Análise de alvos moleculares da via de biossíntese de nucleotídeos: uma nova abordagem do fármaco mebendazol no tratamento de adenocarcinoma gástrico

Abstract

Gastric cancer (GC) is one of the tumors with the highest incidence and mortality rates globally. The nucleotide pathway plays an indispensable role in maintaining the tumor’s replicative potential by synthesizing DNA and RNA building blocks, which are essential for the tumor cell cycle. Thus, drugs capable of modulating and inhibiting this metabolic pathway are of great clinical interest. Mebendazole (MBZ) was originally described as an anthelminthic drug and has demonstrated potential antitumoral effects, in addition to the capacity to modulate tumor metabolism. However, its effect on the nucleotide metabolism pathway is still poorly understood. This study, therefore, aims to investigate the potential modulatory effect of MBZ on the purine and pyrimidine biosynthesis pathways in the context of GC. The expression profile of the following genes was analyzed: PRPS1, HPRT1, MTHFD1, TYMS, and DHODH, which are responsible for translating into the enzymes that participate in the nucleotide pathway. The AGP-01 cell line showed an elevated transcript level for most of the genes analyzed, specifically: HPRT1, MTHFD1, TYMS, and DHODH. Following contact between the drug MBZ and the tumor cell line, a drop in the expression level for all studied genes was observed. Furthermore, in silico expression studies were analyzed, and the genes PRPS1, HPRT1, MTHFD1, and TYMS showed a high transcript level in clinical samples from GC patients. Patients with high expression of HPRT1, MTFHD1 and TYMS exhibit a worse prognosis, making them targets of clinical interest. Moreover, using molecular docking assays, it was possible to predict the mode of interaction that the ligand MBZ causes with the nucleotide pathway enzymes. The analysis of the results indicated that the anthelminthic drug docked close to the catalytic domain of the enzymes in the in silico assay. The information obtained so far suggests that MBZ demonstrated the activity of modulating the nucleotide biosynthesis pathway by causing a depletion in transcript levels. However, further studies are needed to clarify the interaction behavior of MBZ with the enzymes. Consequently, this work contributes to the exploration and validation of promising new pharmacological targets for the treatment of GC.