Efficacy of Resveratrol Against Advanced Breast Cancer-Derived Organoids: A comparison with that of Clinically Relevant Drugs

Background: The lack of reliable drugs is a therapeutic challenge of advanced breast cancers (ABCs). Resveratrol (Res) exerts inhibitory effects on breast cancer cell lines and animal models, while its efficacy against individual breast cancer cases remain unknown. This study aims to address this issues using ABC-derived organoids (ABCOs) as the ex vivo therapeutic model. Methods: The ABCOs derived from 24 ABC patients were treated with 100 mM resveratrol for 96 hours. Paclitaxel, gemcitabine and fulvestrant were cited as the efficacy controls. Trypan blue staining and Calcein-AM/PI double staining were conducted to elucidate the cell viability, and EdU proliferation assay to evaluate ABCO growth activity. Reactive oxygen species (ROS) levels in Res-treated ABCOs were determined by peroxide-dependent DCFH-DA oxidation assay and the statuses of pSTAT3-mediated signaling was examined by immunofluorescent and immunohistochemical labeling. Results: ABCOs were established from 6 surgical specimen, 14 needle biopsies, 3 cancerous pleural effusion and 1 cancerous ascites. Immunohischemical staining confirmed that the ABCOs maintained ER, PR, HER2 and Ki67 expression patterns of their original tumors. ABCO proliferation and viability tests showed > 50% cell death rates in 79.2% (19/24) of Res-treated, 28.6% (2/7) fulvestrant-treated, 66.7% (4/6) paclitaxel-treated and 66.7% (6/9) gemcitabine-treated ABCOs. The increased ROS levels were found in Res-sensitive ABCOs. pSTAT3 nuclear translocation were more frequent in Res-sensitive (14/19; 73.7%) than that (1/5; 20%) of Res-insensitive ABCOs, which were suppressed upon Res treatment. Statistical analysis revealed close correlation of STAT3 activation with the efficacy of Res.Conclusions: We demonstrate for the first time the effectiveness and broader range of Res against different subtypes of ABCOs in comparison with that of conventional anti-breast cancer drugs, providing an alternative approach for better management of breast cancers, especially those at advanced stage.