Histone deacetylases (HDACs) are
enzymes involved in the remodelling of
chromatin, and have a key role in the epigenetic regulation of gene expression.
Histone deacetylase (
HDAC) inhibitors are emerging as an exciting new class of potential anti-
cancer agents. In recent years, a number of structurally diverse
HDAC inhibitors have been identified and these
HDAC inhibitors induce growth arrest, differentiation and/or apoptosis of
cancer cells in vitro and in vivo. However, the underlying molecular mechanisms remain unclear. This study aimed at investigating the anti-
tumor activity of various
HDAC inhibitors,
IN-2001, using T47D human
breast cancer cells. Moreover, the possible mechanism by which
HDAC inhibitors exhibit anti-
tumor activity was also explored. In
estrogen receptor positive T47D cells,
IN-2001,
HDAC inhibitor showed anti-proliferative effects in dose-and time-dependent manner. In T47D human
breast cancer cells showed anti-
tumor activity of
IN-2001 and the growth inhibitory effects of
IN-2001 were related to the cell cycle arrest and induction of apoptosis. Flow cytometry studies revealed that
IN-2001 showed accumulation of cells at G2/M phase. At the same time,
IN-2001 treatment time-dependently increased sub-G1 population, representing apoptotic cells. IN-2001-mediated cell cycle arrest was associated with induction of cdk inhibitor expression. In T47D cells,
IN-2001 as well as other
HDAC inhibitors treatment significantly increased p21(WAF1) and p27(KIP1) expression. In addition,
thymidylate synthase, an essential
enzyme for DNA replication and repair, was down-regulated by
IN-2001 and other
HDAC inhibitors in the T47D human
breast cancer cells. In summary,
IN-2001 with a higher potency than other
HDAC inhibitors induced growth inhibition, cell cycle arrest, and eventual apoptosis in human
breast cancer possibly through modulation of cell cycle and
apoptosis regulatory proteins, such as cdk inhibitors,
cyclins, and
thymidylate synthase.