Gene Expression Alterations Associated With Resveratrol‐Induced Antiproliferative Effects and S‐Phase Cell Cycle Arrest in Osteosarcoma Cancer Cells

Osteosarcoma (OS) is an aggressive primary bone tumour with high metastatic potential. Current treatments including surgery and chemotherapy are limited by side effects and chemoresistance, underscoring the need for novel therapies. This study aimed to investigate the antitumor potential of resveratrol (RSV), a natural polyphenol, as a novel treatment for OS. The effects of RSV were evaluated in two osteosarcoma cell lines (SAOS-2 and U2-OS). A viability assay established 100 μM as the effective concentration, and hyperspectral imaging confirmed cellular uptake. Apoptosis was measured via caspase-3/7 activity and Annexin V/PI staining, while qRT-PCR assessed pro-apoptotic gene expression. Flow cytometry evaluated cell-cycle progression, and a wound-healing assay measured migration. Gene expression analyses (qRT-PCR) examined markers of cell adhesion, tumour progression and epithelial-mesenchymal transition. Finally, RSV's impact on the Wnt/β-catenin pathway was determined by quantifying nuclear β-catenin accumulation and the expression of its downstream oncogenic targets. RSV inhibited cell proliferation and induced apoptosis, increasing caspase-3/7 activity and modulating apoptotic gene expression. RSV also caused cell cycle arrest in S-phase. It reduced the cells' migration and altered the expression of cell adhesion and tumour progression genes, promoting a less invasive phenotype. Notably, RSV decreased nuclear β-catenin accumulation, downregulated oncogenic targets like c-Myc and MMPs, and upregulated E-cadherin while reducing vimentin levels, suggesting a reversal of epithelial-mesenchymal transition. These results suggest that RSV may offer a promising therapeutic approach for osteosarcoma, modulating key pathways involved in tumour progression, metastasis and chemoresistance. Further studies are required to assess its clinical applicability.