α-mangostin induces Ca2+-ATPase-dependent apoptosis via mitochondrial pathway in PC12 cells

We investigated the cell death effects of eight xanthones on PC12 rat pheochromocytoma cells. Among these compounds, alpha-mangostin, from the fruit hull of Garcinia mangostana L., had the most potent effect with the EC50 value of 4 muM. alpha-Mangostin-treated PC12 cells demonstrated typical apoptotic DNA fragmentation and caspase-3 cleavage (equivalent to activation). The flow cytometric analysis indicated that this compound induced apoptosis in time- and concentration-dependent manners. alpha-Mangostin showed the features of the mitochondrial apoptotic pathway such as mitochondrial membrane depolarization and cytochrome c release. Furthermore, a-mangostin inhibited the sarco(endo)plasmic reticulum Ca2+-ATPase markedly. There was a correlation between the Ca2+-ATPase inhibitory effects and the apoptotic effects of the xanthone derivatives. On the other hand, c-Jun NH2-terminal kinase (JNK/SAPK), one of the signaling molecules of endoplasmic reticulum (ER) stress, was activated with alpha-mangostin treatment. These results suggest that alpha-mangostin inhibits Ca2+-ATPase to cause apoptosis through the mitochondorial pathway.