Dados do Trabalho

Título

Effect of 5-FU and Morphine on Cell Migration Potential Is Modulated by PIWIL1 in Gastric Adenocarcinoma Models

Introdução

Gastric adenocarcinoma (GA) has a high mortality rate, with early diagnosis and treatment difficulties. Altered expression of piwi (PIWIL1 product), observed in GA, impacts therapeutic response and some aspects of tumor aggressiveness, such as cell migration potential. Given this scenario, searching for new therapy strategies, such as drug repositioning, focused on impactful molecular alterations, such as those involving piwi, is necessary.

Objetivo

Knowing that 5-Fluorouracil (5-FU) is a chemotherapy drug used for GA and that oncology patients use Morphine to minimize cancer-related pain, this study aimed to evaluate the action of the drugs, alone and in combination, on cell migration under the influence of piwi.

Métodos

For this purpose, the AGP01 (Pará Gastric Ascites 01) and AGP01-PIWIL1 KO (Pará Gastric Ascites 01 with knockout PIWIL-1 gene) cell lines were subjected to Wound Healing (WH) assays to analyze the modulation of cell migration with treatments at concentrations of ½ and ¼ of the IC50 of the individual substances (Morphine - 474 µM and 237 µM) (5-FU - 4 µM and 2 µM) and combined (Morphine - 351 µM + 5-FU - 3 µM) (Morphine - 176 µM + 5-FU - 1.5 µM) obtained in the cell viability assay by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) of the AGP01 cell line at 24 hours. The analysis of the discontinuous areas after treatment at different time points was quantified using the Image J program. Data were analyzed using the mean and standard error of three experiments and were compared by analysis of variance (2-way ANOVA) followed by Bonferroni's test, with a significance level of 95% (p<0.05).

Resultados

The results of this study demonstrated that in the AGP01 cell line, all individual and combined treatments significantly reduced (p<0.001) cell migration after 24 hours. However, treatment with 5-FU proved more efficient as it significantly reduced migration after 6 hours, even at the lowest tested concentration (p<0.01). In the AGP01-PIWIL1 KO cell line, isolated Morphine treatment and the combined drug treatment were more satisfactory than 5-FU alone, significantly reducing (p<0.001) cell migration after 6 hours, even at the lowest treatment concentrations.

Conclusões

Therefore, the combined drug treatment about migration inhibition is highly recommended for patients who do not express the PIWIL1 gene. Furthermore, this repositioning would allow a decrease in the dosage of 5-FU used while maintaining a similar effect on cell migration but with lower toxicity. These findings encourage further investigation into the factors involved in this PIWIL1-dependent differential response.

Palavras-chave

Gastric Adenocarcinoma, PIWIL1, and Cell Migration.

Financiador do resumo

Conselho Nacional de Desenvolvimento Científico e Tecnológico