title: Developing histone deacetylase inhibitors in the therapeutic armamentarium of pancreatic adenocarcinoma.
abstract: BACKGROUND
  Histone deacetylases (HDACs) are commonly dysregulated in pancreatic adenocarcinoma (PA) and have a central role in the development and progression of the disease. HDAC is a family of enzymes involved in deacetylation of lysine residues on histone and non-histone proteins. Deacetylation of histone proteins leads to compaction of the DNA/histone complex resulting in inhibition of gene expression. Deacetylation of non-histone proteins can affect the stability and function of key proteins leading to dysregulation of cellular signaling pathways. HDAC inhibitors have been shown to potentiate the antiproliferative and proapoptotic effects of several cytotoxic agents, in vitro and in vivo PA xenograft models.
  
  
  METHODS
  The areas covered include the biology and function of the HDAC isoenzymes and their significant role in multiple oncogenic pathways in PA. Preclinical and clinical trials evaluating HDAC inhibitors are also reviewed.
  
  
  CONCLUSIONS
  Despite discouraging early phase clinical trials evaluating HDAC inhibitors in PA, this strategy deserves further evaluation guided by better preclinical studies in identifying the role of specific HDAC isoenzyme inhibitors in PA. Evaluation of the effects of HDAC inhibitors on PA stem cell function and epithelial to mesenchymal transformation is also an evolving area that holds future potential for these agents. Such preclinical studies will yield insight into the functionality of HDAC isoenzymes, which can then be translated into rationally designed clinical trials. One such strategy could focus on HDAC inhibition employed in combination with proteasome inhibition targeting the aggresome pathway in PA.
authors.affiliation: Emory University, Winship Cancer Institute, Department of Hematology and Medical Oncology, Atlanta, GA-30322, USA.
authors.forename: Syed F
authors.initials: SF
authors.lastname: Zafar
authors.forename: Ganji Purnachandra
authors.initials: GP
authors.lastname: Nagaraju
authors.forename: Bassel
authors.initials: B
authors.lastname: El-Rayes
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D066246:ErbB Receptors; D006655:Histone Deacetylases