Epigenetic modifications could drive some of the molecular events implicated in proliferation, drug resistance and
metastasis of pancreatic ductal
adenocarcinoma (PDAC). Thus, epigenetic
enzyme inhibitors could be the key to revert those events and transform PDAC into a
drug-sensitive
tumor. We performed a systematic study with five different epigenetic
enzyme inhibitors (1,
UVI5008, MS275,
psammaplin A, and
BIX01294) targeting either
Histone Deacetylase (HDAC) 1 or 1/4,
DNA methyltransferase 3a (DNMT3a), Euchromatic
histone lysine methyltransferase 2 (EHMT2), or
Sirtuin 1 (
SIRT1), as well as one
drug that restores the p53 function (P53R3), in three different human PDAC cell lines (SKPC-1, MIA PaCa-2, and BxPC-3) using 2D and 3D cell cultures. The synergistic effect of these antitumoral drugs with
gemcitabine was tested and the most efficient combinations were characterized by
RNA-seq. The inhibition of HDAC1/4 (MS275), HDAC1/4/
SIRT1/DNMT3a (
UVI5008) or EHMT2 (
BIX01294) induced a significant reduction on the cell viability, even in
gemcitabine-resistance cells. The combination of
UVI5008 or MS275 with
gemcitabine induced a synergistic effect at low concentration and the
RNA-Seq analysis revealed some synergy candidate genes as potential
biomarkers. Reverting aberrant epigenetic modifications in combination with
gemcitabine offers an alternative treatment for PDAC patients, with an important reduction of the therapeutic dose.