Sodium butyrate sensitises human pancreatic cancer cells to both the intrinsic and the extrinsic apoptotic pathways.
Pancreatic cancer is characterised by a highly malignant phenotype with a marked resistance to conventional therapies and to apoptotic activators. Here, we demonstrate that sodium butyrate (NaBt), an inhibitor of histone deacetylases, sensitises human pancreatic cancer cell lines to both mitochondria- and Fas-mediated apoptosis. The analysis of anti-apoptotic and pro-apoptotic members of the Bcl-2 family in untreated pancreatic cancer cell lines shows a generalised low expression of Bcl-2 and a strong expression of Bcl-xL. NaBt treatment results in a marked down-regulation of Bcl-xL expression, mitochondrial membrane depolarization, cytochrome c release from mitochondria, activation of caspase-9 and -3 and apoptosis induction. Furthermore, NaBt sensitises pancreatic cancer cells to Fas-mediated apoptosis as well. In fact, the combined treatment with NaBt and the agonistic antibody anti-Fas (CH11) is able to induce apoptosis at an early time, in which neither NaBt nor CH11 alone induce apoptosis. Down-regulation of FLIP and activation of caspase-8 allow apoptosis to occur. These findings suggest that sodium butyrate could represent a good candidate for the development of new therapeutic strategies aimed at improving chemotherapy and immunotherapy in pancreatic cancer.
Natoni
Federica
F
Department of Environmental Science, University of La Tuscia, Viterbo, Italy.
Diolordi
Laura
L
Santoni
Claudio
C
Gilardini Montani
Maria Saveria
MS
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D017931:DNA Primers; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051336:Mitochondrial Membranes / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; D002087:Butyrates; D017931:DNA Primers; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; D013844:Thiazoles; D051020:bcl-X Protein; D045304:Cytochromes c; D020169:Caspases; C022616:thiazolyl blue