Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumorcells via induction of p21(WAF1/Cip1) and gelsolin

Apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2am ino-8-oxadecanoyl)] is a fungal metabolite shown to exhibit antiparasitic a ctivity 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 activi ty 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 ill vitro. In add ition, apicidin induced selective changes in the expression of p21(WAF1/Cip 1) and gelsolin, which control the cell cycle and cell morphology, respecti vely. Consistent with increased induction of p21(WAF1/Cip1), phosphorylatio n of Rb protein was markedly decreased, indicating the inhibition of cyclin -dependent kinases, which became bound to p21(WAF1/Cip1). Th, effects of ap icidin on cell morphology, expression of gelsolin, and HDAC1 activity in vi vo 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 antiprolife rative activity through selective induction of genes that play important ro les in the cell cycle and cell morphology.