Journal Article Epublish 5 citations
PubMed: 39598733 DOI: 10.3390/molecules29225344
AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway.
Molecules 29(22)
Authors: Valgrícia Matias de Sousa, Sâmia Sousa Duarte, Rafael Carlos Ferreira, Natália Ferreira de Sousa, Marcus Tullius Scotti, Luciana Scotti, Marcelo Sobral da Silva, Josean Fechine Tavares, Ricardo Olímpio de Moura, Juan Carlos Ramos Gonçalves, Marianna Vieira Sobral
Affiliations
- Postgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, Brazil.
- Drug Development and Synthesis Laboratory, Department of Pharmacy, State University of Paraíba, João Pessoa 58070-450, PB, Brazil.
Abstract
Colorectal cancer remains a significant cause of mortality worldwide. A spiro-acridine derivative, ()-1'-((4-bromobenzylidene)amino)-5'-oxo-1',5'-dihydro-10-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.
MeSH
Cells, Cysteine, Acridines, P38 Mitogen-Activated Protein Kinases, Oxidative Stress, Jnk Mitogen-Activated Protein Kinases, Therapeutics