Agapanthussaponin A from the Underground Parts of Agapanthus africanus Induces Apoptosis and Ferroptosis in Human Small-Cell Lung Cancer Cells.

To explore the potential seed compounds from natural products as anticancer agents against small-cell lung cancer (SCLC), the underground parts of Agapanthus africanus, a plant commonly used for ornamental purposes, were investigated. Three spirostan-type steroidal glycosides (1-3) were isolated and identified by nuclear magnetic resonance spectral analysis. Compounds 1-3 exhibited cytotoxicity against SBC-3 human SCLC cells, with IC50 values of 0.56, 1.4, and 7.4 µM, respectively. Compound 1, also known an agapanthussaponin A, demonstrated the most potent cytotoxicity among the isolated compounds and was evaluated for its apoptosis- and ferroptosis-inducing activities. Compound 1 arrested the cell cycle of SBC-3 cells in the G2/M phase and induced apoptosis primarily via the mitochondrial pathway, characterized by caspases-3 and -9 activation, loss of mitochondrial membrane potential, and overproduction of reactive oxygen species. Additionally, 1 triggered ferroptosis via a dual mechanism consisting of enhanced cellular iron uptake through upregulation of transferrin and transferrin receptor 1 expression and impaired glutathione synthesis via downregulation of both xCT and glutathione peroxidase 4 expression. Compound 1 induces cell death via the apoptosis and ferroptosis pathways, suggesting its promise as a seed compound for the development of anticancer therapeutics against SCLC.