Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells
Ik. Wang et al., Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells, EUR J CANC, 35(10), 1999, pp. 1517-1525
The aim of this study was to investigate the mechanism of flavonoid-induced
apoptosis in HL-60 leukaemic cells. Thus, the effect of structurally relat
ed flavonoids on cell viability, DNA fragmentation and caspase activity was
assessed. Loss of membrane potential and reactive oxygen species generatio
n were also monitored by flow cytometry. The structurally related flavonoid
s, such as apigenin, quercetin, myricetin, and kaempferol were able to indu
ce apoptosis in human leukaemia HL-60 cells. Treatment with flavonoids (60
mu M) caused a rapid induction of caspase-3 activity and stimulated proteol
ytic cleavage of poly-(ADP-ribose) polymerase (PARP). Furthermore, these fl
avonoids induced loss of mitochondrial transmembrane potential, elevation o
f reactive oxygen species (ROS) production, release of mitochondrial cytoch
rome c into the cytosol, and subsequent induction of procaspase-9 processin
g. The potency of these flavonoids on these features of apoptosis were in t
he order of apigenin > quercetin > myricetin > kaempferol in HL-60 cells tr
eated with 60 mu M flavonoids. These results suggest that flavonoid-induced
apoptosis is stimulated by the release of cytochrome c to the cytosol, by
procaspase-9 processing, and through a caspase-3-dependent mechanism. The i
nduction of apoptosis by flavonoids may be attributed to their cancer chemo
preventive activity. Furthermore, the potency of flavonoids for inducing ap
optosis may be dependent on the numbers of hydroxyl groups in the 2-phenyl
group and on the absence of the 3-hydroxyl group. This provides new informa
tion on the structure-activity relationship of flavonoids. (C) 1999 Elsevie
r Science Ltd. All rights reserved.