Estudo comparativo do efeito de estilbenos estruturalmente modificados sobre as vias de resposta a danos no DNA em linhagens celulares de mama

• Ano de defesa: 2016
• Autor(a) principal: Gonçalves, Natália dos Santos
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade de Franca; Brasil; Pós-Graduação; Programa de Mestrado em Ciências; UNIFRAN
• Palavras-chave em Português: Estilbenos; Citotoxicidade; Genotoxicidade; Células tumorais; CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA
• Link de acesso: https://repositorio.cruzeirodosul.edu.br/handle/123456789/518

Stilbenes are naturally occurring compounds that exert their antitumoral activity by regulating cell proliferation and death mechanisms. Considering wide range of genetic heterogeneity in tumoral cells, the search for more selective and satisfactory cell death responses is worth of investigation and some structural modification has been proposed to resveratrol stilbene. Replacement of hydroxyl functional groups, for example, can result in significant reduction of biological effective concentrations, improving the target-specific effects to cell. The DNA damage response (DDR) pathway that includes cell cycle regulation, DNA repair and apoptosis cell death represent an important biological target for developing new antineoplastic treatment strategies. Therefore, in the present study the genotoxic and antiproliferative effects of four resveratrol-derivative molecules, the (E)-4-(3,5- dimethoxystyryl)aniline (DMSA), (E) –methyl-4-(3,5-dimethoxystyril)benzoate (DMSB), (E)-1,3-dimethoxy-5-(4-methoxystyryl)benzene (EMSB) and (Z)-1,3-dimethoxy-5-(4- methoxystyryl)benzene (EMSZ) were investigated in the breast tumoral MCF-7 cell line and its normal counterpart MCF-10A. The cytotoxicity investigated by XTT, bromodeoxyuridine and clonogenic survival assays revealed that EMSB and ZMSB, although non-selective, exhibited the higher cytotoxicity when compared to the others. The effects on cellular migration was also evaluated and demonstrated that EMSB and ZMSB reduced significantly the healing remodelation induced mechanically. EMSB at 5 and 10 µM increased the extension of DNA damage in MCF-10A while ZMSB produced the same effect at 1.25 and 2.5 µM in both cell lines. Cell death was also investigated and revealed that ZMSB (2.5 µM) induced mixed cell death (apoptosis and necrosis) in both cell lines while EMSB (10 µM) induced preferentially apoptosis in MCF-7 cells. Finally, cell cycle kinetics was investigated by flow cytometry and MCF-10A exhibited G2/M accumulation in response to the treatment with 10 µM of EMSB and 2.5 µM of ZMSB. According the experimental conditions adopted here, ZMSB and EMSB were more cytotoxic than the other tested stilbenes and exhibited a non-selective and antiproliferative effect in both MCF-7 and MCF-10A cells causing DNA damage that stopped cell cycle progression and lead to cell death.