Avaliação do potencial antagonista da interação p53-MDM2 do composto LQFM030 frente à linhagem tumoral K562

• Ano de defesa: 2016
• Autor(a) principal: Ribeiro, Higor de Oliveira
• Orientador(a): Valadares, Marize Campos
• Banca de defesa: Valadares, Marize Campos, Leite, Paulo Emílio Corrêia, Nascimento, Thaís Leite, Oliveira, Gisele Augusto Rodrigues de
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• dARK ID: ark:/38995/001300000bwrf
• Idioma: por
• Instituição de defesa: Universidade Federal de Goiás
• Programa de Pós-Graduação: Programa de Pós-graduação em Ciências Farmacêuticas (FF)
• Departamento: Faculdade Farmácia - FF (RG)
• País: Brasil
• Palavras-chave em Português: Apoptose; LQFM030; Ciclo celular; Nutlin-3a
• Palavras-chave em Inglês: Apoptosis; LQFM030; Cell cycle; Nutlin-3a
• Área do conhecimento CNPq: FARMACIA::ANALISE TOXICOLOGICA
• Link de acesso: http://repositorio.bc.ufg.br/tede/handle/tede/8746

The cancer encompasses a huge range of different types, requiring several therapeutic approaches for control and/or remission. An approach that has been considered quite promising is the inhibition of the formation of the MDM2/p53 complex. The formation of this complex hinders the triggering of the apoptotic process. The example of the Nutlins, inhibitors of this complex, have stood out as promising prototype drugs and are already in the clinical phase of investigation. The compound LQFM030 originated from the molecular simplification of Nutlin-1, which has already demonstrated antitumor activity against the Ehrlich Ascites Tumor model. In this work, we investigated the cytotoxic effect of compound LQFM030 against the K562 leukemic line, as well as some mechanisms of cytotoxicity. In the evaluation of cytotoxicity using the trypan blue exclusion method, we obtained an IC 50 value of 0.56 mM, similar to results obtained previously. For the other mechanics assays, IC25 (0.283 mM) of compound LQFM030 and 0.01 mM of compound Nutlin-3a were used for treatment for 24 hours. The compound Nutlin-3a was used as the standard for comparison. Morphological analyzes of K562 cells after treatment with compound LQFM030 suggest core fragmentation and chromatin condensation, indicating apoptosis triggered cell death, which was confirmed by flow cytometric analyzes. In cell cycle investigation, LQFM030 treated K562 cells demonstrated increased sub-G1 phase, phosphatidylserine exposure, decreased membrane potential, increased expression of TNF-R1 and caspase -3/7 caspase -9; However, there was a decrease in caspase -8. In turn, the treatment of leukemic cells with Nutlin-3a did not promote changes in the cell cycle, exposure of phosphatidylserine corroborating with data from the literature. In conclusion the studied compound, LQFM030, presented important biological activity with the capacity to induce death in leukemic cells by apoptotic mechanisms and interaction with MDM2 and MDX. The compound presented mechanisms in some aspects similarities to Nutlin-3a, but also showed different mechanisms evidencing its versatility in its biological performance. The discovery of new agents with multiple mechanisms is of great importance to increase the therapeutic armamentarium of cancer in a complementary way and, in addition, it can enhance the effectiveness of the treatment.