, and invade other tissues through the blood and lymphatic systems. Breast cancer is one of the most common and with higher mortality among women. Its heterogeneity represents a critical challenge in the clinic, as it requires specific treatment for each subtype of the disease. The treatments used for breast cancer have a high resistance rate and low selectivity for tumor cells, causing several side effects. The development of antitumor metal-based compounds started with the discovery of antitumor activity of cisplatin and is currently among the most widely used antitumor drugs in the clinic to treat various types of tumors, such as ovary, breast, head, and neck. Ruthenium complexes have attracted significant attention because they have unique properties that can justify their antitumor potential, such as mimicking the iron for binding several biomolecules, including transferrin and albumin, making it more specific to tumor cells. This work aimed to select among different complexes a new ruthenium complex, which would be the candidate for antitumor drug, and evaluate the effects of the selected complex through in vitro studies on breast cells and in vivo through the spontaneous metastases of syngenic an orthotopic model. The results demonstrated that the complex Ru(Amsal) was the most selective against breast tumor cells MDA-MB-231 among the six complexes tested. Morphological studies showed that the Ru(Amsal) complex promoted more significant changes in the morphology of breast cancer cells MDA-MB-231 compared to other cell lines tested and, besides, the complex was able to act in the colony formation process, reducing the number and size of the colonies. In the metastatic cascade assays, the complex Ru(Amsal) inhibited migration, invasion, and take and altered the organization of the cytoskeleton of breast cancer cells MDA-MB-231. The complex also induced cell death by apoptosis, DNA damage, nuclear fragmentation, and mitochondrial membrane potential depolarization. Furthermore, it changed the cell cycle of breast tumor cells MDA-MB-231, increasing the percentage of these cells in the sub-G1 phase. An analysis of the effect of the complex Ru(Amsal) synthesized on a microemulsion (Ru(Amsal)ME) in vivo in a spontaneous metastases syngenic and orthotopic model demonstrated that this complex was able to inhibit pulmonary and bone metastases. Also, there were no signs of acute toxicity in animals treated with the complex. Therefore, the results indicate that the complex Ru(Amsal) has promising properties and might be a good alternative drug for breast cancer treatment. |
publishDate |
2021 |
dc.date.accessioned.fl_str_mv |
2021-06-03T10:58:17Z |
dc.date.available.fl_str_mv |
2021-06-03T10:58:17Z |
dc.date.issued.fl_str_mv |
2021-04-30 |
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info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
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doctoralThesis |
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publishedVersion |
dc.identifier.citation.fl_str_mv |
POPOLIN, Cecília Patrícia. Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados. 2021. Tese (Doutorado em Ciências Fisiológicas) – Universidade Federal de São Carlos, São Carlos, 2021. Disponível em: https://repositorio.ufscar.br/handle/ufscar/14337. |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufscar.br/handle/ufscar/14337 |
identifier_str_mv |
POPOLIN, Cecília Patrícia. Avaliação da atividade antitumoral in vitro e in vivo de novos complexos de rutênio contendo ácido salicílico e derivados. 2021. Tese (Doutorado em Ciências Fisiológicas) – Universidade Federal de São Carlos, São Carlos, 2021. Disponível em: https://repositorio.ufscar.br/handle/ufscar/14337. |
url |
https://repositorio.ufscar.br/handle/ufscar/14337 |
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por |
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600 600 |
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6fbc146e-b953-4aee-ae8e-f34e0b675891 |
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Attribution-NonCommercial-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nc-nd/3.0/br/ info:eu-repo/semantics/openAccess |
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Attribution-NonCommercial-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nc-nd/3.0/br/ |
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openAccess |
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Universidade Federal de São Carlos Câmpus São Carlos |
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Programa Interinstitucional de Pós-Graduação em Ciências Fisiológicas - PIPGCF |
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UFSCar |
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Universidade Federal de São Carlos Câmpus São Carlos |
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