Avaliação da atividade antineoplásica da nifuroxazida e de nove derivados no câncer anaplásico de tireoide
Data
2024-08-26
Autores
Aderaldo, Gabriela Simões 
Orientadores
Rubio, Ileana Gabriela Sanchez de
Tipo
Trabalho de conclusão de curso
Título da Revista
ISSN da Revista
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Resumo
O câncer de tireoide (CT) é cada vez mais prevalente, especialmente entre as mulheres. Dentre os CTs derivados da célula folicular, o subtipo anaplásico (ATC) é altamente agressivo, a sobrevida dos pacientes é de 6 a 15 meses após o diagnóstico pois são resistentes aos tratamentos disponíveis. Portanto, há uma necessidade de explorar novas abordagens terapêuticas e novos fármacos para melhorar a sobrevida dos pacientes. A nifuroxazida (NFZ) é um composto utilizado há anos como antimicrobiano e posteriormente foi observada sua atividade antitumoral em alguns tipos de câncer, mas não no CT. Assim, este estudo teve como objetivo avaliar a atividade antineoplásica da nifuroxazida e de nove derivados em linhagens de ATC. Foram utilizadas duas linhagens de ATC, HTH83 e KTC2, bem como uma linhagem não tumoral de tireoide, Nthy-ori. Os resultados mostraram que a NFZ e três derivados (GPQF-63, GPQF-803 e GPQF-804) reduziram a viabilidade celular nas linhagens de ATC. O teste de estresse oxidativo revelou que a NFZ e GPQF-63 promovem a produção de espécies reativas de oxigênio (ROS) na linhagem HTH83. Na linhagem Nthy-ori, NFZ e GPQF-63 não influenciaram a produção de ROS, assim como GPQF-63 em KTC2, no entanto, NFZ reduziu ROS em KTC2. O teste de morte celular mostrou que a NFZ e GPQF-63 induziram apoptose nas três linhagens e necrose também em Nthy-Ori, assim como GPQF-63 em HTH83. Em suma, em HTH83, a geração de ROS pelos compostos NFZ e GPQF-63 pode ser um dos mecanismos envolvidos na morte celular e consequentemente na diminuição da viabilidade celular. Por outro lado, em KTC2 e Nthy-Ori, a indução de morte celular é independente da geração de ROS. Estes resultados podem ser consequência do genótipo das linhagens, KTC2 possui a mutação em BRAF, HTH83 em RAS, e Nthy-ori nenhuma delas. Os resultados deste estudo mostram que quatro dos nove compostos analisados, têm atividade antineoplásica em linhagens de ATC, e servem de base para próximos estudos sobre mecanismos e vias de sinalização envolvidos nessa ação e potencial uso na clínica.
Thyroid cancer (TC) is increasingly prevalent, especially among women. Among the TCs derived from follicular cells, the anaplastic subtype (ATC) is highly aggressive, with patient survival ranging from 6 to 15 months after diagnosis because they are resistant to available treatments. Therefore, there is a need to explore new therapeutic approaches and new drugs to improve patient survival. Nifuroxazide (NFZ) is a compound used for years as an antimicrobial and its antitumor activity was subsequently observed in some types of cancer, but not in TC. Thus, this study aimed to evaluate the antineoplastic activity of nifuroxazide and nine derivatives in ATC cell lines. Two ATC cell lines, HTH83 and KTC2, as well as a non-tumor thyroid cell line, Nthy-ori, were used. The results showed that NFZ and three derivatives (GPQF-63, GPQF-803 and GPQF-804) reduced cell viability in ATC cell lines. The oxidative stress test revealed that NFZ and GPQF-63 promote the production of reactive oxygen species (ROS) in the HTH83 cell line. In the Nthy-ori cell line, NFZ and GPQF-63 did not influence ROS production, as well as GPQF-63 in KTC2; however, NFZ reduced ROS in KTC2. The cell death test showed that NFZ and GPQF-63 induced apoptosis in the three cell lines and necrosis also in Nthy-Ori, as well as GPQF-63 in HTH83. In summary, in HTH83, the generation of ROS by the compounds NFZ and GPQF-63 may be one of the mechanisms involved in cell death and consequently in the decrease in cell viability. On the other hand, in KTC2 and Nthy-Ori, the induction of cell death is independent of ROS generation. These results may be a consequence of the genotype of the cell lines, KTC2 has the mutation in BRAF, HTH83 in RAS, and Nthy-Ori has none of them. The results of this study show that four of the nine compounds analyzed have antineoplastic activity in ATC cell lines, and serve as a basis for future studies on the mechanisms and signaling pathways involved in this action and potential use in the clinic.
Thyroid cancer (TC) is increasingly prevalent, especially among women. Among the TCs derived from follicular cells, the anaplastic subtype (ATC) is highly aggressive, with patient survival ranging from 6 to 15 months after diagnosis because they are resistant to available treatments. Therefore, there is a need to explore new therapeutic approaches and new drugs to improve patient survival. Nifuroxazide (NFZ) is a compound used for years as an antimicrobial and its antitumor activity was subsequently observed in some types of cancer, but not in TC. Thus, this study aimed to evaluate the antineoplastic activity of nifuroxazide and nine derivatives in ATC cell lines. Two ATC cell lines, HTH83 and KTC2, as well as a non-tumor thyroid cell line, Nthy-ori, were used. The results showed that NFZ and three derivatives (GPQF-63, GPQF-803 and GPQF-804) reduced cell viability in ATC cell lines. The oxidative stress test revealed that NFZ and GPQF-63 promote the production of reactive oxygen species (ROS) in the HTH83 cell line. In the Nthy-ori cell line, NFZ and GPQF-63 did not influence ROS production, as well as GPQF-63 in KTC2; however, NFZ reduced ROS in KTC2. The cell death test showed that NFZ and GPQF-63 induced apoptosis in the three cell lines and necrosis also in Nthy-Ori, as well as GPQF-63 in HTH83. In summary, in HTH83, the generation of ROS by the compounds NFZ and GPQF-63 may be one of the mechanisms involved in cell death and consequently in the decrease in cell viability. On the other hand, in KTC2 and Nthy-Ori, the induction of cell death is independent of ROS generation. These results may be a consequence of the genotype of the cell lines, KTC2 has the mutation in BRAF, HTH83 in RAS, and Nthy-Ori has none of them. The results of this study show that four of the nine compounds analyzed have antineoplastic activity in ATC cell lines, and serve as a basis for future studies on the mechanisms and signaling pathways involved in this action and potential use in the clinic.