title: NPI-0052 enhances tumoricidal response to conventional cancer therapy in a colon cancer model.
abstract: OBJECTIVE
  In the current study, we examine the effects of a novel proteasome inhibitor, NPI-0052 (salinosporamide A), on proteasome function and nuclear factor-kappaB activation and evaluate its ability to enhance treatment response in colon cancer xenografts when administered orally.
  
  
  METHODS
  The effects of treatment on nuclear factor-kappaB activation, cell cycle regulation, and apoptosis were determined. The pharmacodynamic effect of NPI-0052 on 20S proteasome function was assayed in vivo following oral and i.v. drug administration and compared with treatment with bortezomib. The effect of combined treatment with chemotherapy was determined in a colon cancer xenograft model.
  
  
  RESULTS
  We found that NPI-0052 is a potent, well-tolerated proteasome inhibitor that has pharmacodynamic properties distinct from bortezomib in that it achieves significantly higher and more sustained levels of proteasome inhibition. When combined with chemotherapy, NPI-0052 increases apoptosis and shifts cells toward G2 cell cycle arrest. When added to chemotherapy in vivo [using combinations of 5-fluorouracil (5-FU), CPT-11, Avastin (bevacizumab), leucovorin, and oxaliplatin], NPI-0052 significantly improved the tumoricidal response and resulted in a 1.8-fold increased response to CPT-11, 5-FU, and leucovorin triple-drug combination (P=0.0002, t test), a 1.5-fold increased response to the oxaliplatin, 5-FU, and leucovorin triple-drug combination (P=0.013, t test), and a 2.3-fold greater response to the CPT-11, 5-FU, leucovorin, and Avastin regimen (P=0.00057).
  
  
  CONCLUSIONS
  The high level of proteasome inhibition achieved by NPI-0052 is well tolerated and significantly improves the tumoricidal response to multidrug treatment in a colon cancer xenograft model. Further evaluation of this novel proteasome inhibitor in clinical trials is indicated.
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA. jcusack@partners.org
authors.forename: James C
authors.initials: JC
authors.lastname: Cusack
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: Ta-Hsiang
authors.initials: TH
authors.lastname: Chao
authors.forename: Christine
authors.initials: C
authors.lastname: Pien
authors.forename: Wei
authors.initials: W
authors.lastname: Niu
authors.forename: Vito J
authors.initials: VJ
authors.lastname: Palombella
authors.forename: Saskia T C
authors.initials: ST
authors.lastname: Neuteboom
authors.forename: Michael A
authors.initials: MA
authors.lastname: Palladino
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004333:Drug Administration Routes; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D007783:Lactones; D016328:NF-kappa B; D011719:Pyrazines; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; C475865:marizomib; D046988:Proteasome Endopeptidase Complex