title: Molecular basis of differential sensitivity of myeloma cells to clinically relevant bolus treatment with bortezomib.
abstract: The proteasome inhibitor bortezomib (Velcade) is prescribed for the treatment of multiple myeloma. Clinically achievable concentrations of bortezomib cause less than 85% inhibition of the chymotrypsin-like activity of the proteasome, but little attention has been paid as to whether in vitro studies are representative of this level of inhibition. Patients receive bortezomib as an intravenous or subcutaneous bolus injection, resulting in maximum proteasome inhibition within one hour followed by a gradual recovery of activity. In contrast, most in vitro studies use continuous treatment so that activity never recovers. Replacing continuous treatment with 1 h-pulse treatment increases differences in sensitivity in a panel of 7 multiple myeloma cell lines from 5.3-fold to 18-fold, and reveals that the more sensitive cell lines undergo apoptosis at faster rates. Clinically achievable inhibition of active sites was sufficient to induce cytotoxicity only in one cell line. At concentrations of bortezomib that produced similar inhibition of peptidase activities a different extent of inhibition of protein degradation was observed, providing an explanation for the differential sensitivity. The amount of protein degraded per number of active proteasomes correlated with sensitivity to bortezomib. Thus, (i) in vitro studies of proteasome inhibitors should be conducted at pharmacologically achievable concentrations and duration of treatment; (ii) a similar level of inhibition of active sites results in a different extent of inhibition of protein breakdown in different cell lines, and hence a difference in sensitivity.
authors: Norris Cotton Cancer Center, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
authors: Tamer B
authors: TB
authors: Shabaneh
authors: Sondra L
authors: SL
authors: Downey
authors: Ayrton L
authors: AL
authors: Goddard
authors: Michael
authors: M
authors: Screen
authors: Marcella M
authors: MM
authors: Lucas
authors: Alan
authors: A
authors: Eastman
authors: Alexei F
authors: AF
authors: Kisselev
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D001897:Boronic Acids; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex