Daidzein enhances cisplatin sensitivity and inhibits migration of oral squamous cell carcinoma through modulating mitogen-activated protein kinase signaling pathway.

Background/purpose: Oral squamous cell carcinoma (OSCC), a prevalent head and neck malignancy, is associated with poor survival rates in advanced stages. According to the American Society of Clinical Oncology (2023), the 5-year survival rate is 86 % for localized OSCC but drops to 69 % and 40 % for regional and distant metastases, respectively, underscoring the critical role of metastasis in treatment failure. Despite advances, few chemotherapeutic agents effectively target metastatic OSCC. Daidzein (DZ), a plant-derived isoflavone, has demonstrated anti-metastatic properties in breast and colon cancers. Materials and methods: This study evaluated DZ's therapeutic potential in OSCC, focusing on its effects on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) markers, as well as its ability to enhance cisplatin (Cis) sensitivity. Results: Molecular docking showed DZ binds strongly to MMP-2 and MMP-9, with binding energies of -8.87 kcal/mol and -8.96 kcal/mol, respectively. In vitro, DZ dose-dependently inhibited OSCC cell proliferation and significantly reduced anchorage-independent growth, invasion, and migration. When combined with Cis, DZ exerted a synergistic inhibitory effect on metastatic properties. Mechanistically, DZ suppressed MMP-2 and MMP-9 expression, reduced ERK1/2 and p38 phosphorylation in the MAPK pathway, and modulated EMT-associated markers. Conclusion: In conclusion, DZ suppresses MMP-2 and MMP-9 expression, inactivates MAPK signaling (ERK1/2 and p38), and inhibits EMT, thereby reducing OSCC migration and invasion. Its biphasic effects on Cis cytotoxicity highlight the potential for optimized combination therapies to prevent OSCC dissemination and metastasis.