Cholangiocarcinoma, also known as biliary tract cancer,
is an aggressive
adenocarcinoma arising from epithelial cells lining the intra- and
extrahepatic biliary system. The effects of autophagy modulators and
histone deacetylase (HDAC) inhibitors in cholangiocarcinoma are not
fully known. It is essential to understand the molecular mechanisms
and the effects of HDAC inhibitors in the context of cholangiocarcinoma.
The antiproliferative effect of different HDAC inhibitors and autophagy
modulation was investigated by the MTT cell viability assay in TFK-1
and EGI-1 cholangiocarcinoma cell lines. Combination indexes were
calculated using CompuSyn software. Consequently, apoptosis was detected
by Annexin V/PI staining. The effect of the drugs on the cell cycle
was measured by the propidium iodide staining. The HDAC inhibition
was confirmed via acetylated histone protein levels by western blotting.
HDAC inhibitors, MS-275 and romidepsin, showed a better synergistic
effect with the nocodazole combination. The combination treatment
exerted its growth inhibitory effect by cell cycle arrest and induction
of apoptosis. The cell cycle analysis of the combination treatment
showed that the S phase and G2/M phase were achieved. Moreover, the
necrotic and apoptotic cell population increased after single HDAC
inhibitors and combination treatment. The anti-cancer effect of HDAC
inhibitors is revealed by acetylation levels of histones. While acetylation
levels were increased in response to HDAC inhibitors and autophagy
modulator combinations, the HDAC expression decreased. This study
highlights the importance of the combination of HDAC inhibition and
autophagy modulators and demonstrates a synergistic effect, which
could be a promising therapy and novel treatment approach for cholangiocarcinoma.