Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells.
In cells with an altered p53 gene, the expression of p21(WAF1/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 p21(WAF1/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.
D000230:Adenocarcinoma / Q000473:pathology* / Q000517:prevention & control; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000517:prevention & control; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A