Gemcitabine resistant pancreatic cancer cell lines acquire an invasive phenotype with collateral hypersensitivity to histone deacetylase inhibitors.

TitleGemcitabine resistant pancreatic cancer cell lines acquire an invasive phenotype with collateral hypersensitivity to histone deacetylase inhibitors.
Publication TypeJournal Article
Year of Publication2015
AuthorsSamulitis BK, Pond KW, Pond E, Cress AE, Patel H, Wisner L, Patel C, Dorr RT, Landowski TH
JournalCancer Biol Ther
Volume16
Issue1
Pagination43-51
Date Published2015
ISSN1555-8576
KeywordsAntimetabolites, Antineoplastic, Cell Line, Tumor, Cell Movement, Chromatin, Deoxycytidine, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Pancreatic Neoplasms, Phenotype
Abstract

Gemcitabine based treatment is currently a standard first line treatment for patients with advanced pancreatic cancer, however overall survival remains poor, and few options are available for patients that fail gemcitabine based therapy. To identify potential molecular targets in gemcitabine refractory pancreatic cancer, we developed a series of gemcitabine resistant (GR) cell lines. Initial drug exposure selected for an early resistant phenotype that was independent of drug metabolic pathways. Prolonged drug selection pressure after 16 weeks, led to an induction of cytidine deaminase (CDA) and enhanced drug detoxification. Cross resistance profiles demonstrate approximately 100-fold cross resistance to the pyrimidine nucleoside cytarabine, but no resistance to the same in class agents, azacytidine and decitabine. GR cell lines demonstrated a dose dependent collateral hypersensitivity to class I and II histone deacetylase (HDAC) inhibitors and decreased expression of 3 different global heterochromatin marks, as detected by H4K20me3, H3K9me3 and H3K27me3. Cell morphology of the drug resistant cell lines demonstrated a fibroblastic type appearance with loss of cell-cell junctions and an altered microarray expression pattern, using Gene Ontology (GO) annotation, consistent with progression to an invasive phenotype. Of particular note, the gemcitabine resistant cell lines displayed up to a 15 fold increase in invasive potential that directly correlates with the level of gemcitabine resistance. These findings suggest a mechanistic relationship between chemoresistance and metastatic potential in pancreatic carcinoma and provide evidence for molecular pathways that may be exploited to develop therapeutic strategies for refractory pancreatic cancer.

DOI10.4161/15384047.2014.986967
Alternate JournalCancer Biol. Ther.
PubMed ID25485960
PubMed Central IDPMC4623403
Grant ListCA159406 / CA / NCI NIH HHS / United States
P30 CA023074 / CA / NCI NIH HHS / United States
R01 CA159406 / CA / NCI NIH HHS / United States
CA017094 / CA / NCI NIH HHS / United States
P01 CA017094 / CA / NCI NIH HHS / United States
CA023074 / CA / NCI NIH HHS / United States
CA109552 / CA / NCI NIH HHS / United States