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

Abstract

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 (Δ Ψm), 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 Δ Ψm-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 Δ Ψm decrease. These results indicate that α-mangostin and its analogs would be candidates for preventive and therapeutic application for cancer treatment.