Novel Tetrahydroxanthylium-Based Ligands Targeting Mitochondrial DNA G-Quadruplex Structures for Concurrent Induction...

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Liver cancer exhibits significant therapeutic resistance due to dysregulated programmed cell death pathways, including apoptosis evasion and autophagy.
• Resistance mechanisms like p53 mutations, antiapoptotic protein overexpression, and autophagy upregulation impede effective liver cancer treatment.

Purpose of the Study:

• To introduce XAN-5, a novel tetrahydroxanthylium ligand targeting mitochondrial DNA G-quadruplexes (mtG4s).
• To investigate XAN-5's potential to simultaneously induce apoptosis and inhibit autophagy in liver cancer.

Main Methods:

• XAN-5's binding to mtG4s was assessed.
• Mitochondrial dysfunction, reactive oxygen species (ROS) production, and caspase-dependent apoptosis were analyzed.
• Autophagic flux was evaluated by monitoring LC3B-II conversion and p62 levels.
• Tumor growth and immune cell infiltration were studied in a mouse liver cancer model.

Main Results:

• XAN-5 binding to mtG4s induced mitochondrial dysfunction and ROS overproduction, leading to apoptosis.
• XAN-5 effectively inhibited autophagic flux, indicated by reduced LC3B-II and increased p62.
• In vivo, XAN-5 suppressed liver tumor growth and increased CD4+ and CD8+ T cell infiltration.

Conclusions:

• XAN-5 demonstrates a dual mechanism of action by inducing apoptosis and inhibiting autophagy.
• This compound effectively targets key liver cancer resistance pathways.
• XAN-5 shows therapeutic promise for liver cancer, potentially overcoming treatment resistance and enhancing anti-tumor immunity.