Quercetin as a multi-targeted therapeutic candidate in oral cancers: molecular mechanisms and preclinical evidence

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Abstract
Oral malignancies, particularly oral squamous cell carcinoma (OSCC), are among the most prevalent head and neck cancers and remain associated with high morbidity, therapeutic resistance, and frequent recurrence. Despite multimodal treatment approaches, long-term survival remains suboptimal, highlighting the need for novel adjunctive strategies. Quercetin, a naturally occurring dietary flavonoid abundant in fruits and vegetables, has attracted attention due to its antioxidant, anti-inflammatory, and anticancer properties, with growing evidence supporting its relevance in oral cancer. In vitro studies demonstrate that quercetin significantly reduces oral cancer cell viability, proliferation, and clonogenic potential in a dose- and time-dependent manner. These effects are mediated by modulation of key cell-cycle regulators, resulting in arrest at the G1 and G2/M phases. Quercetin also promotes apoptosis through increased intracellular reactive oxygen species (ROS) generation, mitochondrial membrane depolarization, cytochrome c release, and activation of caspase-9 and caspase-3, indicating involvement of the intrinsic pathway. Concurrent activation of Fas/Fas-L signaling and caspase-8 suggests engagement of the extrinsic apoptotic pathway as well. Beyond cytotoxicity, quercetin suppresses migration and invasion by inhibiting epithelial-mesenchymal transition (EMT), characterized by increased E-cadherin and reduced N-cadherin and vimentin expression. It also downregulates MMP-2, MMP-9, and VEGF, thereby limiting extracellular matrix degradation and angiogenesis. In vivo studies further confirm reductions in tumor volume and growth kinetics without significant systemic toxicity. Nonetheless, although these findings underscore quercetin's multi-targeted anticancer potential, clinical translation is limited by poor bioavailability and rapid metabolism. Optimized delivery systems and well-designed clinical trials are necessary to clarify its therapeutic applicability in oral malignancies. This review will summarize current evidence on quercetin's anticancer effects in oral malignancies and highlight the molecular mechanisms underlying its therapeutic potential.

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