Preferential target is mitochondria in α-mangostin-induced apoptosis in human leukemia HL60 cells Original Research Article

Our previous study has shown that α-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 α-mangostin in HL60 cells. α-Mangostin-treated HL60 cells demonstrated caspase-9 and -3 activation but not -8, which leads us to assume that α-mangostin may mediate the mitochondrial pathway in the apoptosis. Parameters of mitochondrial dysfunction including swelling, loss of membrane potential (ΔΨm), 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, α-mangostin-treatment did not affect expression of bcl-2 family proteins and activation of MAP kinases. These findings indicate that α-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 α-mangostin and the potency of ΔΨm-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 ΔΨm decrease. These results indicate that α-mangostin and its analogs would be candidates for preventive and therapeutic application for cancer treatment.