Lycopene Enhances the Sensitivity of Oral Squamous Cell Carcinoma to Cisplatin Through Inhibition of the PI3K/Akt Signaling Pathway and Reversal of Epithelial-Mesenchymal Transition

Background: Cisplatin-based chemotherapy for oral squamous cell carcinoma (OSCC) is limited by intrinsic inefficacy and toxicity. Lycopene, a natural carotenoid, may enhance cisplatin's therapeutic potential. Objective: To explore lycopene's chemo-sensitizing effects on cisplatin and its mechanisms in OSCC. Methods: In vitro, CAL-27/SCC-9 cells were treated with lycopene and/or cisplatin; cell viability, colony formation, migration, invasion, and apoptosis were detected, and protein expression of MRP-1, PI3K/Akt/mTOR pathway components, and EMT markers was analyzed by Western blot. In vivo, a nude mouse xenograft model was used to verify the combination's effect on tumor growth. Results: Compared with cisplatin alone, the lycopene-cisplatin combination significantly inhibited OSCC cell proliferation, colony formation, migration, and invasion, while promoting apoptosis. Mechanistically, lycopene reversed cisplatin-induced upregulation of MRP-1 and activation of the PI3K/Akt/mTOR pathway, and restored cisplatin-suppressed E-cadherin while reducing N-cadherin and EpCAM. In vivo, the combination reduced tumor growth vs cisplatin alone without increasing toxicity. Conclusion: This is the first report that lycopene enhances cisplatin sensitivity in OSCC by coupling inhibition of MRP-1-mediated drug efflux with suppression of PI3K/Akt/mTOR and EMT/stemness-filling the gap of lycopene's synergistic mechanism with cisplatin, offering a strategy to improve therapeutic efficacy without exacerbating toxicity.