Grape Stem Extracts from Vitis vinifera cv. Areni Noir and cv. Rkatsiteli: Rkatsiteli Shows Stronger Antiproliferative Activity and Drives BCL-2/p53-Mediated Apoptosis in MCF-7 Breast Cancer Cells

Abstract Winemaking by-products from grape cultivars grown in Armenia remain an underexplored source of bioactive polyphenols with antioxidant and anticancer potential. This study compared 70% ethanolic extracts from the primary winemaking by-products of Vitis vinifera cv. Areni Noir and cv. Rkatsiteli, characterizing their polyphenolic composition (HPLC–MS), antioxidant activity (DPPH assay), and antiproliferative effects in MCF-7 breast cancer cells (MTT, real-time cell analysis). HPLC–MS revealed a diverse profile of flavonoids, flavan-3-ols, hydroxycinnamic acids, stilbenes, and triterpenoids in both cultivars, with Rkatsiteli particularly rich in catechin and caftaric acid, and Areni Noir higher in gallic acid. Antioxidant activity was comparable between extracts (DPPH IC₅₀ ≈183–189 µg/mL). In MCF-7 cells, both extracts reduced cell growth, but Rkatsiteli produced the stronger antiproliferative response and was therefore selected for downstream mechanistic analysis: it increased SOD activity, elevated MDA, and reduced catalase activity, indicating a controlled oxidative stress response, and markedly downregulated BCL-2 while upregulating p53, consistent with activation of pro-apoptotic signaling. Molecular docking identified ε-viniferin, oleanolic acid, and polydatin as promising ligands for BCL-2 and p53, with oleanolic acid and polydatin combining strong predicted affinity with more favorable ADMET profiles. These findings position Rkatsiteli grape stem extract as a particularly promising source of natural antiproliferative compounds warranting further preclinical investigation.