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.