Synchronous Interventions of Glucose and Mitochondrial Metabolisms for Antitumor Bioenergetic Therapy

Area of Science:

• Biomedical Engineering
• Cancer Therapy
• Metabolic Engineering

Background:

• Hydrogen sulfide (H₂ S)-based therapies show promise for cancer treatment.
• Tumor metabolic plasticity, the ability to switch between oxidative phosphorylation and glycolysis, limits therapeutic efficacy.
• A strategy is needed to overcome this metabolic flexibility for effective antitumor intervention.

Purpose of the Study:

• To develop a novel therapeutic strategy to overcome tumor metabolic plasticity.
• To create a dual-donor system for simultaneous depletion of key energy sources in tumors.
• To enhance the efficacy of hydrogen sulfide-based cancer therapy.

Main Methods:

• Synthesis of a glycopolymer encapsulating glucose oxidase (GOx) and a caged hydrogen sulfide/hydrogen peroxide dual-donor (1-thio-β-D-glucose).
• Investigated the catalytic activity of GOx on thioglucose for generating cytotoxic H₂ S and H₂ O₂.
• Assessed the dual-action mechanism: mitochondrial dysfunction induction and glycolysis inhibition via glucose depletion.

Main Results:

• The synthesized glycopolymer effectively depleted tumor energy sources by inhibiting both mitochondrial function and glycolysis.
• Generated cytotoxic H₂ S and H₂ O₂ synergistically damaged mitochondrial membrane potential and suppressed cytochrome c oxidase.
• Demonstrated significant anticancer performance through this synchronous intervention strategy.

Conclusions:

• A novel glycopolymer-based dual-donor system effectively targets tumor metabolic plasticity.
• This approach offers a promising strategy for overcoming therapeutic limitations in cancer bioenergetics.
• The findings broaden the scope of antitumor bioenergetic therapy.