Dados do Trabalho

Título

IN SILICO AND IN VITRO ANALYSES SHOW THE POTENTIAL ROLE OF MEBENDAZOLE IN THE MODULATION OF NUCLEOTIDE SYNTHESIS IN GASTRIC CANCER

Introdução

Despite advances in treatments and prevention, recent data show that gastric cancer (GC) remains among the most incident and lethal neoplasms in the world1(1,2). The study of the relationship between nucleotide metabolism and tumor development is gaining increasing importance in clinical research, the enzyme hypoxanthine phosphoribosyltransferase 1 (HPRT1) plays a central role in the generation of purine nucleotides through the purine salvage pathway, being a relevant target in the GC treatment(3,4). Previous studies have shown that the metastatic GC cell line AGP-01 presents enhancement in the expression of genes of the glycolytic pathway being related to a worse prognosis. Mebendazole (MBZ), an antihelminthic approved by FDA, showed to modulate the expression levels and the protein structure of these enzymes, leading tumoral cells to death(5,6). Although the modulation of the glycolytic pathway by MBZ was elucidated, its role in nucleotide synthesis remains unexplored.

Objetivo

Therefore, this initial study aimed to evaluate the relationship of HPRT1 gene expression with GC development and patient’s prognosis, as well as, and its modulation by MBZ.

Métodos

Firstly, in silico analyses were performed by GEPIA (http://gepia.cancer-pku.cn/) dataset to verify the global gene expression of HPRT1 in different types of cancer, then the comparative analyses were performed between GC and normal samples. After, we use the Kaplan Meier plotter (https://kmplot.com/analysis/) software to understand the relation between the HPRT1 gene expression and GC patient's prognosis. Thus, the AGP-01 cell line was treated with MBZ (0.1 µM) in a non-cytotoxic time (24 hours), and in vitro gene expression of HPRT1 was analyzed by RT-PCR. At last, molecular docking was performed to observe the interaction of MBZ with the HPRT1 protein.

Resultados

HPRT1 showed to be overexpressed in 25 of the 31 types of cancer analyzed, a significant difference in gene expression was also evidenced between normal patients (n=211) and GC samples (n=408) (p<0.0001). Otherwise, Kaplan–Meier Plotter analysis evidenced a reduced overall survival rate in patients with low HPRT1 gene expression (p<0.0001). MBZ showed to reduce HPRT1 expression in the AGP-01 cell line after 24 hours of treatment, in addition, the molecular docking revealed that MBZ modifies the protein structure of HPRT1 protein, MBZ was able to interact with four amino acid residues (THR1, ARG2, LYS159, and PRO160) with an energy of interaction of 7.253 kcal mol-1.

Conclusões

Based on the founds it is possible to infer the drug MBZ can modulate the expression and function of the HPRT1 enzyme, with potential activity in the nucleotide synthesis pathway. being a relevant pathway to tumor progression. HPRT1 showed to be overexpressed in different types of cancer, not only in GC, creating an enormous potential for the use of the MBZ as a chemotherapeutic, future studies will seek to better describe the role of this drug in nucleotide synthesis pathways and its relationship with tumor proliferation.

Palavras-chave

Gastric Cancer. Mebendazole. HPRT1 gene expression

Financiador do resumo

Cearense Foundation for Scientific and Technological Development Support (FUNCAP), Coordination for the Improvement of Higher Education Personnel (CAPES), and National Council for Scientific and Technological Development (CNPq).

Área

Estudo Clínico - Tumores do Aparelho Digestivo Alto