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Donadelli M, Costanzo C, Beghelli S, Scupoli MT, Dandrea M,
Bonora A, Piacentini P, Budillon A, Caraglia M, Scarpa A,
Palmieri M.
Synergistic inhibition of pancreatic adenocarcinoma cell
growth by trichostatin A and gemcitabine.
Biochim Biophys Acta. 2007 Jul;1773(7):1095-106
Department of Morphological and Biomedical Sciences, Section
of Biochemistry, University of Verona, Verona, Italy.
We investigated the ability of the histone deacetylase (HDAC)
inhibitor trichostatin A (trichostatin A) to interact with
gemcitabine (GEM) in inducing pancreatic cancer cell death. The
combined treatment with trichostatin A and GEM synergistically
inhibited growth of four pancreatic adenocarcinoma cell lines
and induced apoptosis. This effect was associated with the
induction of reactive oxygen species (ROS) by GEM, increased
expression of the pro-apoptotic BIM gene by both trichostatin A
and GEM and downregulation of the 5'-nucleotidase UMPH type II
gene by trichostatin A. The expression of other genes critical
for GEM resistance (nucleoside transporters, deoxycytidine
kinase, cytidine deaminase, and ribonucleotide reductase genes)
was not affected by trichostatin A. The functional role of ROS
in cell growth inhibition by GEM was supported by (i) a
significantly reduced GEM-associated growth inhibition by the
free radical scavenger N-acetyl-L-cysteine, and (ii) a positive
correlation between the basal level of ROS and sensitivity to
GEM in 10 pancreatic cancer cell lines. The functional role of
both Bim and 5'-nucleotidase UMPH type II in cell growth
inhibition by trichostatin A and GEM was assessed by RNA
interference assays. In vivo studies on xenografts of pancreatic
adenocarcinoma cells in nude mice showed that the association of
trichostatin A and GEM reduced to 50% the tumour mass and did
not cause any apparent form of toxicity, while treatments with
trichostatin A or GEM alone were ineffective. In conclusion, the
present study demonstrates a potent anti-tumour activity of
trichostatin A/GEM combination against pancreatic cancer cells
in vitro and in vivo, strongly supporting the use of GEM in
combination with an HDAC inhibitor for pancreatic cancer
therapy.
PMID: 17555830
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