Anticancer activity of triterpene glycosides from the sea star Solaster pacificus

Marine triterpene glycosides are known to exhibit significant anticancer activity. We investigated pacificusoside C and cucumariosides C₁ and C₂ isolated from a sea star Solaster pacificus in prostate cancer models with varying drug resistance and in non-cancerous cells in vitro. Cucumarioside C₁ showed selectivity comparable to cisplatin, whereas the other compounds were less selective. Cucumarioside C₁ induced apoptosis and enhanced cytotoxic effects of cisplatin, carboplatin, docetaxel, and cabazitaxel, making it a potential candidate for combination therapy. All three glycosides were active in docetaxel-resistant cells and were neither inhibitors nor substrates of P-glycoprotein, indicating P-glycoprotein-independent activity. To explore the mechanism of anticancer activity of cucumarioside C₁, we performed functional kinome profiling of treated 22Rv1 cells, predicting activation of kinases involved in stress response and survival (IKKα, IKKβ, IKKε), necroptosis (MLKL), metabolism (GCN2, PDK1), cytoskeletal dynamics (RHOK), mitophagy (PINK1), apoptosis and cell cycle regulation (PITSLRE), and immune modulation (COT). Notably, only MAP kinases p38 and ERK1/2 were predicted to be specifically inhibited, that was further validated by Western blotting. These findings may potentially explain previously reported anticancer effects of cucumarioside C₁ and related marine glycosides. To our knowledge, this is the first study to report triterpene glycosides' effects on the kinome of cancer cells.