Quercetin-Driven Redox Sensitization Enhances the Antitumor Activity of a Thiol-Reactive Agent through Glutathione Disruption

Abstract Targeting redox homeostasis represents a promising strategy to overcome adaptive mechanisms that sustain cancer cell survival under therapeutic stress. Here, we evaluated a pharmacological sensitization strategy based on quercetin (Q) preconditioning followed by treatment with 3′,5′-dimaleamylbenzoic acid (DMAB), aimed at exploiting glutathione-dependent vulnerabilities in cervical cancer cells. Q and DMAB exhibited synergistic interactions across a 6 × 6 concentration matrix, with a marked leftward shift in the dose–response profile within the IC50-proximal range. Combined treatment was associated with significant depletion of intracellular glutathione (GSH) and a reduction in the GSH/GSSG ratio, consistent with disruption of redox buffering capacity. Functionally, Q + DMAB reduced HeLa cell viability to 23% at 48 h and markedly increased apoptotic cell death (75%), accompanied by S-phase cell cycle arrest and inhibition of cell migration. Notably, cytotoxic effects were attenuated in nonmalignant epithelial cells. In vivo, combined administration significantly reduced tumor burden (69%) and improved survival in a murine L5178-Y lymphoma model, without overt signs of systemic toxicity. Collectively, these results demonstrate that Q enhances the antitumor activity of DMAB through modulation of glutathione-dependent redox homeostasis and support the potential of redox-directed combination strategies in cancer therapy.