Apoptosi indotta da inibitori delle deacetilasi istoniche in linee di adenocarcinoma pancreatico
Author(s)
Santoni, Claudio
Date Issued
March 16, 2010
Type
Doctoral Thesis
Abstract
Pancreatic cancer is characterized by a poor prognosis and lack of response to conventional
therapies that provide just limited palliation, without significant improvement of survival.
Therefore new targets for therapeutic agents need to be identified. Histone deacetylase (HDAC)
inhibitors belong to a promising class of antineoplastic agents which affect tumour growth,
differentiation and invasion. In the present study we have assayed the effect of the HDACi
Thrichostatin A and Valproic acid (TSA and VPA) on pancreatic cancer cell lines. Our data have
demonstrated that both TSA and VPA induce apoptosis and growth inhibition in three pancreatic cancer cell lines. Moreover we have shown that the mitochondrial pathway was involved in this model since, following dissipation of mitochondrial transmembrane potential, Citocrome C
translocated from mitochondria to cytosol and activated the execution phase through activation of Caspase 3.
Molecular analyses have revealed that, at the basis of mitochondrial pathway, there was an upregulation, at both genetic and protein level, of some BH3-only proteins like Bim and Puma,
especially with VPA treatment. Bad and Bmf expression level remained unchanged. Moreover we
have shown that Bcl-xL protein was strongly down-regulated after VPA apoptotic induction, while TSA didn’t show this capability. The analyses of Bax and Bak expression and activation have shown that while Bax protein amount did not change following treatments, Bak protein was lightly up-regulated after VPA treatment. However both HDACi were able to activate Bax and Bak
proteins, inducing a conformational change that results in the N-terminal exposition and the
induction of apoptosis.
Concluding, these data highlight that the intrinsic apoptotic pathway may be activated in
pancreatic cancer cells both with TSA and VPA even if they act through different molecular
targets. Hence these findings suggest that the two HDACi represent promising therapeutic agents
for human pancreatic cancer.
Additional information
Dottorato di ricerca in Genetica e biologia cellulare
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