Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells

In cells with an altered p53 gene, the expression of p21WAF1/CIP1, a potent inhibitor of cyclin‐dependent kinases, can be induced by histone deacetylase (HDAC) inhibitors via a p53‐independent pathway, which may play a critical role in arrest of cell growth. Accordingly, HDAC inhibitors such as tric...

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Published in:Molecular carcinogenesis 2003-10, Vol.38 (2), p.59-69
Main Authors: Donadelli, Massimo, Costanzo, Chiara, Faggioli, Laura, Scupoli, Maria Teresa, Moore, Patrick S., Bassi, Claudio, Scarpa, Aldo, Palmieri, Marta
Format: Article
Language:English
Subjects:
Adenocarcinoma - pathology
Adenocarcinoma - prevention & control
apoptosis
Apoptosis - drug effects
caspase-3
cell cycle
Cell Cycle - drug effects
Cell Division - drug effects
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - metabolism
Enzyme Inhibitors - pharmacology
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids - pharmacology
p21WAF1/CIP1
p53
pancreatic cancer
Pancreatic Neoplasms - pathology
Pancreatic Neoplasms - prevention & control
TSA
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - metabolism
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Summary:In cells with an altered p53 gene, the expression of p21WAF1/CIP1, a potent inhibitor of cyclin‐dependent kinases, can be induced by histone deacetylase (HDAC) inhibitors via a p53‐independent pathway, which may play a critical role in arrest of cell growth. Accordingly, HDAC inhibitors such as trichostatin A (TSA) have potential utility in pancreatic cancer, as most of these tumors possess mutations in p53, which in fact is the main cause of chemoresistance to 5‐fluorouracil. We have analyzed the effect of TSA on the proliferation of nine pancreatic adenocarcinoma cell lines, all containing a mutated p53 gene. TSA strongly inhibited the cellular growth of all these cell lines at submicromolar concentrations. The cellular mechanisms underlying this effect consisted of cell cycle arrest at the G2 phase and apoptotic cell death. The expression of p21WAF1/CIP1 normally induced at the transcriptional level by p53 was also strongly activated by TSA. These findings suggest that inhibitors of HDAC may represent a novel therapeutic strategy for treatment of pancreatic cancer. © 2003 Wiley‐Liss, Inc.
ISSN:0899-1987
1098-2744
DOI:10.1002/mc.10145