Abstract
The identification of new isoform-specific histone deacetylase inhibitors is important
for revealing the biological functions of individual histone deacetylase and for determining
their potential use as therapeutic agents. Among the 11 zinc-dependent histone deacetylases
that have been identified in humans, histone deacetylase 6 is a structurally and functionally
unique enzyme. Here, we tested the inhibitory activity of diarylheptanoids isolated
from Betula platyphylla against histone deacetylase 6. Aceroside VIII selectively inhibited histone deacetylase
6 catalytic activity and the combined treatment of aceroside VIII or (−)-centrolobol
with A452, another selective histone deacetylase 6 inhibitor, led to a synergistic
increase in levels of acetylated α-tubulin. Aceroside VIII, paltyphyllone, and (−)-centrolobol synergistically enhanced
the induction of apoptosis and growth inhibition by A452. Consistent with these results,
A452 in combination with aceroside VIII, paltyphyllone, or (−)-centrolobol was more
potent than either drug alone for the induction of apoptosis. Together, these findings
indicate that aceroside VIII is a specific histone deacetylase 6 inhibitor and points
to a mechanism by which natural histone deacetylase 6-selective inhibitors may enhance
the efficacy of other histone deacetylase 6 inhibitors in colon cancer cells.
Key words
histone deacetylase 6 - HDAC6-selective inhibitor - aceroside VIII - colon cancer
- apoptosis - combination therapy
