Our previous study has shown that
alpha-mangostin, a
xanthone from the pericarps of mangosteen, induces caspase-3-dependent apoptosis in HL60 cells. In the current study, we investigated the mechanism of apoptosis induced by
alpha-mangostin in HL60 cells.
Alpha-mangostin-treated HL60 cells demonstrated
caspase-9 and -3 activation but not -8, which leads us to assume that
alpha-mangostin may mediate the mitochondrial pathway in the apoptosis. Parameters of
mitochondrial dysfunction including swelling, loss of membrane potential (deltapsim), decrease in intracellular
ATP, ROS accumulation, and
cytochrome c/AIF release, were observed within 1 or 2 h after the treatment. On the other hand,
alpha-mangostin-treatment did not affect expression of bcl-2 family
proteins and activation of MAP
kinases. These findings indicate that
alpha-mangostin preferentially targets mitochondria in the early phase, resulting in indication of apoptosis in HL60 cells. Furthermore, we examined the structure-activity relationship between
xanthone derivatives including
alpha-mangostin and the potency of deltapsim-loss in HL60 cells. Interestingly, replacement of
hydroxyl group by methoxy group remarkably decreased its potency. It was also shown that the cytotoxicity substantially correlated with deltapsim decrease. These results indicate that
alpha-mangostin and its analogs would be candidates for preventive and therapeutic application for
cancer treatment.