title: Probing the specificity and activity profiles of the proteasome inhibitors bortezomib and delanzomib.
abstract: The ubiquitin proteasome system is an attractive pharmacological target for the treatment of cancer. The proteasome inhibitor bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma but is associated with substantial adverse effects and the occurrence of resistance, underscoring the continued need for novel proteasome inhibitors. In this study, bortezomib and the novel proteasome inhibitor delanzomib were compared for their ability to inhibit proteasome activity using both fluorogenic substrates and a recently developed fluorescent proteasome activity probe. Bortezomib and delanzomib were equipotent in inhibiting distinct subunits of the proteasome in a panel of cell lines in vitro. In a preclinical multiple myeloma model, both inhibitors inhibited the proteasome in normal tissues to a similar extent. Tumor proteasome activity was inhibited to a significantly higher extent by delanzomib (60%) compared to bortezomib (32%). In addition, delanzomib was able to overcome bortezomib resistance in vitro. The present findings demonstrate that proteasome activity probes can accurately monitor the effects of proteasome inhibitors on both normal and tumor tissues in preclinical models and can be used as a diagnostic approach to predict resistance against treatment with proteasome inhibitors.  Furthermore, the data presented here provide rationale for further clinical development of delanzomib.
authors.affiliation: Division of Cell Biology II, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Celia R
authors.initials: CR
authors.lastname: Berkers
authors.forename: Yves
authors.initials: Y
authors.lastname: Leestemaker
authors.forename: Karianne G
authors.initials: KG
authors.lastname: Schuurman
authors.forename: Bruce
authors.initials: B
authors.lastname: Ruggeri
authors.forename: Susan
authors.initials: S
authors.lastname: Jones-Bolin
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex