Icaritin Induces Apoptosis of HepG2 Cells via the JNK1 Signaling Pathway Independent of the Estrogen Receptor

Chinese herbs have become a focus in cancer treatment. Icaritin, a prenylflavonoid derivative from Chinese herbs of the Epimedium genus, has selective estrogen receptor (ER) modulating activity. This study evaluates the effects of icaritin on the apoptosis of HepG2 hepatocellular carcinoma cells. Icaritin (at 5-50 mu M) induced apoptosis of HepG2 cells. Few changes in icaritin-induced apoptosis were observed after pretreatment with ICI182780. Consistent with apoptosis induction, icaritin increased the Bax/Bcl-2 ratio and caspase-3 activation in HepG2 cells. Furthermore, icaritin was capable of stimulating the c-Jun N-terminal kinase 1 (JNK1), but not the JNK2, ERK1/2, and p38 subgroups of the mitogen-activated protein kinase (MAPK) family. Coincidently, icaritin-induced cell apoptosis was abolished by SP600125, a specific inhibitor for JNK. Collectively, our results suggest a novel pro-apoptotic activity of icaritin mediated via the JNK1 signaling pathway that is not associated with ER in HepG2 cells.