Journal Article

AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway

Silva, Marcelo Sobral da, Scotti, Luciana, Gonçalves, Juan Carlos Ramos, Sousa, Natália Ferreira de, Sobral, Marianna Vieira, Moura, Ricardo Olímpio de, Sousa, Valgrícia Matias de, Duarte, Sâmia Sousa, Tavares, Josean Fechine, Scotti, Marcus Tullius, Ferreira, Rafael Carlos

2024

Overview

Colorectal cancer remains a significant cause of mortality worldwide. A spiro-acridine derivative, (E)-1′-((4-bromobenzylidene)amino)-5′-oxo-1′,5′-dihydro-10H-spiro[acridine-9,2′-pyrrole]-4′-carbonitrile (AMTAC-19), showed significant cytotoxicity in HCT-116 colorectal carcinoma cells (half maximal inhibitory concentration, IC50 = 10.35 ± 1.66 µM) and antioxidant effects after 48 h of treatment. In this study, Molegro Virtual Docker v.6.0.1 software was used to investigate the interactions between AMTAC-19 and the Extracellular Signal-Regulated Kinase 1 (ERK1), c-Jun N-terminal Kinase 1 (JNK1), and p38 Mitogen-Activated Protein Kinase α (p38α MAPK). In vitro assays were conducted in HCT-116 cells to evaluate the effect of AMTAC-19 on the modulation of these proteins’ activities using flow cytometry. Furthermore, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in the presence or absence of ERK1/2, JNK, and p38 MAPK inhibitors was used to evaluate the involvement of these enzymes in AMTAC-19 cytotoxicity. ROS production was assessed using the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay at various incubation times (30 min, 1 h, 6 h, 12 h, and 24 h), and the MTT assay using N-acetyl-L-cysteine (NAC) was performed. In silico results indicated that AMTAC-19 interacts with ERK1, JNK1, and p38α MAPK. Additionally, AMTAC-19 activated ERK1/2 and JNK1 in HCT-116 cells, and its cytotoxicity was significantly reduced in the presence of ERK1/2 and JNK inhibitors. AMTAC-19 also induced a significant increase in ROS production (30 min and 1 h), while NAC pretreatment reduced its cytotoxicity. These findings support AMTAC-19′s in vitro antitumor effect through ROS-dependent activation of ERK and JNK pathways.

• Publisher: MDPI AG,MDPI
• Subject: Acridines - chemistry / Acridines - pharmacology / Adenosine triphosphate / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Antioxidants / Apoptosis / Brazil / Cell cycle / Colorectal cancer / colorectal carcinoma / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - pathology / Communication / Cysteine / Cytotoxicity / Enzymes / Ethylenediaminetetraacetic acid / HCT116 Cells / Health aspects / Humans / Hydrogen bonds / Kinases / Ligands / MAP Kinase Signaling System - drug effects / MAPKs / Missouri / Mitogens / Molecular Docking Simulation / Mortality / oxidative stress / Protein kinases / Proteins / Reactive Oxygen Species - metabolism / Spiro Compounds - chemistry / Spiro Compounds - pharmacology / United States