title: Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts.
abstract: BACKGROUND
  Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly fatal malignancy characterized by resistance to chemotherapy. Currently, gemcitabine is the agent used most commonly but demonstrates only a partial response. The transcription factor nuclear factor-kappaB (NF-κB), known to be involved in the inflammatory response, is constitutively activated in PDAC and further activated by gemcitabine. Our aim was to examine the effects of targeted NF-κB suppression on gemcitabine resistance using an in vivo tumor growth model.
  
  
  METHODS
  To suppress the NF-κB pathway, the mutant IκBα super-repressor protein was stably expressed in PaCa-2 human PDAC cells. Athymic mice were injected subcutaneously with IκBα-super-repressor (SR) or vector-expressing PaCa-2 cells and randomized to receive phosphate-buffered saline (PBS) or 100 mg/kg gemcitabine(gem) for 4 weeks.
  
  
  RESULTS
  The mean increase in tumor volume was 47 mm(3) (89%) and 196 mm(3) (326%) in gem/SR and gem/vector groups, respectively (P = .03). The PBS-treated groups demonstrated greater tumor growth, ∼340 mm(3) (850%) increase, in both PBS/vector and PBS/SR groups. Intratumoral NF-κB activity was decreased in gem/SR compared with the gem/vector group (P = .04). Decreased Ki-67 positivity was noted in gem/SR (49%) versus gem/vector tumors (73%) (P = .04), with no difference in apoptosis (apoptag, P = .3) or angiogenesis (CD31+, P = .9).
  
  
  CONCLUSIONS
  Stable IκBα-SR expression in vivo potentiated the antitumor effects of gemcitabine, resulting in decreased tumor growth in association with decreased cell proliferation. Molecular suppression of the NF-κB pathway decreases successfully gemcitabine resistance in a relatively chemoresistant PDAC line. Thus, NF-κB-targeted agents may complement gemcitabine-based therapies and decrease chemoresistance in patients with PDAC.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Waters
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Jesus
authors.initials: J
authors.lastname: Matos
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN. Electronic address: myipschn@iupui.edu.
authors.forename: Michele
authors.initials: M
authors.lastname: Yip-Schneider
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Aguilar-Saavedra
authors.affiliation: Department of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Crean
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Joal D
authors.initials: JD
authors.lastname: Beane
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Dumas
authors.affiliation: Department of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Attaya
authors.initials: A
authors.lastname: Suvannasankha
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; Department of Biochemistry/Molecular Biology, Indiana University School of Medicine, Indianapolis, IN; Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN; Indiana University Cancer Center, Indianapolis, IN; Richard L. Roudebush VA Medical Center, Indianapolis, IN. Electronic address: maxschmi@iupui.edu.
authors.forename: C Max
authors.initials: CM
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D020672:I-kappa B Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D003841:Deoxycytidine; D000072000:NF-KappaB Inhibitor alpha; D000093542:Gemcitabine