Apoptosis, proliferation and differentiation patterns are influenced by Zebularine and SAHA in pancreatic cancer models

• Published in: Scandinavian journal of gastroenterology 2007, Vol.42 (1), p.103-116
• Main Authors: Neureiter, Daniel, Zopf, Steffen, Leu, Thorsten, Dietze, Otto, Hauser-Kronberger, Cornelia, Hahn, Eckhart G., Herold, Christoph, Ocker, Matthias
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; Biological and medical sciences; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cytidine - analogs & derivatives; Cytidine - pharmacology; differentiation; DNA, Neoplasm - biosynthesis; Epigenesis, Genetic - drug effects; epigenetics; Gastroenterology. Liver. Pancreas. Abdomen; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids - pharmacology; Immunohistochemistry; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Nude; Neoplasm Proteins - metabolism; pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; proliferation; SAHA; Tumor Cells, Cultured; Tumors; Zebularine
• ISSN: 0036-5521; 1502-7708
• DOI: 10.1080/00365520600874198

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. Material and 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.