Avaliação do efeito do OTSSP167 em linhagens de adenocarcinoma gástrico com amplificação do gene MELK

Abstract

Gastric cancer is considered the fifth most common type of tumor in the world, and due to its heterogeneity, it is necessary to use individualized therapies that present less toxicity and greater efficacy during treatment. In a previous study, our group reported an increased copy number of the MELK gene in approximately 55.9% of tumors in patients with gastric adenocarcinoma and such tumor cell lines. This gene encodes maternal embryonic leucine zipper kinase (MELK) protein, a member of the serine/threonine kinase family, which participates in multiple cellular processes including cell cycle progression, cell proliferation, apoptosis, cell migration, and others. The increased expression has been observed in different cancers, including gastric cancer. Thus, the present study evaluated by in silico analysis the pharmacokinetic and pharmacodynamic properties of OTSSP167, its antineoplastic activity in gastric cancer cell lines ACP03 and AGP01, analyzing cell viability, the interference of this inhibitor in the protein expression of MELK in lineages, the ability of cell invasion and migration. In silico analyses, OTSSP167 showed a high probability of intestinal absorption, grade III toxicity and higher activity score for kinase inhibition. In vitro experiments, OTSSP167 showed cytotoxic activity in gastric strains, with higher cytotoxic activity against ACP03 (IC50 = 8.5nM). Also, this inhibitor was able to reduce MELK expression in ACP03 and AGP01 strains gradually according to the concentration of the compound. Regarding migration capacity, OTSSP167 was able to significantly inhibit the migration of ACP03 cells treated for 12 hours with three different concentrations of compound (4.25nM, 8.5nM, and 17nM), but in the 24-hour analyzes, there was only significance. OTSSP167 8.5nM and 17nM concentrations. However, the evaluation of cell invasion capacity after treatment with OTSSP167 for 48 hours did not yield significant statistical results. Thus, the results suggest that OTSSP167 has antineoplastic activity in lines with MELK gene amplification and inhibits cell migration capacity. Therefore, OTSSP167 has potential applicability in future therapies, requiring additional tests to delimit the mechanism of action of the compound.