Therapeutic potential of quercetin in oral squamous cell carcinoma: Mechanisms, epigenetic modulation, and anti-metastatic effects

INTRODUCTION

Quercetin, a vibrant yellow pigment found in plants, is more than just a natural colorant; it is a bioactive compound with significant therapeutic promise. This flavonoid is abundant in onions, apples, berries, and tea, providing a crucial link between diet and health. Known for its potent antioxidant and anti-inflammatory properties, quercetin protects cells from oxidative damage – a precursor to various chronic diseases, including cancer.^[1,2]

In cancer research, particularly oral squamous cell carcinoma (OSCC), quercetin has garnered attention for its multifaceted biological activities demonstrated primarily in preclinical studies. These include the modulation of signaling pathways, induction of apoptosis, inhibition of cell cycle progression, and suppression of metastasis.^[3,4] Notably, quercetin has demonstrated the ability to influence epigenetic mechanisms, such as microRNA (miR) regulation, that are pivotal in OSCC pathogenesis.^[5,6] By targeting these pathways, quercetin curtails tumor progression and reverses aberrant epigenetic changes, offering a potentially novel approach to cancer therapy. As a natural and widely accessible compound, quercetin holds promise for innovative and safer therapeutic strategies.

QUERCETIN’S ROLE AND MECHANISM OF ACTION IN OSCC THERAPY

The chemopreventive potential of flavonoids in oral cancer has been established through extensive preclinical research, with systematic reviews confirming their diverse mechanisms of action across multiple studies.^[7,8] Among the various flavonoid subclasses, quercetin belongs to the flavonol group alongside kaempferol and myricetin, sharing the characteristic C6-C3-C6 carbon skeleton that underlies their biological activities.^[7]

Quercetin combats OSCC through diverse mechanisms, encompassing molecular, metabolic, and epigenetic pathways [Figure 1]. Key mechanisms include:

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Figure 1:

Schematic diagram of quercetin’s mechanisms in oral squamous cell carcinoma (OSCC). ↑: Upregulation/enhancement, ↓: Downregulation/inhibition, EMT: Epithelial-mesenchymal transition, Bax: BCL2-associated X protein, BCL2: B-cell lymphoma 2, MMP-2/9: Matrix metalloproteinase-2/9, CDK-1: Cyclin-dependent kinase 1, mi-R22: microRNA-22, CD36: Cluster of differentiation-36.

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Quercetin halts OSCC cell proliferation by arresting cells at the G1 or G2/M phases in in vitro studies. This is achieved through the downregulation of cyclins and upregulation of CDK inhibitors, effectively blocking progression through critical cell cycle checkpoints.^[3,9]

The compound enhances apoptosis by upregulating proapoptotic proteins (e.g., BCL2-associated X protein [Bax]) and suppressing anti-apoptotic molecules (e.g., B-cell lymphoma 2 [Bcl-2]). Mitochondrial dysfunction and cytochrome c release are central to this process.^[2,9]

Quercetin inhibits epithelial mesenchymal transition (EMT), a key step in metastasis, by targeting transcription factors such as Slug. It also reduces matrix metalloproteinase (MMP) (MMP-2 and MMP-9) activity, impeding cellular migration and invasion in cell culture studies.^[4,10] These effects have been demonstrated primarily in vitro, with limited validation in animal OSCC models. Epigenetic changes, including miRNA regulation, are pivotal in OSCC. Quercetin upregulates tumor-suppressing miRNAs such as miR-22 and miR-1254, which target the wingless/Int-1 beta (WNT/β)-catenin and cluster of differentiation (CD)-36 pathways, respectively, inhibiting tumor progression in OSCC cell lines.^[5,6]

Quercetin disrupts glycolysis by targeting the G3BP1/ YWHAZ axis, reducing glucose uptake and lactate production – key metabolic adaptations in OSCC.^[11] In preclinical models, quercetin suppressed nuclear factor-kappa B (NF-κB) signaling, reducing tumor incidence and severity in 7,12-dimethylbenz[a]anthracene (DMBA)-induced OSCC in a hamster model, which may limit direct translation to human applications.^[2]

EPIGENETIC CHANGES INDUCED BY QUERCETIN IN OSCC

Epigenetic dysregulation plays a critical role in OSCC by altering gene expression profiles, promoting malignancy, and enabling immune evasion. Quercetin’s influence on epigenetic mechanisms is profound, offering a reversal of such aberrations:

Quercetin upregulates miR-22, which directly targets WNT1 and β-catenin, key regulators of proliferation and metastasis. Its activity suppresses the WNT/β-catenin axis, leading to reduced tumor growth and increased apoptosis.^[5] Similarly, quercetin induces miR-1254, which downregulates CD36, curbing OSCC cell invasion and survival.^[6]

By reversing EMT-associated epigenetic changes, quercetin reduces the expression of transcription factors like Slug, pivotal in the transition of epithelial cells to a mesenchymal phenotype. This inhibits metastasis and enhances chemotherapeutic sensitivity.^[4]

While quercetin has been implicated in altering histone acetylation and DNA methylation patterns in other cancer types, these mechanisms have not been fully confirmed in OSCC and require further investigation. The therapeutic implications of these epigenetic modifications in OSCC remain to be established.

QUERCETIN’S ROLE IN OTHER CANCERS AND THERAPEUTIC CONSIDERATIONS

Beyond OSCC, quercetin demonstrates remarkable anticancer effects across various malignancies. In human papillomavirus-positive head and neck cancers, it synergizes with dichloroacetate to inhibit glucose metabolism and lactate production, bolstering immune-mediated tumor clearance.^[12] Similarly, in epidermal growth factor receptor-overexpressing head-and-neck squamous cell carcinoma, quercetin suppresses migration and invasion by downregulating MMP-2 and MMP-9.^[4]

A critical advantage of quercetin over other clinically studied flavonoids lies in its oral bioavailability profile. Unlike many flavonoid glycosides that require extensive gut metabolism, quercetin glucosides can be hydrolyzed directly in the oral cavity by salivary and epithelial β-glucosidases, producing active aglycones locally.^[7] This intraoral bioactivation mechanism provides a unique advantage for OSCC treatment, as therapeutic concentrations can potentially be achieved at the target site without relying solely on systemic circulation. However, significant inter-individual variability in hydrolysis rates has been reported, which may impact therapeutic consistency. At present, clinical trials specifically evaluating quercetin in OSCC are lacking, highlighting the urgent need for human studies to validate preclinical findings.

CONCLUSION

Quercetin represents a promising therapeutic agent for OSCC, with its multifaceted actions spanning molecular, metabolic, and epigenetic pathways demonstrated primarily in preclinical models. By reversing aberrant epigenetic changes, it restores tumor suppressor function and curtails malignancy in experimental settings. However, significant limitations remain, including bioavailability challenges, dose dependency, and the lack of robust clinical data in human subjects. These findings highlight the need for further clinical research to optimize quercetin’s use in OSCC and beyond, while addressing formulation and delivery challenges, offering hope for more effective and safer cancer therapies as a complementary strategy alongside conventional treatments such as cisplatin and radiation therapy.