title: The flavonoid apigenin potentiates the growth inhibitory effects of gemcitabine and abrogates gemcitabine resistance in human pancreatic cancer cells.
abstract: OBJECTIVE
  The aim of the study was to evaluate the effect of combination therapy of apigenin and gemcitabine on cell proliferation, the cell cycle, and gemcitabine resistance in human pancreatic cancer cells.
  
  
  METHODS
  Cell counting was used to assess the effect of single-agent and combination treatment on the proliferation of CD18 and AsPC-1 pancreatic cancer cells. Flow cytometry was performed to assess the effect of combination treatment on cell cycle progression and induction of apoptosis. Western blot analysis was used to evaluate phosporylated AKT (pAkt) and cell cycle proteins. The effect of apigenin on gemcitabine-resistant AsPC-1 cells was assessed via thymidine incorporation.
  
  
  RESULTS
  Apigenin in combination with gemcitabine inhibited pancreatic cancer cell proliferation more than either agent alone. Combination treatment induced both S and G2/M phase arrest and increased apoptosis. Apigenin down-regulated pAkt expression and abrogated gemcitabine-mediated pAkt induction. In gemcitabine-resistant AsPC-1 cells, apigenin significantly inhibited cell proliferation in a dose-dependent manner.
  
  
  CONCLUSIONS
  Combination treatment with apigenin and gemcitabine inhibited pancreatic cancer cell growth via cell cycle arrest, down-regulation of the prosurvival factor pAkt, and induction of apoptosis. Combination therapy may prove useful for the treatment of pancreatic cancer.
authors.affiliation: Department of Surgery and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Strouch
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Milam
authors.forename: Laleh G
authors.initials: LG
authors.lastname: Melstrom
authors.forename: John J
authors.initials: JJ
authors.lastname: McGill
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Salabat
authors.forename: Michael B
authors.initials: MB
authors.lastname: Ujiki
authors.forename: Xian-Zhong
authors.initials: XZ
authors.lastname: Ding
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D018797:Cell Cycle Proteins; D003841:Deoxycytidine; D047310:Apigenin; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine