Apigenin (4',5,7,-trihydroxyflavone), an
anticancer agent, selectively toxic to
cancer cells induces cell cycle arrest and apoptosis through mechanisms that have not been fully elucidated. Our studies indicate that
apigenin-mediated growth inhibitory responses are due to inhibition of
class I histone deacetylases (HDACs) in
prostate cancer cells. Treatment of PC-3 and 22Rv1 cells with
apigenin (20-40 µM) resulted in the inhibition of HDAC
enzyme activity, specifically HDAC1 and HDAC3 at the
protein and message level.
Apigenin-mediated HDAC inhibition resulted in global
histone H3 and H4 acetylation, as well as localized hyperacetylation of
histone H3 on the p21/waf1 promoter. A corresponding increase was observed in p21/waf1 and
bax protein and
mRNA expression after
apigenin exposure, consistent with the use of
HDAC inhibitor,
trichostatin A. The downstream events demonstrated cell cycle arrest and induction of apoptosis in both
cancer cells. Studies of PC-3 xenografts in athymic nude mice further demonstrated that oral intake of
apigenin at doses of 20 and 50 µg/mouse/d over an 8-wk period resulted in a marked reduction in
tumor growth, HDAC activity, and HDAC1 and HDAC3
protein expression at both doses of
apigenin. An increase in p21/waf1 expression was observed in
apigenin-fed mice, compared to the control group. Furthermore,
apigenin intake caused a significant decrease in bcl2 expression with concomitant increase in bax, shifting the bax/bcl2 ratio in favor of apoptosis. Our findings confirm for the first time that
apigenin inhibits class I HDACs, particularly HDAC1 and HDAC3 and its exposure results in reversal of aberrant epigenetic events that promote
malignancy. © 2011 Wiley Periodicals, Inc.