Alpha-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 EC(50) value of 4 microM. 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, alpha-mangostin inhibited the sarco(endo)plasmic reticulum Ca(2+)-ATPase markedly. There was a correlation between the Ca(2+)-ATPase inhibitory effects and the apoptotic effects of the xanthone derivatives. On the other hand, c-Jun NH(2)-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 Ca(2+)-ATPase to cause apoptosis through the mitochondrial pathway.
Sato
Ayumi
A
Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Fujiwara
Hironori
H
Oku
Hisae
H
Ishiguro
Kyoko
K
Ohizumi
Yasushi
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D016716:PC12 Cells; D051381:Rats; D044004:Xanthones / Q000494:pharmacology*
D044004:Xanthones; D017301:Ca(2+) Mg(2+)-ATPase; C021053:mangostin