title: Luteolin and Gemcitabine Protect Against Pancreatic Cancer in an Orthotopic Mouse Model.
abstract: OBJECTIVE
  This study aimed to evaluate the ability of luteolin (Lut), gemcitabine (Gem), and their combination (Lut + Gem) to prevent the growth of pancreatic tumors in vivo.
  
  
  METHODS
  The antitumor effect of intraperitoneally administered Lut, Gem, and Lut + Gem was evaluated using an orthotopic mouse model for 6 weeks. Tumor growth after injection of human pancreatic cancer cells was assessed by measuring pancreatic tumor mass. The mechanism of action of antitumor effect was assessed by immunohistochemistry and Western blot procedures.
  
  
  RESULTS
  Luteolin + Gem significantly lowered (P = 0.048) the pancreatic tumor mass compared with control. Luteolin, Gem, and Lut + Gem significantly reduced the proliferating cell nuclear antigen expression (25%, 37%, and 37%, respectively). Luteolin + Gem treatment led to a significant reduction in the expressions of K-ras (46%, P = 0.0006), GSK-3β (34%, P = 0.014), P(Tyr216)GSK-3β (16%, P = 0.033), P(Ser311)NF-κB p65 (27%, P = 0.036), and bcl-2/bax ratio (68%, P = 0.006) while significantly increasing the expressions of cytochrome c (44%, P = 0.035) and caspase 3 (417%, P = 0.003).
  
  
  CONCLUSIONS
  Luteolin + Gem promoted apoptotic cell death in pancreatic tumor cells in vivo through inhibition of the K-ras/GSK-3β/NF-κB signaling pathway, leading to a reduction in the Bcl-2/Bax ratio, release of cytochrome c, and activation of caspase 3.
authors.affiliation: From the *Division of Nutritional Sciences, †Department of Food Science and Human Nutrition, and ‡Department of Pathobiology, University of Illinois, Urbana-Champaign, Urbana, IL.
authors.forename: Jodee L
authors.initials: JL
authors.lastname: Johnson
authors.forename: Vermont P
authors.initials: VP
authors.lastname: Dia
authors.forename: Matthew
authors.initials: M
authors.lastname: Wallig
authors.forename: Elvira
authors.initials: E
authors.lastname: Gonzalez de Mejia
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D008297:Male; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D051017:Apoptosis Regulatory Proteins; C117307:KRAS protein, human; D016328:NF-kappa B; D003841:Deoxycytidine; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D016283:Proto-Oncogene Proteins p21(ras); D047311:Luteolin; D000093542:Gemcitabine