Avaliação do potencial de modulação do metabolismo tumoral gástrico pelo fármaco Mebendazol

• Autor(a) principal: Aragão, Dyane Rocha
• Data de Publicação: 2022
• Tipo de documento: Trabalho de conclusão de curso
• Idioma: por
• Título da fonte: Repositório Institucional da Universidade Federal do Ceará (UFC)
• Texto Completo: http://www.repositorio.ufc.br/handle/riufc/69973
• topic: Câncer gástrico; Metabolismo; Mebendazol; Docking

In 2020, gastric cancer (GC) was responsible for more than one million new cases worldwide. It is the fifth most incident and the fourth most lethal. Cancer development is supported by metabolic reprogramming, a process that alters the flow of crucial cellular metabolic pathways to provide the energy needed for the uncontrolled proliferation of neoplastic cells. Although there are several treatments for patients with this tumor, there are still many barriers to surpass, such as drug resistance. Thus, making it necessary to search for new therapeutic options. So, this work aims to evaluate the modulating potential of the drug Mebendazole (MBZ) in gastric tumor metabolism through in silico and in vitro analyses. First, the MBZ drug molecule was designed and optimized in MarvinSketch® and Avogadro® software. Afterward, corresponding structures of the proteins of the glucose metabolism GLUT1, HK1, GAPDH, and LDHA were searched in the Protein Data Bank database to perform molecular docking on the DockThor® online server. The online tool GEPIA® was used to analyze the in silico global expression of the SLC2A1, HK1, GAPDH, and LDHA genes, which were also correlated with the overall survival rate using the Kaplan Meier plotter® tool. For in vitro analysis, the gastric tumor cell line AGP-01 was used. Assays were performed to evaluate the cytotoxicity of MBZ and to assess gene expression in vitro with MBZ's treatment. Dockings performed with MBZ showed scores of -8.560, -7.457, -7.195, and -7.550 for proteins GLUT1, HK1, GAPDH, and LDHA, respectively, in addition to the observed polar interactions. MBZ showed high toxicity in the AGP-01 cell line, with IC50 of 0.11 µM. It also significantly reduced the expression of all genes evaluated (p<0.0001 for SLC2A1 and HK1 and p<0.05 for GAPDH and LDHA). GEPIA® analysis showed that, except for the HK1 gene, all of them were overexpressed in gastric cancer (p<0.05). By correlating the increase in gene expression with the survival rate, only LDHA high expression is not related to a worse prognosis. Therefore, MBZ has promising potential in gastric cancer treatment due to the possibility of modulating the expression of essential genes for tumor metabolism.