title: Antiprotease strategy in pancreatic cancer treatment: emergence from a preclinical study.
abstract: OBJECTIVE
  Resistance to gemcitabine is one of the main causes of treatment failure in pancreatic cancer. Compelling evidences have shown the involvement of nuclear factor κB (NF-κB) activation in such phenomenon. The protease inhibitor gabexate mesilate has been shown to inhibit NF-κB. We here investigated if combined treatment with this drug could improve gemcitabine antitumoral efficacy in pancreatic cancer cells.
  
  
  METHODS
  The effect of gabexate mesilate and gemcitabine, both used at concentrations achievable in human plasma, was assessed on in vitro pancreatic cancer cell growth, invasion, and tumor angiogenesis. The molecular mechanism at the basis of these effects was also investigated.
  
  
  RESULTS
  Gabexate mesilate significantly increased gemcitabine anti-invasive and antiangiogenic efficacy. This effect was related to inhibition of gemcitabine-induced NF-κB activation by gabexate mesilate, which prevented RelA/p65 nuclear translocation and resulted in metalloproteinase 2, metalloproteinase 9, vascular endothelial growth factor, and interleukin 8 down-regulation. Combined treatment with gabexate mesilate also inhibited gemcitabine-induced extracellular-regulated kinase 1/2 and AKT activation by increased expression of Raf kinase inhibitor protein and phosphatase and tensin homolog.
  
  
  CONCLUSIONS
  Combined treatment with gabexate mesilate sensitizes pancreatic cancer cells to gemcitabine by inhibition of the NF-κB pathway. The efficacy of this therapeutic strategy in pancreatic cancer patients remains to be established and deserves future clinical investigation.
authors.affiliation: From the *Department of Experimental, Diagnostic and Specialty Medicine, †"G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), and ‡Center for Applied Biomedical Research (C.R.B.A.), S. Orsola-Malpighi University Hospital; §Department of Biological, Geological and Environmental Sciences; and ∥Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Brandi
authors.forename: Simona
authors.initials: S
authors.lastname: Tavolari
authors.forename: Tiziana
authors.initials: T
authors.lastname: Guarnieri
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Di Marco
authors.forename: Paola
authors.initials: P
authors.lastname: Paterini
authors.forename: Marina
authors.initials: M
authors.lastname: Macchini
authors.forename: Stefania
authors.initials: S
authors.lastname: Di Girolamo
authors.forename: Alessio
authors.initials: A
authors.lastname: Papi
authors.forename: Francesco
authors.initials: F
authors.lastname: De Rosa
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016670:Gabexate / Q000008:administration & dosage / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D016209:Interleukin-8; D016328:NF-kappa B; D015842:Serine Proteinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D016670:Gabexate; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000093542:Gemcitabine