Discovery of an acridine-based fluorescent ligand for selectively targeting mitochondrial G-quadruplexes DNA and
Nuan Li1, Hui Yuan1, Wenbo Yan1
1School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
Abstract:
Mitochondrial G-quadruplexes (mtG4s) have recently emerged as a highly promising therapeutic target in oncology. This is because the frequency of their formation in the mitochondrial DNA (mtDNA) of cancer cells is significantly higher than that in normal cells. The stabilization of mtG4s induces instability in mtDNA, which subsequently triggering mitochondrial dysfunction and programmed cell death-a mechanistic paradigm that unveils novel avenues for cancer therapy. Despite promising prospects, the development of specific ligands targeting mtG4s remains a substantial unaddressed challenge. In this study, we designed and synthesized an acridine derivative, YWB-6. YWB-6 demonstrated remarkable mitochondrial targeting specificity and inherent fluorescence properties. Biophysical characterization confirmed that YWB-6 selectively recognizes and stabilizes mtG4 structures with high affinity. In SiHa cervical cancer cell models, YWB-6 exhibited precise binding to mtG4, leading to mitochondrial membrane integrity disruption, ATP depletion, ROS imbalance, and ultimately cell cycle arrest and apoptosis. Mechanistic investigations revealed that YWB-6 exerts its antitumor effects primarily through mtG4-mediated mitochondrial dysfunction. Cellular assays further verified its potent antitumor activity, with IC50 values reaching the low micromolar range. Our research not only introduces a pioneering mtG4-targeting fluorescent ligand but also initiates an innovative strategy for anticancer drug design based on the modulation of mitochondrial nucleic acid topology.
Insights
Researchers developed YWB-6, a fluorescent ligand that targets mitochondrial G-quadruplexes (mtG4s) in cancer cells. This novel approach disrupts mitochondrial function, leading to cancer cell death and offering a new strategy for anticancer drug development.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Mitochondrial G-quadruplexes (mtG4s) are increasingly recognized as therapeutic targets in oncology due to their higher prevalence in cancer cells.
- mtG4 stabilization can induce mitochondrial DNA instability, dysfunction, and programmed cell death, presenting a novel cancer therapy paradigm.
Purpose of the Study:
- To design and synthesize a specific ligand targeting mtG4s for potential anticancer applications.
- To investigate the mechanism of action and antitumor efficacy of the novel ligand.
Main Methods:
- Synthesis of an acridine derivative, YWB-6, with mitochondrial targeting and fluorescence properties.
- Biophysical characterization to confirm selective binding and stabilization of mtG4 structures.
- In vitro studies using SiHa cervical cancer cells to assess mitochondrial function, cell cycle, apoptosis, and antitumor activity.
Main Results:
- YWB-6 demonstrated high affinity and selectivity for mtG4 structures.
- YWB-6 induced mitochondrial dysfunction, including membrane disruption, ATP depletion, and ROS imbalance in cancer cells.
- YWB-6 triggered cell cycle arrest and apoptosis, exhibiting potent antitumor activity with IC50 values in the low micromolar range.
Conclusions:
- YWB-6 is a pioneering fluorescent ligand that specifically targets mtG4s, initiating a novel anticancer drug design strategy.
- Modulating mitochondrial nucleic acid topology via mtG4 targeting offers a promising approach for cancer therapy by inducing mtG4-mediated mitochondrial dysfunction.
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