G-quadruplex DNA reprograms the photochemistry of CX-5461 toward radical-driven anticancer activity

Area of Science:

• Oncology
• Photochemistry
• Molecular Biology

Background:

• CX-5461 is a G-quadruplex (G4) targeting small molecule with demonstrated activity in DNA repair-deficient tumors.
• Clinical use of CX-5461 is limited by dose-limiting phototoxicity.

Purpose of the Study:

• To investigate CX-5461 as a G-quadruplex-associated, light-activated antitumor scaffold by repurposing its phototoxicity.
• To elucidate the photochemical properties of CX-5461 in solution and when complexed with G4 DNA.

Main Methods:

• Investigated CX-5461's photochemical properties (ROS production) in solution and G4 DNA complexes.
• Assessed the cytotoxicity of photoactivated CX-5461 in cancer cells, measuring intracellular ROS, 8-oxoG, and γ-H2AX.
• Evaluated the in vivo efficacy of light-activated CX-5461 in immunocompetent syngeneic tumor models.

Main Results:

• CX-5461 produces both Type I and Type II reactive oxygen species (ROS) in solution.
• G4 DNA complexation shifts CX-5461's photochemistry towards Type I oxidation, destabilizing G4 DNA.
• Photoactivated CX-5461 demonstrated a two-log enhancement in cytotoxicity, increased DNA damage markers, and altered nuclear G4 structures in cancer cells.
• In vivo, light-activated CX-5461 suppressed tumor growth and extended survival, inducing immunogenic genome stress.

Conclusions:

• CX-5461 can be repositioned as a clinically relevant scaffold for G-quadruplex-associated photogenomic cancer therapy.
• The findings support a model where broader oxidative DNA damage contributes to the biological response of light-activated CX-5461.