Neferine inhibits proliferation and migration of human prostate cancer stem cells through p38 MAPK/JNK activation.

Cancer stem cells (CSCs) are one of the significant causes of cancer treatment failure and metastasis, as they have significant chemo-and radio-resistance leading to tumor recurrence. Here we investigated the possible anticancer properties of neferine, a natural alkaloid, on human prostate cancer (PCa) cells and their stem cells. CD44⁺ CSCs were isolated from androgen-insensitive PC3 cells by magnetic-activated cell sorting system (MACS). Neferine dose-and time-dependently inhibited the viability of PC3 and CSCs as well as androgen-sensitive LNCaP cells through inducing apoptosis and cell cycle arrest at G1 phase. Neferine was shown to downregulate the expression of Bcl-2 and CDK4, and upregulate caspase 3, clePARP, p21, p27, and p53. The treatment significantly inhibits the migration of CSCs. Neferine induces JNK and p38 MAPK phosphorylation, and downregulates PI3K and NF-ĸβ signaling. In conclusion, neferine may have a therapeutic effect inhibiting the PCa cell proliferation as well as by eliminating CSCs. PRACTICAL APPLICATIONS: Neferine is an alkaloid found in the seed embryo of Nelumbo nucifera and has recently been shown to have anticancer effects on various human cancer cells. More than 90% of cancer-related deaths develop after metastasis, and CSCs are considered to be largely responsible for the cell migration and invasion. It has been shown that treatment of neferine kills not only PCa cells but also CSCs, and may contribute to the prevention of progression of PCa and metastasis by inhibiting cell proliferation and migration.