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Orientador: Patricia da Silva Melo / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Aplicadas / Made available in DSpace on 2018-08-27T21:30:15Z (GMT). No. of bitstreams: 1 Ferreira_IasminRosanneSilva_M.pdf: 836058 bytes, checksum: 5beb54192fc88a1ebf1ce80d1b2424bd (MD5) Previous issue date: 2014 / Resumo: Compostos encontrados na natureza, mostram uma enorme gama de diversidade em termos de estrutura e atividades farmacológicas. Apesar dos avanços na sintese química, as plantas se mostram cada vez mais eficientes na busca de novos tratamentos contra o câncer. Assim, o objetivo deste estudo foi avaliar seis fitoterápicos pertencentes à classe de lignoides (dimethoxymagnolol, grandisina e iangambina) e riparinas (I, II e III) , com e sem suplementação de glutationa (GSH - 1mM) em três linhagens de células leucêmicas K562, U937 e HL60. A viabilidade celular foi avaliada por ensaio de redução de MTT em células leucemicas tratadas com os fitoquímicos (com ou sem suplementação de GSH). Nas células U937 foram encontrados valores de IC50 de 100 ?M, 30 ?M e 500 ?M em células tratadas com dimethoximagnolol, grandisina e iangambina, respectivamente, e 60, 25 e 15 ?M (riparina I, II e III, respectivamente). Nas células K562, o tratamento com riparinas foi o mais eficaz dos compostos estudados , uma vez que foram determinados valores de IC50 de 125, 27 e 15 ?M ( riparina I, II e III, respectivamente). Diferentes valores foram encontrados em células HL60 tratadas com riparinas (140, 100 e 75 ?M para riparina I, II e III, respectivamente). A suplementação com GSH amenizou apenas os efeitos tóxicos após tratamento das células U937 com riparina II, uma vez que não foram observados resultados diferentes em outras linhagens celulares tratadas com os compostos estudados com a suplementação de GSH. A citotoxicidade desses fitoquímicos também foi avaliada em linhagem de células de fibroblasto de pulmão permanente (V79), que são células de cultura utilizadas para os estudos de citotoxicidade. Todos os fitoquímicos investigados, com exceção da iangambina, foram menos tóxicos para células V79 do que para as células leucêmicas. Estes resultados se mostram positivos, uma vez que a atividade farmacológica foi maior nas células leucêmicas do que nas células V79. Todos os compostos estudados neste trabalho apresentaram efeitos anti-tumorais, no entanto, o mecanismo de ação da riparina II é diferente em células U937 já que a suplementação com GSH foi eficaz contra os efeitos tóxicos. Provavelmente, a riparina II provocou a morte celular por estresse oxidativo / Abstract: Compounds found in nature, show an enormous range of diversity in terms of structure and pharmacologic activities. Plants play a surprisingly important source of new treatments for cancer, despite advances in chemical synthesis. Thus the aim of this study was to evaluate six phytomedicine belonging to the class of lignoid (dimethoxymagnolol, grandisin and yangambin) and riparins (I, II and III) with and without glutathione supplementation (GSH ¿ 1mM) in three leukemic lines, K562, U937 and HL60. The cell viability was evaluated by MTT reduction assay in leukemic cells treated with the phytochemicals (with or without GSH supplementation). In the U937 cell IC50 values found were 100 µM, 30 µM and 500 µM in the cells treated with dimethoximagnolol, grandisin and yangambin, respectively and 60, 25 and 15 µM (riparin I, II and III, respectively). In K562 cells the treatment with riparins were the most effective class of compounds studied since it was determined IC50 values of 125, 27 and 15µM (riparin I, II and III, respectively). Different values were determined in the HL60 cells treated with riparins (140, 100 and 75 ?M for riparin I, II and III, respectively). GSH ameliorated only the toxic effects evaluated in U937 cell treated with riparin II, since it was not observed different results in the others cell lines treated with the studied compounds plus GSH. The cytotoxicity of phytochemicals was also assessed in a permanent lung fibroblast cell line (V79) culture that are cells commonly used for cytotoxicity studies. All the phytochemicals investigated, with the yangambin exception, were less cytotoxic to V79 cells than to leukemic cells. These results indicate a positive pharmacologic application since the leukemic activity was major than to the toxic effects evaluated in the V79 cells. All the compounds investigated in this work has antitumoral effects, however the action mechanism of riparin II is different on U937 cell since GSH supplementation protected the toxic effects. Probably, riparin II triggered cell death by stress oxidative pathway / Mestrado / Metabolismo e Biologia Molecular / Mestra em Ciências da Nutrição e do Esporte e Metabolismo

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La leucémie myéloïde aigüe (LMA) est la forme de leucémie la plus fréquente chez l’adulte au Canada. Bien que de nombreux réarrangements chromosomiques récurrents aient été identifiés chez les patients LMA, près de la moitié des cas présentent un caryotype normal (LMA-CN). L’étude de la LMA-CN in vitro est rendue difficile par le fait que la survie des cellules primaires de patients est défectueuse sur le long terme et que les lignées cellulaires leucémiques ont un caryotype hautement anormal. En 2009, Munker et son équipe ont établi une nouvelle lignée cellulaire, CG-SH, ayant la particularité d’avoir un caryotype normal. L’objectif principal de ce projet d’étude est de caractériser plus en détail ce nouveau modèle d’étude. Nous avons identifié l’ensemble des variants génétiques présents dans CG-SH grâce au séquençage du génome entier. Les variants susceptibles de participer à la leucémogénèse ont été isolés, tels que des insertions détectées dans EZH2 et GATA2, et de nombreux variants faux-sens détectés dans des gènes pertinents pour la LMA. Nous avons montré que les cellules CG-SH sont sensibles à l’effet prolifératif d’une combinaison de cytokines, qui agissent sur le comportement des cellules en modifiant l’expression des gènes associés à la régulation de la prolifération, de l’apoptose et de la différentiation. De plus, les cytokines diminuent le taux de nécrose des cellules en culture sur le court terme. La présente étude a permis d’approfondir notre connaissance sur les caractéristiques moléculaires de la lignée cellulaire CG-SH, un nouveau modèle d’étude in vitro de la LMA-CN. / Acute myeloid leukemia (AML) is the most frequent form of leukemia in the adult population in Canada. Although many recurrent chromosomal rearrangements have been identified in AML, almost half of all adult patients will present with a normal karyotype (NK-AML). The in vitro study of NK-AML is difficult because the long-term survival of primary patient samples is deficient and AML cell lines have a highly abnormal karyotype. In 2009, Munker and collegues established a new cell line, CG-SH, with the advantage of having a normal karyotype. The main goal of this research project is to further characterize this new model system. We identified all the genetic variants present in the CG-SH cells using whole genome sequencing. We also isolated the variants that are susceptible to participate to leukemogenesis, including the insertions detected in EZH2 and GATA2, and several missense mutations occurring in relevant genes for AML. We found that a combination of cytokines promotes the proliferation of CG-SH cells, and that cytokines act on the cells behavior through expression changes of the genes involved in the regulation of proliferation, apoptosis and differentiation. Moreover, cytokines trigger a decrease of the necrotic rate of CG-SH on the short-term. The current study allowed us to better appreciate molecular characteristics of the CG-SH cell line, a new model to study NK-AML in vitro.