Apoptosis, proliferation and differentiation patterns are influenced by Zebularine and SAHA in pancreatic cancer models.
OBJECTIVE
Pancreatic cancer continues to be an urgent clinical problem. We used the novel DNA methyltransferase inhibitor Zebularine and the histone deacetylase inhibitor SAHA to investigate the epigenetic influence on viability and differentiation of the pancreatic cancer cell lines YAP C, DAN G and Panc-89 in vitro and in vivo.


METHODS
Cell vitality, proliferation and expression of PDX-1, cytokeratin 7 and 20, chromogranin A, vimentin, bax and bcl-2 were determined on the protein and mRNA level in vitro and in a subcutaneous xenograft model.


RESULTS
A time- and dose-dependent increase of apoptosis, paralleled by decreased proliferation, was observed after incubation with single agents or a combination therapy with lower concentrations. This was associated with up-regulation of pro-apoptotic bax and a phenotypic stabilization by the enhanced expression of cytokeratin 7. In vivo, growth of xenografts was delayed with the most pronounced effect in Panc-89 after 1 week of daily intraperitoneal injections of Zebularine paralleled with CK7 up-regulation and down-regulation of dedifferentiation markers.


CONCLUSIONS
Epigenetic modulation via inhibition of DNA methyltransferase and histone deacetylase induces apoptosis in human pancreatic cancer cells in vitro and delays xenograft growth in vivo, which is associated with a morphological/molecular phenotypic stabilization. These compounds may therefore be suitable as adjunctive therapeutic agents in the treatment of pancreatic cancer.
Neureiter
Daniel
D
Institute of Pathology, Landeskliniken Salzburg, Salzburg, Austria.
Zopf
Steffen
S
Leu
Thorsten
T
Dietze
Otto
O
Hauser-Kronberger
Cornelia
C
Hahn
Eckhart G
EG
Herold
Christoph
C
Ocker
Matthias
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D044127:Epigenesis, Genetic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000077337:Vorinostat; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D051028:bcl-2-Associated X Protein; D000077337:Vorinostat; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside