Novel Silver(I) and Gold(I) N-Heterocyclic Carbene Complexes Induce ROS-Dependent Autophagic Cell Death in Human...

Area of Science:

• Oncology
• Medicinal Chemistry
• Cell Biology

Background:

• Hepatocellular carcinoma (HCC) is a highly aggressive cancer with limited treatment options.
• Resistance to conventional therapies necessitates novel therapeutic strategies targeting alternative cell death pathways.

Purpose of the Study:

• To evaluate the cytotoxicity of novel sulfonated silver(I) and gold(I) N-heterocyclic carbene (NHC) complexes against human liver cancer cells.
• To investigate the cell death mechanisms induced by these complexes, focusing on their selectivity towards cancer cells.

Main Methods:

• Synthesis and evaluation of eight sulfonated silver(I) and gold(I) NHC complexes.
• Cytotoxicity assays on liver cancer cells and non-malignant liver cells.
• Morphological analysis, apoptosis marker assessment (caspase-3, PARP-1), and autophagy marker analysis (Beclin-1, LC3-II).
• Investigation of the AKT/mTOR signaling pathway and reactive oxygen species (ROS) production.
• Assessment of the role of ROS using N-acetyl-L-cysteine (antioxidant).

Main Results:

• NHC complexes exhibited selective cytotoxicity against liver cancer cells.
• Cell death was characterized by autophagy, not apoptosis, with upregulated Beclin-1 and LC3-II.
• The AKT/mTOR signaling pathway was inhibited.
• Cytotoxicity and autophagy were dependent on increased ROS production, as evidenced by complete abolition with N-acetyl-L-cysteine pre-treatment.

Conclusions:

• Silver(I) and gold(I) NHC complexes induce ROS-dependent autophagic cell death in hepatocellular carcinoma cells.
• These compounds offer a promising strategy to overcome apoptosis resistance in HCC therapy.
• Further in vivo investigations are warranted to explore their therapeutic potential.