Preferential antiproliferative activity of an oleandrigenin-derived androstane toward prostate cancer cells

Cardiac glycosides, traditionally used for heart failure, are increasingly recognized for their anticancer potential. This study evaluated the in vitro antitumor activity of ten cardiac glycoside derivatives on androgen-insensitive (DU-145) and androgen-sensitive (LNCaP) prostate cancer cells, utilizing non-tumorigenic RWPE-1 cells as a control. Key assays included cell viability, proliferation, cell cycle distribution, apoptosis, and nuclear steroid receptor analysis. Among the tested series, compound 10, an oleandrigenin-derived androstane, exhibited the most significant therapeutic potential. It demonstrated pronounced effects on cell viability, proliferation, and apoptosis, while significantly altering molecular pathways and receptor dynamics specifically in prostate cancer cells. Crucially, compound 10 exhibited preferential cytotoxicity toward prostate cancer cells compared with non-tumorigenic RWPE-1 cells. It modulated AR signaling by reducing AR expression, nuclear localization, and transcriptional activity, while largely preserving ER-α and ER-β expression. Together with its effects on cell-cycle progression and apoptosis, these findings support 10 as a lead structure for further investigation in prostate cancer.