Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)

Detalhes bibliográficos
Autor(a) principal: Moura, Andréa Felinto
Data de Publicação: 2018
Tipo de documento: Tese
Idioma: por
Título da fonte: Repositório Institucional da Universidade Federal do Ceará (UFC)
Texto Completo: http://www.repositorio.ufc.br/handle/riufc/38717
Resumo: Cancer is a complex diseases characterized by the uncontrolled growth of abnormal cells with high invasive potential and is considered a global public health problem. The incidence of cancer has increased every year, showing the relevance in conducting research on cancer treatment in its various modalities. New chalcones have been developed from the insertion of organic groups, among them sulfonamides. The cytotoxic, antiinvasive and antimigratory effect of some chalcone-sulfonamides have been described, however, few studies have described the cytotoxic mechanism of action of these molecules. With this, the aim of this study was to determine the cytotoxic potential of new synthetic chalcone-sulfonamides and the mechanisms involved in the antiproliferative activity of synthetic chalcone-sulfonamide 185 (CSS185). Four synthetic chalcone-sulfonamides with similar molecular structure were tested against tumor cell lines to evaluate the cytotoxic potential of these molecules using MTT assay. Among them, chalcone-sulfonamide 185 (CSS185) showed a selective cytotoxic effect against colorectal cancer cell lines, with an IC50 value four times lower when compared to the other cell lines tested. Therefore, the cytotoxic effect of CSS185 against the metastatic lymph node-derived colorectal cancer cell line (SW-620) was carried out. For the determination of the antitumor effect of this molecule, we used techniques of optical microscopy and fluorescence, flow cytometry and Western blot. The molecule induced a cytostatic and cytotoxic effect against this cell line in a time and concentration dependent manner, interfering with cell cycle progression with increasing G2/M cell number, inducing DNA damage and consequent cell death with the appearance of cell morphology alterations associated with apoptosis and necrosis characteristics, loss of membrane integrity and mitochondrial depolarization. Cell death was associated with activation and cleavage of PARP, with reduced expression of pro-apoptotic Bax protein and caspases 3 and 8 depending of the concentration tested, as well as reduction of the expression of proteins related to the activation of the necroptosis death pathway, RIP and MLKL, that may be associated with the activation of the phosphorylated form of these proteins and induction of death by necroptosis. In addition, due to the antimigratory effect of chalcones-sulfonamides previously described in the literature, a preliminary cellular migration assay was performed using the B16F10 murine melanoma cell line. CSS185 presented an antimigratory effect in non-cytotoxic concentrations, opening up prospects for a more study of this effect. With this, it is suggested that the mechanism involved in the in vitro cytotoxic effect of CSS185 may be related to induction of cell cycle arrest in the G2/M phase and consequent DNA damage and cell death by necroptosis, and antimigratory effect is also observed in non-tumor concentrations cytotoxic, being a promising molecule against cancer.
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spelling Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)Prospection of new synthetic molecules and determination of antitumor effect of a new synthetic chalcone-sulfonamide (css185)Ciclo CelularMorte CelularMovimento CelularChalconaCancer is a complex diseases characterized by the uncontrolled growth of abnormal cells with high invasive potential and is considered a global public health problem. The incidence of cancer has increased every year, showing the relevance in conducting research on cancer treatment in its various modalities. New chalcones have been developed from the insertion of organic groups, among them sulfonamides. The cytotoxic, antiinvasive and antimigratory effect of some chalcone-sulfonamides have been described, however, few studies have described the cytotoxic mechanism of action of these molecules. With this, the aim of this study was to determine the cytotoxic potential of new synthetic chalcone-sulfonamides and the mechanisms involved in the antiproliferative activity of synthetic chalcone-sulfonamide 185 (CSS185). Four synthetic chalcone-sulfonamides with similar molecular structure were tested against tumor cell lines to evaluate the cytotoxic potential of these molecules using MTT assay. Among them, chalcone-sulfonamide 185 (CSS185) showed a selective cytotoxic effect against colorectal cancer cell lines, with an IC50 value four times lower when compared to the other cell lines tested. Therefore, the cytotoxic effect of CSS185 against the metastatic lymph node-derived colorectal cancer cell line (SW-620) was carried out. For the determination of the antitumor effect of this molecule, we used techniques of optical microscopy and fluorescence, flow cytometry and Western blot. The molecule induced a cytostatic and cytotoxic effect against this cell line in a time and concentration dependent manner, interfering with cell cycle progression with increasing G2/M cell number, inducing DNA damage and consequent cell death with the appearance of cell morphology