Avaliação de novos alvos do fármaco Mebendazol no tratamento do adenocarcinoma gástrico

Abstract

Gastric cancer (GC) is among the most common cancers in the world, being considered the fifth most common and fourth most lethal type of cancer in the world. Despite the therapeutic benefits observed in the addition of chemotherapy/chemoradiotherapy to surgery, the rates of local recurrence and the appearance of tumors in distant sites remain high. Therefore, the study of new therapies should be encouraged to offer new treatments to individuals who are not responsive to current regimens. Studies have evaluated the repositioning of the anthelmintic Mebendazole (MBZ) in the oncology clinic, demonstrating its high antitumor potential in different types of cancer, including GC. Although several targets have already been related to its mechanism of action, its potential in the reprogramming of tumor metabolism and the regulation of transcripts in the AGP-01 gastric metastatic cell line has not yet been elucidated. These findings may provide new dimensions to the pharmacological potential of MBZ, as well as clarify its mechanism of action in vitro. Therefore, this work aims to evaluate new pharmacological targets of MBZ in the AGP-01 gastric cancer cell line, through the analysis of metabolic pathways and the transcriptome of this cell after MBZ treatment. Initial results showed that MBZ has antitumor and selective activity against the AGP-01 cell line, modulating the tumor metabolism by inhibiting the expression of enzymes from glycolytic pathway (SLC2A1, HK1, GAPDH, and LDHA) and nucleotide synthesis (PRPS1, HPRT1, TYMS, and DHODH) in a non-cytotoxic time. These enzymes, when overexpressed, are related to reducing the overall survival rates of patients with GC. Data also demonstrated that, after transcription inhibition of these enzymes, MBZ leads to morphological changes, increased cell membrane fragmentation, and decreased mitochondrial membrane potential, in conjunction with Caspase 3/7 activation and cell cycle arrest. in G0/G1, showing a relationship between the antitumor activity of MBZ and its ability to modulate tumor metabolism. Analysis of the AGP-01 cell line’s transcriptome after treatment with MBZ demonstrated an increase in the expression of the CCL2, IL1A, and CDKN1A genes, while the H3C7, H3C11, and H1-5 transcripts had their expression significantly reduced. These modifications in the mRNA expression were validated by Real-Time PCR, and expression analysis in online databases demonstrated that low expression of ILI1A and high expression of H3C11 and H1-5 are associated with a reduction in overall survival rates in patients with GC. Thus, the data found so far have demonstrated that the drug MBZ alters the tumor metabolism of the AGP-01 cell line, being related to its antitumor activity, and that MBZ modulates the gene expression of histone proteins and inflammatory cytokines, indicating a possible epigenetic and immunological effect in tumor cells. The findings demonstrate new targets of MBZ that have not yet been described in the literature, leading to a better clarification of its mechanism of action and to benefit clinically patients with GC that do not respond to current therapies.