Synchronous Interventions of Glucose and Mitochondrial Metabolisms for Antitumor Bioenergetic Therapy.

Hydrogen sulfide (H 2 S)-based mitochondrial bioenergetic intervention is an attractive therapeutic modality. However, its therapeutic efficacy is limited owning to metabolic plasticity, which allows tumors to shift their metabolic phenotype between oxidative phosphorylation and glycolysis for energy compensation. To overcome this flexibility, a glycopolymer containing a caged H 2 S and hydrogen peroxide (H 2 O 2 ) dual-donor (1-thio-β-D-glucose [thioglucose]) was synthesized to wrap glucose oxidase (GOx) for complete depletion of tumorigenic energy sources. The loaded GOx catalyzed the glutathione-activated thioglucose to generate cytotoxic H 2 S/H 2 O 2 , which further induced synergistic defects in mitochondrial function by suppressing cytochrome c oxidase (COX IV) expression and damaging the mitochondrial membrane potential. GOx also blocked glycolysis by depleting endogenous glucose. This synchronous intervention strategy exhibited good anticancer performance, broadening the horizon of antitumor bioenergetic therapy. This article is protected by copyright. All rights reserved.