Combination of resveratrol and epirubicin to overcome chemoresistance in lung adenocarcinoma organoids: synergistic effects and translational implications†

Lung adenocarcinoma (LAC) is the main histological type of non-small cell lung cancer (NSCLC). Adjuvant therapy is required in LAC management but usually encounters drug resistance. Resveratrol (RES) enhances the anti-NSCLC effects of chemotherapeutic agents in vitro, while the efficacy for LAC individuals remains unclear. To address this issue and explore RES as an alternative candidate in LAC therapy, the responses of 32 organoids derived from the surgical tissues of LAC patients (LACOs) to RES are evaluated. Remarkably, RES effectively inhibits cell proliferation in 83.3% (20/24) of LACO cases without causing cell death. Our research has unveiled that the cytotoxic effects of the RES and EPI combination on LACOs are distinct in terms of >50% intraorganoid cell mortality in 93.75% (30/32) of LACO cases and increased TUNEL-labeling rates. In contrast, the adjusted mortality of 87.5% (28/32) of low-dose EPI-treated LACO cases ranged from 8.51% to 43.4%. Moreover, the IHC results demonstrated the reduced intracytoplasmic Wnt2 and β-catenin levels and the infrequent β-catenin nuclear translocation upon RES and EPI combined treatment. The RES and EPI combination exerts promising anti-LAC effects in comparison with conventional chemotherapeutic regimens by suppressing the Wnt2/β-catenin signaling pathway, providing an alternative approach for better management of LACs.