title: The human immunodeficiency virus-1 protease inhibitor nelfinavir impairs proteasome activity and inhibits the proliferation of multiple myeloma cells in vitro and in vivo.
abstract: BACKGROUND
  Multiple myeloma is characterized by the accumulation of tumor plasma cells in the bone marrow. Despite therapeutic improvements brought by proteasome inhibitors such as bortezomib, myeloma remains an incurable disease. In a variety of human cancers, human immunodeficiency virus protease inhibitors (e.g. nelfinavir) effectively inhibit tumor progression, but their impact on myeloma is unknown. We assessed the in vitro and in vivo effects of nelfinavir on multiple myeloma.
  
  
  METHODS
  The effects of nelfinavir (1-10 μM) on proteasome activity, proliferation and viability of myeloma cell lines and plasma cells from patients were assessed by measuring PERK, AKT, STAT3 and ERK1/2 phosphorylation and CHOP expression with immunoblotting or flow cytometry. The in vivo effect was assessed in NOD/SCID mice injected with luciferase expressing human myeloma cell lines and treated with nelfinavir at a dose of 75 mg/kg/day. Tumor progression was evaluated using a bioluminescent system.
  
  
  RESULTS
  Nelfinavir inhibited 26S chymotrypsin-like proteasome activity, impaired proliferation and triggered apoptosis of the myeloma cell lines and fresh plasma cells. It activated the pro-apoptotic unfolded protein response pathway by inducing PERK phosphorylation and CHOP expression. Cell death triggered by nelfinavir treatment correlated with decreased phosphorylation of AKT, STAT3 and ERK1/2. Nelfinavir enhanced the anti-proliferative activity of bortezomib, dexamethasone and histone deacetylase inhibitors and delayed tumor growth in a myeloma mouse model.
  
  
  CONCLUSIONS
  These results suggest that nelfinavir, used at a pharmacological dosage, alone or in combination, may be useful in the treatment of myeloma. Our data provide a preclinical basis for clinical trials using nelfinavir in patients with myeloma.
authors.affiliation: EA 3963, Univ Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Bono
authors.forename: Lionel
authors.initials: L
authors.lastname: Karlin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Harel
authors.forename: Enguerran
authors.initials: E
authors.lastname: Mouly
authors.forename: Sylvaine
authors.initials: S
authors.lastname: Labaume
authors.forename: Lionel
authors.initials: L
authors.lastname: Galicier
authors.forename: Sébastien
authors.initials: S
authors.lastname: Apcher
authors.forename: Hélène
authors.initials: H
authors.lastname: Sauvageon
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Fermand
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Bories
authors.forename: Bertrand
authors.initials: B
authors.lastname: Arnulf
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017930:Genes, Reporter; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008156:Luciferases; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D019888:Nelfinavir / Q000494:pharmacology*; D010950:Plasma Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D017320:HIV Protease Inhibitors; D056572:Histone Deacetylase Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone; D008156:Luciferases; D046988:Proteasome Endopeptidase Complex; D019888:Nelfinavir