MAPK/NF-κB pathway modulation and oxidative stress–driven apoptosis by Solanum jabrense and solamargine in breast cancer cells

Cancer is characterized by uncontrolled cell proliferation, immune evasion, and tissue invasion, ranking as the second leading cause of mortality worldwide. Breast cancer is the most prevalent type, accounting for 11.7% of newly diagnosed cases annually. Solanum jabrense , a plant endemic to Brazil, is rich in phytocompounds, particularly antitumor alkaloids. The antitumor potential of the hydroalcoholic extract of S. jabrense (ESJ) and an alkaloid-enriched fraction (FSJ) was investigated against human mammary adenocarcinoma cells (MCF-7 and MDA-MB-231). FSJ activity was further evaluated using a three-dimensional spheroid model. Mechanistic analyses in MCF-7 cells included apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) generation. Solamargine, isolated from S. jabrense , was also investigated in vitro and in silico . Half maximal inhibitory concentration (IC₅₀) values were determined at 24, 48, and 72 h. FSJ exhibited enhanced selectivity toward tumor cells, reduced spheroid size, and inhibited cell migration. Annexin V-FITC/PI staining confirmed apoptosis induction, while the JC-1 assay indicated mitochondrial depolarization. N-acetylcysteine (NAC) pre-treatment attenuated FSJ-induced cytotoxicity, indicating ROS involvement. Solamargine showed potent cytotoxicity at 48 h (IC₅₀: 8.65 ± 0.04 µM), and molecular docking analysis revealed interactions involving mitogen-activated protein kinases (MAPKs) (ERK2, JNK1, p38α) and IKKβ. This study provides the first evidence of the antitumor activity of S. jabrense against human mammary adenocarcinoma cells, demonstrating apoptosis and oxidative stress involvement, likely mediated by solamargine through modulation of MAPK- and NF-κB-related signaling pathways