alterations associated with apoptosis and necrosis characteristics, loss of membrane integrity and mitochondrial depolarization. Cell death was associated with activation and cleavage of PARP, with reduced expression of pro-apoptotic Bax protein and caspases 3 and 8 depending of the concentration tested, as well as reduction of the expression of proteins related to the activation of the necroptosis death pathway, RIP and MLKL, that may be associated with the activation of the phosphorylated form of these proteins and induction of death by necroptosis. In addition, due to the antimigratory effect of chalcones-sulfonamides previously described in the literature, a preliminary cellular migration assay was performed using the B16F10 murine melanoma cell line. CSS185 presented an antimigratory effect in non-cytotoxic concentrations, opening up prospects for a more study of this effect. With this, it is suggested that the mechanism involved in the in vitro cytotoxic effect of CSS185 may be related to induction of cell cycle arrest in the G2/M phase and consequent DNA damage and cell death by necroptosis, and antimigratory effect is also observed in non-tumor concentrations cytotoxic, being a promising molecule against cancer.Câncer é o nome dado a um conjunto de doenças complexas caracterizadas pelo crescimento descontrolado de células anormais com alto potencial invasivo, sendo considerado um dos maiores problema de saúde pública mundial. A incidência de câncer tem aumentado a cada ano, mostrando a relevância na realização de pesquisas cujo objetivo seja o tratamento do câncer em suas diversas modalidades. Novas chalconas têm sido desenvolvidas a partir da inserção de grupos orgânicos, dentre eles as sulfonamidas. O efeito antitumoral, antiinvasivo e antimigratório de algumas chalconas-sulfonamidas têm sido descrito, no entanto, poucos são os estudos que descrevem o mecanismo de ação antitumoral destas moléculas. Com isso, este trabalho teve como objetivo determinar o potencial antitumoral de novas chalconas-sulfonamidas sintéticas e os mecanismos envolvidos na atividade antiproliferativa da chalcona-sulfonamida sintética 185 (CSS185). Quatro chalconas-sulfonamidas sintéticas com estrutura molecular semelhante foram testadas contra linhagens tumorais para avaliação do potencial antitumoral destas moléculas, utilizando o método do MTT. Dentre elas, a chalcona-sulfonamida 185 (CSS185) apresentou seletivo efeito antitumoral em linhagens de câncer colorretal, apresentando valor de CI50 quatro vezes menor quando comparado às demais linhagens de células testadas. Com isso, foi realizado um estudo mais aprofundado do efeito antitumoral da CSS185 frente à linhagem de câncer colorretal derivada de linfonodo metastático (SW-620). Para determinação do efeito antitumoral desta molécula foram utilizadas técnicas de microscopia óptica e de fluorescência, citometria de fluxo e Western blot. A molécula induziu efeito citostático e citotóxico frente à linhagem SW-620 de maneira tempo e concentração dependente, interferindo na progressão do ciclo celular com aumento do número de células na fase G2/M, induzindo dano ao DNA e consequente morte celular com o aparecimento de alterações na morfologia celular condizente com apoptose e necrose, associada com perda da integridade de membrana e despolarização mitocondrial. A morte celular foi acompanhada de ativação e clivagem de PARP, com redução da expressão da proteína pró-apoptótica Bax e das caspases 3 e 8 dependendo da concentração testada, além de redução da expressão de proteínas relacionadas com a ativação da via de morte de necroptose, RIP e MLKL, podendo estar associado com a ativação de suas formas fosforiladas e indução de morte por necroptose. Em adição, devido ao efeito antimigratório de chalconas-sulfonamidas previamente descrito na literatura, foi realizado um ensaio preliminar de migração celular, utilizando a linhagem de melanoma murino B16F10. A CSS185 apresentou efeito antimigratório em concentrações não citotóxicas, abrindo perspectivas para um estudo mais aprofundado deste efeito. Com isso, sugere-se que o mecanismo envolvido no efeito antitumoral in vitro da CSS185 pode estar relacionado com indução de parada do ciclo celular na fase G2/M e consequente dano ao DNA e morte por necroptose, sendo observado também efeito antimigratório desta em concentrações não citotóxicas, sendo esta uma molécula promissora no combate ao câncer.Moraes Filho, Manoel Odorico deAraújo, Ana JérsiaMoura, Andréa Felinto2019-01-08T15:29:07Z2019-01-08T15:29:07Z2018-10-30info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfMOURA, A. F. Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185), 2018, 118 f. Tese (Doutorado em Farmacologia) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2018.http://www.repositorio.ufc.br/handle/riufc/38717porreponame:Repositório Institucional da Universidade Federal do Ceará (UFC)instname:Universidade Federal do Ceará (UFC)instacron:UFCinfo:eu-repo/semantics/openAccess2019-10-23T14:45:39Zoai:repositorio.ufc.br:riufc/38717Repositório InstitucionalPUBhttp://www.repositorio.ufc.br/ri-oai/requestbu@ufc.br || repositorio@ufc.bropendoar:2024-09-11T18:20:35.439853Repositório Institucional da Universidade Federal do Ceará (UFC) - Universidade Federal do Ceará (UFC)false
dc.title.none.fl_str_mv Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)
