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.