AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway
Valgrícia Matias de Sousa1, Sâmia Sousa Duarte1, Rafael Carlos Ferreira1
1Postgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, Brazil.
Molecules (Basel, Switzerland)
|November 27, 2024
Summary
A novel compound, AMTAC-19, demonstrates potent cytotoxicity against colorectal cancer cells by activating Extracellular Signal-Regulated Kinase (ERK) and c-Jun N-terminal Kinase (JNK) pathways. This activation leads to increased reactive oxygen species (ROS) production, contributing to the antitumor effect.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Colorectal cancer (CRC) is a leading cause of cancer mortality globally.
- Spiro-acridine derivatives are being investigated for their potential anticancer properties.
- Understanding the molecular mechanisms of novel compounds is crucial for developing effective CRC therapies.
Purpose of the Study:
- To investigate the cytotoxic effects of AMTAC-19 on HCT-116 colorectal carcinoma cells.
- To elucidate the molecular interactions of AMTAC-19 with key signaling proteins, including ERK1, JNK1, and p38α MAPK.
- To determine the role of reactive oxygen species (ROS) and specific MAPK pathways in AMTAC-19-induced cytotoxicity.
Main Methods:
- In silico molecular docking using Molegro Virtual Docker v.6.0.1 to predict interactions between AMTAC-19 and target kinases.
- In vitro assays including flow cytometry and MTT assays in HCT-116 cells to assess protein modulation and cytotoxicity.
- Evaluation of ROS production using DCFH-DA assay and assessment of AMTAC-19 cytotoxicity in the presence of antioxidants like N-acetyl-L-cysteine (NAC).
Main Results:
- AMTAC-19 exhibited significant cytotoxicity against HCT-116 cells (IC50 = 10.35 ± 1.66 µM).
- In silico analysis revealed interactions between AMTAC-19 and ERK1, JNK1, and p38α MAPK.
- AMTAC-19 activated ERK1/2 and JNK1 pathways, and its cytotoxicity was dependent on these pathways and ROS production.
Conclusions:
- AMTAC-19 possesses significant in vitro antitumor activity against colorectal cancer cells.
- The compound's mechanism involves the ROS-dependent activation of ERK and JNK signaling pathways.
- AMTAC-19 represents a potential therapeutic candidate for colorectal cancer treatment.
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