title: Ritonavir, nelfinavir, saquinavir and lopinavir induce proteotoxic stress in acute myeloid leukemia cells and sensitize them for proteasome inhibitor treatment at low micromolar drug concentrations.
abstract: BACKGROUND
  Protein metabolism is an innovative potential therapeutic target for AML. Proteotoxic stress (PS) sensitizes malignant cells for proteasome inhibitor treatment. Some HIV protease inhibitors (HIV-PI) induce PS and may therefore be combined with proteasome inhibitors to achieve PS-targeted therapy of AML.
  
  
  METHODS
  We investigated the effects of all nine approved HIV-PI alone and in combination with proteasome inhibitors on AML cell lines and primary cells in vitro.
  
  
  RESULTS
  Ritonavir induced cytotoxicity and PS at clinically achievable concentrations, and induced synergistic PS-triggered apoptosis with bortezomib. Saquinavir, nelfinavir and lopinavir were likewise cytotoxic against primary AML cells, triggered PS-induced apoptosis, inhibited AKT-phosphorylation and showed synergistic cytotoxicity with bortezomib and carfilzomib at low micromolar concentrations. Exclusively nelfinavir inhibited intracellular proteasome activity, including the β2 proteasome activity that is not targeted by bortezomib/carfilzomib.
  
  
  CONCLUSIONS
  Of the nine currently approved HIV-PI, ritonavir, saquinavir, nelfinavir and lopinavir can sensitize AML primary cells for proteasome inhibitor treatment at low micromolar concentrations and may therefore be tested clinically toward a proteotoxic stress targeted therapy of AML.
authors.affiliation: Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Kraus
authors.affiliation: Department of Medicine II, University of Tübingen, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Müller-Ide
authors.affiliation: Department of Medicine II, University of Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückrich
authors.affiliation: Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bader
authors.affiliation: Leiden Institute of Chemistry, University of Leiden, The Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Overkleeft
authors.affiliation: Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland; Department of Medicine II, University of Tübingen, Germany. Electronic address: christoph.driessen@kssg.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Driessen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D003603:Cytotoxins / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D061466:Lopinavir / Q000494:pharmacology; D019888:Nelfinavir / Q000494:pharmacology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D003603:Cytotoxins; D017320:HIV Protease Inhibitors; D061988:Proteasome Inhibitors; D061466:Lopinavir; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir
keywords: Acute myeloid leukemia; HIV protease inhibitor; Proteasome inhibitions; Unfolded protein response