title: AduPARE1A and gemcitabine combined treatment trigger synergistic antitumor effects in pancreatic cancer through NF-κB mediated uPAR activation.
abstract: BACKGROUND
  Combined treatment of oncolytic adenoviruses with chemotherapeutic agents is foreseen as a therapeutic option for cancer. Here we have investigated the potential to use gemcitabine in combination with the oncolytic adenovirus AduPARE1A to treat pancreatic cancer and evaluate the underlying mechanism.
  
  
  METHODS
  We treated pancreatic cancer cell lines BxPC-3 and PANC-1 with AduPARE1A and gemcitabine individually or in combination and analyzed cell viability, combination index, apoptosis and viral production. We also investigated the effects of the combination on tumor growth and mice survival in two xenograft models. Furthermore, we analyzed uPAR promoter activity from different uPAR-controlled adenovirus and studied NF-κB mediated effects.
  
  
  RESULTS
  Synergistic cell killing from the combination AduPARE1A/Gemcitabine was observed in BxPC-3 and PANC-1 cells. Moreover, the combination treatment produced therapeutic benefits over either individual modality in two mouse models bearing orthotopic tumors, showing reduced tumor progression and significant prolonged mouse survival. Mechanistic studies showed that the synergistic cell death was not due to an increase in viral replication but occurred through an enhancement of apoptotic cell death. Gemcitabine stimulation increased the transcription of uPAR-controlled transgenes through the induction of NF-κB acting on the uPAR promoter. Interestingly, NF-κB gemcitabine-mediated induction of AduPAR adenoviruses interfered with the activation of NF-κB regulated genes, probably as a result of an intracellular competition for NF-κB DNA binding. Consequently, AduPARE1A infection sensitized cells to gemcitabine-induced apoptosis in the combined treatment.
  
  
  CONCLUSIONS
  These data highlights the potential of the combination as a treatment modality for pancreatic cancer patients.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Rosselló 149-153, Barcelona, 08036, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Maliandi
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Rosselló 149-153, Barcelona, 08036, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Mato-Berciano
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Rosselló 149-153, Barcelona, 08036, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Luciano
authors.initials: L
authors.lastname: Sobrevals
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Rosselló 149-153, Barcelona, 08036, Spain.
authors.forename: Gaël
authors.initials: G
authors.lastname: Roué
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Rosselló 149-153, Barcelona, 08036, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Anabel
authors.initials: A
authors.lastname: José
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Rosselló 149-153, Barcelona, 08036, Spain. cfillat@clinic.ub.es.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain. cfillat@clinic.ub.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fillat
mesh_terms: D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D016328:NF-kappa B; D055293:Receptors, Urokinase Plasminogen Activator; D003841:Deoxycytidine; D000093542:Gemcitabine