title: Gamma-secretase inhibitor enhances the cytotoxic effect of bortezomib in multiple myeloma.
abstract: BACKGROUND
  Targeting of Notch signaling with γ-secretase inhibitors (GSIs) has been considered a promising strategy for the treatment of hematological malignancies including multiple myeloma (MM). Here we investigated whether the cytotoxic effect of bortezomib, an agent commonly used in MM, could be enhanced by the addition of a GSI.
  
  
  METHODS
  MM cells were treated with GSI, bortezomib or the combination thereof. Apoptosis of MM cells, proteasome activity and Notch signaling activation were determined. The effect of the drug combination was also evaluated in MM cells transfected with the active domain of Notch-1.
  
  
  RESULTS
  Using MM cell lines and primary MM cells isolated from the bone marrow of patients with MM we found a strong synergistic effect of bortezomib in combination with one of the GSIs studied. We next investigated the mechanism underlying this synergistic effect and determined that the effect of the drug combination was mainly dependent on the ability of the selected GSI to inhibit proteasome activity in MM cells.
  
  
  CONCLUSIONS
  Our study demonstrates that selected GSIs that inhibit proteasome activity may be successfully used in combination with bortezomib enhancing its anti-MM effect.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pisklakova
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Rachid
authors.initials: R
authors.lastname: Baz
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.forename: Yulia
authors.initials: Y
authors.lastname: Nefedova
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D053829:Amyloid Precursor Protein Secretases