Prospection of new synthetic molecules and determination of antitumor effect of a new synthetic chalcone-sulfonamide (css185)
title Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)
spellingShingle Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)
Moura, Andréa Felinto
Ciclo Celular
Morte Celular
Movimento Celular
Chalcona
title_short Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)
title_full Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)
title_fullStr Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)
title_full_unstemmed Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)
title_sort Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185)
author Moura, Andréa Felinto
author_facet Moura, Andréa Felinto
author_role author
dc.contributor.none.fl_str_mv Moraes Filho, Manoel Odorico de
Araújo, Ana Jérsia
dc.contributor.author.fl_str_mv Moura, Andréa Felinto
dc.subject.por.fl_str_mv Ciclo Celular
Morte Celular
Movimento Celular
Chalcona
topic Ciclo Celular
Morte Celular
Movimento Celular
Chalcona
description Cancer is a complex diseases characterized by the uncontrolled growth of abnormal cells with high invasive potential and is considered a global public health problem. The incidence of cancer has increased every year, showing the relevance in conducting research on cancer treatment in its various modalities. New chalcones have been developed from the insertion of organic groups, among them sulfonamides. The cytotoxic, antiinvasive and antimigratory effect of some chalcone-sulfonamides have been described, however, few studies have described the cytotoxic mechanism of action of these molecules. With this, the aim of this study was to determine the cytotoxic potential of new synthetic chalcone-sulfonamides and the mechanisms involved in the antiproliferative activity of synthetic chalcone-sulfonamide 185 (CSS185). Four synthetic chalcone-sulfonamides with similar molecular structure were tested against tumor cell lines to evaluate the cytotoxic potential of these molecules using MTT assay. Among them, chalcone-sulfonamide 185 (CSS185) showed a selective cytotoxic effect against colorectal cancer cell lines, with an IC50 value four times lower when compared to the other cell lines tested. Therefore, the cytotoxic effect of CSS185 against the metastatic lymph node-derived colorectal cancer cell line (SW-620) was carried out. For the determination of the antitumor effect of this molecule, we used techniques of optical microscopy and fluorescence, flow cytometry and Western blot. The molecule induced a cytostatic and cytotoxic effect against this cell line in a time and concentration dependent manner, interfering with cell cycle progression with increasing G2/M cell number, inducing DNA damage and consequent cell death with the appearance of cell morphology alterations associated with apoptosis and necrosis characteristics, loss of membrane integrity and mitochondrial depolarization. Cell death was associated with activation and cleavage of PARP, with reduced expression of pro-apoptotic Bax protein and caspases 3 and 8 depending of the concentration tested, as well as reduction of the expression of proteins related to the activation of the necroptosis death pathway, RIP and MLKL, that may be associated with the activation of the phosphorylated form of these proteins and induction of death by necroptosis. In addition, due to the antimigratory effect of chalcones-sulfonamides previously described in the literature, a preliminary cellular migration assay was performed using the B16F10 murine melanoma cell line. CSS185 presented an antimigratory effect in non-cytotoxic concentrations, opening up prospects for a more study of this effect. With this, it is suggested that the mechanism involved in the in vitro cytotoxic effect of CSS185 may be related to induction of cell cycle arrest in the G2/M phase and consequent DNA damage and cell death by necroptosis, and antimigratory effect is also observed in non-tumor concentrations cytotoxic, being a promising molecule against cancer.
publishDate 2018
dc.date.none.fl_str_mv 2018-10-30
2019-01-08T15:29:07Z
2019-01-08T15:29:07Z
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 MOURA, A. F. Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185), 2018, 118 f. Tese (Doutorado em Farmacologia) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2018.
http://www.repositorio.ufc.br/handle/riufc/38717
identifier_str_mv MOURA, A. F. Prospecção de novas moléculas sintéticas e determinação do efeito antitumoral de uma nova chalcona-sulfonamida sintética (css185), 2018, 118 f. Tese (Doutorado em Farmacologia) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2018.
url http://www.repositorio.ufc.br/handle/riufc/38717
dc.language.iso.fl_str_mv por
language por
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Institucional da Universidade Federal do Ceará (UFC)
instname:Universidade Federal do Ceará (UFC)
instacron:UFC
instname_str Universidade Federal do Ceará (UFC)
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reponame_str Repositório Institucional da Universidade Federal do Ceará (UFC)
collection Repositório Institucional da Universidade Federal do Ceará (UFC)
repository.name.fl_str_mv Repositório Institucional da Universidade Federal do Ceará (UFC) - Universidade Federal do Ceará (UFC)
repository.mail.fl_str_mv bu@ufc.br || repositorio@ufc.br
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