Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin.
2000
Apicidin[
cyclo( N - O -methyl-l-tryptophanyl-l-isoleucinyl-d-pipecolinyl-l-2-amino-8-oxodecanoyl)]
is a fungal metabolite shown to exhibit antiparasitic activity by the
inhibition of histone deacetylase (HDAC). In this study, we evaluated
apicidin as a potential antiproliferative agent. Apicidin showed a
broad spectrum of antiproliferative activity against various cancer
cell lines, although with differential sensitivity. The
antiproliferative activity of apicidin on HeLa cells was accompanied by
morphological changes, cell cycle arrest at G 1 phase, and
accumulation of hyperacetylated histone H4 in vivo as
well as inhibition of partially purified HDAC in vitro .
In addition, apicidin induced selective changes in the expression of
p21 WAF1/Cip1 and gelsolin, which control the cell cycle and
cell morphology, respectively. Consistent with increased induction of
p21 WAF1/Cip1 , phosphorylation of Rb protein was markedly
decreased, indicating the inhibition of cyclin-dependent kinases, which
became bound to p21 WAF1/Cip1 . The effects of apicidin on
cell morphology, expression of gelsolin, and HDAC1 activity in
vivo and in vitro appeared to be irreversible,
because withdrawal of apicidin did not reverse those effects, whereas
the induction of p21 WAF1/Cip1 by apicidin was reversible.
Taken together, the results suggest that induction of histone
hyperacetylation by apicidin is responsible for the antiproliferative
activity through selective induction of genes that play important roles
in the cell cycle and cell morphology.
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