Abstract
Resveratrol-rich extracts from Vitis vinifera cane have gained recognition as natural compounds with significant anticancer potential. This study examined the impact of this extract on A549 lung cancer cells using both 2D monolayer culture and a more physiologically relevant 3D co-culture model incorporating peripheral blood mononuclear cells (PBMCs). In monolayer culture, at 40 µg/mL we evaluated the extract's impact on cell viability, colony formation ability, morphological changes, and oxidative stress markers. A 3D co-culture model was employed to examine the effects of the extract on matrix metalloproteinase ( MMP-2 and MMP-9) activity, c-Jun N-terminal kinase (JNK) signaling pathway, and nitric oxide (NO) production. Our results demonstrated that the extract significantly reduced A549 cell viability (IC50 39.11 ± 0.32 µg/mL) and colony formation while inducing morphological changes and cellular redox imbalance markers malondialdehyde (MDA) (p ≤ 0.001), protein carbonyl (p ≤ 0.0001), Advanced Oxidation Protein Products (AOPP) (p ≤ 0.01), nitric oxide (NO) (p ≤ 0.0001), Superoxide Dismutase (SOD) activity (p ≤ 0.01), and glutathione (GSH) level (p ≤ 0.01). and in monolayer cultures. In the 3D co-culture system, treatment with the extract significantly decreased the growth rate of the 3D structures (P ≤ 0.1), reduced MMP-2 and MMP-9 activities (P ≤ 0.1), and JNK phosphorylation, with an overproduction of nitric oxide (P ≤ 0.001). These findings reveal novel mechanisms by which resveratrol-rich extracts from Vitis vinifera cane may exert anticancer effects by modulating the JNK/MMPs/NO axis in lung cancer cells A549. This extract could represent a promising therapeutic alternative for lung cancer treatment.