L. Qiu et al., Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells, MOL BIOL CE, 11(6), 2000, pp. 2069
Important aspects of cell cycle regulation are the checkpoints, which respo
nd to a variety of cellular stresses to inhibit cell cycle progression and
act as protective mechanisms to ensure genomic integrity. An increasing num
ber of tumor suppressors are being demonstrated to have roles in checkpoint
mechanisms, implying that checkpoint dysfunction is likely to be a common
feature of cancers. Were we report that histone deacetylase inhibitors, in
particular azelaic bishydroxamic acid, triggers a G2 phase cell cycle check
point response in normal human cells, and this checkpoint is defective in a
range of tumor cell lines. Loss of this G2 checkpoint results in the tumor
cells undergoing an aberrant mitosis resulting in fractured multinuclei an
d micronuclei and eventually cell death. This histone deacetylase inhibitor
-sensitive checkpoint appears to be distinct from G2/M checkpoints activate
d by genotoxins and microtubule poisons and may be the human homologue of a
yeast G2 checkpoint, which responds to aberrant histone acetylation states
. Azelaic bishydroxamic acid may represent a new class of anticancer drugs
with selective toxicity based on its ability to target a dysfunctional chec
kpoint mechanism in tumor cells.