title: Apicidin sensitizes pancreatic cancer cells to gemcitabine by epigenetically regulating MUC4 expression.
abstract: OBJECTIVE
  Mucin 4 (MUC4) has been linked to resistance to gemcitabine in pancreatic cancer cells. The aim of the present study was to assess whether epigenetic control of MUC4 expression can sensitize pancreatic cancer cells to gemcitabine treatment.
  
  
  METHODS
  A 76-member combined epigenetics and phosphatase small-molecule inhibitor library was screened for anti-proliferative activity against the MUC4(+) gemcitabine-resistant pancreatic cancer cell line Capan-1, followed by high-content screening of protein expression.
  
  
  RESULTS
  Apicidin, a histone deacetylase inhibitor, showed the greatest anti-proliferative activity with a lethal dose 50 (LD50) value of 5.17 μM. Apicidin significantly reduced the expression of MUC4 and its transcription factor hepatocyte nuclear factor 4α. Combined treatment with a sub-therapeutic concentration of apicidin and gemcitabine synergistically inhibited growth of Capan-1 cells.
  
  
  CONCLUSIONS
  Apicidin appears to be a novel anti-proliferative agent against pancreatic cancer cells that may reverse chemoresistance by epigenetically regulating MUC4 expression.
authors.affiliation: Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ansari
authors.affiliation: Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden.
authors.forename: Carlos
authors.initials: C
authors.lastname: Urey
authors.affiliation: Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden.
authors.forename: Katarzyna Said
authors.initials: KS
authors.lastname: Hilmersson
authors.affiliation: Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden.
authors.forename: Monika P
authors.initials: MP
authors.lastname: Bauden
authors.affiliation: Chemical Biology & Therapeutics, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ek
authors.affiliation: Chemical Biology & Therapeutics, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
authors.affiliation: Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden roland.andersson@med.lu.se.
authors.forename: Roland
authors.initials: R
authors.lastname: Andersson
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D055264:Mucin-4 / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D054852:Small Molecule Libraries; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D056572:Histone Deacetylase Inhibitors; D055264:Mucin-4; D010456:Peptides, Cyclic; D054852:Small Molecule Libraries; C102351:apicidin; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Apicidin; HNF4α; MUC4; capan-1; epigenetics; histone deacetylase inhibitor; pancreatic cancer; phosphatase inhibitor; small-molecule inhibitor library; targeted treatment